Self-disseminating vaccines for emerging infectious diseases.

Modern human activity fueled by economic development is profoundly altering our relationship with microorganisms. This altered interaction with microbes is believed to be the major driving force behind the increased rate of emerging infectious diseases from animals. The spate of recent infectious disease outbreaks, including Ebola virus disease and Middle East respiratory syndrome, emphasize the need for development of new innovative tools to manage these emerging diseases. Disseminating vaccines are one such novel approach to potentially interrupt animal to human (zoonotic) transmission of these pathogens

Perceptions of psychological momentum of elite soccer players

The purpose of this research was to investigate elite soccer players’ perceptions and experiences of psychological momentum (PM) using a mixed methodological approach. Specifically, by comparing responses, the study aimed to provide coaches with a more appropriate method for collecting PM data. Interviews and focus groups were conducted with 10 English Academy, elite male soccer players. In addition, 75 professional male soccer players completed a 49-item measure about their experiences of PM. Interviews and focus groups were manually analysed using a combination of inductive and deductive approaches with Chi-square tests used to assess differences between responses to the PM measure. The majority of questionnaire responses were supported by themes highlighted by players interviewed. Scoring and conceding goals were the most frequently reported match variables associated with positive and negative PM, respectively. In addition, ‘feeling confident’, ‘having a positive attitude’ and ‘being cohesive as a team’ were important aspects of positive PM. A ‘perceived lack of ability’ and ‘feeling anxious’ were the most frequently reported experiences of negative PM. The similarity of results from both methods support the measure as a useful tool for coaches to collect data pertaining to players’ experiences and perceptions of PM. Overall, findings suggest that PM is a complex (dynamic) process whereby triggers, characteristics, and consequences can hardly be separated. By understanding players’ experiences and perceptions of PM, coaches may incorporate specific training methods to help players maximise positive PM, reduce negative PM as well as develop strategies to optimise PM

Cytomegalovirus-based vaccine expressing Ebola virus glycoprotein protects nonhuman primates from Ebola virus infection.

Ebolaviruses pose significant public health problems due to their high lethality, unpredictable emergence, and localization to the poorest areas of the world. In addition to implementation of standard public health control procedures, a number of experimental human vaccines are being explored as a further means for outbreak control. Recombinant cytomegalovirus (CMV)-based vectors are a novel vaccine platform that have been shown to induce substantial levels of durable, but primarily T-cell-biased responses against the encoded heterologous target antigen. Herein, we demonstrate the ability of rhesus CMV (RhCMV) expressing Ebola virus (EBOV) glycoprotein (GP) to provide protective immunity to rhesus macaques against lethal EBOV challenge. Surprisingly, vaccination was associated with high levels of GP-specific antibodies, but with no detectable GP-directed cellular immunity

CXCR2 Inhibition – a novel approach to treating CoronAry heart DiseAse (CICADA): study protocol for a randomised controlled trial

Abstract Background There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Patients with lower neutrophil counts following acute coronary syndromes tend to have a greater coronary flow reserve, which is a strong predictor of long-term cardiovascular health. But so far, no data are available regarding the impact of neutrophil inhibition on cardiovascular clinical or surrogate endpoints. Therefore, the aim of this study is to investigate the effects of AZD5069, a cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibitor, on coronary flow reserve and coronary structure and function in patients with coronary artery disease. Methods/Design Ninety subjects with coronary artery disease undergoing percutaneous coronary intervention will be included in this investigator-driven, randomised, placebo-controlled, double-blind, phase IIa, single-centre study. Participants will be randomised to receive either AZD5069 (40 mg) administered orally twice daily or placebo for 24 weeks. Change in coronary flow reserve as determined by 13N-ammonia positron emission tomography-computed tomography will be the primary outcome. Change in the inflammatory component of coronary plaque structure and the backward expansion wave, an invasive coronary physiological measure of diastolic function, will be assessed as secondary outcomes. Discussion Cardiovascular surrogate parameters, such as coronary flow reserve, may provide insights into the potential mechanisms of the cardiovascular effects of CXCR2 inhibitors. Currently, ongoing trials do not specifically focus on neutrophil function as a target of intervention, and we therefore believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease. Trial registration EudraCT, 2016-000775-24 . Registered on 22 July 2016. International Standard Randomised Controlled Trial Number, ISRCTN48328178 . Registered on 25 February 2016

Dapsone‐ and nitroso dapsone‐specific activation of T cells from hypersensitive patients expressing the risk allele HLA‐B*13:01

BACKGROUND:Research into drug hypersensitivity associated with expression of specific HLA alleles has focussed on the interaction between parent drug and the HLA with no attention given to reactive metabolites. For this reason, we have studied HLA-B*13:01-linked dapsone hypersensitivity to (1) explore whether the parent drug and/or nitroso metabolite activates T-cells and (2) determine whether HLA-B*13:01 is involved in the response. METHODS:PBMC from 6 patients were cultured with dapsone and nitroso dapsone and proliferative responses and IFN-γ release were measured. Dapsone- and nitroso dapsone-specific T-cell clones were generated and phenotype, function, HLA allele restriction and cross-reactivity assessed. Dapsone intermediates were characterized by mass spectrometry. RESULTS:PBMC from 6 patients and cloned T-cells proliferated and secreted Th1/2/22 cytokines when stimulated with dapsone (clones: n=395; 80% CD4+ CXCR3hi CCR4hi , 20% CD8+CXCR3hi CCR4hi CCR6hi CCR9hi CCR10hi ) and nitroso dapsone (clones: n=399; 78% CD4+, 22% CD8+ with same chemokine receptor profile). CD4+ and CD8+ clones were HLA-class II and class I restricted, respectively, and displayed three patterns of reactivity: compound-specific, weakly crossreactive and strongly cross reactive. Nitroso dapsone formed dimers in culture and was reduced to dapsone, providing a rationale for the crossreactivity. T-cell responses to nitroso dapsone were dependent on the formation of a cysteine-modified protein adduct, while dapsone interacted in a labile manner with antigen presenting cells. CD8+ clones displayed an HLA-B*13:01-restricted pattern of activation. CONCLUSION:These studies describe the phenotype and function of dapsone- and nitroso dapsone-responsive CD4+ and CD8+ T-cells from hypersensitive patients. Discovery of HLA-B*13:01-restricted CD8+ T-cell responses indicates that drugs and their reactive metabolites participate in HLA allele-linked forms of hypersensitivity. This article is protected by copyright. All rights reserved

Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls

Background The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders