Applying ethics to AI in the workplace: the design of a scorecard for Australian workplace health and safety.

Artificial Intelligence (AI) is taking centre stage in economic growth and business operations alike. Public discourse about the practical and ethical implications of AI has mainly focussed on the societal level. There is an emerging knowledge base on AI risks to human rights around data security and privacy concerns. A separate strand of work has highlighted the stresses of working in the gig economy. This prevailing focus on human rights and gig impacts has been at the expense of a closer look at how AI may be reshaping traditional workplace relations and, more specifically, workplace health and safety. To address this gap, we outline a conceptual model for developing an AI Work Health and Safety (WHS) Scorecard as a tool to assess and manage the potential risks and hazards to workers resulting from AI use in a workplace. A qualitative, practice-led research study of AI adopters was used to generate and test a novel list of potential AI risks to worker health and safety. Risks were identified after cross-referencing Australian AI Ethics Principles and Principles of Good Work Design with AI ideation, design and implementation stages captured by the AI Canvas, a framework otherwise used for assessing the commercial potential of AI to a business. The unique contribution of this research is the development of a novel matrix itemising currently known or anticipated risks to the WHS and ethical aspects at each AI adoption stage.

Performance enhancement of charge plasma-based junctionless TFET (JL-TFET) using stimulated n-pocket and heterogeneous gate dielectric.

Junctionless tunneling field-effect transistor (JL-TFET) is an excellent potential alternative to conventional MOSFET and TFET due to the lack of a steep doping profile, which makes it easier to fabricate. JL-TFET not only offers a lower subthreshold swing (SS) compared to MOSFET, but mitigates the low on-current problem associated with conventional TFET. The DC and analog characteristics of JL-TFET can be further improved by design modifications. In this research, we have presented two novel structures of JL-TFET: stimulated n-pocket JL-TFET (SNPJL-TFET) and SNPJL-TFET with heterogeneous gate dielectric. The performance of these devices has been gauged against conventional JL-TFET. Both novel structures exhibit excellent performance including point SS around 20 mV/dec, highION/IOFFin the order of 1014and lower threshold voltage (VT). By analyzing RF and linearity parameters such as the transconductance generation factor,FT, transit time, total factor productivity, second-order voltage intercept point, third-order voltage intercept point, third-order input intercept point and third-order intermodulation distortion, it is observed that the proposed devices are more suitable for RF applications since they show superiority in most of the analyzed parameters.

Investigating the effect of autoinduction in cynomolgus monkeys of a novel anticancer MDM2 antagonist, idasanutlin, and relevance to humans.

1. Idasanutlin (RG7388) is a potent p53-MDM2 antagonist currently in clinical development for treatment of cancer. The purpose of the present studies was to investigate the cause of marked decrease in plasma exposure after repeated oral administration of RG7388 in monkeys and whether the autoinduction observed in monkeys is relevant to humans. 2. In monkey liver and intestinal microsomes collected after repeated oral administration of RG7388 to monkeys, significantly increased activities of homologue CYP3A8 were observed (ex vivo). Investigation using a physiologically based pharmacokinetic (PBPK) model suggested that the loss of exposure was primarily due to induction of metabolism in the gut of monkeys. 3. Studies in monkey and human primary hepatocytes showed that CYP3A induction by RG7388 only occurred in monkey hepatocytes but not in human hepatocytes, which suggests the observed CYP3A induction is monkey specific. 4. The human PK data obtained from the first cohorts confirmed the lack of relevant induction as predicted by the human hepatocytes and the PBPK modelling based on no induction in humans.

Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach.

PURPOSE: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens. EXPERIMENTAL DESIGN: A pharmacokinetic-pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system. RESULTS: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options. CONCLUSION: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing.

Phase I trial of capecitabine rapidly disintegrating tablets and concomitant radiation therapy in children with newly diagnosed brainstem gliomas and high-grade gliomas.

BACKGROUND: We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas. METHODS: Children 3-21 y with newly diagnosed intrinsic brainstem or high-grade gliomas were eligible for enrollment. The starting dose was 500 mg/m(2), given twice daily, with subsequent cohorts enrolled at 650 mg/m(2) and 850 mg/m(2) using a 3 + 3 phase I design. Children received capecitabine at the assigned dose daily for 9 wks starting from the first day of radiation therapy (RT). Following a 2-wk break, patients received 3 courses of capecitabine 1250 mg/m(2) twice daily for 14 days followed by a 7-day rest. Pharmacokinetic sampling was performed in consenting patients. Six additional patients with intrinsic brainstem gliomas were enrolled at the maximum tolerated dose to further characterize the pharmacokinetic and toxicity profiles. RESULTS: Twenty-four patients were enrolled. Twenty were fully assessable for toxicity. Dose-limiting toxicities were palmar plantar erythroderma (grades 2 and 3) and elevation of alanine aminotransferase (grades 2 and 3). Systemic exposure to capecitabine and metabolites was similar to or slightly lower than predicted based on adult data. CONCLUSIONS: Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m(2), administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030).

In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials.

The cyclin-dependent protein kinases are key regulators of cell cycle progression. Aberrant expression or altered activity of distinct cyclin-dependent kinase (CDK) complexes results in escape of cells from cell cycle control, leading to unrestricted cell proliferation. CDK inhibitors have the potential to induce cell cycle arrest and apoptosis in cancer cells, and identifying small-molecule CDK inhibitors has been a major focus in cancer research. Several CDK inhibitors are entering the clinic, the most recent being selective CDK2 and CDK4 inhibitors. We have identified a diaminopyrimidine compound, R547, which is a potent and selective ATP-competitive CDK inhibitor. In cell-free assays, R547 effectively inhibited CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D1 (K(i) = 1-3 nmol/L) and was inactive (K(i) > 5,000 nmol/L) against a panel of >120 unrelated kinases. In vitro, R547 effectively inhibited the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC(50)s