The Sussex COVID-19 Modelling Cell: the methods and successes of a collaboration between public health teams in local authorities, NHS hospital trusts, NHS commissioners, and universities.

BACKGROUND: The Sussex Modelling Cell (SMC) is a consortium, formed during the COVID-19 pandemic, of representatives from NHS Sussex, and the local authorities and universities in Sussex. The SMC aimed to provide public health teams with local-data-driven modelling, data analysis, and policy and commissioning advice to mitigate the impact of the pandemic on the local population. It also aimed to answer operational questions, since the Government's forecasts were not suitably applicable. METHODS: From March 23, 2020, the SMC met (virtually) every Thursday to monitor COVID-19 situation reports, answer queries related to data and modelling, and provide interpretations of data or reports from many internal and external sources. SMC also provided quantitative information for public health teams to use within their organisations to advise on the local epidemic picture. Among other tools, the SMC calibrated a mathematical model to local COVID-19 data that could forecast health-care and hospital demand and COVID-19-related deaths. FINDINGS: Throughout the pandemic, the SMC provided scientific and data-driven evidence on the necessity of body storage contracts, monetary support for urgent care, and operational adjustments surrounding health-care provisions. The scientific evidence was generated and used repeatedly in each organisation to make beneficial decisions in a time of crisis. Although chasing an ever-changing pandemic picture was challenging, our swift reaction to national policy and pandemic changes allowed us to support policymakers, reduce anxiety, and provide clarity on the next steps. Our collaboration is one among few across the country and thus should be not only celebrated but also replicated, with appropriate resources and funding. INTERPRETATION: Besides mitigating the direct impact of the COVID-19 situation in Sussex, we have established a scientific collaboration relationship, in contrast to a customer-consultant setting, allowing the group to incorporate both the technical and applied perspectives into the work. With a clear structure, ethos and methodology, the SMC is able to step into the gap between academia and public health modelling to consider different impactful questions of operational importance where underlying complicated models exist, such as waiting times or system demand and capacity, and provide data analytic upskilling to public health teams. FUNDING: Brighton and Hove City Council, East and West Sussex County Council, and Sussex Health and Care Partnership.

Predicting and forecasting the impact of local outbreaks of COVID-19: use of SEIR-D quantitative epidemiological modelling for healthcare demand and capacity.

BACKGROUND: The world is experiencing local/regional hotspots and spikes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19 disease. We aimed to formulate an applicable epidemiological model to accurately predict and forecast the impact of local outbreaks of COVID-19 to guide the local healthcare demand and capacity, policy-making and public health decisions. METHODS: The model utilized the aggregated daily COVID-19 situation reports (including counts of daily admissions, discharges and bed occupancy) from the local National Health Service (NHS) hospitals and COVID-19-related weekly deaths in hospitals and other settings in Sussex (population 1.7 million), Southeast England. These data sets corresponded to the first wave of COVID-19 infections from 24 March to 15 June 2020. A novel epidemiological predictive and forecasting model was then derived based on the local/regional surveillance data. Through a rigorous inverse parameter inference approach, the model parameters were estimated by fitting the model to the data in an optimal sense and then subsequent validation. RESULTS: The inferred parameters were physically reasonable and matched up to the widely used parameter values derived from the national data sets by Biggerstaff M, Cowling BJ, Cucunubá ZM et al. (Early insights from statistical and mathematical modeling of key epidemiologic parameters of COVID-19, Emerging infectious diseases. 2020;26(11)). We validate the predictive power of our model by using a subset of the available data and comparing the model predictions for the next 10, 20 and 30 days. The model exhibits a high accuracy in the prediction, even when using only as few as 20 data points for the fitting. CONCLUSIONS: We have demonstrated that by using local/regional data, our predictive and forecasting model can be utilized to guide the local healthcare demand and capacity, policy-making and public health decisions to mitigate the impact of COVID-19 on the local population. Understanding how future COVID-19 spikes/waves could possibly affect the regional populations empowers us to ensure the timely commissioning and organization of services. The flexibility of timings in the model, in combination with other early-warning systems, produces a time frame for these services to prepare and isolate capacity for likely and potential demand within regional hospitals. The model also allows local authorities to plan potential mortuary capacity and understand the burden on crematoria and burial services. The model algorithms have been integrated into a web-based multi-institutional toolkit, which can be used by NHS hospitals, local authorities and public health departments in other regions of the UK and elsewhere. The parameters, which are locally informed, form the basis of predicting and forecasting exercises accounting for different scenarios and impacts of COVID-19 transmission.

Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFß) Production in Regulatory T-Cells.

We report the design, synthesis, and biological evaluation of some potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229. The design of these molecules was informed and supported by X-ray crystal structures. Compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays and was shown to have antiangiogenic, antimigratory, and antitumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, and CD25+ populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFß production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies.

Sources and timing of anthropogenic pollution in the Ensenada de San Simon (inner Ria de Vigo), Galicia, NW Spain: an application of mixture-modelling and nonlinear optimization to recent sedimentation.

The Ensenada de San Simon is the inner part of the Ria de Vigo, one of the major mesotidal rias of the Galician coast, NW Spain. The geochemistry of its bottom sediments can be accounted for in terms of both natural and anthropogenic sources. Mixture-modelling enables much of the Cr, Ni, V, Cu, Pb and Zn concentrations of the bottom and subaqueous sediments to be explained by sediment input from the river systems and faecal matter from manmade mussel rafts. The compositions and relative contributions of additional, unknown, sources of anomalous heavy-metal concentrations are quantified using constrained nonlinear optimization. The pattern of metal enrichment is attributed to: material carried in solution and suspension in marine water entering the Ensenada from the polluted industrial areas of the adjacent Ria de Vigo; wind-borne urban dusts and/or vehicular emissions from the surrounding network of roads and a motorway road-bridge over the Estrecho de Rande; industrial and agricultural pollution from the R. Redondela; and waste from a former ceramics factory near the mouth of the combined R. Oitaben and R. Verdugo. Using (137)Cs dating, it is suggested that heavy metal build-up in the sediments since the late 1970s followed development of inshore fisheries and introduction of the mussel rafts (ca. 1960) and increasing industrialisation.

Stereoselective synthesis of C-glycosides from carboxylic acids: the tandem Tebbe-Claisen approach.

A variety of beta- or alpha-C-glycosides may be readily accessed in an entirely stereoselective fashion from esters derived from the reaction of carboxylic acids and 3-hydroxy glycals, by way of a tandem reaction sequence of Tebbe methylenation and Claisen rearrangement. Though of wide scope, for example allowing the synthesis of 1-6 linked C-disaccharides, the methodology does not currently allow the synthesis of C-glycosyl alpha-amino acids.

Studies on the Asymmetric Oxidation of Ester Derivatives of 1,3-Dithiane-2-carboxylates. Asymmetric Synthesis of trans-1,3-Dithiane 1,3-Dioxide.

Asymmetric oxidation of a range of 1,3-dithianes was studied using the Kagan protocol [CHP (4 equiv), (+)-DET (2 equiv), Ti(OiPr)(4) (1 equiv), and H(2)O (1 equiv) at -35 degrees C for 48 h]. 1,3-Dithiane itself gave monoxide (30% ee) and the trans bis-sulfoxide (59% ee) but with low enantioselectivity. In contrast, ester derivatives (Me, Et, t-Bu, Ph) of 1,3-dithiane-2-carboxylates gave monoxides (80-95% ee) and trans bis-sulfoxides (>97% ee) in high enantioselectivity. Optimum conditions for the oxidation of ethyl 1,3-dithiane-2-carboxylate required the Modena protocol [CHP (4 equiv), (+)-DET (2 equiv), and Ti(OiPr)(4) (0.5 equiv) at -22 degrees C for 24 h], and this gave the trans bis-sulfoxide in 60% yield and high enantioselectivity. The bis-sulfoxides were found to be acid sensitive and required rapid workup and purification for optimum yields. The differences between the Modena and Kagan oxidants are discussed together with a discussion on the origin of the high enantio- and diastereoselectivity of the reaction. Finally, hydrolysis and decarboxylation furnished trans-1,3-dithiane 1,3-dioxide.