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In 2009, the Vito field was discovered in more than 4,000 ft of water approximately 150 miles offshore from New Orleans, Louisiana. The project produces from reservoirs nearly 30,000 feet below sea level. The project underwent major redesign to remain competitive, and this paper describes changes within the subsea system. This paper is part of a Vito Project series at OTC 2023, and the other papers are listed in the references. As the industry and market began to change in 2015, the project faced significant financial hurdles, and the project team decided to refresh the field development concept to reduce cost and simplify. This paper focuses on the subsea production system and some of the key decisions leading to the selected design and the approach the team used for making these decisions. It also discusses how the project execution model was established, and the modifications made during project execution to react to schedule challenges, the unprecedented impacts of COVID-19, and a tightening offshore market. © 2023, Offshore Technology Conference.
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Background: Ensovibep is a multi-specific DARPin (designed ankyrin repeat protein) therapeutic in clinical development for treatment of COVID-19. In Part A (Phase 2) of the EMPATHY study, ensovibep treatment demonstrated greater viral load decline versus placebo (Pbo), and a relative risk reduction for hospitalization, ER visits and death. We report the sustained clinical recovery data from Phase 2 of EMPATHY. Method(s): Patients (pts) were eligible for EMPATHY (NCT04828161) when presenting >=2 mild-to-moderate COVID19 symptoms (onset within 7 days) and a positive SARS-CoV-2 rapid antigen test on day of dosing. 407 pts were randomised (1:1:1:1) to ensovibep (600, 225 or 75mg) or Pbo as single, IV infusion. The FDA COVID-19 symptom questionnaire was used (daily to Day 15, and on Days 22, 29) to assess time to sustained clinical recovery (secondary endpoint). Result(s): Ensovibep treatment was associated with a shorter time to sustained clinical recovery versus Pbo (Fig 1). The median time to sustained recovery were 23 days, 15 days, 14 days, and 29 days in 600mg, 225mg, 75mg, placebo arms, respectively. The cumulative proportion of patients with sustained clinical recovery by Day 15 were 44%, 54%, 55% and 36% in 600mg, 225mg, 75mg, and placebo arms, respectively. Conclusion(s): Ensovibep administration was associated with earlier sustained clinical recovery versus placebo.
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An automated model representing communicating states for a given moment in actual time is theorized in an Automated Supply Chain Dual (SC). When handling instability threats in SCs, we look at the circumstances surrounding the architecture and deployment of the digital twins. Combining models with data-driven methods show interrelationships between data risk, modeling disturbances, and performance evaluation. Digital network networking maps are distinctly visually illustrated by the SC blow and modifications amidst the COVID-19 pandemic, along with the after-event recovery method. The findings of this research complement SC risk management's science and experience by enriching forecasting and corrective findings to exploit the merits of SC modeling, quantitative predictive data, and evidence of disruptions in real-time. The supply chains have been severely impacted by the recent coronavirus pandemic, known as the COVID-19 outbreak. Due to supply failure, demand for certain items has increased significantly, while raw materials supply required to produce those items has decreased;therefore, to address these issues, this paper proposes some strategies for improving service levels for the most sought-after products, such as toilet paper, during a severe pandemic, such as COVID-19.
