Flood impacts on emergency responders operating at a city-scale

Emergency responders often have to operate and respond to emergency situations during dynamic weather conditions, including floods. This paper demonstrates a novel method using existing tools and datasets to evaluate emergency responder accessibility during flood events within the City of Leicester, UK. Accessibility was quantified using the 8- and 10-minute legislative targets for emergency provision for the Ambulance and Fire & Rescue services respectively under ‘normal’, no flood conditions, as well as flood scenarios of various magnitudes (namely the 1 in 20 year-, 1 in 100-year and 1 in 1,000-year recurrence intervals), with both surface water and fluvial flood conditions considered. Flood restrictions were processed based on previous hydrodynamic inundation modelling undertaken and inputted into a Network Analysis framework as restrictions for surface water and fluvial flood events. Surface water flooding was shown to cause more disruption to emergency responders operating within the city due to its widespread and spatially distributed footprint when compared to fluvial flood events of comparable magnitude. Fire & Rescue 10-minute accessibility was shown to decrease from 100 %, 66.5 %, 39.8 % and 26.2 % under the no flood, 1 in 20-year, 1 in 100-year and 1 in 1,000- year surface water flood scenarios respectively. Furthermore, total inaccessibility was shown to increase with flood magnitude, increasing from 6.0 % to 31.0 % under the 1 in 20-year and 1 in 100-year surface water flooding scenarios respectively. Further, the evolution of emergency service accessibility through a surface water flood event is outlined, demonstrating the rapid onset of impacts on emergency service accessibility within the first 15-minutes of the surface water flood event, with a reduction in service coverage and overlap being witnessed for the Ambulance service under a 1 in 100-year flood event. The study provides evidence to guide strategic planning for decision makers prior to and during emergency response to flood events at the cityscale and provides a readily transferable method to explore the impacts of natural hazards or disruptions on additional cities or regions based on historic, scenario-based events or real-time forecasting if such data is available

Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris

Fungal infections pose a significant and increasing threat to human health, but the current arsenal of antifungal drugs is inadequate. We screened the Medicines for Malaria Venture (MMV) Pathogen Box for new antifungal agents against three of the most critical Candida species (Candida albicans, Candida auris, and Candida glabrata). Of the 14 identified hit compounds, most were active against C. albicans and C. auris. We selected the pyrazolo-pyrimidine MMV022478 for chemical modifications to build structure–activity relationships and study their antifungal properties. Two analogues, 7a and 8g, with distinct fluorine substitutions, greatly improved the efficacy against C. auris and inhibited fungal replication inside immune cells. Additionally, analogue 7a had improved selectivity toward fungal killing compared to mammalian cytotoxicity. Evolution experiments generating MMV022478-resistant isolates revealed a change in morphology from oblong to round cells. Most notably, the resistant isolates blocked the uptake of the fluorescent dye rhodamine 6G and showed reduced susceptibility toward fluconazole, indicative of structural changes in the yeast cell surface. In summary, our study identified a promising antifungal compound with activity against high-priority fungal pathogens. Additionally, we demonstrated how structure–activity relationship studies of known and publicly available compounds can expand the repertoire of molecules with antifungal efficacy and reduced cytotoxicity to drive the development of novel therapeutics

Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris

Fungal infections pose a significant and increasing threat to human health, but the current arsenal of antifungal drugs is inadequate. We screened the Medicines for Malaria Venture (MMV) Pathogen Box for new antifungal agents against three of the most critical Candida species (Candida albicans, Candida auris, and Candida glabrata). Of the 14 identified hit compounds, most were active against C. albicans and C. auris. We selected the pyrazolo-pyrimidine MMV022478 for chemical modifications to build structure–activity relationships and study their antifungal properties. Two analogues, 7a and 8g, with distinct fluorine substitutions, greatly improved the efficacy against C. auris and inhibited fungal replication inside immune cells. Additionally, analogue 7a had improved selectivity toward fungal killing compared to mammalian cytotoxicity. Evolution experiments generating MMV022478-resistant isolates revealed a change in morphology from oblong to round cells. Most notably, the resistant isolates blocked the uptake of the fluorescent dye rhodamine 6G and showed reduced susceptibility toward fluconazole, indicative of structural changes in the yeast cell surface. In summary, our study identified a promising antifungal compound with activity against high-priority fungal pathogens. Additionally, we demonstrated how structure–activity relationship studies of known and publicly available compounds can expand the repertoire of molecules with antifungal efficacy and reduced cytotoxicity to drive the development of novel therapeutics

Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris

Fungal infections pose a significant and increasing threat to human health, but the current arsenal of antifungal drugs is inadequate. We screened the Medicines for Malaria Venture (MMV) Pathogen Box for new antifungal agents against three of the most critical Candida species (Candida albicans, Candida auris, and Candida glabrata). Of the 14 identified hit compounds, most were active against C. albicans and C. auris. We selected the pyrazolo-pyrimidine MMV022478 for chemical modifications to build structure–activity relationships and study their antifungal properties. Two analogues, 7a and 8g, with distinct fluorine substitutions, greatly improved the efficacy against C. auris and inhibited fungal replication inside immune cells. Additionally, analogue 7a had improved selectivity toward fungal killing compared to mammalian cytotoxicity. Evolution experiments generating MMV022478-resistant isolates revealed a change in morphology from oblong to round cells. Most notably, the resistant isolates blocked the uptake of the fluorescent dye rhodamine 6G and showed reduced susceptibility toward fluconazole, indicative of structural changes in the yeast cell surface. In summary, our study identified a promising antifungal compound with activity against high-priority fungal pathogens. Additionally, we demonstrated how structure–activity relationship studies of known and publicly available compounds can expand the repertoire of molecules with antifungal efficacy and reduced cytotoxicity to drive the development of novel therapeutics

Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris

Fungal infections pose a significant and increasing threat to human health, but the current arsenal of antifungal drugs is inadequate. We screened the Medicines for Malaria Venture (MMV) Pathogen Box for new antifungal agents against three of the most critical Candida species (Candida albicans, Candida auris, and Candida glabrata). Of the 14 identified hit compounds, most were active against C. albicans and C. auris. We selected the pyrazolo-pyrimidine MMV022478 for chemical modifications to build structure–activity relationships and study their antifungal properties. Two analogues, 7a and 8g, with distinct fluorine substitutions, greatly improved the efficacy against C. auris and inhibited fungal replication inside immune cells. Additionally, analogue 7a had improved selectivity toward fungal killing compared to mammalian cytotoxicity. Evolution experiments generating MMV022478-resistant isolates revealed a change in morphology from oblong to round cells. Most notably, the resistant isolates blocked the uptake of the fluorescent dye rhodamine 6G and showed reduced susceptibility toward fluconazole, indicative of structural changes in the yeast cell surface. In summary, our study identified a promising antifungal compound with activity against high-priority fungal pathogens. Additionally, we demonstrated how structure–activity relationship studies of known and publicly available compounds can expand the repertoire of molecules with antifungal efficacy and reduced cytotoxicity to drive the development of novel therapeutics

DataSheet_2_Improved capabilities of global ocean reanalyses for analysing sea level variability near the Atlantic and Gulf of Mexico Coastal U.S..xlsx

Realistic representation of monthly sea level anomalies in coastal regions has been a challenge for global ocean reanalyses. This is especially the case in coastal regions where sea levels are influenced by western boundary currents such as near the U.S. Atlantic Coast and the Gulf of Mexico. For these regions, most ocean reanalyses compare poorly to observations. Problems in reanalyses include errors in data assimilation and horizontal resolutions that are too coarse to simulate energetic currents like the Gulf Stream and Loop Current System. However, model capabilities are advancing with improved data assimilation and higher resolution. Here, we show that some current-generation ocean reanalyses produce monthly sea level anomalies with improved skill when compared to satellite altimetry observations of sea surface heights. Using tide gauge observations for coastal verification, we find the highest skill associated with the GLORYS12 and HYCOM ocean reanalyses. Both systems assimilate altimetry observations and have eddy-resolving horizontal resolutions (1/12°). We found less skill in three other ocean reanalyses (ACCESS-S2, ORAS5, and ORAP6) with coarser, though still eddy-permitting, resolutions (1/4°). The operational reanalysis from ECMWF (ORAS5) and their pilot reanalysis (ORAP6) provide an interesting comparison because the latter assimilates altimetry globally and with more weight, as well as assimilating ocean observations over continental shelves. We find these attributes associated with improved skill near many tide gauges. We also assessed an older reanalysis (CFSR), which has the lowest skill likely due to its lower resolution (1/2°) and lack of altimetry assimilation. ACCESS-S2 likewise does not assimilate altimetry, although its skill is much better than CFSR and only somewhat lower than ORAS5. Since coastal flooding is influenced by sea level anomalies, the recent development of skilful ocean reanalyses on monthly timescales may be useful for better understanding the physical processes associated with flood risks.</p

DataSheet_1_Improved capabilities of global ocean reanalyses for analysing sea level variability near the Atlantic and Gulf of Mexico Coastal U.S..pdf

Realistic representation of monthly sea level anomalies in coastal regions has been a challenge for global ocean reanalyses. This is especially the case in coastal regions where sea levels are influenced by western boundary currents such as near the U.S. Atlantic Coast and the Gulf of Mexico. For these regions, most ocean reanalyses compare poorly to observations. Problems in reanalyses include errors in data assimilation and horizontal resolutions that are too coarse to simulate energetic currents like the Gulf Stream and Loop Current System. However, model capabilities are advancing with improved data assimilation and higher resolution. Here, we show that some current-generation ocean reanalyses produce monthly sea level anomalies with improved skill when compared to satellite altimetry observations of sea surface heights. Using tide gauge observations for coastal verification, we find the highest skill associated with the GLORYS12 and HYCOM ocean reanalyses. Both systems assimilate altimetry observations and have eddy-resolving horizontal resolutions (1/12°). We found less skill in three other ocean reanalyses (ACCESS-S2, ORAS5, and ORAP6) with coarser, though still eddy-permitting, resolutions (1/4°). The operational reanalysis from ECMWF (ORAS5) and their pilot reanalysis (ORAP6) provide an interesting comparison because the latter assimilates altimetry globally and with more weight, as well as assimilating ocean observations over continental shelves. We find these attributes associated with improved skill near many tide gauges. We also assessed an older reanalysis (CFSR), which has the lowest skill likely due to its lower resolution (1/2°) and lack of altimetry assimilation. ACCESS-S2 likewise does not assimilate altimetry, although its skill is much better than CFSR and only somewhat lower than ORAS5. Since coastal flooding is influenced by sea level anomalies, the recent development of skilful ocean reanalyses on monthly timescales may be useful for better understanding the physical processes associated with flood risks.</p