Albumin versus balanced crystalloid for resuscitation in the treatment of sepsis: A protocol for a randomised controlled feasibility study, "ABC-Sepsis".

Background: Patients presenting with suspected sepsis to secondary care often require fluid resuscitation to correct hypovolaemia and/or septic shock. Existing evidence signals, but does not demonstrate, a benefit for regimes including albumin over balanced crystalloid alone. However, interventions may be started too late, missing a critical resuscitation window. Methods: ABC Sepsis is a currently recruiting randomised controlled feasibility trial comparing 5% human albumin solution (HAS) with balanced crystalloid for fluid resuscitation in patients with suspected sepsis. This multicentre trial is recruiting adult patients within 12 hours of presentation to secondary care with suspected community acquired sepsis, with a National Early Warning Score ≥5, who require intravenous fluid resuscitation. Participants are randomised to 5% HAS or balanced crystalloid as the sole resuscitation fluid for the first 6 hours. Objectives: Primary objectives are feasibility of recruitment to the study and 30-day mortality between groups. Secondary objectives include in-hospital and 90-day mortality, adherence to trial protocol, quality of life measurement and secondary care costs. Discussion: This trial aims to determine the feasibility of conducting a trial to address the current uncertainty around optimal fluid resuscitation of patients with suspected sepsis. Understanding the feasibility of delivering a definitive study will be dependent on how the study team are able to negotiate clinician choice, Emergency Department pressures and participant acceptability, as well as whether any clinical signal of benefit is detected.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Pulmonary embolism management in the emergency department: part 2.

Pulmonary embolism (PE) can present with a range of severity. Prognostic risk stratification is important for efficacious and safe management. This second of two review articles discusses the management of high-, intermediate- and low-risk PE. We discuss strategies to identify patients suitable for urgent outpatient care in addition to identification of patients who would benefit from thrombolysis. We discuss specific subgroups of patients where optimal treatment differs from the usual approach and identify emerging management paradigms exploring new therapies and subgroups.

Interferon-γ release assay screening in biologics: safe and reliable, but not perfect.

Background: Systemic biologic agents can increase the risk of re-activation of latent tuberculosis (TB). Prior to initiation, screening for latent TB using an interferon-γ release assay (IGRA) is recommended. There is concern that false-negative IGRAs may be more likely in this context. Methods: This retrospective analysis of IGRAs, specifically T-SPOT.TB, results and outcomes of patients already on or due to start biologics identifies the rate of TB re-activation in a low TB incidence setting. Additionally, we estimate the negative predictive value (NPV) of IGRAs in this population. Results: Patients on biologics were more likely to have a negative IGRA result than patients not on biologics. There was no statistically significant change in conversion or reversion rates between groups. Of 9263 patients on biologics, 19 developed active TB after starting biologics at an incidence rate of 55.1 per 100 000 patient-years. This occurred despite screening in half of the 16 patients for whom we were able to review medical records. Most drugs implicated were known to be high risk, although rituximab and natalizumab were being taken by five patients and one patient, respectively. The T-SPOT.TB NPV was 99.20% and dropped only slightly to 99.17% when we simulated an approach where all borderline IGRA results were regarded as being negative. Conclusions: Negative IGRA results confer a low risk of subsequent active TB in patients on biologics in a low TB incidence setting. However, continued awareness is needed given that a number of active TB cases will have had a prior negative result.

Pulmonary embolism diagnosis part 1: clinical assessment at the front door.

This first of two practice reviews addresses pulmonary embolism (PE) diagnosis considering important aspects of PE clinical presentation and comparing evidence-based PE testing strategies. A companion paper addresses the management of PE. Symptoms and signs of PE are varied, and emergency physicians frequently use testing to 'rule out' the diagnosis in people with respiratory or cardiovascular symptoms. The emergency clinician must balance the benefit of reassuring negative PE testing with the risks of iatrogenic harms from over investigation and overdiagnosis.

Open extent IV thoracoabdominal aneurysm repair: 22-year experience of the Scottish National Service.