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Background. Ensovibep is a multi-specific DARPin (designed ankyrin repeat protein) antiviral in clinical development for treatment of COVID-19. In the Phase 2 EMPATHY study, ensovibep demonstrated greater viral load decline versus placebo. Here we report (1) the efficacy of ensovibep in patients with and without anti-SARS-CoV-2 antibodies at baseline and (2) SARS-CoV-2 mutation emergence data with treatment. Methods. Eligible ambulatory patients with >=2 COVID-19 symptoms (onset within 7 days) and positive SARS-CoV-2 rapid antigen test on day of dosing, were randomized (1:1:1:1) to ensovibep (600, 225 or 75 mg) or placebo as single, IV infusion. Chemiluminescent immunoassays were used for antibody detection (SARS-CoV-2 S1/S2 IgG and SARS-CoV-2 IgM). A pre-specified subgroup analysis was performed based on baseline anti-SARS-CoV-2 antibody status. Analysis of changes in viral genome from baseline to post baseline was performed to evaluate treatment-emergent mutations. Results. Of the patients analyzed, 48.5% had anti-SARS-CoV-2 antibodies at baseline. Baseline log10 SARS-CoV-2 viral load (mean +/-SD) was similar across groups [ensovibep (all doses) 6.5 +/-1.5, placebo 6.2 +/-1.5];> 90% were infected with the Delta (B.1.617.2) variant. SARS-CoV-2 viral load reduction up to Day 8 showed similar effects in favor of ensovibep compared with placebo regardless of the presence of anti-SARS-CoV-2 antibodies (Figure 1). Patients in ensovibep 75 mg, 600 mg, and placebo groups had comparable incidences of emergent mutations, with a higher incidence in the 225 mg group. Based on analysis of 70% of the expected viral sequencing data, two mutations in the key binding residues of ensovibep were observed (Y489H and F486L) in a total of three patients treated with ensovibep. These patients either cleared virus by Day 8 or mutations were transient (occurred at a single time point but not later in the course of infection). (Figure Presented) Conclusion. Ensovibep effectively reduces SARS-CoV-2 viral load regardless of the presence of anti-SARS-CoV-2 antibodies at baseline. Furthermore, there were no emerging mutations of concern, indicating that a single dose administration of ensovibep is associated with minimal selective pressure.
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Background: Reports of thrombosis post COVID-19 mRNA vaccination have sparked concerns about safety. Aim(s): We prospectively evaluated blood samples of 18 participants who had received 2 doses of the BNT162b2 mRNA vaccine to determine if vaccination results in endothelial activation or hypercoagulability. Method(s): 18 participants who received the BNT162b2 vaccine were enrolled. Participants completed a questionnaire on their cardiovascular and thrombotic risk factors. Blood samples were collected at three time points: Pre-vaccination (day of vaccination), a median of 17 (IQR 16-18) days after the first dose and a median of 9 (IQR 7.5-14.5) days after the second dose of BNT162b2 vaccine. Endothelial markers included ICAM-1, VCAM-1 and P-selectin. Coagulation tests included PT and aPTT with clot waveform analysis, von Willebrand factor levels, Factor VIII and D-dimer levels. Statistical tests of association between endothelial and coagulation parameters were performed with repeated measures ANOVA and Mauchly's test of sphericity. Result(s): The median age of the participants was 35 years (IQR 31 -44), and 14 (78%) were female. 15 did not have any cardiovascular risk factors. There was a statistically significant increase in median ICAM levels post first (66.1ng/ml) and second dose of vaccination (69.5ng/ml)(p = 0.04), although this remained within the normal limit of ICAM levels. A statistically significant decrease in median PT (p = 0.005) and aPTT (p = 0.03) was observed post vaccination, with a corresponding statistically significant increase in aPTT clot waveform analysis (CWA) for maximum acceleration (max2)(p = 0.03) and maximum deceleration (max2)(p = 0.04) post first and second dose of vaccination. However, all evaluated endothelial and coagulation parameters remain within the reference ranges (Table 1). Conclusion(s): Our findings provide reassuring preliminary data that BNT162b2 vaccination does not result in endothelial activation or hypercoagulability. Mild variations in endothelial markers and coagulation parameters, though statistically significant, remain within the reference ranges and may be related to an inflammatory immune response to vaccination. (Table Presented).
