Sodium fluoride preserves blood metabolite integrity for biomarker discovery in large-scale, multi-site metabolomics investigations.

Background: Metabolite profiling of blood by nuclear magnetic resonance (NMR) is invaluable to clinical biomarker discovery. To ensure robustness, biomarkers require validation in large cohorts and across multiple centres. However, collection procedures are known to impact on the stability of biofluids that may, in turn, degrade biomarker signals. We trialled three blood collection tubes with the aim of solving technical challenges due to preanalytical variation in blood metabolite levels that are common in cohort studies. Methods: We first investigated global NMR-based metabolite variability between biobanks, including the large-scale UK Biobank and TwinsUK biobank of the general UK population, and more targeted biobanks derived from multicentre clinical trials relating to inflammatory bowel disease. We then compared the blood metabolome of 12 healthy adult volunteers when collected into either sodium fluoride/potassium oxalate, lithium heparin, or serum blood tubes using different pre-processing parameters. Results: Preanalytical variation in the method of blood collection strongly influences metabolite composition within and between biobanks. This variability can largely be attributed to glucose and lactate. In the healthy control cohort, the fluoride oxalate collection tube prevented fluctuation in glucose and lactate levels for 24 hours at either 4 °C or room temperature (20 °C). Conclusions: Blood collection into a fluoride oxalate collection tube appears to preserve the blood metabolome with delayed processing up to 24 hours at 4 °C. This method may be considered as an alternative when rapid processing is not feasible.

SPIKE-1: A Randomised Phase II/III trial in a community setting, assessing use of camostat in reducing the clinical progression of COVID-19 by blocking SARS-CoV-2 Spike protein-initiated membrane fusion.

OBJECTIVES: The primary objective is to evaluate the efficacy of camostat to prevent respiratory deterioration in patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Secondary objectives include assessment of the ability of camostat to reduce the requirement for Coronavirus disease 2019 (COVID-19) related hospital admission and to reduce the requirement for supplementary oxygen and ventilation as treatment for SARS-CoV-2 infection, to evaluate overall mortality related to COVID-19 and to evaluate the efficacy of camostat by effect on clinical improvement. Research objectives include to assess change in COVID-19 symptom severity, to evaluate the ability of camostat to reduce viral load throughout duration of illness as well as translational research on host and viral genomics, serum antibody production, COVID-19 diagnostics, and validation of laboratory testing methods and biomarkers. TRIAL DESIGN: SPIKE-1 is a randomised, multicentre, prospective, open label, community-based clinical trial. Eligible patients will be randomised 1:1 to the camostat treatment arm and control arm (best supportive care). The trial is designed to include a pilot phase recruiting up to 50 patients in each arm. An initial review at the end of the pilot phase will allow assessment of available data and inform the requirement for any protocol adaptations to include refinement of eligibility criteria to enrich the patient population and sample size calculations. Up to 289 additional patients will be randomised in the continuation phase of the trial. A formal interim analysis will be performed once 50% of the maximum sample size has been recruited PARTICIPANTS: The trial will recruit adults (≥ 18 years) who score moderate to very high risk according to COVID-age risk calculation, with typical symptoms of COVID-19 infection as per Public Health England guidance or equivalent organisations in the UK, Health Protection Scotland, Public Health Wales, Public Health Agency (Northern Ireland) and with evidence of current COVID-19 infection from a validated assay. The trial is being conducted in the UK and patients are recruited through primary care and hospital settings. INTERVENTION AND COMPARATOR: Eligible patients with be randomised to receive either camostat tablets, 200 mg four times daily (qds) for 14 days (treatment arm) or best supportive care (control arm). MAIN OUTCOMES: Primary outcome measure: the rate of hospital admissions requiring supplemental oxygen. Secondary outcome measures include: the rate of COVID-19 related hospital admission in patients with SARS-CoV-2 infection; the number of supplementary oxygen-free days and ventilator-free days measured at 28 days from randomisation; the rate of mortality related to COVID-19 one year from randomisation; the time to worst point on the nine-point category ordinal scale (recommended by the World Health Organization: Coronavirus disease (COVID-2019)) or deterioration of two points or more, within 28 days from randomisation. Research outcomes include the assessment of change in COVID-19 symptom severity on days 1-14 as measured by (1) time to apyrexia (maintained for 48 hrs) by daily self-assessment of temperature, time to improvement (by two points) in peripheral oxygenation saturation defined by daily self-assessment of fingertip peripheral oxygenation saturation levels, (3) assessment of COVID-19 symptoms using the Flu-iiQ questionnaire (determined by app recording and/or daily video call (or phone) consultation and (4) assessment of functional score (where possible) at screening, day 7 and 14. The ability of camostat to reduce viral load throughout duration of illness will be assessed by (1) change in respiratory (oropharyngeal/nasopharyngeal swab RT-PCR) log10 viral load from baseline to Days 7 and 14, (2) change in respiratory (saliva RT-PCR) log10 viral load from baseline to Days 1-14 and (3) change in upper respiratory viral shedding at Day 1 -14 measured as time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs by qPCR. Additional translational research outcomes include assessment of host and viral genomics, serum antibody production and COVID-19 diagnostics at baseline and on Days 7 and 14. RANDOMISATION: Eligible patients will be randomised using an interactive web response system (IWRS) in a 1:1 ratio to one of two arms: (1) treatment arm or (2) control arm. BLINDING (MASKING): The trial is open-label. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The trial is designed to include a pilot and a continuation phase. Up to 100 patients (randomised 1:1 treatment and control arm) will be recruited in the pilot phase and a maximum of 289 patients (randomised 1:1 treatment and control) will be recruited as part of the continuation phase. The total number of patients recruited will not exceed 389. TRIAL STATUS: Protocol version number v3 25 September 2020. Trial opened to recruitment on 04 August 2020. The authors anticipate recruitment to be completed by October 2021. TRIAL REGISTRATION: EudraCT 2020-002110-41; 18 June 2020 ClinicalTrials.gov NCT04455815 ; 02 July 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). Unpublished PK data provided under confidentiality agreement to the trial Sponsor has been removed from the background section of the protocol to allow for publication of the trial protocol. In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Clinical Performance Status and Technical Factors Affecting Outcomes from Percutaneous Transhepatic Biliary Interventions; A Multicentre, Prospective, Observational Cohort Study.

