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Background Participants in clinical research studies often do not reflect the populations for which healthcare interventions are needed or will be used. Enhancing representation of under-served groups in clinical research is important to ensure that research findings are widely applicable. We describe a multicomponent workstream project to improve representation of under-served groups in clinical trials. Methods The project comprised three main strands: (1) a targeted scoping review of literature to identify previous work characterising under-served groups and barriers to inclusion, (2) surveys of professional stakeholders and participant representative groups involved in research delivery to refine these initial findings and identify examples of innovation and good practice and (3) a series of workshops bringing together key stakeholders from funding, design, delivery and participant groups to reach consensus on definitions, barriers and a strategic roadmap for future work. The work was commissioned by the UK National Institute for Health Research Clinical Research Network. Output from these strands was integrated by a steering committee to generate a series of goals, workstream plans and a strategic roadmap for future development work in this area. Results ‘Under-served groups’ was identified and agreed by the stakeholder group as the preferred term. Three-quarters of stakeholders felt that a clear definition of under-served groups did not currently exist; definition was challenging and context-specific, but exemplar groups (e.g. those with language barriers or mental illness) were identified as under-served. Barriers to successful inclusion of under-served groups could be clustered into communication between research teams and participant groups; how trials are designed and delivered, differing agendas of research teams and participant groups; and lack of trust in the research process. Four key goals for future work were identified: building long-term relationships with under-served groups, developing training resources to improve design and delivery of trials for under-served groups, developing infrastructure and systems to support this work and working with funders, regulators and other stakeholders to remove barriers to inclusion. Conclusions The work of the INCLUDE group over the next 12 months will build on these findings by generating resources customised for different under-served groups to improve the representativeness of trial populations.

\"In celebration of the 50th anniversary of the Apollo 11 landing, the endlessly-mysterious moon is explored in this reprint short science fiction anthology from award-winning editor and anthologist Neil Clarke ... On July 20, 1969, mankind made what had only years earlier seemed like an impossible leap forward: when Apollo 11 became the first manned mission to land on the moon, and Neil Armstrong the first person to step foot on the lunar surface. While there have only been a handful of new missions since, the fascination with our planet's satellite continues, and generations of writers and artists have imagined the endless possibilities of lunar life. From adventures in the vast gulf of space between the earth and the moon, to journeys across the light face to the dark side, to the establishment of permanent residences on its surface, science fiction has for decades given readers bold and forward-thinking ideas about our nearest interstellar neighbor and what it might mean to humankind, both now and in our future. [This book] collects the best stories written in the fifty years since mankind first stepped foot on the lunar surface, serving as a shining reminder that the moon is and always has been our most visible and constant example of all the infinite possibility of the wider universe\"-- Provided by publisher.

To determine the validity of the esophageal Doppler monitor (EDM) and echo-esophageal Doppler (Echo-ED) in measuring cardiac output in the critically ill. Systematic search of relevant international literature and data synthesis. Literature search (1989-2003) using Ovid interface to Medline, Embase and Cochrane databases aimed at finding studies comparing EDM or Echo-ED cardiac output with that derived from simultaneous pulmonary artery thermodilution (PAC(TD)) with Bland Altman measures of validity. Critically ill adults in operating departments or intensive care units. Summary validity measures synthesized from Bland Altman analyses included pooled median bias and the median percentage of clinical agreement (PCA) derived from the limits of agreement. Eleven validation papers for EDM (21 studies) involving 314 patients and 2,400 paired measurements. The pooled median bias for PAC(TD) versus EDM was 0.19 l/min (range -0.69 to 2.00 l/min) for cardiac output (16 studies), and 0.6% (range 0-2.3%) for changes in cardiac output (5 studies). The pooled median percentage of clinical agreement for PAC(TD) versus EDM was 52% (interquartile range 42-69%) for cardiac output and 86% (interquartile range 55-93%) for changes in cardiac output. These differences in PCA were significant ( p=0.03 Mann-Whitney) for bolus PAC(TD) as the clinical \"gold standard\". We found an insufficient number of studies (2 papers) to assess the validity of Echo-ED. The esophageal Doppler monitor has high validity (no bias and high clinical agreement with pulmonary artery thermodilution) for monitoring changes in cardiac output.

ObjectiveTo provide guidance to researchers, funders, regulators and study delivery teams to ensure that research on COVID-19 is inclusive, particularly of groups disproportionately affected by COVID-19 and who may have been historically under-served by research.Summary of key pointsGroups who are disproportionately affected by COVID-19 include (but are not limited to) older people, people with multiple long-term conditions, people with disabilities, people from Black, Asian and Ethnic minority groups, people living with obesity, people who are socioeconomically deprived and people living in care homes. All these groups are under-served by clinical research, and there is an urgent need to rectify this if COVID-19 research is to deliver relevant evidence for these groups who are most in need. We provide a framework and checklists for addressing key issues when designing and delivering inclusive COVID-19 research, based on the National Institute for Health Research INnovations in CLinical trial design and delivery for the UnDEr-served project roadmap. Strong community engagement, codevelopment and prioritisation of research questions and interventions are essential. Under-served groups should be represented on funding panels and ethics committees, who should insist on the removal of barriers to participation. Exclusion criteria should be kept to a minimum; intervention delivery and outcome measurement should be simple, flexible and tailored to the needs of different groups, and local advice on the best way to reach and engage with under-served communities should be taken by study delivery teams. Data on characteristics that allow identification of under-served groups must be collected, analyses should include these data to enable subgroup comparisons and results should be shared with under-served groups at an early stage.ConclusionInclusive COVID-19 research is a necessity, not a luxury, if research is to benefit all the communities it seeks to serve. It requires close engagement with under-served groups and attention to aspects of study topic, design, delivery, analysis and dissemination across the research life cycle.