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Background: Mortality for patients receiving extracorporeal membrane oxygenation (ECMO) for COVID-19 has increased over time. We investigated the association between immunomodulators and mortality for patients receiving ECMO for COVID-19. Method(s): We analysed the Extracorporeal Life Support Organisation Registry from Jan 1, 2020 through Dec 31, 2021, comparing in-hospital mortality and the overall survival since ECMO initiation of patients who did and did not receive immunomodulators (selective interleukin blockers, corticosteroids, janus-kinase inhibitors, convalescent plasma, and intravenous immunoglobulins) before or during ECMO, by using logistic regression and Cox regression. We calculated the propensity scores, and applied the overlap-weightage method to account for confounding factors. We conducted sensitivity analyses including regression models using inverse propensity score weightage method, models adjusted by propensity score, and unadjusted models to ensure robustness of results. A subgroup analysis on patients receiving corticosteroids was conducted. Result(s): 7180 patients were included in the final analysis. Immunomodulators were associated with increased mortality (OR: 1.168, 95%CI: 1.059-1.289, p=0.0020) and shorter survival since ECMO (HR: 1.05, 95%- CI: 1.078, 95%CI: 1.007-1.154, p=0.031). Similarly, corticosteroids were associated with a significant increase in mortality (OR: 1.302, 95%-CI: 1.180-1.437, p<0.0001) and shorter survival (HR: 1.221, 95%-CI: 1.139- 1.308, p<0.0001). Sensitivity analyses did not significantly change the overall results. Conclusion(s): Immunomodulators and corticosteroids, in particular, were associated with a significant increase in mortality amongst patients receiving ECMO for COVID-19, even after adjusting for potential confounding variables. Further studies are required to evaluate the timing of immunomodulators and understand the possible mechanisms behind this association.
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Introduction: The respiratory mechanics, particularly static compliance of the respiratory system ( CRS) in COVID-19 acute respiratory distress syndrome (CARDS) is poorly understood. Whether or not distinct ARDS phenotypes based on CRS exist is still widely debated. Methods: We conducted a systematic review and meta-analysis, searching three international databases from 1st December 2019 to 15th July 2021 for studies reporting on the respiratory mechanics of patients with CARDS. The primary outcome was the CRS of both COVID-19 ARDS. Secondary outcomes included the mortality rates, lengths of stay, and ventilator free days. Random-effects (DerSimonian and Laird) meta-analyses were conducted. Results: 45 studies (13,334 patients) were included for analysis. The pooled CRS in patients mechanically ventilated for COVID-19 was 34.6 (95%-CI: 33.4-35.8), and displayed a normal distribution (Shapiro- Wilk test: p = 0.35). CRS was significantly associated with an PaO2/FiO2 ratio, positive end-expiratory pressure, and tidal volume;driving pressure was negatively associated with CRS. The pooled mortality rate was 36.2% (95%-CI: 30.3-42.4%, ICU) and 38.9% (95%- CI: 32.3-45.7%, 28-day). Conclusions: The respiratory mechanics of CARDS at the time closest to the initiation of invasive mechanical ventilation was normally distributed and did not reveal any distinct CRS- based phenotypes. However, to what extent the proposed unique pathophysiology of CARDS affects the current definition of ARDS and “exposes” its potential limitations remains a question for a high-quality, large prospective dataset to answer. Nonetheless, from our study-level analysis, CRS appears to be a heterogenous metric affected by both disease and intervention factors (Fig. 1) and physicians should treat patients with personalised and precise interventions in this context. (Table Presented).
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Objective: Report characteristics of COVID-19 infections in people with multiple sclerosis (pwMS) receiving subcutaneous 20mg of atumumab, a human anti-CD20 monoclonal antibody, every 4 weeks. Background: A global pandemic of COVID-19 has resulted in over 40 million cases as of 19 October 2020. Risks of COVID-19 in pwMS receiving disease-modifying therapies are of increased interest, but still under investigation. Design/Methods: Demographics, COVID-19 seriousness category, of atumumab treatment duration and action taken with of atumumab, interventions and COVID-19 outcomes were recorded for pwMS in the open-label extension study ALITHIOS or in the post-marketing setting. Results: As of 28 September 2020, 12/1623 pwMS (5/12 females;9/12 white) in the ALITHIOS study were reported to have laboratory-confirmed SARS-CoV-2 infection. Mean age was 37.8 years (median 44 years, range 25-51 years), disease duration 3 to 23 years, and EDSS score 0-5.5. Ofatumumab exposure range was 8.5-13.8 months (n=6 who received of atumumab only in ALITHIOS) and 17.4-44.2 months (n=6 who continued of atumumab from prior trials). One of 12 had COVID-19 seriousness grade 3-A 39 year old white male with bilateral pneumonia requiring hospitalization who recovered with normal follow-up chest X-ray. The remaining 11 cases were non-serious grades 1 or 2: Seven reported as completely recovered, one recovering, two as ongoing and one asymptomatic with SARS-CoV-2 IgM and IgG positive. Six patients were treated with anti-infectives (three received both antivirals and antibacterials and three received antibacterials). Ofatumumab treatment was unchanged in seven and interrupted in four (resumed in three;information not available for one) patients;action unknown in one. To date, no post-marketing COVID-19 cases have been reported. Conclusions: We report 12 cases (11 non-serious;one serious hospitalized for bilateral pneumonia) of laboratory-confirmed SARS-CoV-2 infection in pwMS treated with of atumumab. More surveillance data are needed to determine the risks associated with COVID19 in pwMS treated with of atumumab.
