ABSTRACT
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.
ABSTRACT
PETRONAS completed well H-X on B field in Malaysia with a digital intelligent artificial lift (DIAL) gas lift production optimization system. This DIAL installation represents the first ever successful installation of the technology in an Offshore well for Dual String production. This paper provides complete details of the installation planning and operational process undertaken to achieve this milestone. DIAL is a unique technology that enhances the efficiency of gas lift production. Downhole monitoring of production parameters informs remote surface-controlled adjustment of gas lift valves. This enables automation of production optimization removing the need for well intervention. This paper focusses on a well completed in November 2020, the fourth well to be installed with the DIAL technology across PETRONAS Assets. The authors will provide details of the well and the installation phases: system design, pre-job preparations, improvements implementation, run in hole and surface hookup. For each phase, challenges encountered, and lessons learned will be listed together with observed benefits. DIAL introduces a paradigm shift in design, installation and operation of gas lifted wells. This paper will briefly highlight the justifications of this digital technology in comparison with conventional gas lift techniques. It will consider value added from the design stage, through installation operations, to production optimization. This DIAL system installation confirms the ability to be implement the technology in a challenging dual string completion design to enable deeper injection while avoiding interventions on a well with a greater than 60-degree deviation. With remotely operated, non-pressure dependent multi-valve in-well gas lift units, the technology removes the challenges normally associated with gas-injected production operation in a dual completion well - gas robbing and multi-pointing. Despite the additional operational & planning complications due to COVID-19 restrictions, the well was completed with zero NPT and LTI. Once brought online, this DIAL-assisted production well will be remotely monitored and controlled ensuring continuous production optimization, part of PETRONAS' upstream digitization strategic vision. © Copyright 2021, Society of Petroleum Engineers
ABSTRACT
Objectives/Scope: This paper describes a pilot installation of a digital intelligent artificial lift (DIAL) gas lift production optimization system. The work was inspired by PETRONAS' upstream digitalization strategy with five single and dual-string gas lift completions planned from 2018 to 2020, offshore Malaysia. The authors evaluate the impact of the DIAL system in terms of increasing production, optimizing lift-gas injection, reducing well intervention frequency, as well as OPEX and risk reduction. Methods, Procedure, Process: DIAL is a unique technology that enhances the efficiency of gas lift production. Downhole monitoring of production parameters informs remote surface-controlled adjustment of gas lift valves. This enables automation of production optimization removing the need for well intervention. The paper focuses on a well installed in June 2020, the first in a five well campaign. The authors will provide details of the technology, and pilot program phases: system design;pre-job preparations;run in hole and surface hook-up;commissioning and unloading;and subsequent production operations. For each phase, challenges encountered, and lessons learned will be listed together with observed benefits. Results, Observations, Conclusions: DIAL introduces a paradigm shift in the design, installation, and operation of gas lifted wells. This paper will compare the differences between this digital technology and conventional gas lift techniques. It will consider the value added from the design stage through installation operations to production optimization. The DIAL system's ability to operate at greater than 80-degree deviation enabled deeper injection while avoiding tractor interventions for GLV maintenance in the highly deviated section of the well. Built-in downhole sensors provided real-time pressure monitoring that enabled a better understanding of reservoir behaviour and triggered data-driven reservoir stimulation decisions. The technology also proved very beneficial for production optimization, with the intervention-less adjustment of gas injection rate and depth downhole, based on the observed reservoir response in real time. The variable port sizes can be manipulated by means of surface switch/control. Overcoming the completion challenges due to COVID-19 restrictions, the well was unloaded and brought online with the assistance of personnel located in Houston and Dubai using Silverwell's visualization software. The well continues to be remotely monitored and controlled ensuring continuous production optimization, part of PETRONAS' upstream digitization strategic vision. Novel/Additive Information: First deployment worldwide of new and unique gas lift production optimization technology in offshore highly deviated well. The technology deployment was the result of collaborative work between a multi-discipline engineering team in PETRONAS, Silverwell, and Neural Oilfield Service. © 2021, Society of Petroleum Engineers.
ABSTRACT
BACKGROUND: Reducing COVID-19 transmission relies on controlling droplet and aerosol spread. Fluorescein staining reveals microscopic droplets. AIM: To compare the droplet spread in non-laminar and laminar air flow operating theatres. METHODS: A 'cough-generator' was fixed to a theatre trolley at 45°. Fluorescein-stained 'secretions' were projected on to a series of calibrated targets. These were photographed under UV light and 'source detection' software measured droplet splatter size and distance. FINDINGS: The smallest droplet detected was â¼120 µm and the largest â¼24,000 µm. An average of 25,862 spots was detected in the non-laminar theatre, compared with 11,430 in the laminar theatre (56% reduction). The laminar air flow mainly affected the smaller droplets (<1000 µm). The surface area covered with droplets was: 6% at 50 cm, 1% at 2 m, and 0.5% at 3 m in the non-laminar air flow; and 3%, 0.5%, and 0.2% in the laminar air flow, respectively. CONCLUSION: Accurate mapping of droplet spread in clinical environments is possible using fluorescein staining and image analysis. The laminar air flow affected the smaller droplets but had limited effect on larger droplets in our 'aerosol-generating procedure' cough model. Our results indicate that the laminar air flow theatre requires similar post-surgery cleaning to the non-laminar, and staff should consider full personal protective equipment for medium- and high-risk patients.