PURPOSE: The purpose of this study was to evaluate the predictive value of a 'Modified Karnofsky Scoring System' on outcomes and provide real-world data regarding the UK practice of biliary interventions. MATERIALS AND METHODS: A prospective multi-centred cohort study was performed. The pre-procedure modified Karnofsky score, the incidence of sepsis, complications, biochemical improvement and mortality were recorded out to 30 days post procedure. RESULTS: A total of 292 patients (248 with malignant lesions) were suitable for inclusion in the study. The overall 7 and 30 day mortality was 3.1% and 16.1%, respectively. The 30 day sepsis rate was 10.3%. In the modified Karnofsky 'high risk' group the 7 day mortality was 9.7% versus 0% for the 'low risk' group (p = 0.002), whereas the 30 day mortality was 28.8% versus 13.3% (p = 0.003). The incidence of sepsis at 30 days was 19% in the high risk group versus 3.3% at the low risk group (p = 0.001) CONCLUSION: Percutaneous biliary interventions in the UK are safe and effective. Scoring systems such as the Karnofsky or the modified Karnofsky score hold promise in allowing us to identify high risk groups that will need more careful consideration and enhanced patient informed consent but further research with larger studies is warranted in order to identify their true impact on patient selection and outcomes post biliary interventions.

Editor's Choice - Systematic Review of the Use of Endoanchors in Endovascular Aortic Aneurysm Repair.

