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2. Influenza Hospitalisations in England during the 2022/23 Season: do different data sources drive divergence in modelled waves? A comparison of surveillance and administrative data

Author

Mellor, Jonathon, Christie, Rachel, Guilder, James, Paton, Robert S, Elgohari, Suzanne, Watson, Conall, Deeny, Sarah, and Ward, Thomas

Subjects
Quantitative Biology - Populations and Evolution
Abstract

Accurate and representative data is vital for precisely reporting the impact of influenza in healthcare systems. Northern hemisphere winter 2022/23 experienced the most substantial influenza wave since the COVID-19 pandemic began in 2020. Simultaneously, new data streams become available within health services because of the pandemic. Comparing these data, surveillance and administrative, supports the accurate monitoring of population level disease trends. We analysed admissions rates per capita from four different collection mechanisms covering National Health Service hospital Trusts in England over the winter 2022/23 wave. We adjust for difference in reporting and extracted key epidemic characteristics including the maximum admission rate, peak timing, cumulative season admissions and growth rates by fitting generalised additive models at national and regional levels. By modelling the admission rates per capita across surveillance and administrative data systems we show that different data measuring the epidemic produce different estimates of key quantities. Nationally and in most regions the data correspond well for the maximum admission rate, date of peak and growth rate, however, in subnational analysis discrepancies in estimates arose, particularly for the cumulative admission rate. This research shows that the choice of data used to measure seasonal influenza epidemics can influence analysis substantially at sub-national levels. For the admission rate per capita there is comparability in the sentinel surveillance approach (which has other important functions), rapid situational reports, operational databases and time lagged administrative data giving assurance in their combined value. Utilising multiple sources of data aids understanding of the impact of seasonal influenza epidemics in the population.

Published
2023

3. Real-time COVID-19 hospital admissions forecasting with leading indicators and ensemble methods in England

Author

Mellor, Jonathon, Christie, Rachel, Paton, Robert S, Leslie, Rhianna, Tang, Maria, Fyles, Martyn, Deeny, Sarah, Ward, Thomas, and Overton, Christopher E

Subjects
Statistics - Applications
Abstract

Hospitalisations from COVID-19 with Omicron sub-lineages have put a sustained pressure on the English healthcare system. Understanding the expected healthcare demand enables more effective and timely planning from public health. We collect syndromic surveillance sources, which include online search data, NHS 111 telephonic and online triages. Incorporating this data we explore generalised additive models, generalised linear mixed-models, penalised generalised linear models and model ensemble methods to forecast over a two-week forecast horizon at an NHS Trust level. Furthermore, we showcase how model combinations improve forecast scoring through a mean ensemble, weighted ensemble, and ensemble by regression. Validated over multiple Omicron waves, at different spatial scales, we show that leading indicators can improve performance of forecasting models, particularly at epidemic changepoints. Using a variety of scoring rules, we show that ensemble approaches outperformed all individual models, providing higher performance at a 21-day window than the corresponding individual models at 14-days. We introduce a modelling structure used by public health officials in England in 2022 to inform NHS healthcare strategy and policy decision making. This paper explores the significance of ensemble methods to improve forecasting performance and how novel syndromic surveillance can be practically applied in epidemic forecasting., Comment: arXiv admin note: substantial text overlap with arXiv:2303.12037

Published
2023

8. Forecasting influenza hospital admissions within English sub-regions using hierarchical generalised additive models

Author

Mellor, Jonathon, Christie, Rachel, Overton, Christopher E, Paton, Robert S, Leslie, Rhianna, Tang, Maria, Deeny, Sarah, and Ward, Thomas

Subjects
Statistics - Applications, Quantitative Biology - Populations and Evolution
Abstract

