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Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations. Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK's AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified. [ABSTRACT FROM AUTHOR]

ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at SARS-CoV-2 transmission sites in 12 patients enrolled in AGILE Candidate-Specific Trial-2. Saliva, nasal, and tear NHC concentrations were 3%, 21%, and 22% that of plasma. Saliva and nasal NHC were significantly correlated with plasma (P  < .0001). Clinical Trials Registration. NCT04746183. [ABSTRACT FROM AUTHOR]

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID‐19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically‐based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high‐dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice‐daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self‐limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID‐19. [ABSTRACT FROM AUTHOR]

Quantifying the routing of snowmelt to surface water is critical for predicting the impacts of atmospheric deposition and changing land use on water quality in montane catchments. To investigate solute sources and streamflow in the montane Provo River watershed (Utah, USA), we used time‐series 87Sr/86Sr ratios sampled at three sites (Soapstone, Woodland and Hailstone) across a gradient of bedrock types. Soils are influenced by aeolian dust contributions, with distinct 87Sr/86Sr ratios relative to siliciclastic bedrock, providing an opportunity to investigate shallow versus deeper flow paths for controlling water chemistry. At the most upstream site (Soapstone), Sr concentrations averaged ~17 μg/L with minimal dilution during snowmelt suggesting subsurface flow paths dominated streamflow. However, a decrease in 87Sr/86Sr ratios from ~0.717 during baseflow to as low as ~0.713 during snowmelt indicated the activation of shallow flow paths through dust‐derived soils. In contrast, downstream sites receiving water inputs from Sr‐rich carbonate bedrock (Woodland and Hailstone) exhibited strong dilution of Sr from ~120 to 20 μg/L and an increase in 87Sr/86Sr ratios from ~0.7095 to ~0.712 during snowmelt. A three‐component mixing model using 87Sr/86Sr ratios and Sr concentrations at Soapstone showed water inputs were dominated by direct snowmelt and flushed soil water during runoff and groundwater during baseflow. At Woodland and Hailstone, a two‐component mixing model showed that the river was a mixture of groundwater and up to 75% upstream channel water during snowmelt. Our findings highlight the importance of flushed soil water for controlling stream water discharge and chemistry during snowmelt, with the signal from the upstream site propagating downstream in a nested catchment. Further, aeolian dust contributes to the solute chemistry of montane streams with potential impacts on water quality along shallow flow paths. Potential contaminants in these surface soils (e.g., Pb deposition in dust) may have significant impacts on water quality during snowmelt runoff. [ABSTRACT FROM AUTHOR]

In this paper, we aim to explore students' experiences of support mechanisms that support their wellbeing on an engineering degree programme at a research-intensive higher education institution and understand how theory relates to practice. This study was conducted using a mixed-methods approach involving student survey responses (N = 173), interviews with 16 students and focus groups. Kahu and Nelson's conceptual framework was used as a lens through which to explore student support mechanisms. Preliminary data analysis indicates that the intense workload adversely affects students as do some of the interactions they have with personal tutors and their peers. Our findings suggest that workload needs to be reduced, personal tutors need to fill gaps in their skills set, especially associated with student support, and institutional and departmental protocols be continually updated to support student wellbeing. Additionally, student wellbeing officers and professional, dedicated wellbeing advisors could be part of a long-term solution. [ABSTRACT FROM AUTHOR]

Background: The effect of the posture of semirecumbent patients on the hemodynamics and performance of intra-aortic balloon (IAB) were studied in vivo and in vitro. Methods: An IAB was inserted into a glass tube filled with saline, fully inflated and deflated using an intra-aortic balloon pump (IABP). Three successive cycles were filmed at 125 frames/s with the tube positioned at various angles between 0° (horizontal) and 90° (vertical). Pressure and flow were measured distal to both ends of the balloon. In parallel, coronary left anterior descending (LAD) flow velocity and aortic pressure were recorded in 6 patients using IABP, postcardiac surgery in the intensive care unit. Recordings were made when the patient was lying horizontally (recumbent) and when the patient's torso was inclined at 30° to the horizontal (semirecumbent). Results: With the tube horizontal, the inflation was effectively uniform along the length of the balloon. At all other angles, the higher end of the balloon inflated first, and mean pressure and flow measured distal to the higher end of the balloon were less than those measured at 0°. Mean aortic pressure and LAD flow decreased by 10 ± 2% (P = 0.001) and 15 ± 3% (P = 0.001), respectively, when the patient was semirecumbent compared to when the patient was recumbent. Conclusion: The decreased mean aortic pressure and LAD flow velocity suggests that unless patients using IABP are required to be semirecumbent, it may be best to position them horizontally to gain the full benefits of balloon counter pulsation to the coronary circulation. [ABSTRACT FROM AUTHOR]