Exploring attitudes towards a randomised controlled trial of venous access devices – a nested pre-trial qualitative study

Purpose: This pre-trial qualitative research study was carried out to explore patient and clinical staff attitudes to central venous access devices (CVADs). In addition, views about participation in a randomised controlled trial (RCT) were explored with the aim of maximising recruitment to an imminent RCT of three CVADs. Methods: Three patient focus groups (each comprising three patients) and 23 interviews with clinical staff were conducted. Interviews and focus group discussions were digitally recorded, transcribed verbatim, anonymised, uploaded to the QSR NVivo10 qualitative software programme and thematically analysed. Results: Analysis of focus group interviews revealed the added challenges that a CVAD poses to patients with cancer. Four key themes emerged: continuity of daily life, pain and discomfort, stigma (a mark of disgrace associated with certain conditions) and self-preservation. The findings show the impact of a CVAD on patients’ ability to manage their condition. Clinical staff interviews highlighted several potential barriers to recruitment; a lack of equipoise (genuine clinical uncertainty as to which intervention is the most beneficial), concerns about the logistics of device insertion and a perceived requirement for education and training. Conclusions: This qualitative study raises awareness of key areas of concern to patients who need a CVAD for chemotherapy delivery. It was identified that there is a need for clearer patient information around CVADs. Additionally it allows investigators to identify barriers to recruitment in a timely manner in order to minimise the potential for conflict between the roles of carer and researcher and consequently, maximise recruitment to the RCT

Social Ontology

Traditionally, social entities (i.e., social properties, facts, kinds, groups, institutions, and structures) have not fallen within the purview of mainstream metaphysics. In this chapter, we consider whether the exclusion of social entities from mainstream metaphysics is philosophically warranted or if it instead rests on historical accident or bias. We examine three ways one might attempt to justify excluding social metaphysics from the domain of metaphysical inquiry and argue that each fails. Thus, we conclude that social entities are not justifiably excluded from metaphysical inquiry. Finally, we ask how focusing on social entities could change the character of metaphysical inquiry. We suggest that starting from examples of social entities might lead metaphysicians to rethink the assumption that describing reality in terms of intrinsic, independent, and individualistic features is preferable to describing it in terms of relational, dependent, and non-individualistic features

Delving Into Teachers’ Development Through Portfolio Reflections: Case Studies of Three Teachers

As part of longitudinal research on the role and scope of portfolios in teacher education programs, this study employs a case study approach to systematically examine the portfolio contents and reflections of three teachers enrolled in an advanced professional development master’s degree program in education; the three teachers were purposely selected as representative of the teachers in our program. Specifically, we examined the written reflections submitted in their program portfolios and transcripts from their exit presentations to identify connections to program learning outcomes and to gain insight into the scope and nature of the change of the teachers during the program. We sought to identify influences that program experiences had on their growth and their teaching practice. We contend that by thorough and systematic examination of portfolio contents, and in particular teachers’ reflections included in the portfolios, programs can gain insights into teachers’ learning, practices, and critical reflection which, in turn, may be used to inform program decisions

Nitroxyl, the novel redox sibling of NO, suppresses cerebrovascular NADPH oxidase

Background: Nitroxyl (HNO), the reduced and protonated congener of nitric oxide (NO), is emerging as a novel entity with distinct pharmacology and therapeutic advantages over NO• [1]. Importantly, HNO has vasoprotective actions with the potential to serve as an antioxidant. Here we explored the ability of HNO to modulate cerebrovascular NADPH oxidase activity, a major source of superoxide (.O2-) in the vasculature. Materials and methods: Intracranial (pooled middle cerebral and basilar) and extracranial (carotid) cerebral arteries from male C57BL/6J mice were treated with angiotensin II (10 nM) acutely (30 min) and chronically (24 h), respectively, in the absence and presence of the HNO donor, Angeli's salt (AS). NADPH (100 μM)-stimulated .O2- production was then measured using lucigenin (5 μM)-enhanced chemiluminescence. Results: AS (1 μM) did not scavenge .O2- generated in a cell free xanthine (100 μM)/xanthine oxidase (0.05 U/ml) activity assay (control: 447.9 ± 90.8; AS 507.1 ± 113.3 counts, n = 4). In contrast, acute and chronic treatment with AS (0.01–1 μM) caused a concentration-dependent decrease in NADPH oxidase-derived .O2- production by intracranial and extracranial cerebral arteries, respectively (carotid 0.59 ± 0.05; AS 0.1 μM 0.33 ± 0.08; AS 1 μM 0.16 ± 0.03 103 counts/s/mg, P < 0.05, n = 8). The effects of AS were reversed by the HNO scavenger, L-cysteine (3 mM) but unchanged in the presence of the NO• scavenger carboxy-PTIO (200 μM) and sGC inhibitor, ODQ (10 μM). Conclusion: HNO suppresses vascular NADPH-oxidase activity both acutely and chronically, possibly via a cGMP-independent mechanism. Such antioxidant actions of HNO may confer therapeutic advantages in the treatment of cerebrovascular disorders

Reducing biting rates of Aedes aegypti with metofluthrin: investigations in time and space