Background: Seasonal influenza causes a substantial burden on healthcare services over the winter period when these systems are already under pressure. Policies during the COVID-19 pandemic supressed the transmission of season influenza, making the timing and magnitude of a potential resurgence difficult to predict. Methods: We developed a hierarchical generalised additive model (GAM) for the short-term forecasting of hospital admissions with a positive test for the influenza virus sub-regionally across England. The model incorporates a multi-level structure of spatio-temporal splines, weekly seasonality, and spatial correlation. Using multiple performance metrics including interval score, coverage, bias, and median absolute error, the predictive performance is evaluated for the 2022/23 seasonal wave. Performance is measured against an autoregressive integrated moving average (ARIMA) time series model. Results: The GAM method outperformed the ARIMA model across scoring rules at both high and low-level geographies, and across the different phases of the epidemic wave including the turning point. The performance of the GAM with a 14-day forecast horizon was comparable in error to the ARIMA at 7 days. The performance of the GAM is found to be most sensitive to the flexibility of the smoothing function that measures the national epidemic trend. Interpretation: This study introduces a novel approach to short-term forecasting of hospital admissions with influenza using hierarchical, spatial, and temporal components. The model is data-driven and practical to deploy using information realistically available at time of prediction, addressing key limitations of epidemic forecasting approaches. This model was used across the winter for healthcare operational planning by the UK Health Security Agency and the National Health Service in England.

Published
2023

16. [18F]Difluorocarbene for positron emission tomography

Author

Sap, Jeroen B. I., Meyer, Claudio F., Ford, Joseph, Straathof, Natan J. W., Dürr, Alexander B., Lelos, Mariah J., Paisey, Stephen J., Mollner, Tim A., Hell, Sandrine M., Trabanco, Andrés A., Genicot, Christophe, am Ende, Christopher W., Paton, Robert S., Tredwell, Matthew, and Gouverneur, Véronique

Published
2022
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17. Fungal indole alkaloid biogenesis through evolution of a bifunctional reductase/Diels–Alderase

Author

Dan, Qingyun, Newmister, Sean A, Klas, Kimberly R, Fraley, Amy E, McAfoos, Timothy J, Somoza, Amber D, Sunderhaus, James D, Ye, Ying, Shende, Vikram V, Yu, Fengan, Sanders, Jacob N, Brown, W Clay, Zhao, Le, Paton, Robert S, Houk, KN, Smith, Janet L, Sherman, David H, and Williams, Robert M

Subjects
Biotechnology, Emerging Infectious Diseases, Vaccine Related, Ascomycota, Biocatalysis, Cycloaddition Reaction, Indole Alkaloids, Models, Molecular, Molecular Structure, Oxidoreductases, Chemical Sciences, Organic Chemistry
Abstract

Prenylated indole alkaloids such as the calmodulin-inhibitory malbrancheamides and anthelmintic paraherquamides possess great structural diversity and pharmaceutical utility. Here, we report complete elucidation of the malbrancheamide biosynthetic pathway accomplished through complementary approaches. These include a biomimetic total synthesis to access the natural alkaloid and biosynthetic intermediates in racemic form and in vitro enzymatic reconstitution to provide access to the natural antipode (+)-malbrancheamide. Reductive cleavage of an L-Pro-L-Trp dipeptide from the MalG non-ribosomal peptide synthetase (NRPS) followed by reverse prenylation and a cascade of post-NRPS reactions culminates in an intramolecular [4+2] hetero-Diels-Alder (IMDA) cyclization to furnish the bicyclo[2.2.2]diazaoctane scaffold. Enzymatic assembly of optically pure (+)-premalbrancheamide involves an unexpected zwitterionic intermediate where MalC catalyses enantioselective cycloaddition as a bifunctional NADPH-dependent reductase/Diels-Alderase. The crystal structures of substrate and product complexes together with site-directed mutagenesis and molecular dynamics simulations demonstrate how MalC and PhqE (its homologue from the paraherquamide pathway) catalyse diastereo- and enantioselective cyclization in the construction of this important class of secondary metabolites.

Published
2019

19. Malaria hospitalisation in East Africa: age, phenotype and transmission intensity

Author

Kamau, Alice, Paton, Robert S., Akech, Samuel, Mpimbaza, Arthur, Khazenzi, Cynthia, Ogero, Morris, Mumo, Eda, Alegana, Victor A., Agweyu, Ambrose, Mturi, Neema, Mohammed, Shebe, Bigogo, Godfrey, Audi, Allan, Kapisi, James, Sserwanga, Asadu, Namuganga, Jane F., Kariuki, Simon, Otieno, Nancy A., Nyawanda, Bryan O., Olotu, Ally, Salim, Nahya, Athuman, Thabit, Abdulla, Salim, Mohamed, Amina F., Mtove, George, Reyburn, Hugh, Gupta, Sunetra, Lourenço, José, Bejon, Philip, and Snow, Robert W.