OBJECTIVE: Endoanchor fixation might be a potential adjunct for the prevention and treatment of type Ia endoleak (TIaE) and graft migration in thoracic or abdominal endovascular aortic aneurysm repairs (TEVAR or EVAR). This review aimed to explore the safety and effectiveness of endoanchor fixation in TEVAR and EVAR. METHODS: A systematic review and random effects meta-analysis was conducted. Data sources were PubMed/MEDLINE, Embase, and the Cochrane Library. RESULTS: Seven EVAR and three TEVAR studies using the Heli-FX™ EndoAnchor™ system were included in the meta-analysis. A total of 455 EVAR patients underwent primary endoanchor fixation. Technical success was 98.4% (95% CI 95.7-99.8%). The rate of TIaE and graft migration was 3.5% (95% CI 1.7-5.9%) and 2.0% (95% CI 0.12-6.0%), respectively, after 15.4 months (95% CI 1.76-29.0) follow up. A total of 107 EVAR patients underwent secondary fixation with a technical success of 91.8% (95% CI 86.1-96.2%). Rates of TIaE and graft migration were 22.6% (95% CI 9.1-40.0%) and 0% after a mean 10.7 month (95% CI 7.8-13.6) follow up. Adverse events included three endoanchor fractures, three dislocated endoanchors, one entrapped endoanchor, and one common iliac artery dissection. All cause 30 day EVAR mortality was 0.82% (95% CI 0.20-1.85%). Sixty-six TEVAR patients underwent endoanchor fixation with a mean 9.8 month (95% CI 8.1-11.5) follow up. Technical success was 90.3% (95% CI 72.1-99.4%). The rates of TIaE and migration were 8.7% (95% CI 1.0-18.9%) and 0%, respectively. Adverse events included two misdeployed endoanchors with one fatal aortic dissection. All cause 30 day TEVAR mortality was 11.9% (95% CI 5.4-20.6%). CONCLUSION: Endoanchor fixation in EVAR is technically feasible and safe, with at least comparable early outcomes to the latest generation of stent grafts. Endostapling in TEVAR is associated with lower technical success, higher peri-operative mortality, and potential serious adverse events. Current evidence lacks long term follow up and case controlled trials to recommend endoanchor use in routine practice.

Pain Management Protocols During Uterine Fibroid Embolisation: A Systematic Review of the Evidence.

BACKGROUND: Uterine fibroid embolisation (UFE) is an effective treatment for fibroids. There are varying analgesia protocols published to control procedure associated pain. We aimed to assess what protocols are most effective in controlling post-procedural pain. MATERIALS AND METHODS: A systematic review of the Embase and Medline databases was conducted according to PRISMA guidelines. Studies regarding analgesia protocols post-uterine fibroid embolisation with Visual Analogue Scale or Numerical Rating Scale pain scores were included. The mean maximal pain scores of patients post-procedure were evaluated. ANOVA and t tests were performed. RESULTS: We identified 26 studies (total 3353 patients), with a mean procedural success rate of > 87%. We stratified protocols into four groups. Mean pain scores were: opioids ± NSAIDs ± acetaminophen (4.84, SD = 1.56); opioids ± NSAIDs ± acetaminophen + nerve block (4.7, SD = 1.37); opioids ± NSAIDs ± acetaminophen + intrauterine artery drug administration (4.09, SD = 0.60); and opioids ± NSAIDs ± acetaminophen + other (5.30, SD = 1.13) without significant difference between groups (p = 0.71). Similarly, there was no difference (p = 0.057) between groups for time to discharge or side effects. CONCLUSIONS: There is no evidence to suggest that there is any superiority of one protocol above another in the published literature. Appropriate use of opioids ± NSAIDs ± acetaminophen alone appears to be sufficient to control pain post-UFE. However, due to large heterogeneity of the literature no firm conclusions can be reached, and further research is warranted. LEVEL OF EVIDENCE: Level 1, Systematic review.

The Suspected CANcer (SCAN) pathway: protocol for evaluating a new standard of care for patients with non-specific symptoms of cancer.

