A single-centre observational cohort study to evaluate volume and severity of emergency general surgery admissions during the COVID-19 pandemic: Is there a "lockdown" effect?

INTRODUCTION: The COVID-19 pandemic has led to changes in NHS surgical service provision, including reduced elective surgical and endoscopic activity, with only essential emergency surgery being undertaken. This, combined with the government-imposed lockdown, may have impacted on patient attendance, severity of surgical disease, and outcomes. The aim of this study was to investigate a possible 'lockdown' effect on the volume and severity of surgical admissions and their outcomes. METHODS: Two separate cohorts of adult emergency general surgery inpatient admissions 30 days immediately before (February 16, 2020 to March 15, 2020), and after UK government advice (March 16, 2020 to April 15, 2020). Data were collected relating to patient characteristics, severity of disease, clinical outcomes, and compared between these groups. RESULTS: Following lockdown, a significant reduction in median daily admissions from 7 to 3 per day (p < 0.001) was observed. Post-lockdown patients were significantly older, frailer with higher inflammatory indices and rates of acute kidney injury, and also were significantly more likely to present with gastrointestinal cancer, obstruction, and perforation. Patients had significantly higher rates of Clavien-Dindo Grade ≥3 complications (p = 0.001), all cause 30-day mortality (8.5% vs. 2.9%, p = 0.028), but no significant difference was observed in operative 30-day mortality. CONCLUSION: There appears to be a "lockdown" effect on general surgical admissions with a profound impact; fewer surgical admissions, more acutely unwell surgical patients, and an increase in all cause 30-day mortality. Patients should be advised to present promptly with gastrointestinal symptoms, and this should be reinforced for future lockdowns during the pandemic.

In vitro assay of six UDP-glucuronosyltransferase isoforms in human liver microsomes, using cocktails of probe substrates and liquid chromatography-tandem mass spectrometry.

UDP-glucuronosyltransferase (UGT)-mediated drug-drug interactions are commonly evaluated during drug development. We present a validated method for the simultaneous evaluation of drug-mediated inhibition of six major UGT isoforms, developed in human liver microsomes through the use of pooled specific UGT probe substrates (cocktail assay) and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The six probe substrates used in this assay were estradiol (UGT1A1), chenodeoxycholic acid (UGT1A3), trifluoperazine (UGT1A4), 4-hydroxyindole (UGT1A6), propofol (UGT1A9), and naloxone (UGT2B7). In a cocktail incubation, UGT1A1, UGT1A9, and UGT2B7 activities were substantially inhibited by other substrates. This interference could be eliminated by dividing substrates into two incubations: one containing estradiol, trifluoperazine, and 4-hydroxyindole, and the other containing chenodeoxycholic acid, propofol, and naloxone. Incubation mixtures were pooled for the simultaneous analysis of glucuronyl conjugates in a single LC-MS/MS run. The optimized cocktail method was further validated against single-probe substrate assays using compounds known to inhibit UGTs. The degree of inhibition of UGT isoform activities by such known inhibitors in this cocktail assay was not substantially different from that in single-probe assays. This six-isoform cocktail assay may be very useful in assessing the UGT-based drug-interaction potential of candidates in a drug-discovery setting.

LC-MS/MS for the simultaneous analysis of arachidonic acid and 32 related metabolites in human plasma: Basal plasma concentrations and aspirin-induced changes of eicosanoids.

Eicosanoids play an important role in various biological responses and can be used as biomarkers for specific diseases. Therefore, we developed a highly selective, sensitive, and robust liquid chromatography-tandem mass spectrometric method to measure arachidonic acid and its 32 metabolites in human plasma. Sample preparation involved solid phase extraction, which efficiently removed sources of interference present in human plasma. Chromatographic separation was performed using a Luna C(8)-column with 0.5mM ammonium formate buffer and acetonitrile as the mobile phase under gradient conditions. Detection was performed using tandem mass spectrometry equipped with an electrospray ionization interface in negative ion mode. The matrix did not affect the reproducibility and reliability of the assay. All analytes showed good linearity over the investigated concentration range (r>0.997). The validated lower limit of quantitation for the analytes ranged from 10 to 400pg/mL. Intra- and inter-day precision (RDS%) over the concentration ranges for all eicosanoids were within 16.8%, and accuracy ranged between 88.1 and 108.2%. This assay was suitable for the determination of basal plasma levels of eicosanoids and the evaluation of effect of aspirin on eicosanoid plasma levels in healthy subjects.