Students and Refugees Together (START): Inter-Professional Learning and Service Innovation

This paper presents four perspectives of an innovative organisation which was set up in 2001 to respond to the unmet needs of refugees and asylum seekers in the far south west of England. Social Work students were supported to undertake one of their assessed practice placements working with families referred by the Ethnic Minority Achievement Service (EMAS) teacher and the local Social Services referral co-ordinator. The organisation has grown from a small \u27virtual \u27 organisation , staffed only by students, to a registered charity employing health and social care staff who supervise students from increasingly diverse professions to learn through service provision. The perspectives of a service user, a student and the manager are presented to illustrate the philosophy, principles and practice of the agency. Consideration is given to the relationship of academic institutions to health and social care provision and practice. The intention here is to promote debate about the potential of academic institutions to stimulate change through action as well as teaching and research

The Cytokine Release Inhibitory Drug CRID3 Targets ASC Oligomerisation in the NLRP3 and AIM2 Inflammasomes

Background: The Inflammasomes are multi-protein complexes that regulate caspase-1 activation and the production of the pro-inflammatory cytokine IL-1 beta. Previous studies identified a class of diarylsulfonylurea containing compounds called Cytokine Release Inhibitory Drugs (CRIDs) that inhibited the post-translational processing of IL-1 beta. Further work identified Glutathione S-Transferase Omega 1 (GSTO1) as a possible target of these CRIDs. This study aimed to investigate the mechanism of the inhibitory activity of the CRID CP-456,773 (termed CRID3) in light of recent advances in the area of inflammasome activation, and to clarify the potential role of GSTO1 in the regulation of IL-1 beta production

Antimicrobial octapeptin C4 analogues active against Cryptococcus species

Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with minimum inhibitory concentration of 1.56 μg/mL. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed MIC 1.56-3.13 μg/mL while 20 clinical isolates of C. neoformans var. gattii had MIC 0.78-12.5 μg/mL. In each case MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogens sensitivity to octapeptin C4 while degree of melanisation had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents

Synthesis of deuterium-labelled analogues of NLRP3 inflammasome inhibitor MCC950

This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl)propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24. All of the compounds exhibited similar activity to MCC950 (IC50 = 8 nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies

Antifungal benzo[b]thiophene 1,1-dioxide IMPDH inhibitors exhibit pan-assay interference (PAINS) profiles

Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor

A mixed-methods feasibility study of a new digital health support package for people after stroke : The Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS) intervention

Background Evidence for digital health programmes to support people living with stroke is growing. We assessed the feasibility of a protocol and procedures for the Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS) trial. Methods We conducted a mixed-method feasibility study. Participants with acute stroke were recruited from three hospitals (Melbourne, Australia). Eligibility: Adults with stroke discharged from hospital to home within 10 days, modified Rankin Score 0–4 and prior use of Short Message System (SMS)/email. While in hospital, recruited participants contributed to structured person-centred goal setting and completed baseline surveys including self-management skills and health-related quality of life. Participants were randomised 7–14 days after discharge via REDCap® (1:1 allocation). Following randomisation, the intervention group received a 12-week programme of personalised electronic support messages (average 66 messages sent by SMS or email) aligned with their goals. The control group received six electronic administrative messages. Feasibility outcomes included the following: number of patients screened and recruited, study retainment, completion of outcome measures and acceptability of the ReCAPS intervention and trial procedures (e.g. participant satisfaction survey, clinician interviews). Protocol fidelity outcomes included number of goals developed (and quality), electronic messages delivered, stop messages received and engagement with messages. We undertook inductive thematic analysis of interview/open-text survey data and descriptive analysis of closed survey questions. Results Between November 2018 and October 2019, 312 patients were screened; 37/105 (35%) eligible patients provided consent (mean age 61 years; 32% female); 33 were randomised (17 to intervention). Overall, 29 (88%) participants completed the12-week outcome assessments with 12 (41%) completed assessments in the allocated timeframe and 16 also completing the satisfaction survey (intervention=10). Overall, trial participants felt that the study was worthwhile and most would recommend it to others. Six clinicians participated in one of three focus group interviews; while they reported that the trial and the process of goal setting were acceptable, they raised concerns regarding the additional time required to personalise goals. Conclusion The study protocol and procedures were feasible with acceptable retention of participants. Consent and goal personalisation procedures should be centralised for the phase III trial to reduce the burden on hospital clinicians. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12618001468213 (date 31/08/2018); Universal Trial Number: U1111-1206-723

Spectators’ Negotiations of Risk, Masculinity and Performative Mobilities at the TT Races

This paper explores the particular assemblage of place, event and individual identity performances that occur each year in the Isle of Man in and through the TT (Tourist Trophy) motorcycle races. These road races are associated with a high degree of risk for the racers and the confluence of over 30,000 visitors and 10,000 motorcycles also presents potential risks for spectators and residents alike. Both motorcycling and risk-taking have been associated with particular forms of masculinity, notably hegemonic, working class and youthful masculinities. Using detailed surveys of spectators we argue that the TT races, while undoubtedly dominated by men and predicated on a cultural privileging of speed and skill, are grounded in varying combinations of determinate and reflexive attitudes to risk, reflecting the performance of a variety of gendered, ‘biker’ and wider identity-based positionalities. Findings also highlight a particular inter-relation of mobilities and place identities at the TT races and bring to light the highly significant and under-researched embodied, performative and emotional mobilities of spectators. The conceptual and methodological importance of (a) situated research of both mobilities and gender in specific place-temporalities and (b) wider surveys of motorcyclists to complement ethnographic studies of small cohorts are also stressed

Protocol of a randomized controlled trial investigating the effectiveness of Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS)

Rationale: To address unmet needs, electronic messages to support person-centred goal attainment and secondary prevention may avoid hospital presentations/readmissions after stroke, but evidence is limited. Hypothesis: Compared to control participants, there will be a 10% lower proportion of intervention participants who represent to hospital (emergency/admission) within 90 days of randomisation. Methods and design: Multicentre, double-blind, randomised controlled trial with intention-to-treat analysis. The intervention group receives 12 weeks of personalised, goal-centred and administrative electronic messages, while the control group only receives administrative messages. The trial includes a process evaluation, assessment of treatment fidelity and an economic evaluation. Participants: Confirmed stroke (modified Rankin Score: 0-4), aged �18 years with internet/mobile phone access, discharged directly home from hospital. Randomisation: 1:1 computer-generated, stratified by age and baseline disability. Outcomes Assessments: Collected at 90 days and 12 months following randomisation. Outcomes: Primary: Hospital emergency presentations/admissions within 90 days of randomisation. Secondary outcomes include goal attainment, self-efficacy, mood, unmet needs, disability, quality-of-life, recurrent stroke/cardiovascular events/deaths at 90 days and 12 months, and death and cost-effectiveness at 12 months. Sample size: To test our primary hypothesis, we estimated a sample size of 890 participants (445 per group) with 80% power and two-tailed significance threshold of α=0.05. Given uncertainty for the effect size of this novel intervention, the sample size will be adaptively re-estimated when outcomes for n=668 are obtained, with maximum sample capped at 1100. Discussion: We will provide new evidence on the potential effectiveness, implementation and cost-effectiveness of a tailored eHealth intervention for survivors of stroke

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1 beta (IL-1 beta) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease

Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.

Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics