Inhibition of classical and alternative modes of respiration in Candida albicans leads to cell wall remodelling and increased macrophage recognition

The human fungal pathogen Candida albicans requires respiratory function for normal growth, morphogenesis and virulence. Mitochondria therefore represent an enticing target for the development of new antifungal strategies. This possibility is bolstered by the presence of characteristics specific to fungi. However, respiration in C. albicans, as in many fungal organisms, is facilitated by redundant electron transport mechanisms, making direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we make use of chemicals with low toxicity to efficiently inhibit respiration in C. albicans. We find that use of the Nitric Oxide donor, Sodium Nitroprusside (SNP), and the alternative oxidase inhibitor, SHAM, prevents respiration, leads to a loss of viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo. We propose that SNP+SHAM treatment leads to transcriptional changes that drive cell wall re-arrangement but which also prime cells to activate transition to hyphal growth. In line with this we find that pre-treatment of C. albicans with SNP+SHAM leads to an increase in virulence. Our data reveals strong links between respiration, cell wall remodelling and activation of virulence factors. Our findings demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals, which are not damaging to the mammalian host, but that we need to develop a deeper understanding of the roles of mitochondria in cellular signalling if they are to be developed successfully as a target for new antifungals

Clinicians’ perspectives on supporting individuals with severe anorexia nervosa in specialist eating disorder intensive treatment settings during the COVID-19 pandemic

Background: The COVID-19 pandemic has significantly affected intensive treatment settings (i.e., inpatient [IP] and day patient [DP]) in specialist eating disorder services. However, the impact on clinicians working in these services is largely unknown. We therefore explored the perspectives of those supporting individuals with severe anorexia nervosa (AN) in intensive treatment settings during the pandemic. Methods: Between May 2020 and June 2021, we interviewed clinicians (n = 21) who delivered IP and/or DP treatment to patients with severe AN in four specialist eating disorder services in the United Kingdom. Data relating to experiences during COVID-19 were analysed using reflexive thematic analysis. Results: We identified six themes: Disruptions to Routine Treatment; Introduction of Virtual Treatment; Separation from Treatment, Others and the World; Impact on Recovery; Impact on Staff; and Pressure on Referral Pathways. COVID-19 posed significant challenges to IP and DP services: forcing closures, operating with restrictions and virtual treatment, and impacting delivery of essential treatment components, referral pathways, clinician wellbeing, risk management, and patient isolation and recovery trajectories. Opportunities arose, in particular in DP services offering virtual support. Conclusions: COVID-19 challenged the continuation of multidisciplinary treatment. The findings underline the necessity for medical, psychological, practical, and nutritional support, as well as carer involvement and fostering social connections to remain at the forefront of intensive treatment for severe AN. They also emphasise the uncertainty surrounding which intensive treatment may be best suited to which patient when, particularly within the context of virtual DP support

Clinicians' perspectives on supporting individuals with severe anorexia nervosa in specialist eating disorder intensive treatment settings

BACKGROUND: Admissions to intensive treatment (i.e., inpatient [IP] and/or day patient [DP]) for individuals with severe anorexia nervosa (AN) are common. Growing literature indicates potential risks and benefits of each intensive treatment approach; however, existing research has focused on patient and carer perspectives of these treatments. Also, there is scant empirical evidence available for guiding the parameters of intensive treatments for AN. We therefore explored clinicians' perspectives and experience of supporting adults with severe AN in intensive settings. METHODS: We conducted twenty one semi-structured interviews with clinicians who deliver intensive treatments (i.e., IP and/or DP) for individuals with severe AN across four specialist Eating Disorder Services in the United Kingdom between May 2020 and June 2021. We asked clinicians about their views and experiences of supporting individuals with severe AN in intensive treatment settings and the challenges and opportunities associated with IP and DP treatment. Data were analysed using reflexive thematic analysis supported by NVivo software. RESULTS: Five broad and interrelated themes were identified: (1) Intensive Support; (2) The Severity of Patients' Illnesses; (3) Hope and Recovery; (4) Which Treatment When; (5) Limited Resources; and (6) Carer Burden. We identified various similarities between the two intensive treatment approaches, including the value of intensive and multidisciplinary support and carer involvement, and the challenge of managing complex and unique needs in resource-limited intensive settings. We also found differences in the relationship of treatment to patients' home environments, the necessity of patient motivation, and the management of risk. CONCLUSIONS: Both intensive treatment settings are valued by clinicians; however, there are unique challenges and opportunities for supporting individuals with severe AN within each. Our findings suggest DP treatment may be used as an alternative to IP treatment for individuals with severe AN. However, clear questions remain over which intensive treatment setting is best suited to which patient when and should be the focus of future research

Air Data Boom System Development for the Max Launch Abort System (MLAS) Flight Experiment

In 2007, the NASA Exploration Systems Mission Directorate (ESMD) chartered the NASA Engineering Safety Center (NESC) to demonstrate an alternate launch abort concept as risk mitigation for the Orion project's baseline "tower" design. On July 8, 2009, a full scale and passively, aerodynamically stabilized MLAS launch abort demonstrator was successfully launched from Wallops Flight Facility following nearly two years of development work on the launch abort concept: from a napkin sketch to a flight demonstration of the full-scale flight test vehicle. The MLAS flight test vehicle was instrumented with a suite of aerodynamic sensors. The purpose was to obtain sufficient data to demonstrate that the vehicle demonstrated the behavior predicted by Computational Fluid Dynamics (CFD) analysis and wind tunnel testing. This paper describes development of the Air Data Boom (ADB) component of the aerodynamic sensor suite

'Sexercise': Working out heterosexuality in Jane Fonda’s fitness books

This is an Author's Accepted Manuscript of an article published in Leisure Studies, 30(2), 237 - 255, 2011, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/02614367.2010.523837.This paper explores the connection between the promotion of heterosexual norms in women’s fitness books written by or in the name of Jane Fonda during the 1980s and the commodification of women’s fitness space in both the public and private spheres. The paper is set in the absence of overt discussions of normative heterosexuality in leisure studies and draws on critical heterosexual scholarship as well as the growing body of work theorising geographies of corporeality and heterosexuality. Using the principles of media discourse analysis, the paper identifies three overlapping characteristics of heterosexuality represented in Jane Fonda’s fitness books, and embodied through the exercise regimes: respectable heterosexual desire, monogamous procreation and domesticity. The paper concludes that the promotion and prescription of exercise for women in the Jane Fonda workout books centred on the reproduction and embodiment of heterosexual corporeality. Set within an emerging commercial landscape of women’s fitness in the 1980s, such exercise practices were significant in the legitimation and institutionalisation of heteronormativity

Peripheral blood-derived mesenchymal stem cells demonstrate immunomodulatory potential for therapeutic use in horses

Previously, we showed that mesenchymal stem cells (MSC) can be mobilized into peripheral blood using electroacupuncture (EA) at acupoints, LI-4, LI-11, GV-14, and GV-20. The purpose of this study was to determine whether EA-mobilized MSC could be harvested and expanded in vitro to be used as an autologous cell therapy in horses. Peripheral blood mononuclear cells (PBMC) isolated from young and aged lame horses (n = 29) showed a marked enrichment for MSCs. MSC were expanded in vitro (n = 25) and administered intravenously at a dose of 50 x 106 (n = 24). Treatment resulted in significant improvement in lameness as assessed by the American Association of Equine Practitioners (AAEP) lameness scale (n = 23). MSCs exhibited immunomodulatory function by inhibition of lymphocyte proliferation and induction of IL-10. Intradermal testing showed no immediate or delayed immune reactions to MSC (1 x 106 to 1 x 104). In this study, we demonstrated an efficient, safe and reproducible method to mobilize and expand, in vitro, MSCs in sufficiently high concentrations for therapeutic administration. We confirm the immunomodulatory function of these cells in vitro. This non-pharmacological and non-surgical strategy for stem cell harvest has a broad range of biomedical applications and represents an improved clinically translatable and economical cell source for humans

