Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

Background: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

BackgroundThe safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population.MethodsPANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031.FindingsBetween Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.InterpretationMolnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community

Reduction in Natural Gas Consumption in Sulfur Recovery Units through Kinetic Simulation Using a Detailed Reaction Mechanism

H₂S, a toxic gas present in raw natural gas and in oil fields, is converted to sulfur using the Claus process in sulfur recovery units. The low and fluctuating demand and sale price of sulfur and its increasing production due to the discovery of new sour fields have mandated optimization studies to reduce the production cost. Natural gas (mainly methane) is continuously cofired with acid gas (H₂S and CO₂) in the Claus furnace to maintain temperatures above 1050 °C, which adds to the operating cost. This study aims at reducing the usage of natural gas in sulfur recovery units using a detailed reaction mechanism for Claus feed combustion, while maintaining the desired furnace temperature. An optimal combination of feed-preheating using natural gas and its cofiring in the furnace is determined through furnace and fired heater simulations. A model for the feed preheater is developed using plant measurements. Through simulation studies by varying natural gas flow rates into the Claus furnace and to the air preheater, it is observed that (a) a considerable amount of natural gas can be saved to maintain the required furnace temperature, if air is preheated to a higher temperature rather than natural gas cofiring (also validated in an operational sulfur recovery plant); (b) a reduction in natural gas to the furnace improves the sulfur recovery efficiency; and (c) the destruction of aromatic contaminants (that are harmful for the catalysts present downstream) in the furnace is enhanced with decreasing natural gas cofiring and increasing feed temperature. The rate-of-production analysis is also presented to understand the chemical effects of natural gas in the furnace

Coronary Artery Calcification, Cardiovascular Events, and Death: A Prospective Cohort Study of Incident Patients on Hemodialysis

Background: Coronary calcification in patients with end-stage renal disease (ESRD) is associated with an increased risk of cardiovascular outcomes and death from all causes. Previous evidence has been limited by short follow-up periods and inclusion of a heterogeneous cluster of events in the primary analyses. Objective: To describe coronary calcification in patients incident to ESRD, and to identify whether calcification predicts vascular events or death. Design: Prospective substudy of an inception cohort. Setting: Tertiary care haemodialysis centre in Ontario (St Joseph's Healthcare Hamilton). Participants: Patients starting haemodialysis who were new to ESRD. Measurements: At baseline, clinical characterization and spiral computed tomography (CT) to score coronary calcification by the Agatston-Janowitz 130 scoring method. A primary outcome composite of adjudicated stroke, myocardial infarction, or death. Methods: We followed patients prospectively to identify the relationship between cardiac calcification and subsequent stroke, myocardial infarction, or death, using Cox regression. Results: We recruited 248 patients in 3 centres to our main study, which required only biochemical markers. Of these 164 were at St Joseph's healthcare, and eligible to participate in the substudy; of these, 51 completed CT scanning (31 %). Median follow up was 26 months (Q 1 , Q 3 : 14, 34). The primary outcome occurred in 16 patients; 11 in the group above the median and 5 in the group below ( p = 0.086). There were 26 primary outcomes in 16 patients; 20 (77 %) events in the group above the coronary calcification median and 6 (23 %) in the group below ( p = 0.006). There were 10 deaths; 8 in the group above the median compared with 2 in the group below ( p = 0.04). The hazard ratios for coronary calcification above, compared with below the median, for the primary outcome composite were 2.5 (95 % CI 0.87, 7.3; p = 0.09) and 1.7 (95 % CI 0.55, 5.4; p = 0.4), unadjusted and adjusted for age, respectively. For death, the hazard ratios were 4.6 (95 % CI 0.98, 21.96; p = 0.054) and 2.4 (95 % CI 0.45, 12.97; p = 0.3) respectively. Limitations: We were limited by a small sample size and a small number of events. Conclusions: Respondent burden is high for additional testing around the initiation of dialysis. High coronary calcification in patients new to ESRD has a tendency to predict cardiovascular outcomes and death, though effects are attenuated when adjusted for age

A randomised double-blind placebo-controlled 12- week feasibility trial of methotrexate added to treatment as usual in early schizophrenia: study protocol for a randomised controlled trial.

BACKGROUND: Methotrexate is a commonly used anti-inflammatory and immunosuppressive drug. There is growing evidence that inflammatory processes are involved in the pathogenesis of schizophrenia. In our recent randomised double-blind placebo-controlled clinical trial in Pakistan and Brazil, the addition of minocycline (antibiotic and anti-inflammatory drug) for 1 year to treatment as usual reduced negative symptoms and improved some cognitive measures. A meta-analysis of cytokine changes in the peripheral blood has identified IL-2, IFN-gamma, TNF-alpha and soluble IL-2 receptor as trait markers of schizophrenia because their levels were elevated during acute exacerbations and reduced in remission. This suggests immune activation and an inflammatory syndrome in schizophrenia. Based on the evidence of the strong anti-inflammatory properties of methotrexate, we propose that low-dose methotrexate may be an effective therapy in early schizophrenia. METHODS/DESIGN: This is a double-blind placebo-controlled study of methotrexate added to treatment as usual for patients suffering from schizophrenia, schizoaffective disorder, psychosis not otherwise specified or schizophreniform disorder. This will be with 72 patients, 36 in each arm over 3 months. There will be screening, randomisation and follow-up visits. Full clinical assessments will be carried out at baseline, 2, 4, 8 and 12 weeks. Social and cognitive assessments will be carried out at baseline and 12 weeks. Methotrexate will be given at a dose of 10 mgs orally once a week for a 3-month period. DISCUSSION: Evidence suggests inflammatory processes are involved in the pathogenesis of schizophrenia and anti-inflammatory treatments have shown to have some beneficial effects. Methotrexate is a known immunosuppressant and anti-inflammatory drug. The aim of this study is to establish the degree of improvement in positive and negative symptoms, as well as cognitive functioning with the addition of methotrexate to treatment as usual. ClinicalTrials.gov identifier: NCT02074319 (24 February 2014)