More than two decades after its discovery, contaminant microbial DNA in PCR reagents continues to impact the sensitivity and integrity of broad-range PCR diagnostic techniques. This is particularly relevant to their use in the setting of human sepsis, where a successful diagnostic on blood samples needs to combine universal bacterial detection with sensitivity to 1-2 genome copies, because low levels of a broad range of bacteria are implicated. We investigated the efficacy of ethidium monoazide (EMA) and propidium monoazide (PMA) treatment as emerging methods for the decontamination of PCR reagents. Both treatments were able to inactivate contaminating microbial DNA but only at concentrations that considerably affected assay sensitivity. Increasing amplicon length improved EMA/PMA decontamination efficiency but at the cost of assay sensitivity. The same was true for UV exposure as an alternative decontamination strategy, likely due to damage sustained by oligonucleotide primers which were a significant source of contamination. However, a simple combination strategy with UV-treated PCR reagents paired with EMA-treated primers produced an assay capable of two genome copy detection and a <5% contamination rate. This decontamination strategy could have important utility in developing improved pan-bacterial assays for rapid diagnosis of low pathogen burden conditions such as in the blood of patients with suspected blood stream infection.

BackgroundContinuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are considered ‘aerosol-generating procedures’ in the treatment of COVID-19.ObjectiveTo measure air and surface environmental contamination with SARS-CoV-2 virus when CPAP and HFNO are used, compared with supplemental oxygen, to investigate the potential risks of viral transmission to healthcare workers and patients.Methods30 hospitalised patients with COVID-19 requiring supplemental oxygen, with a fraction of inspired oxygen ≥0.4 to maintain oxygen saturation ≥94%, were prospectively enrolled into an observational environmental sampling study. Participants received either supplemental oxygen, CPAP or HFNO (n=10 in each group). A nasopharyngeal swab, three air and three surface samples were collected from each participant and the clinical environment. Real-time quantitative polymerase chain reaction analyses were performed for viral and human RNA, and positive/suspected-positive samples were cultured for the presence of biologically viable virus.ResultsOverall 21/30 (70%) participants tested positive for SARS-CoV-2 RNA in the nasopharynx. In contrast, only 4/90 (4%) and 6/90 (7%) of all air and surface samples tested positive (positive for E and ORF1a) for viral RNA respectively, although there were an additional 10 suspected-positive samples in both air and surfaces samples (positive for E or ORF1a). CPAP/HFNO use or coughing was not associated with significantly more environmental contamination than supplemental oxygen use. Only one nasopharyngeal sample was culture positive.ConclusionsThe use of CPAP and HFNO to treat moderate/severe COVID-19 did not appear to be associated with substantially higher levels of air or surface viral contamination in the immediate care environment, compared with the use of supplemental oxygen.

Background Healthcare associated infections, including ventilator associated pneumonia, are difficult to diagnose and treat, and are associated with significant morbidity, mortality and cost. We aimed to demonstrate proof of concept that breath volatile profiles were associated with the presence of clinically relevant pathogens in the lower respiratory tract. Methods Patients with sterile brain injury requiring intubation and ventilation on the intensive care unit were eligible for inclusion. Serial clinical and breath data were obtained three times a week, from admission up to a maximum of 10 days. Bronchial lavage for semiquantitative culture was collected immediately prior to breath sampling. Breath samples were collected in triplicate for off-line analysis by thermal-desorption/gas chromatography/time-of-flight mass spectrometry. Breath data were recorded as retention time/mass ion pairs, and analysed (pathogen present vs absent) by ANOVA-mean centre principal component analysis. Results Samples were collected from 46 patients (mean (SD) age 49 (19) years; 27 male). The dominant factors affecting breath sample analysis were the individual breath profile and duration of intubation. When these were taken into account, clear separation was seen between breath profiles at each time point by the presence/absence of pathogens. Loadings plots identified consistent metabolite peaks contributing to this separation at each time point. Conclusions Breath volatile analysis is able to classify breath profiles of patients with and without significant pathogen load in the lower respiratory tract. If validated in independent cohorts, these findings could lead to development of rapid non-invasive point-of-care surveillance systems and diagnostics for lower respiratory tract infection in the intensive care unit.

BackgroundCOVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from ‘classical’ ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template.MethodsAn 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1–9 (where 1–3 is inappropriate, 4–6 is uncertain and 7–9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again.ResultsDisagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease.ConclusionThe expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.

Patients suspected of ventilator-associated lower respiratory tract infections (VA-LRTIs) commonly receive broad-spectrum antimicrobial therapy unnecessarily. We tested whether exhaled breath analysis can discriminate between patients suspected of VA-LRTI with confirmed infection, from patients with negative cultures. Breath from 108 patients suspected of VA-LRTI was analysed by gas chromatography-mass spectrometry. The breath test had a sensitivity of 98% at a specificity of 49%, confirmed with a second analytical method. The breath test had a negative predictive value of 96% and excluded pneumonia in half of the patients with negative cultures. Trial registration number: UKCRN ID number 19086, registered May 2015.