Manufacturing and use of human placenta-derived mesenchymal stromal cells for phase I clinical trials: Establishment and evaluation of a protocol

Background/Aim. Mesenchymal stromal cells (MSCs) have been utilised in many clinical trials as an experimental treatment in numerous clinical settings. Bone marrow remains the traditional source tissue for MSCs but is relatively hard to access in large volumes. Alternatively, MSCs may be derived from other tissues including the placenta and adipose tissue. In an initial study no obvious differences in parameters such as cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability, were detected when we compared human marrow derived- MSCs to human placenta-derived MSCs. The aim of this study was to establish and evaluate a protocol and related processes for preparation placenta-derived MSCs for early phase clinical trials. Methods. A full-term placenta was taken after delivery of the baby as a source of MSCs. Isolation, seeding, incubation, cryopreservation of human placentaderived MSCs and used production release criteria were in accordance with the complex regulatory requirements applicable to Code of Good Manufacturing Practice manufacturing of ex vivo expanded cells. Results. We established and evaluated instructions for MSCs preparation protocol and gave an overview of the three clinical areas application. In the first trial, MSCs were co-transplanted iv to patient receiving an allogeneic cord blood transplant as therapy for treatmentrefractory acute myeloid leukemia. In the second trial, MSCs were administered iv in the treatment of idiopathic pulmonary fibrosis and without serious adverse effects. In the third trial, MSCs were injected directly into the site of tendon damage using ultrasound guidance in the treatment of chronic refractory tendinopathy. Conclusion. Clinical trials using both allogeneic and autologous cells demonstrated MSCs to be safe. A described protocol for human placenta-derived MSCs is appropriate for use in a clinical setting, relatively inexpensive and can be relatively easily adjusted to a different set of regulatory requirements, as applicable to early phase clinical trials.

Behavior of sprayed tricyclazole in rice paddy lysimeters

The behavior of sprayed tricyclazole in rice paddy lysimeters was studied. Tricyclazole residues were measured from rice leaves and paddy water after tricyclazole spraying in paddy lysimeters. The rate of photolysis and hydrolysis of tricyclazole on the surface of rice leaves was also determined in a laboratory experiment. Tricyclazole was extracted from leaf and water samples and determined by liquid chromatography with UV or mass spectrometry. The hydrolysis half-lives of tricyclazole on rice leaves were 11.9 and 5.1 d for the formulated product and standard, respectively. The photolysis half-lives were longer, 16.4 d for the formulated product and 20.9 d for the standard. In the paddy lysimeter, tricyclazole dissipation on leaves involved either biphasic first-order kinetics or single-phase first-order kinetics, depending on the rainfall pattern. Half-lives of tricyclazole on lysimeter rice leaves were from 3.0 to 5.7 d. The dissipation of tricyclazole in paddy water followed single-phase first-order kinetics with half-lives ranging from 2.1 to 5.0 d.

Determination of tricyclazole in water using solid phase extraction and liquid chromatography

A method for determination of tricyclazole in water using solid phase extraction and high performance liquid chromatography (HPLC) with UV detection at 230nm and a mobile phase of acetonitrile:water (20:80, v/v) was developed. A performance comparison between two types of solid phase sorbents, the C18 sorbent of Supelclean ENVI-18 cartridge and the styrene-divinyl benzene copolymer sorbent of Sep-Pak PS2-Plus cartridge was conducted. The Sep-Pak PS2-Plus cartridges were found more suitable for extracting tricyclazole from water samples than the Supelclean ENVI-18 cartridges. For this cartridge, both methanol and ethyl acetate produced good results. The method was validated with good linearity and with a limit of detection of 0.008gL-1 for a 500-fold concentration through the SPE procedure. The recoveries of the method were stable at 80% and the precision was from 1.1-6.0% within the range of fortified concentrations. The validated method was also applied to measure the concentrations of tricyclazole in real paddy water.