BACKGROUND: Since 1999, the Scottish National Service for Thoracoabdominal Aneurysms has offered repair of thoracoabdominal aneurysms (TAAAs) to a population of 5.5 million people. The open operation most commonly performed by the service is the extent IV TAAA repair. METHODS: All extent IV open TAAA repairs performed at the Scottish National Service for TAAAs from June 1999 until April 2021 were evaluated for clinical features, technical details, and clinical outcomes. The primary outcome measure was 30-day mortality; secondary outcomes included short-term (90 days, 6 months, 1 and 2 years) and long-term (5 and 10 years) survival, perioperative complications, and reintervention. Survival was assessed using Kaplan-Meier analysis. RESULTS: Some 248 patients underwent extent IV TAAA repair, with elective surgery in 204 (82.3 per cent). A totally abdominal transperitoneal approach was used for all patients, with a median visceral ischaemia time of 40 (i.q.r. 35-48) min. Overall, 18 patients (7.3 per cent) died within 30 days. The proportion of patients surviving at 90 days, 6 months, 1, 2, 5, and 10 years was 0.91, 0.90, 0.89, 0.85, 0.72, and 0.41, respectively. Ten patients (4.0 per cent) required a reintervention while in hospital, four (1.6 per cent) experienced permanent spinal cord ischaemia, 19 (7.9 per cent) required temporary renal replacement therapy (RRT), and four (1.6 per cent) required permanent RRT. CONCLUSION: Open extent IV TAAA repair performed in a high-volume national centre is associated with favourable short- and long-term survival, and acceptable complication rates.

Experimental Antiviral Therapeutic Studies for Human Rhinovirus Infections.

Rhinovirus infection is common and usually causes mild, self-limiting upper respiratory tract symptoms. Rhinoviruses can cause exacerbation of chronic respiratory diseases, such as asthma or chronic obstructive pulmonary disease, leading to a significant burden of morbidity and mortality. There has been a great deal of progress in efforts to understand the immunological basis of rhinovirus infection. However, despite a number of in vitro and in vivo attempts, there have been no effective treatments developed. This review article summarises the up to date virological and immunological understanding of these infections. We discuss the challenges researchers face, and key solutions, in their work to investigate potential therapies including in vivo rhinovirus challenge studies. Finally, we explore past and present experimental therapeutic strategies employed in the treatment of rhinovirus infections and highlight promising areas of future work.

Review: The Nose as a Route for Therapy. Part 2 Immunotherapy.

The nose provides a route of access to the body for inhalants and fluids. Unsurprisingly it has a strong immune defense system, with involvement of innate (e.g., epithelial barrier, muco- ciliary clearance, nasal secretions with interferons, lysozyme, nitric oxide) and acquired (e.g., secreted immunoglobulins, lymphocytes) arms. The lattice network of dendritic cells surrounding the nostrils allows rapid uptake and sampling of molecules able to negotiate the epithelial barrier. Despite this many respiratory infections, including SARS-CoV2, are initiated through nasal mucosal contact, and the nasal mucosa is a significant "reservoir" for microbes including Streptococcus pneumoniae, Neisseria meningitidis and SARS -CoV-2. This review includes consideration of the augmentation of immune defense by the nasal application of interferons, then the reduction of unnecessary inflammation and infection by alteration of the nasal microbiome. The nasal mucosa and associated lymphoid tissue (nasopharynx-associated lymphoid tissue, NALT) provides an important site for vaccine delivery, with cold-adapted live influenza strains (LAIV), which replicate intranasally, resulting in an immune response without significant clinical symptoms, being the most successful thus far. Finally, the clever intranasal application of antibodies bispecific for allergens and Intercellular Adhesion Molecule 1 (ICAM-1) as a topical treatment for allergic and RV-induced rhinitis is explained.

