Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity

A new regulatory T (T reg) cell–specific, FoxP3-GFP-hCre bacterial artificial chromosome transgenic mouse was crossed to a conditional Dicer knockout (KO) mouse strain to analyze the role of microRNAs (miRNAs) in the development and function of T reg cells. Although thymic T reg cells developed normally in this setting, the cells showed evidence of altered differentiation and dysfunction in the periphery. Dicer-deficient T reg lineage cells failed to remain stable, as a subset of cells down-regulated the T reg cell–specific transcription factor FoxP3, whereas the majority expressed altered levels of multiple genes and proteins (including Neuropilin 1, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4) associated with the T reg cell fingerprint. In fact, a significant percentage of the T reg lineage cells took on a T helper cell memory phenotype including increased levels of CD127, interleukin 4, and interferon γ. Importantly, Dicer-deficient T reg cells lost suppression activity in vivo; the mice rapidly developed fatal systemic autoimmune disease resembling the FoxP3 KO phenotype. These results support a central role for miRNAs in maintaining the stability of differentiated T reg cell function in vivo and homeostasis of the adaptive immune system

Developing a computerised search to help UK General Practices identify more patients for palliative care planning:a feasibility study

We would like to thank all practices, patients and their carers who helped us successfully conduct this project. We are grateful for advice from Libby Morris, the eHealth Clinical Lead for NHS Scotland and a GP in Lothian. The project was funded by Marie Curie Cancer Care (ref A13575).Peer reviewedPublisher PD

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Mapping the progress and impacts of public health approaches to palliative care:a scoping review protocol

Introduction: Public health palliative care is a term\ud that can be used to encompass a variety of approaches\ud that involve working with communities to improve\ud people’s experience of death, dying and bereavement.\ud Recently, public health palliative care approaches have\ud gained recognition and momentum within UK health\ud policy and palliative care services. There is general\ud consensus that public health palliative care approaches\ud can complement and go beyond the scope of formal\ud service models of palliative care. However, there is no\ud clarity about how these approaches can be undertaken\ud in practice or how evidence can be gathered relating to\ud their effectiveness. Here we outline a scoping review\ud protocol that will systematically map and categorise the\ud variety of activities and programmes that could be\ud classified under the umbrella term ‘public health\ud palliative care’ and highlight the impact of these\ud activities where measured.\ud Methods and analysis: This review will be guided\ud by Arksey and O’Malley’s scoping review methodology\ud and incorporate insights from more recent innovations\ud in scoping review methodology. Sensitive searches of\ud 9 electronic databases from 1999 to 2016 will be\ud supplemented by grey literature searches. Eligible\ud studies will be screened independently by two\ud reviewers using a data charting tool developed for this\ud scoping review.\ud Ethics and dissemination: This scoping review will\ud undertake a secondary analysis of data already\ud collected and does not require ethical approval. The\ud results will facilitate better understanding of the\ud practical application of public health approaches to\ud palliative care, the impacts these activities can have and\ud how to build the evidence base for this work in future.\ud The results will be disseminated through traditional\ud academic routes such as conferences and journals and\ud also policy and third sector seminars