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Objective: A Phase II trial was conducted to determine if nasal disinfection with a commercial Good Manufacturing Practice‐manufactured 0.5% povidone‐iodine nasal spray (Nasodine®) may be a useful adjunct in the management of COVID‐19 by reducing viral shedding and prevention of transmission of SARS‐CoV‐2. The aim was to confirm the results from a human single‐dose pilot study by assessing repeated and frequent doses on nasal shedding of SARS‐CoV‐2 from adult subjects with confirmed COVID‐19. Methods: A multicenter, randomized, double‐blinded, placebo‐controlled Phase II clinical trial involving adults with early COVID‐19 symptoms. Baseline nasal swabs were collected to quantify pretreatment SARS‐CoV‐2 nasal viral load, followed by Nasodine treatment eight times daily over 3 calendar days. Daily nasal swabs were collected post‐dose to assess the impact of treatment on nasal viral load, measured by log10 TCID50 in quantitative culture. Results: Nasodine subjects exhibited significantly improved reduction in viral load (log10 TCID50) on Days 2–4 compared to placebo recipients (p = 0.028), rate of nasal clearance of viable virus (p = 0.032), and complete (100%) nasal and throat clearance of the virus by Day 5. No difference was seen in antigen shedding as measured by time transition from Rapid Antigen Test (RAT) positivity to RAT negativity. Conclusion: A total of 20 doses of Nasodine® nasal spray administered over 2.5 days significantly reduced the titers of viable SARS‐CoV‐2 virus in the nasal passages of COVID‐19 subjects. This is the first study demonstrating the efficacy of a tolerable intranasal formulation of povidone‐iodine on viral shedding in COVID‐19 subjects. Nasal disinfection may diminish viral transmission to others. Level of Evidence: 2 Laryngoscope, 134:3947–3952, 2024 [ABSTRACT FROM AUTHOR]

Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities, including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation. Herein, we report the in vitro and in vivo characterization of compound SHD865, the first compound to be studied in vivo in a newly discovered class of imidazolopyrazine mitochondrial uncouplers. SHD865 is a derivative of the furazanopyrazine uncoupler BAM15. SHD865 is a milder mitochondrial uncoupler than BAM15 that results in a lower maximal respiration rate. In a mouse model of diet-induced adiposity, 6-week treatment with SHD865 completely restored normal body composition and glucose tolerance to levels like those of chow-fed controls, without altering food intake. SHD865 treatment also corrected liver steatosis and plasma hyperlipidemia to normal levels comparable with chow-fed controls. SHD865 has maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. Collectively, these data identify the potential of imidazolopyrazine mitochondrial uncouplers as drug candidates for the treatment of obesity-related disorders. Article Highlights: A growing body of evidence suggests that targeting negative energy balance with mitochondrial uncouplers has potential for the treatment of metabolic disease. We report the discovery and characterization of compound SHD865 as a new class imidazolopyrazine mitochondrial uncoupler. SHD865 is liver selective, safely reverses diet-induced adiposity, and improves glucose homeostasis in mice without altering food intake or decreasing lean mass. SHD865 and related compounds have translational potential for the treatment of obesity, diabetes, and related metabolic disorders. [ABSTRACT FROM AUTHOR]

Anthropogenic climate change is changing the Earth system processes that control the characteristics of natural hazards both globally and across Australia. Model projections of hazards under future climate change are necessary for effective adaptation. This paper presents BARPA-R (the Bureau of Meteorology Atmospheric Regional Projections for Australia), a regional climate model designed to downscale climate projections over the Australasian region with the purpose of investigating future hazards. BARPA-R, a limited-area model, has a 17 km horizontal grid spacing and makes use of the Met Office Unified Model (MetUM) atmospheric model and the Joint UK Land Environment Simulator (JULES) land surface model. To establish credibility and in compliance with the Coordinated Regional Climate Downscaling Experiment (CORDEX) experiment design, the BARPA-R framework has been used to downscale ERA5 reanalysis. Here, an assessment of this evaluation experiment is provided. Performance-based evaluation results are benchmarked against ERA5, with comparable performance between the free-running BARPA-R simulations and observationally constrained reanalysis interpreted as a good result. First, an examination of BARPA-R's representation of Australia's surface air temperature, precipitation, and 10 m winds finds good performance overall, with biases including a 1 ∘ C cold bias in daily maximum temperatures, reduced diurnal temperature range, and wet biases up to 25 mm per month in inland Australia. Recent trends in daily maximum temperatures are consistent with observational products, while trends in minimum temperatures show overestimated warming and trends in precipitation show underestimated wetting in northern Australia. Precipitation and temperature teleconnections are effectively represented in BARPA-R when present in the driving boundary conditions, while 10 m winds are improved over ERA5 in six out of eight of the Australian regions considered. Secondly, the paper considers the representation of large-scale atmospheric circulation features and weather systems. While generally well represented, convection-related features such as tropical cyclones, the South Pacific Convergence Zone (SPCZ), the Northwest Cloudband, and the monsoon westerlies show more divergence from observations and internal interannual variability than mid-latitude phenomena such as the westerly jets and extratropical cyclones. Having simulated a realistic Australasian climate, the BARPA-R framework will be used to downscale two climate change scenarios from seven CMIP6 global climate models (GCMs). [ABSTRACT FROM AUTHOR]