Fate and transport of bensulfuron-methyl and imazosulfuron in paddy fields: Experiments and model simulation

Experiments were conducted to determine the fate of bensulfuron-methyl (BSM) and imazosulfuron (IMS) under paddy conditions. Initially, laboratory experiments were conducted and the photolysis half-lives of the two herbicides were found to be much shorter than their hydrolysis half-lives in aqueous solutions. In the aerobic water–soil system, dissipation followed first-order kinetics with water half-lives of 9.1 and 11.0 days and soil half-lives of 12.4 and 18.5 days (first phase) and 35.0 and 44.1 days (second phase) for bensulfuron-methyl and imazosulfuron, respectively. However, the anaerobic soil half-lives were only 12.7 and 9.8 days for BSM and IMS, respectively. The values of K d were determined to be 16.0 and 13.8 for BSM and IMS, respectively. Subsequent field measurements for the two herbicides revealed that dissipation of both herbicides in paddy water involved biphasic first-order kinetics, with the dissipation rates in the first phase being much faster than those in the second phase. The dissipation of bensulfuron-methyl and imazosulfuron in the paddy surface soil were also followed biphasic first-order kinetics. These results were then used as input parameters for the PCPF-1 model to simulate the fate and transport of BSM and IMS in the paddy environment (water and 1-cm surface soil layer). The measured and simulated values agreed well and the mass balance error during the simulation period was −1.2 and 2.8% of applied pesticide, respectively, for BSM and IMS.

Designs for phase I clinical trials with multiple courses of subjects at different doses

The goal of this article is to provide a new design framework and its corresponding estimation for phase I trials. Existing phase I designs assign each subject to one dose level based on responses from previous subjects. Yet it is possible that subjects with neither toxicity nor efficacy responses can be treated at higher dose levels, and their subsequent responses to higher doses will provide more information. In addition, for some trials, it might be possible to obtain multiple responses (repeated measures) from a subject at different dose levels. In this article, a nonparametric estimation method is developed for such studies. We also explore how the designs of multiple doses per subject can be implemented to improve design efficiency. The gain of efficiency from "single dose per subject" to "multiple doses per subject" is evaluated for several scenarios. Our numerical study shows that using "multiple doses per subject" and the proposed estimation method together increases the efficiency substantially.

A Bayesian decision approach for sample size determination in phase II trials

Stallard (1998, Biometrics 54, 279-294) recently used Bayesian decision theory for sample-size determination in phase II trials. His design maximizes the expected financial gains in the development of a new treatment. However, it results in a very high probability (0.65) of recommending an ineffective treatment for phase III testing. On the other hand, the expected gain using his design is more than 10 times that of a design that tightly controls the false positive error (Thall and Simon, 1994, Biometrics 50, 337-349). Stallard's design maximizes the expected gain per phase II trial, but it does not maximize the rate of gain or total gain for a fixed length of time because the rate of gain depends on the proportion: of treatments forwarding to the phase III study. We suggest maximizing the rate of gain, and the resulting optimal one-stage design becomes twice as efficient as Stallard's one-stage design. Furthermore, the new design has a probability of only 0.12 of passing an ineffective treatment to phase III study.

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.

Minimizing overprocessing waste in business processes via predictive activity ordering

Overprocessing waste occurs in a business process when effort is spent in a way that does not add value to the customer nor to the business. Previous studies have identied a recurrent overprocessing pattern in business processes with so-called "knockout checks", meaning activities that classify a case into "accepted" or "rejected", such that if the case is accepted it proceeds forward, while if rejected, it is cancelled and all work performed in the case is considered unnecessary. Thus, when a knockout check rejects a case, the effort spent in other (previous) checks becomes overprocessing waste. Traditional process redesign methods propose to order knockout checks according to their mean effort and rejection rate. This paper presents a more fine-grained approach where knockout checks are ordered at runtime based on predictive machine learning models. Experiments on two real-life processes show that this predictive approach outperforms traditional methods while incurring minimal runtime overhead.

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.

Hip power analysis in individuals with transfemoral amputation: A different strategy different from stabilisation during gait stance

Introduction and Objectives Joint moments and joint powers during gait are widely used to determine the effects of rehabilitation programs as well as prosthetic fitting. Following the definition of power (dot product of joint moment and joint angular velocity) it has been previously proposed to analyse the 3D angle between both vectors, αMw. Basically, joint power is maximised when both vectors are parallel and cancelled when both vectors are orthogonal. In other words, αMw < 60° reveals a propulsion configuration (more than 50% of the moment contribute to positive power) while αMw > 120° reveals a resistance configuration (more than 50% of the moment contribute to negative power). A stabilisation configuration (less than 50% of the moment contribute to power) corresponds to 60° < αMw < 120°. Previous studies demonstrated that hip joints of able-bodied adults (AB) are mainly in a stabilisation configuration (αMw about 90°) during the stance phase of gait. [1, 2] Individuals with transfemoral amputation (TFA) need to maximise joint power at the hip while controlling the prosthetic knee during stance. Therefore, we tested the hypothesis that TFAs should adopt a strategy that is different from a continuous stabilisation. The objective of this study was to compute joint power and αMw for TFA and to compare them with AB. Methods Three trials of walking at self-selected speed were analysed for 8 TFAs (7 males and 1 female, 46±10 years old, 1.78±0.08 m 82±13 kg) and 8 ABs (males, 25±3 years old, 1.75±0.04, m 67±6 kg). The joint moments are computed from a motion analysis system (Qualisys, Goteborg, Sweden) and a multi-axial transducer (JR3, Woodland, USA) mounted above the prosthetic knee for TFAs and from a motion analysis system (Motion Analysis, Santa Rosa, USA) and force plates (Bertec, Columbus, USA) for ABs. The TFAs were fitted with an OPRA (Integrum, AB, Gothengurg, Sweden) osseointegrated implant system and their prosthetic designs include pneumatic, hydraulic and microprocessor knees. Previous studies showed that the inverse dynamics computed from the multi-axial transducer is the proper method considering the absorption at the foot and resistance at the knee. Results The peak of positive power at loading response (H1) was earlier and lower for TFA compared to AB. Although the joint power is lower, the 3D angle between joint moment and joint angular velocity, αMw, reveals an obvious propulsion configuration (mean αMw about 20°) for TFA compared to a stabilisation configuration (mean αMw about 70°) for AB. The peaks of negative power at midstance (H2) and of positive power at preswing / initial swing (H3) occurred later, lower and longer for TFA compared to AB. Again, the joint powers are lower for TFA but, in this case, αMw is almost comparable (with a time lag), demonstrating a stabilisation (almost a resistance for TFA, mean αMw about 120°) and a propulsion configuration, respectively. The swing phase is not analysed in the present study. Conclusion The analysis of hip joint power may indicate that TFAs demonstrated less propulsion and resistance than ABs during the stance phase of gait. This is true from a quantitative point of view. On the contrary, the 3D angle between joint moment and joint angular velocity, αMw, reveals that TFAs have a remarkable propulsion strategy at loading response and almost a resistance strategy at midstance while ABs adopted a stabilisation strategy. The propulsion configuration, with αMw close to 0°, seems to aim at maximising the positive joint power. The configuration close to resistance, with αMw far from 180°, might aim at unlocking the prosthetic knee before swing while minimising the negative power. This analysis of both joint power and 3D angle between the joint moment and the joint angular velocity provides complementary insights into the gait strategies of TFA that can be used to support evidence-based rehabilitation and fitting of prosthetic components.

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.

Ordering within moral orders to manage classroom trouble

This paper demonstrates how classroom trouble warranting teacher intervention can stem from transgressions in different layers of the complex moral order regulating classroom interactions. The paper builds from Durkheim’s treatment of schooling as the institution responsible for the inculcation of a shared moral order, Bernstein’s distinction between the instructional and regulative discourses in any pedagogic setting, and the concept of verticality in the instructional discourse to illuminate how curricular knowledge might apply across different contexts. This paper proposes a similar vertical dimension of moral gravity in the regulative discourse, such that some moral expectations apply across any context, while others are highly contextualized. This paper then applies this frame to data from classroom observations conducted in prevocational pathways for 16 years olds created under Australia’s “earning or learning till 17” policy. This paper describes the variety of moral premises teachers invoked in different teacher/class combinations, according to their level of moral gravity to display the dominant use of highly contextualized moral premises seeking institutional compliance, and minimal use of broader moral frames for these students on the brink of entry to the adult world.

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.

Mathematical modelling of human corneal oxygenation and cell kinetics in corneal epithelial wound healing

Healthy transparent cornea depends upon the regulation of fluid, nutrient and oxygen transport through the tissue to sustain cell metabolism and other critical processes for normal functioning. This research considers the corneal geometry and investigates oxygen distribution using a two-dimensional Monod kinetic model, showing that previous studies make assumptions that lead to predictions of near-anoxic levels of oxygen tension in the limbal regions of the cornea. It also considers the comparison of experimental spatial and temporal data with the predictions of novel mathematical models with respect to distributed mitotic rates during corneal epithelial wound healing.

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.