Novel approaches for image analysis of in vitro epithelial cultures with application to silver nanoparticle toxicity

A novel imaging approach was developed for the purpose of counting cells from phase contrast microscopy images of laboratory grown (in vitro} cultures of epithelial cells. Validation through comparison with standard laboratory cell counting techniques showed this approach provided consistent and comparable results, whilst overcoming limitations of these existing techniques, such as operator variability and sample destruction. The imaging approach was subsequently applied to investigate the effects of silver nanoparticles (AgNP} on H400 oral keratinocytes. Concurrent investigations into antimicrobial effects of AgNP were performed on Escherichia coli, Staphylococcus aureus and Streptococcus mutans to provide models for Gram-positive and Gram-negative infection, and to compare with the literature and oral keratinocyte toxicity. It was found that AgNP elicit size-, dose- and time-dependent growth inhibition in both human cells and bacteria, although bacterial inhibition was not achieved without significant cytotoxicity at the same concentrations

A review of clinical trials with an adaptive design and health economic analysis

An adaptive design uses data collected as a clinical trial progresses to inform modifications to the trial. Hence, adaptive designs and health economics aim to facilitate efficient and accurate decision-making. However, it is unclear whether the methods are considered together in the design, analysis and reporting of trials. This review aims to establish how health economic outcomes are utilised in the design, analysis and reporting of adaptive designs. Registered and published trials up to August 2016 with an adaptive design and health economic analysis were identified. The use of health economics in the design, analysis and reporting was assessed. Summary statistics are presented and recommendations formed based on the research team’s experiences and a practical interpretation of the results. Thirty-seven trials with an adaptive design and health economic analysis were identified. It was not clear whether the health economic analysis accounted for the adaptive design in 17/37 trials where this was thought necessary, nor whether health economic outcomes were utilised at the interim analysis for 18/19 of trials with results. The reporting of health economic results was sub-optimal for the (17/19) trials with published results. Appropriate consideration is rarely given to the health economic analysis of adaptive designs. Opportunities to utilise health economic outcomes in the design and analysis of adaptive trials are being missed. Further work is needed to establish whether adaptive designs and health economic analyses can be used together to increase the efficiency of health technology assessments without compromising accuracy

Costs and staffing resource requirements for adaptive clinical trials: quantitative and qualitative results from the Costing Adaptive Trials project.

BACKGROUND: Adaptive designs offer great promise in improving the efficiency and patient-benefit of clinical trials. An important barrier to further increased use is a lack of understanding about which additional resources are required to conduct a high-quality adaptive clinical trial, compared to a traditional fixed design. The Costing Adaptive Trials (CAT) project investigated which additional resources may be required to support adaptive trials. METHODS: We conducted a mock costing exercise amongst seven Clinical Trials Units (CTUs) in the UK. Five scenarios were developed, derived from funded clinical trials, where a non-adaptive version and an adaptive version were described. Each scenario represented a different type of adaptive design. CTU staff were asked to provide the costs and staff time they estimated would be needed to support the trial, categorised into specified areas (e.g. statistics, data management, trial management). This was calculated separately for the non-adaptive and adaptive version of the trial, allowing paired comparisons. Interviews with 10 CTU staff who had completed the costing exercise were conducted by qualitative researchers to explore reasons for similarities and differences. RESULTS: Estimated resources associated with conducting an adaptive trial were always (moderately) higher than for the non-adaptive equivalent. The median increase was between 2 and 4% for all scenarios, except for sample size re-estimation which was 26.5% (as the adaptive design could lead to a lengthened study period). The highest increase was for statistical staff, with lower increases for data management and trial management staff. The percentage increase in resources varied across different CTUs. The interviews identified possible explanations for differences, including (1) experience in adaptive trials, (2) the complexity of the non-adaptive and adaptive design, and (3) the extent of non-trial specific core infrastructure funding the CTU had. CONCLUSIONS: This work sheds light on additional resources required to adequately support a high-quality adaptive trial. The percentage increase in costs for supporting an adaptive trial was generally modest and should not be a barrier to adaptive designs being cost-effective to use in practice. Informed by the results of this research, guidance for investigators and funders will be developed on appropriately resourcing adaptive trials

Propylene glycol inactivates respiratory viruses and prevents airborne transmission.

Publication status: PublishedFunder: Royal Society of Chemistry (RSC)Viruses are vulnerable as they transmit between hosts, and we aimed to exploit this critical window. We found that the ubiquitous, safe, inexpensive and biodegradable small molecule propylene glycol (PG) has robust virucidal activity. Propylene glycol rapidly inactivates a broad range of viruses including influenza A, SARS-CoV-2 and rotavirus and reduces disease burden in mice when administered intranasally at concentrations commonly found in nasal sprays. Most critically, vaporised PG efficiently abolishes influenza A virus and SARS-CoV-2 infectivity within airborne droplets, potently preventing infection at levels well below those tolerated by mammals. We present PG vapour as a first-in-class non-toxic airborne virucide that can prevent transmission of existing and emergent viral pathogens, with clear and immediate implications for public health

Practical guidance for planning resources required to support publicly-funded adaptive clinical trials.

Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely