SALIVA, NASAL & TEAR PK of EIDD-1931 in PATIENTS with COVID-19 RECEIVING MOLNUPIRAVIR

Background: Molnupiravir, a prodrug of the broadly active, direct-acting antiviral, ribonucleoside analogue EIDD-1931, is a promising COVID-19 drug. Given the primary route of SARS-CoV-2 transmission through respiratory droplets we evaluated EIDD-1931 PK in saliva, nasal secretions and tears of patients with mild-to-moderate COVID-19 through the phase Ib/IIa AGILE platform (NCT04746183). Methods: Patients with PCR-confirmed SARS-CoV-2 infection, within 5 days of symptom onset with mild-to-moderate disease were randomised to oral molnupiravir 300, 600 or 800 mg twice daily. Plasma and non-plasma (saliva, nasal and tear swabs) samples were collected pre-dose, 0.5, 1, 2, and 4 hours post-dose on study days 1 and 5 and molnupiravir and EIDD-1931 measured by LC/MS (lower limit of quantification, 2.5 ng/mL). PK parameters were determined (Phoenix 64, WinNonlin, v. 8.3) and non-plasma:plasma (NP:P) ratios (based on AUC0-4) calculated. Relationships between paired non-plasma and plasma samples were evaluated by linear regression. Results: Twelve participants (n=4 per dose;75% female) completed the study contributing 111, 112 and 97 saliva, nasal and tear samples, respectively. Molnupiravir was detected in 11% of saliva samples [median (range) 4.86 ng/mL (2.63-31.44)] and not evaluated in swabs. Quantifiable EIDD-1931, following molnupiravir 300, 600 and 800 mg twice daily were i) saliva: 17.7 (2.8-133), 16.6 (2.9-469), 25.8 (4.0-230) ng/mL, ii) nasal swabs: 182 (18-1700), 136 (18-917), 295 (24-1879) ng/mL and iii) tears: 297 (24-1650), 176 (16-1260), 307 (32-2760) ng/mL. PK parameters are shown (Table 1). Median (range, CV%) pooled NP:P ratio for saliva was 0.03 (0.01-0.11, 60%;n=16). Nasal and tear ratios were 6-fold higher with values of 0.21 (0.05-0.73, 70%;n=17) and 0.22 (0.09-1.05, 92%;n=12), respectively. Non-plasma and plasma concentrations were significantly correlated (r2: 0.360-0.677;p<0.0001). Of measured saliva, nasal and tear samples, 6, 50 and 61%, respectively were within or above the EIDD-1931 EC90 against SARS-CoV-2 in primary human airway epithelia cultures (approximately 0.5-1 μ M ≈ 130-260 ng/mL). Conclusion: This is the first report of EIDD-1931 PK at sites of initial SARS-CoV-2 exposure in patients with COVID-19. Investigations of PK/PD relationships are warranted;however, these data suggest therapeutic concentrations are potentially achieved in nasal and tear compartments, but not saliva and have important implications for prophylactic coverage.

The quantitative impact of COVID-19 on surgical training in the United Kingdom.

BACKGROUND: COVID-19 has had a global impact on all aspects of healthcare including surgical training. This study aimed to quantify the impact of COVID-19 on operative case numbers recorded by surgeons in training, and annual review of competency progression (ARCP) outcomes in the UK. METHODS: Anonymized operative logbook numbers were collated from electronic logbook and ARCP outcome data from the Intercollegiate Surgical Curriculum Programme database for trainees in the 10 surgical specialty training specialties.Operative logbook numbers and awarded ARCP outcomes were compared between predefined dates. Effect sizes are reported as incident rate ratios (IRR) with 95 per cent confidence intervals. RESULTS: Some 5599 surgical trainees in 2019, and 5310 in surgical specialty training in 2020 were included. The IRR was reduced across all specialties as a result of the COVID-19 pandemic (0.62; 95 per cent c.i. 0.60 to 0.64). Elective surgery (0.53; 95 per cent c.i. 0.50 to 0.56) was affected more than emergency surgery (0.85; 95 per cent c.i. 0.84 to 0.87). Regional variation indicating reduced operative activity was demonstrated across all specialties. More than 1 in 8 trainees in the final year of training have had their training extended and more than a quarter of trainees entering their final year of training are behind their expected training trajectory. CONCLUSION: The COVID-19 pandemic has had a major effect on surgical training in the UK. Urgent, coordinated action is required to minimize the impacts from the reduction in training in 2020.

2 New COVID initiative – introduction of the just in time emergency medicine pack (JEMP)

BackgroundDuring the coronavirus pandemic, it was essential to ensure access to End of life (EoL) medications while protecting the medications supply chain. Traditional Just in Case prescribing could have exhausted the national supply. Consequently, a new NHS Wales Interim End of Life COVID-19 Medicines Service was implemented to provide access to a medication box a Just-In-Time Emergency Medication Pack (JEMP).MethodsThe JEMP scheme ensured that end of life medications could be delivered directly to the patient within 2 hours, 24 hours a day 7 days a week, across the whole of Wales. The JEMP contained an agreed list of medications. The Health Courier Service Wales managed a Single Point of Contact, and directed the JEMP request to the most appropriate EoL Pharmacy Hub situated at one of five strategic sites around Wales. To access the service, a healthcare professional would call a 24/7 phone line and send a digital image of the prescription for EoL medications via Hospify (like an NHS Whatsapp). The JEMP then would be delivered directly to the patient‘s house and the prescription would be collected.Results17 requests were activated. 1 call was stood down. 15 out of the 16 requests had a JEMP delivered within 2 hours. This ranged from 34 minutes to 111 minutes. The mean time was 72 minutes.ConclusionThis is a pioneering service that developed during the coronavirus pandemic, it went from concept to a national pilot in 6 days. The uptake of services was less than originally predicted. However, it has been successful in its primary aims to maintain the supply chain and deliver vital EoL medications directly to the patient anywhere in Wales (24 hours 7 days a week) within 2 hours from the initial request. Further work needs to be done on collecting feedback and assessing sustainability.

The impact of COVID-19 on surgical training: a systematic review.

BACKGROUND: Coronavirus disease (COVID-19) has caused global disruption to health care. Non-urgent elective surgical cases have been cancelled, outpatient clinics have reduced and there has been a reduction in the number of patients presenting as an emergency. These factors will drastically affect the training opportunities of surgical trainees. The aim of this systematic review is to describe the impact of COVID-19 on surgical training globally. METHODS: The review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with the Open Science Framework (OSF). Medline, EMBASE, PubMed and the Cochrane Central Register of Controlled Trials were searched. RESULTS: The searches identified 499 articles, 29 of which were included in the review. This contained data from more than 20 countries with 5260 trainees and 339 programme directors. Redeployment to non-surgical roles varied across studies from 6% to 35.1%. According to all of the studies, operative experience has been reduced. Knowledge learning had been switched to online platforms across 17 of the studies and 7 reported trainees had increased time to devote to educational/academic activities. All of the studies reporting on mental health report negative associations with increased stress, ranging from 54.9% to 91.6% of trainees. CONCLUSIONS: The impact of COVID-19 on surgical trainees has been experienced globally and across all specialities. Negative effects are not limited to operative and clinical experience, but also the mental health and wellbeing of trainees. Delivery of surgical training will need to move away from traditional models of learning to ensure trainees are competent and well supported.