Changing contexts and critical moments: interim outcomes for children and young people living through involuntary relocation

The aim of this article is to understand how involuntary relocation – in the context of transformational regeneration – affects children and young people’s (CYP) interim outcomes through its impacts on residential contexts, and its intersections with their transitions and critical moments. Findings are based on a longitudinal qualitative study of 13 families’ (comprising 32 CYP) lives as they relocated from high rise flats to different housing and neighbourhoods over three years. Relocation altered two key contexts directly, home and neighbourhood, and may have indirectly altered the other contexts – peers, school and family. However, we found there were as many non-relocation related factors as relocation factors associated with outcomes, and a number of significant critical moments affecting CYP’s lives. Whilst relocation can seem the ‘big thing’ from the point of view of practitioners and researchers, from the perspective of CYP, it can seem a small part of the much bigger picture of change in their lives

Airway Microbiota Dynamics Uncover a Critical Window for Interplay of Pathogenic Bacteria and Allergy in Childhood Respiratory Disease.

Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. In this study, the occurrence of acute respiratory tract illnesses (ARIs) and the nasopharyngeal microbiome (NPM) were characterized in 244 infants through their first five years of life. Through this analysis, we demonstrate that >80% of infectious events involve viral pathogens, but are accompanied by a shift in the NPM toward dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change frequently precedes the detection of viral pathogens and acute symptoms. Colonization of illness-associated bacteria coupled with early allergic sensitization is associated with persistent wheeze in school-aged children, which is the hallmark of the asthma phenotype. In contrast, these bacterial genera are associated with "transient wheeze" that resolves after age 3 years in non-sensitized children. Thus, to complement early allergic sensitization, monitoring NPM composition may enable early detection and intervention in high-risk children

Looking inside the black box: results of a theory-based process evaluation exploring the results of a randomized controlled trial of printed educational messages to increase primary care physicians' diabetic retinopathy referrals [Trial registration number ISRCTN72772651]

Background: Theory-based process evaluations conducted alongside randomized controlled trials provide the opportunity to investigate hypothesized mechanisms of action of interventions, helping to build a cumulative knowledge base and to inform the interpretation of individual trial outcomes. Our objective was to identify the underlying causal mechanisms in a cluster randomized trial of the effectiveness of printed educational materials (PEMs) to increase referral for diabetic retinopathy screening. We hypothesized that the PEMs would increase physicians’ intention to refer patients for retinal screening by strengthening their attitude and subjective norm, but not their perceived behavioral control. Methods: Design: A theory based process evaluation alongside the Ontario Printed Educational Material (OPEM) cluster randomized trial. Postal surveys based on the Theory of Planned Behavior were sent to a random sample of trial participants two months before and six months after they received the intervention. Setting: Family physicians in Ontario, Canada. Participants: 1,512 family physicians (252 per intervention group) from the OPEM trial were invited to participate, and 31.3% (473/1512) responded at time one and time two. The final sample comprised 437 family physicians fully completing questionnaires at both time points. Main outcome measures: Primary: behavioral intention related to referring patient for retinopathy screening; secondary: attitude, subjective norm, perceived behavioral control. Results: At baseline, family physicians reported positive intention, attitude, subjective norm, and perceived behavioral control to advise patients about retinopathy screening suggesting limited opportunities for improvement in these constructs. There were no significant differences on intention, attitude, subjective norm, and perceived behavioral control following the intervention. Respondents also reported additional physician- and patient-related factors perceived to influence whether patients received retinopathy screening. Conclusions: Lack of change in the primary and secondary theory-based outcomes provides an explanation for the lack of observed effect of the main OPEM trial. High baseline levels of intention to advise patients to attend retinopathy screening suggest that post-intentional and other factors may explain gaps in care. Process evaluations based on behavioral theory can provide replicable and generalizable insights to aid interpretation of randomized controlled trials of complex interventions to change health professional behavior