Use of the HoloLens2 Mixed Reality Headset for Protecting Health Care Workers During the COVID-19 Pandemic: Prospective, Observational Evaluation.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has led to rapid acceleration in the deployment of new digital technologies to improve both accessibility to and quality of care, and to protect staff. Mixed-reality (MR) technology is the latest iteration of telemedicine innovation; it is a logical next step in the move toward the provision of digitally supported clinical care and medical education. This technology has the potential to revolutionize care both during and after the COVID-19 pandemic. OBJECTIVE: This pilot project sought to deploy the HoloLens2 MR device to support the delivery of remote care in COVID-19 hospital environments. METHODS: A prospective, observational, nested cohort evaluation of the HoloLens2 was undertaken across three distinct clinical clusters in a teaching hospital in the United Kingdom. Data pertaining to staff exposure to high-risk COVID-19 environments and personal protective equipment (PPE) use by clinical staff (N=28) were collected, and assessments of acceptability and feasibility were conducted. RESULTS: The deployment of the HoloLens2 led to a 51.5% reduction in time exposed to harm for staff looking after COVID-19 patients (3.32 vs 1.63 hours/day/staff member; P=.002), and an 83.1% reduction in the amount of PPE used (178 vs 30 items/round/day; P=.02). This represents 222.98 hours of reduced staff exposure to COVID-19, and 3100 fewer PPE items used each week across the three clusters evaluated. The majority of staff using the device agreed it was easy to set up and comfortable to wear, improved the quality of care and decision making, and led to better teamwork and communication. In total, 89.3% (25/28) of users felt that their clinical team was safer when using the HoloLens2. CONCLUSIONS: New technologies have a role in minimizing exposure to nosocomial infection, optimizing the use of PPE, and enhancing aspects of care. Deploying such technologies at pace requires context-specific information security, infection control, user experience, and workflow integration to be addressed at the outset and led by clinical end-users. The deployment of new telemedicine technology must be supported with objective evidence for its safety and effectiveness to ensure maximum impact.

Human rhinovirus infection and COPD: role in exacerbations and potential for therapeutic targets.

INTRODUCTION: Respiratory virus infections (predominantly rhinoviruses) are the commonly identified in COPD exacerbations but debate about their role as a trigger of exacerbations continues. Experimental infection studies have provided significant new evidence establishing a causal relationship between virus infection and COPD exacerbations and contributed to a better understanding of the mechanisms of virus-induced exacerbations. However as yet no anti-viral treatments have undergone clinical trials in COPD patients. AREAS COVERED: This review discusses the evidence for and against respiratory viruses being the main trigger of COPD exacerbations from both epidemiological studies and experimental infection studies. The host immune response to rhinovirus infection and how abnormalities in host immunity may underlie increased susceptibility to virus infection in COPD are discussed and the role of dual viral-bacterial infection in COPD exacerbations. Finally the current state of anti-viral therapy is discussed and how these may be used in the future treatment of COPD exacerbations. EXPERT OPINION: Respiratory virus infections are the trigger of a substantial proportion of COPD exacerbations and rhinoviruses are the most common virus type. Clinical trials of anti-viral agents are needed in COPD patients to determine whether they are effective in virus-induced COPD exacerbations.

Cochrane systematic reviews of interventions for risk factors correlate weakly with global risk factor burden: a cross-sectional study.

BACKGROUND AND OBJECTIVES: Systematic reviews (SRs) are important for health-care decision-makers requiring evidence for interventions that target modifiable risk factors to prevent disease. We investigated whether Cochrane SR output correlated with risk factor burden as assessed by the Global Burden of Disease Study 2015. METHODS: We screened and extracted data from Cochrane reviews and protocols published since January 2011 investigating modifiable risk factors as outcomes. We calculated Spearman's rank correlation between number of occasions a risk factor was an SR outcome and that risk factor's global disease burden in disability-adjusted life years (DALYs). We also calculated standardized Pearson residuals (SPRs) of the variance between the observed and expected frequency of a risk factor featuring as an outcome. RESULTS: We obtained 400 unique SRs and 174 unique protocols from 6,392 Cochrane publications. Risk factors were an outcome a total of 965 times. The number of SR outcomes and DALYs per risk factor shared a weak-positive correlation (r = 0.45) for all risk factors, but was high (r = 0.83) for metabolic risks, similar for behavioral risks (r = 0.46), and weak negative for occupational and environmental risks (r = -0.40). SPRs for "high total cholesterol", "low bone mineral density", "alcohol and drug use" , and "child and maternal malnutrition" inferred a higher than expected frequency of outcomes, and for "air pollution", "dietary risk", and "unsafe water, sanitation, and hand-washing", fewer than expected. CONCLUSION: Our study investigated whether Cochrane risk factor SRs align with global risk factor burden, demonstrating a weak-positive correlation. Interventions modifying air pollution and dietary risks were sparsely studied, given disease burden.