Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5

Vomocytosis, or non-lytic extrusion, is a poorly understood process through which macrophages release live pathogens that they have failed to kill back into the extracellular environment. Vomocytosis is conserved across vertebrates and occurs with a diverse range of pathogens, but to date the host signaling events that underpin expulsion remain entirely unknown. Here we use a targeted inhibitor screen to identify the MAP-kinase ERK5 as a critical suppressor of vomocytosis. Pharmacological inhibition or genetic manipulation of ERK5 activity significantly raises vomocytosis rates in human macrophages whilst stimulation of the ERK5 signaling pathway inhibits vomocytosis. Lastly, using a zebrafish model of cryptococcal disease, we show that reducing ERK5 activity in vivo stimulates vomocytosis and results in reduced dissemination of infection. ERK5 therefore represents the first host regulator of vomocytosis to be identified and a potential target for the future development of vomocytosis-modulating therapies

The Implementation of Video and Telephone Psychological Therapy for Adults Accessing Secondary NHS Community Mental Health Services A mixed-methods Evaluation to Understand What Works, for Whom and In What Circumstances

Background The urgent response to the COVID-19 pandemic has precipitated many changes in the delivery of health services. One such change is the introduction of telemedicine (i.e. virtual consultations) at pace and in services that had previously relied on face-to-face interaction. NHS mental health services are at the forefront of this change, with the delivery of therapeutic interventions transitioning to virtual consultations rapidly. Healthcare innovation is rarely a simple linear process; accordingly, it is crucial evaluation approaches focus on how contextual factors influence implementation success or failure. The discipline of implementation science provides this approach, defined as the scientific study of methods to promote the systematic uptake of research findings into routine practice. Aim The study used an implementation science to evaluate the implementation of virtual therapy consultations and assess impact on service user outcomes

Symptoms and risk factors for long COVID in non-hospitalized adults

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors

Preventing unscheduled hospitalisations from asthma:a retrospective cohort study using routine primary and secondary care data in the UK (The PUSH-Asthma Study): protocol paper

INTRODUCTION: Asthma is the most common chronic respiratory disease in children and adults. Asthma results in significant disease-related morbidity, healthcare costs and, in some cases, death. Despite efforts through implementation of national guidelines to improve asthma care, the UK has one of the highest asthma-related morbidity and mortality rates in the western world. New approaches are necessary to prevent asthma attacks in children and adults. The objectives of this study are to assess the association between demographic and clinical factors and asthma-related hospital admissions in children and adults, describe the epidemiology of asthma phenotypes among hospital attenders, and externally validate existing asthma risk prediction models. METHODS AND ANALYSIS: This is a retrospective cohort study of children and adults with asthma. Data will be extracted from the Clinical Practice Research Datalink (CPRD) Aurum database, which holds anonymised primary care data for over 13 million actively registered patients and covers approximately 19% of the UK population. The primary outcome will be asthma-related hospital admissions. The secondary outcomes will be prescriptions of short courses of oral corticosteroids (as a surrogate measure for asthma exacerbations), a composite outcome measure including hospital admissions and prescriptions of short courses of oral corticosteroids and delivery of asthma care management following hospital discharge. The primary analysis will use a Poisson regression model to assess the association between demographic and clinical risk factors and the primary and secondary outcomes. Latent class analysis will be used to identify distinct subgroups, which will further our knowledge on potential phenotypes of asthma among patients at high risk of asthma-related hospital admissions. A Concordance statistic (C-statistic) and logistic regression model will also be used to externally validate existing risk prediction models for asthma-related hospitalisations to allow for the optimal model to be identified and evaluated provide evidence for potential use of the optimal performing risk prediction model in primary care. ETHICS AND DISSEMINATION: This study was approved by the CPRD Independent Scientific Advisory Committee (reference number: 21_000512). Findings from this study will be published in a peer-reviewed journal and disseminated at national and international conferences