Background: Indoor residual spraying is key to dengue control in Cairns and other parts of northern Queensland, Australia, where Aedes aegypti is prevalent, but the strategy faces challenges with regards to slow application time and, therefore, community coverage. A faster potential improvement might be the use of polyethylene netting impregnated with the volatile pyrethroid metofluthrin (SumiOne™). This formulation was assessed in rooms in three houses in Cairns, Australia. One emanator was placed in each room and cages of 10 female Aedes aegypti were exposed at distances of 1 and 3 m. Knockdown and landings on a human hand were counted before metofluthrin exposure and at 10, 30, 60, 90 and 120 min during exposure. In addition, two trials continued over 48 h of exposure to assess the long-term sublethal effects of metofluthrin on caged mosquitoes. Results: Percentage landing rates fell to 0-2.5% in the first 10 min of exposure. Knockdown was most evident between 10 and 30 min (54% at 1 m and 33% at 3 m). Distance from the emanator strongly affected the results: mosquitoes at 3 m exhibited less knockdown and more landings than those at 1 m. As room volume increased, knockdown decreased and the number of landing increased. There is a cumulative mortality and landing inhibition and, for mosquitoes exposed to metofluthrin for > 48 h, mortality was 100% at 1 m and 90% at 3 m. Of those still alive, a small number continued to land and bite. After being removed from metofluthrin-treated rooms, exposed insect cages were found to reducing landing rates for up to 2 h. Conclusions: Despite only moderate levels of knockdown during the initial hours of exposure, metofluthrin emanators were effective in reducing mosquito landing rates, especially within 1 m, even when exposed on an open veranda. The evaluation methods and results described in this paper will help inform the optimal conditions of deployment of metofluthrin emanators. These devices have the potential to reduce contact between humans and urban disease vectors faster than indoor residual spraying so supplement our current arsenal of dengue control tools

Generation of MicroRNA-34 Sponges and Tough Decoys for the Heart: Developments and Challenges

Heart failure (HF) is a debilitating and deadly chronic disease, with almost 50% of patients with HF dying within 5 years of diagnosis. With limited effective therapies to treat or cure HF, new therapies are greatly needed. microRNAs (miRNAs) are small non-coding RNA molecules that are powerful regulators of gene expression and play a key role in almost every biological process. Disruptions in miRNA gene expression has been functionally linked to numerous diseases, including cardiovascular disease. Molecular tools for manipulating miRNA activity have been developed, and there is evidence from preclinical studies demonstrating the potential of miRNAs to be therapeutic targets for cardiovascular disease. For clinical application, miRNA sponges and tough decoys have been developed for more stable suppression and targeted delivery of the miRNA of choice. The aim of this study was to generate miRNA sponges and tough decoys to target miR-34 in the mouse heart. We present data to show that using both approaches we were unable to get significant knockdown of miR-34 or regulate miR-34 target genes in the heart in vivo. We also review recent applications of this method in the heart and discuss further considerations for optimisation in construct design and testing, and the obstacles to be overcome before they enter the clinic

Thermostabilization of adenovirus-vectored vaccines, removing the need for continual cold-chain storage

Challenges around affordable and reliable supply of vaccines that need to be transported and maintained in the cold-chain to remain effective are a hindrance to realizing their full potential. We will describe preparation for GMP manufacture and Phase I clinical trial of a new technology for vaccine thermostabilisation. We will also describe application of the same technology to a novel veterinary vaccine which is entering advanced development. The sugar-matrix thermostabilisation (SMT) technology involves application of vaccine in a simple disaccharide-based buffer to a non-woven matrix, similar to a pad of filter paper. This is followed by drying at ambient temperature and pressure (i.e. without a freezing step, enhancing suitability for freeze-sensitive products). The materials and process are simple and cheap. We have previously shown that SMT allows for the storage of viral vectored vaccines such as modified vaccinia virus Ankara (MVA) and adenovirus vectors at up to 45oC for several months with minimal losses1,2. More recently we have shown the technique can improve stability of various other vaccine types, ranging from virus-like particles through to enveloped RNA viruses. In many cases, the level of thermostability achieved would allow for “last mile” vaccine distribution via the ‘extended controlled temperature chain’ (ECTC), or even allow prolonged storage at uncontrolled ambient temperature. This would decrease distribution-associated costs/ losses and increase vaccination feasibility in hard-to-reach areas. We have now received funding for GMP manufacture and Phase I clinical trial of an SMT-formulated adenovirus-vectored rabies vaccine, ChAdOx2 RabG. We will describe the production of custom wet-laid non-woven matrices with optimized SMT performance, using processes and materials suitable for use as an input to a GMP process. We will further describe the development of simple apparatus suitable for executing the process for pilot GMP batches, the optimization of the drying process and excipient composition, and the application of frequency modulation spectroscopy for non-destructive analysis of residual moisture content. Finally, we will describe the application of the technology to a formulation of ChAdOx1 RVF, an adenovirus-vectored vaccine against Rift Valley Fever Virus which is being developed for both human and veterinary use. In this case, SMT is applied to an ultra-low-cost drug substance designed for veterinary use (cell lysate which has been clarified and ultrafiltered but not chromatographically purified), emphasizing the suitability of the approach for low-cost and One Health applications. 1. Alcock, R., et al., Long-Term Thermostabilization of Live Poxviral and Adenoviral Vaccine Vectors at Supraphysiological Temperatures in Carbohydrate Glass. Science Translational Medicine, 2010. 2(19):19ra12. 2. Dulal, P., et al., Potency of a thermostabilised chimpanzee adenovirus Rift Valley Fever vaccine in cattle. Vaccine, 2016. 34(20): p. 2296-8