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Background: the antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19.Methods: this randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing.Findings: between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial.Interpretation: we found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive.Funding: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

The establishment of national trauma networks have resulted in significant benefits to injured patients. Older people are the majority of major trauma patients and there is need to study variations in care and performance against clinical metrics for them. We aim to describe this patient group in terms of injury, demographics, episode of care assessment and variation between component regions of the Major Trauma Network of England and Wales.The Trauma Audit and Research Network (TARN) database was analysed from April 2017 to March 2019. Patients aged 65 years and above with injury severity score (ISS) greater than eight were selected for analysis. Patients were compared by care pathway in terms of first and second treating hospitals and by demographics, injury mechanism, severity, physiology at arrival to hospital (including Glasgow Coma Score (GCS)) and mortality, where known, at discharge.Fifty-three thousand three hundred and forty-seven older injured patients (median age 82.5 years and 58.2% female), were treated in 165 hospitals within the 17 regional trauma networks over the two-year study period. Aside from GCS and gender, all other patient characteristics were significantly different between networks and specifically, a large variation between the network with the highest proportion of older patients (60.4%) and that with a preponderance of younger patients (40.2%) is seen. 84% of cases were due to a fall2 m and 36.7% of cases had a brain injury. 73.5% of cases had one or more comorbidities.We have increased the understanding of how older patients contribute to and are managed by a national trauma service. We have demonstrated variation in numbers and patient characteristics throughout regional trauma networks. We have detailed the whole patient episode, allowing us to comment on disparities in management such as senior review and access to specialist clinical care settings. Older patients dominate United Kingdom major trauma and considerable variations and shortfalls have been identified. Work is needed to focus on the whole clinical episode for these patients both to improve outcome and patient experience but to also to ensure sustainable clinical care in a resource deplete era.

Spontaneous hypertensive-corpulent rats (SHR/N-corpulent), homozygous for the corpulent gene (cp/cp), are obese, hyperinsulinemic and exhibit abnormal glucose tolerance and thus represent a model for type II diabetes and obesity. In view of their overall insulin resistance, we examined liver insulin receptor binding and tyrosine kinase activity from corpulent rats and lean littermates fed purified diets containing 54% sucrose or starch for about 12 wk. Specific 125I-insulin binding to crude liver membranes from female corpulent rats fed either starch or sucrose was reduced to approximately 50% of that seen in lean rats (14 vs. 7%). Affinity of insulin receptors was similar in all groups, suggesting that hyperinsulinemic corpulent rats possess fewer hepatic insulin receptors than do lean rats. Using similar numbers of wheat germ agglutinin-agarose (WGA)-purified insulin receptors with similar affinities for insulin, it was found that basal and insulin-stimulated phosphorylation of the synthetic tyrosine-specific kinase substrate poly(Glu, Tyr)4:1 was similar in lean and obese rats fed sucrose or starch. It is suggested that the contribution of the liver to the insulin resistance in obese SHR/N-cp rats probably lies distal to the insulin receptor tyrosine kinase.

Objectives. The purpose of the present study was to assess the influence of variations in the relative degree of dilation of left and right ventricular chambers on the clinical outcome of patients with dilated cardiomyopathy. Background. Dilated cardiomyopathy, a primary myocardial disease characterized by ventricular dilation and systolic dysfunction, is generally associated with a poor prognosis. However, considerable variability has been observed in the clinical course and the morphologic and hemodynamic features in individual patients. Methods. We evaluated 67 consecutive patients with dilated cardiomyopathy and without evidence of ischemic or primary valvular heart disease. On the basis of diastolic ventricular chamber area measurements obtained by echocardiography, patients were classified into two groups: 38 patients with a relatively equal degree of left and right ventricular dilation (LV ⋍ RV) and 29 patients with predominant and disproportionate dilation of the left ventricle (LV > RV). Results. The 67 patients ranged in age from 19 to 81 years (mean 56); 49 (73%) were male. The two subsets of patients with dilated cardiomyopathy did not differ with regard to age, left ventricular diastolic dimension, wall thickness and mass or ejection fraction. However, patients in the LV⋍RV group showed more severe mitral and tricuspid regurgitation by Doppler echocardiography than did those in the LV > RV group (p = 0.01 for mitral and 0.004 for tricuspid regurgitation). Over the follow-up period of 2 to 60 months (mean 28), there were 19 deaths. Survival in the LV > RV group was significantly better than in the LV⋍RV group (p = 0.03). Conclusions. Patients with dilated cardiomyopathy represent a heterogeneous group with regard to both clinical outcome and the relative degree of left and right ventricular chamber dilation. Patients in the LV > RV subset appear to have better overall survival and less severe mitral and tricuspid regurgitation than do patients in the LV ⋍ RV subset. Longitudinal studies are needed to determine whether these morphologic subsets in fact represent a continuum within the disease spectrum of dilated cardiomyopathy.

A method is described for the chronic implantation of a lucite window in the uterus of a pregnant ewe which allows direct access to the amniotic fluid compartment in the unanesthetized state. The window can be directly connected to an extrauterine viewing compartment allowing repeated observations and measurements of physiologic function. The compartment also provides an easy method of changing the fetal environment.