INTRODUCTION: Cancer survival in England lags behind most European countries, due partly to lower rates of early stage diagnosis. We report the protocol for the evaluation of a multidisciplinary diagnostic centre-based pathway for the investigation of 'low-risk but not no-risk' cancer symptoms called the Suspected CANcer (SCAN) pathway. SCAN is a new standard of care being implemented in Oxfordshire; one of a number of pathways implemented during the second wave of the Accelerate, Coordinate, Evaluate (ACE) programme, an initiative which aims to improve England's cancer survival rates through establishing effective routes to early diagnosis. METHODS AND ANALYSIS: To evaluate SCAN, we are collating a prospective database of patients referred onto the pathway by their general practitioner (GP). Patients aged over 40 years, with non-specific symptoms such as weight loss or fatigue, who do not meet urgent cancer referral criteria or for whom symptom causation remains unclear after investigation via other existing pathways, can be referred to SCAN. SCAN provides rapid CT scanning, laboratory testing and clinic review within 2 weeks. We will follow all patients in the primary and secondary care record for at least 2 years. The data will be used to understand the diagnostic yield of the SCAN pathway in the short term (28 days) and the long term (2 years). Routinely collected primary and secondary care data from patients not referred to SCAN but with similar symptoms will also be used to evaluate SCAN. We will map the routes to diagnosis for patients referred to SCAN to assess cost-effectiveness. Acceptability will be evaluated using patient and GP surveys. ETHICS AND DISSEMINATION: The Oxford Joint Research Office Study Classification Group has judged this to be a service evaluation and so outside of research governance. The results of this project will be disseminated by peer-reviewed publication and presentation at conferences.

Effects of Sublingual Glyceryl Trinitrate Administration on the Quality of Preprocedure CT Angiography Performed to Plan Prostate Artery Embolization.

PURPOSE: To determine the effects of sublingual glyceryl trinitrate (GTN) on the quality of planning computed tomography (CT) angiography performed prior to prostate artery embolization (PAE). MATERIALS AND METHODS: A retrospective cohort study was performed on patients who had previously undergone CT angiography before a procedure for PAE at our institution. Early CT angiography studies for PAE at our single center had initially been performed without GTN. These were compared to subsequent CT angiography studies that had been performed with GTN, after a previously implemented change in practice. Prostate arteries were examined by 2 blinded observers for peak enhancement (Hounsfield units [HU]) and lumen diameter. In addition, assessors' interpretation of the prostate artery origin from CT angiography was compared with the true anatomy demonstrated at the time of procedure. RESULTS: A total of 16 patients, corresponding to 32 prostate arteries, were examined on CT angiography. Mean diameter of the prostate artery was found to be significantly greater in those receiving GTN (2.2 mm vs. 1.6 mm, P < .001). Peak prostate artery enhancement was also greater in the GTN group (218 HU vs 173 HU, P = 0.042). Observers correctly identified the prostate artery origin more frequently in the GTN group; however, this difference was not statistically significant (56% vs 25%, odds ratio = 3.9, P = .149). CONCLUSIONS: The administration of sublingual GTN immediately prior to CT angiography is associated with a significant increase in prostate artery diameter and peak opacification. This was not associated with a statistically significant increase in the ability of observers to correctly identify the origin of the prostate artery.

Outcome following a negative CT Angiogram for gastrointestinal hemorrhage.

OBJECTIVE: This study was designed to evaluate the role of a negative computed tomography angiogram (CTA) in patients who present with gastrointestinal (GI) hemorrhage. METHODS: A review of all patients who had CTAs for GI hemorrhage over an 8-year period from January 2005 to December 2012 was performed. Data for patient demographics, location of hemorrhage, hemodynamic stability, and details of angiograms and/or the embolization procedure were obtained from the CRIS/PACS database, interventional radiology database, secure electronic medical records, and patient's clinical notes. RESULTS: A total of 180 patients had 202 CTAs during the 8-year period: 87 CTAs were performed for upper GI hemorrhage (18 positive for active bleeding, 69 negative) and 115 for lower GI hemorrhage (37 positive for active bleeding, 78 negative); 58.7 % (37/63) of patients with upper GI bleed and 77.4 % (48/62) of patients with lower GI bleed who had an initial negative CTA did not rebleed without the need for radiological or surgical intervention. This difference was statistically significant (p = 0.04). The relative risk of rebleeding, following a negative CTA, in lower GI bleeding versus upper GI bleeding patients is 0.55 (95 % confidence interval 0.32-0.95). CONCLUSIONS: Patients with upper GI bleed who had negative CTAs usually require further intervention to stop the bleeding. In contrast, most patients presenting with lower GI hemorrhage who had a negative first CTA were less likely to rebleed.