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Objective: To identify the incidence of infections in those receiving immunomodulatory drugs for COVID- 19 during ECMO and the risk factors for infection. Methods: Deidentified data on all patients who had ECMO for COVID-19 till July 2020 were analysed from the ELSO Registry. A comparison cohort of patients who did not acquire superinfections during ECMO was used to identify risk factors for infection. Our primary outcome measure was incidence of infections pre- or on ECMO in patients receiving immunomodulatory drugs. Univariate analysis assessed potential associations between survival and various pre-ECMO/ECMOrelated factors. Variables (p< 0.1) entered a logistic regression model which identified predictors of infections in this cohort. Results: Of the 1237 patients who required ECMO for COVID-19 related complications, 911 patients (73.6%) received immunomodulatory drugs. 47% of these patients had superinfections, predominantly with gram negative bacteria (56%). Pre-ECMO factors associated with a higher odds of infection included immunodeficiency and treatment with selective cytokine blockers. ECMO complications (mechanical, renal, pulmonary, infectious and metabolic) increased the odds of infection. (Table 1) Patients who developed an infection preor on ECMO had significantly longer ECMO runs than those who did not (491.1±308.9 hours vs 293.4± 240.6hours, p< 0.001) with no mortality difference (45.7% Vs 43.4%, p = 0.45). Conclusions: Of the three quarter of patients who received immunomodulatory drugs for COVID-19 during ECMO, 47% had superinfections. Immunodeficiency and use of selective cytokine blockers were risk factors for infections pre or on ECMO in addition to ECMO related complications.
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INTRODUCTION: Coronavirus disease 2019 (COVID-19)-induced coagulopathy (CIC) has been widely reported in the literature. However, the spectrum of abnormalities associated with CIC has been highly variable. METHODS: We conducted a systematic review of the literature (until 1 June 2020) to assess CIC and disease severity during the early COVID-19 pandemic. Primary outcomes were pooled mean differences in platelet count, D-dimer level, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen level between non-severe and severe patients, stratified by degree of hypoxaemia or those who died. The risk factors for CIC were analysed. Random-effects meta-analyses and meta-regression were performed using R version 3.6.1, and certainty of evidence was rated using the Grading of Recommendation, Assessment, Development, and Evaluation approach. RESULTS: Of the included 5,243 adult COVID-19 patients, patients with severe COVID-19 had a significantly lower platelet count, and higher D-dimer level, prothrombin time and fibrinogen level than non-severe patients. Pooled mean differences in platelet count (-19.7×109/L, 95% confidence interval [CI] -31.7 to -7.6), D-dimer level (0.8μg/mL, 95% CI 0.5-1.1), prothrombin time (0.4 second, 95% CI 0.2-0.6) and fibrinogen level (0.6g/L, 95% CI 0.3-0.8) were significant between the groups. Platelet count and D-dimer level were significant predictors of disease severity on meta-regression analysis. Older men had higher risks of severe coagulopathic disease. CONCLUSION: Significant variability in CIC exists between non-severe and severe patients, with platelet count and D-dimer level correlating with disease severity. Routine monitoring of all coagulation parameters may help to assess CIC and decide on the appropriate management.