OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Transcriptional regulation of N6-methyladenosine orchestrates sex-dimorphic metabolic traits.

Males and females exhibit striking differences in the prevalence of metabolic traits including hepatic steatosis, a key driver of cardiometabolic morbidity and mortality. RNA methylation is a widespread regulatory mechanism of transcript turnover. Here, we show that presence of the RNA modification N6-methyladenosine (m6A) triages lipogenic transcripts for degradation and guards against hepatic triglyceride accumulation. In male but not female mice, this protective checkpoint stalls under lipid-rich conditions. Loss of m6A control in male livers increases hepatic triglyceride stores, leading to a more 'feminized' hepatic lipid composition. Crucially, liver-specific deletion of the m6A complex protein Mettl14 from male and female mice significantly diminishes sex-specific differences in steatosis. We further surmise that the m6A installing machinery is subject to transcriptional control by the sex-responsive BCL6-STAT5 axis in response to dietary conditions. These data show that m6A is essential for precise and synchronized control of lipogenic enzyme activity and provide insights into the molecular basis for the existence of sex-specific differences in hepatic lipid traits.

Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA.

Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type-specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17. The identification of MeXis as a lncRNA modulator of LXR-dependent gene expression expands understanding of the mechanisms underlying cell type-selective actions of nuclear receptors in physiology and disease.

Recognizing European cancer nursing: Protocol for a systematic review and meta-analysis of the evidence of effectiveness and value of cancer nursing.

AIM: To identify, appraise and synthesize the available evidence relating to the value and impact of cancer nursing on patient experience and outcomes. BACKGROUND: There is a growing body of literature that recognizes the importance and contribution of cancer nurses, however, a comprehensive review examining how cancer nurses have an impact on care quality, patient outcomes and overall experience of cancer, as well as cost of services across the entire cancer spectrum is lacking. DESIGN: A systematic review and meta-analysis using Cochrane methods. METHODS: We will systematically search 10 electronic databases from 2000, with pre-determined search terms. No language restrictions will be applied. We will include all randomized and controlled before-and-after studies that compare cancer nursing interventions to a standard care or no intervention. Two reviewers will independently assess the eligibility of the studies and appraise methodological quality using the Cochrane Risk of Bias tool. Disagreements will be resolved by discussion and may involve a third reviewer if necessary. Data from included studies will be extracted in accordance with the Template for intervention Description and Replication reporting guidelines. Missing data will be actively sought from all trialists. Data will be synthesized in evidence tables and narrative to answer three key questions. If sufficient data are available, we will perform meta-analyses. DISCUSSION: This review will allow us to systematically assess the impact of cancer nursing on patient care and experience. This evidence will be used to determine implications for clinical practice and used to inform future programme and policy decisions in Europe.

Parental response to the introduction of a vaccine against human papilloma virus.

The introduction of a vaccine against human papillomavirus (HPV), a sexually transmitted virus that is the causal factor of at least 95% of invasive cervical cancer, could significantly reduce the number of cases of cervical cancer occurring in the UK each year. To ensure that individuals are protected before onset of sexual activity, it is likely that the vaccine will be offered to children around 10 years of age. It is important that parents' attitudes to HPV vaccination are taken into account, particularly as the subject relates to sexual health issues. In order to gauge parents' initial responses to the addition of HPV vaccine to the immunisation programme and identify the issues needing further research, in-depth interviews were held with parents of girls and boys aged 8-10 years. Our results show that most parents have not heard of HPV and were not aware of the role of HPV in cervical cancer. There were concerns about offering a vaccine that protects against a sexually transmitted infection to children and that the vaccine should be offered at an older age in conjunction with a sex education program. In order to avoid rejection of this vaccine, work needs to take place now to raise awareness of HPV as a cause of cervical cancer prior to any introduction of the vaccination program.