Molnupiravir inhibits SARS-CoV-2 variants including Omicron in the hamster model.

The recent emergence of the SARS-CoV-2 Omicron variant of concern (VOC) containing a heavily mutated spike protein capable of escaping preexisting immunity identifies a continued need for interventional measures. Molnupiravir (MK-4482), an orally administered nucleoside analog, has demonstrated efficacy against earlier SARS-CoV-2 lineages and was recently approved for SARS-CoV-2 infections in high-risk adults. Here we assessed the efficacy of MK-4482 against the earlier Alpha, Beta and Delta VOCs and Omicron in the hamster COVID-19 model. Omicron replication and associated lung disease in vehicle treated hamsters was reduced compared to the earlier VOCs. MK-4482 treatment inhibited virus replication in the lungs of Alpha, Beta and Delta VOC infected hamsters. Importantly, MK-4482 profoundly inhibited virus replication in the upper and lower respiratory tract of hamsters infected with the Omicron VOC. Consistent with its mutagenic mechanism, MK-4482 treatment had a more pronounced inhibitory effect on infectious titers compared to viral RNA genome load. Histopathologic analysis showed that MK-4482 treatment caused a concomitant reduction in the level of lung disease and viral antigen load in infected hamsters across all VOCs examined. Together, our data indicate the potential of MK-4482 as an effective antiviral against known SARS-CoV-2 VOCs, especially Omicron, and likely future SARS-CoV-2 variants

Cigarette smoking, health status, socio-economic status and access to health care in diabetes mellitus: a cross-sectional survey

BACKGROUND: In diabetes mellitus, cigarette smoking is associated with increased risk of cardiovascular mortality and microvascular complications. We evaluated cigarette smoking in people with diabetes mellitus in a socio-economically deprived area. METHODS: We carried out a cross-sectional survey of people registered with diabetes mellitus at 29 general practices in inner London. Responses were analysed for 1,899 (64%) respondents out of 2,983 eligible. RESULTS: There were 1,899 respondents of whom 968 (51%) had never smoked, 296 (16%) were current smokers and 582 (31%) were ex-smokers. Smoking was more frequent in white Europeans (men 22%, women 20%), than in African Caribbeans (men 15%, women 10%) or Africans (men 8%, women 2%). Smoking prevalence decreased with age. Smokers were more likely to be living in rented accommodation (odds ratio, OR 2.02, 95% confidence interval 1.48 to 2.74). After adjusting for confounding, current smokers had lower SF-36 scores than subjects who had never smoked (mean difference in physical functioning score -5.6, 95% confidence interval -10.0 to -1.2; general health -6.1, -9.7 to -2.5). Current smokers were less likely to have attended a hospital diabetic clinic in the last year (OR 0.59, 0.44 to 0.79), and their hypertension was less likely to be treated (OR 0.47, 0.30 to 0.74). CONCLUSIONS: Compared with non-smokers, smokers had lower socio-economic status and worse health status, but were less likely to be referred to hospital or treated for their hypertension. People with diabetes who smoke can be regarded as a vulnerable group who need more intensive support and treatment

A qualitative study of enablers and barriers influencing the incorporation of social accountability values into organisational culture: a perspective from two medical schools

Background: Definitions of social accountability describe the obligation of medical schools to direct education, research and service activities towards addressing the priority health concerns of the population they serve. While such statements give some direction as to how the goal might be reached, it does not identify what factors might facilitate or hinder its achievement. This study set out to identify and explore enablers and barriers influencing the incorporation of social accountability values into medical schools. Methods: Semi structured interviews of fourteen senior staff in Bar Ilan and Leeds medical schools were undertaken following a literature review. Participants were recruited by purposive sampling in order to identify factors perceived to play a part in the workings of each institution. Results: Academic prestige was seen as a key barrier that was dependent on research priorities and student selection. The role of champions was considered to be vital to tackle staff perceptions and facilitate progress. Including practical community experience for students was felt to be a relevant way in which the curriculum could be designed through engagement with local partners. Conclusions: Successful adoption of social accountability values requires addressing concerns around potential negative impacts on academic prestige and standards. Identifying and supporting credible social accountability champions to disseminate the values throughout research and education departments in medical and other faculties is also necessary, including mapping onto existing work streams and research agendas. Demonstrating the contribution the institution can make to local health improvement and regional development by a consideration of its economic footprint may also be valuable

Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis.

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility

Exotic states in a simple network of nanoelectromechanical oscillators.

Synchronization of oscillators, a phenomenon found in a wide variety of natural and engineered systems, is typically understood through a reduction to a first-order phase model with simplified dynamics. Here, by exploiting the precision and flexibility of nanoelectromechanical systems, we examined the dynamics of a ring of quasi-sinusoidal oscillators at and beyond first order. Beyond first order, we found exotic states of synchronization with highly complex dynamics, including weak chimeras, decoupled states, traveling waves, and inhomogeneous synchronized states. Through theory and experiment, we show that these exotic states rely on complex interactions emerging out of networks with simple linear nearest-neighbor coupling. This work provides insight into the dynamical richness of complex systems with weak nonlinearities and local interactions

Managing soil fertility in organic farming systems

Complex relationships exist between different components of the organic farm and the quantity and quality of the end products depend on the functioning of the whole system. As such, it is very difficult to isolate soil fertility from production and environmental aspects of the system. Crop rotation is the central tool that integrates the maintenance and development of soil fertility with different aspects of crop and livestock production in organic systems. Nutrient supply to crops depends on the use of legumes to add nitrogen to the system and limited inputs of supplementary nutrients, added in acceptable forms. Manures and crop residues are carefully managed to recycle nutrients around the farm. Management of soil organic matter, primarily through the use of short-term leys, helps ensure good soil structure and biological activity, important for nutrient supply, health and productivity of both crops and livestock. Carefully planned diverse rotations help reduce the incidence of pests and diseases and allow for cultural methods of weed control. As a result of the complex interactions between different system components, fertility management in organic farming relies on a long-term integrated approach rather than the more short-term very targeted solutions common in conventional agriculture