Objectives: Bacterial biofilms on the sinonasal mucosa, especially biofilms of Staphylococcus aureus, are associated with greater severity and recalcitrance of chronic rhinosinusitis (CRS). There are few, if any, antibiofilm agents suitable for sinonasal application available for the management of this problem. Nasodine® Nasal Spray (Nasodine) is a 0.5% povidone‐iodine‐based formulation that has been developed for sinonasal application. We investigated the antibiofilm efficacy of Nasodine to determine whether it may be a candidate for the treatment of biofilm‐associated CRS. Methods: Biofilms of S. aureus ATCC 6538 were grown in vitro using the Centers for Disease Control biofilm reactor. Intact biofilms were treated by immersion in 0.9% saline (control), half concentration Nasodine, or full concentration Nasodine for between 5 min and 6 h. Further biofilm cells were dispersed into suspension then treated for between 30 s and 5 min. Surviving bacteria were then enumerated by culture and counting colonies, and the log10 reduction in viable bacteria was compared with control. Results: Nasodine demonstrated time and concentration‐dependent bacterial killing against intact biofilm. Statistically significant reductions in viable bacteria from intact biofilms were seen with exposures as brief as 5 min. Nasodine consistently eradicated dispersed biofilm within 1 min. Conclusion: Nasodine is highly active against biofilms of S. aureus ATCC 6538 in vitro. Biofilm killing is impeded by the presence of the intact biofilm structure. Lay summary: In chronic rhinosinusitis (CRS), bacterial communities called biofilms are associated with more severe inflammation. An iodine‐based nasal spray called Nasodine almost completely eradicates bacterial biofilms after 6 h of exposure. Nasodine may be useful for treating CRS. Laryngoscope, 133:2490–2495, 2023 [ABSTRACT FROM AUTHOR]

Anthropogenic climate change is changing the earth system processes that control the characteristics of natural hazards both globally and across Australia. Model projections of hazards under future climate change are necessary for effective adaptation. This paper presents BARPA-R (the Bureau of Meteorology Atmospheric Regional Projections for Australia), a regional climate model designed to downscale climate projections over the Australasian region with the purpose to investigate future hazards. BARPA-R, a limited area model, has a 17 km horizontal grid-spacing and makes use of the Met Office Unified Model (MetUM) atmospheric model and the Joint UK Land Environment Simulator (JULES) land surface model. To establish credibility and in compliance with the Coordinated Regional Climate Downscaling Experiment (CORDEX) experiment design, the BARPA-R framework has been used to downscale ERA-5 reanalysis. Here, an assessment of this evaluation experiment is provided. First, an examination of BARPA-R's representation of Australia's surface air temperature, rainfall and 10-m winds finds good performance overall, with biases including a 1K cold bias in daily maximum temperatures, reduced diurnal temperature range, and wet biases up to 25 mm/month in inland Australia. Recent trends in diurnal maximum temperatures are consistent with observational products, while trends in minimum temperatures show overestimated warming and trends in rainfall show underestimated wetting in northern Australia. Rainfall and temperature teleconnections are effectively represented in BARPA-R when present in the driving boundary conditions, while 10-metre winds are improved over ERA5 in six out of eight of the Australian regions considered. The second section of the paper considers the representation of large-scale atmospheric circulation features and weather systems. While generally well represented, convection-related features such as tropical cyclones, the SPCZ, Northwest Cloud-Bands and the monsoon westerlies show more divergence from observations and internal interannual variability than mid-latitude phenomena such as the westerly jets and extra-tropical cyclones. Having simulated a realistic Australasian climate, the BARPA-R framework will be used to downscale two climate change scenarios from seven CMIP6 GCMs. [ABSTRACT FROM AUTHOR]