Published
2022
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22. Site-selective photocatalytic functionalization of peptides and proteins at selenocysteine

Author

Dowman, Luke J., Kulkarni, Sameer S., Alegre-Requena, Juan V., Giltrap, Andrew M., Norman, Alexander R., Sharma, Ashish, Gallegos, Liliana C., Mackay, Angus S., Welegedara, Adarshi P., Watson, Emma E., van Raad, Damian, Niederacher, Gerhard, Huhmann, Susanne, Proschogo, Nicholas, Patel, Karishma, Larance, Mark, Becker, Christian F. W., Mackay, Joel P., Lakhwani, Girish, Huber, Thomas, Paton, Robert S., and Payne, Richard J.

Published
2022
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26. Ligand Design for Asymmetric Catalysis: Combining Mechanistic and Chemoinformatics Approaches

Author

Ardkhean, Ruchuta, Fletcher, Stephen P., Paton, Robert S., Beller, Matthias, Series Editor, Dixneuf, Pierre H., Series Editor, Dupont, Jairton, Series Editor, Fürstner, Alois, Series Editor, Glorius, Frank, Series Editor, Gooßen, Lukas J., Series Editor, Nolan, Steven P., Series Editor, Okuda, Jun, Series Editor, Oro, Luis A., Series Editor, Willis, Michael, Series Editor, Zhou, Qi-Lin, Series Editor, Lledós, Agustí, editor, and Ujaque, Gregori, editor

Published
2020
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27. Phosphorus-mediated sp.sup.2-sp.sup.3 couplings for C-H fluoroalkylation of azines

Author

Zhang, Xuan, Nottingham, Kyle G., Patel, Chirag, Alegre-Requena, Juan V., Levy, Jeffrey N., Paton, Robert S., and McNally, Andrew

Subjects
Fluorine compounds -- Physiological aspects, Cyclic compounds -- Physiological aspects, Phosphorus in the body -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence almost all metrics associated with their pharmacokinetic and pharmacodynamic profile.sup.1-4. Drug candidates increasingly contain trifluoromethyl (CF.sub.3) and difluoromethyl (CF.sub.2H) groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect and plant life.sup.5,6. New fluoroalkylation reactions have undoubtedly stimulated this shift; however, methods that directly convert C-H bonds into C-CF.sub.2X groups (where X is F or H) in complex drug-like molecules are rare.sup.7-13. Pyridines are the most common aromatic heterocycles in pharmaceuticals.sup.14, but only one approach--via fluoroalkyl radicals--is viable for achieving pyridyl C-H fluoroalkylation in the elaborate structures encountered during drug development.sup.15-17. Here we develop a set of bench-stable fluoroalkylphosphines that directly convert the C-H bonds in pyridine building blocks, drug-like fragments and pharmaceuticals into fluoroalkyl derivatives. No preinstalled functional groups or directing groups are required. The reaction tolerates a variety of sterically and electronically distinct pyridines, and is exclusively selective for the 4-position in most cases. The reaction proceeds through initial formation of phosphonium salts followed by sp.sup.2-sp.sup.3 coupling of phosphorus ligands--an underdeveloped manifold for forming C-C bonds. Bench-stable fluoroalkylphosphine reagents are used to form C-CF.sub.2X bonds in a one-pot process, reliably fluoroalkylating pyridine building blocks and drug and agrochemical intermediates., Author(s): Xuan Zhang [sup.1] , Kyle G. Nottingham [sup.1] , Chirag Patel [sup.1] , Juan V. Alegre-Requena [sup.1] , Jeffrey N. Levy [sup.1] , Robert S. Paton [sup.1] , Andrew [...]

Published
2021
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36. Fungal-derived brevianamide assembly by a stereoselective semipinacolase

Author

Ye, Ying, Du, Lei, Zhang, Xingwang, Newmister, Sean A., McCauley, Morgan, Alegre-Requena, Juan V., Zhang, Wei, Mu, Shuai, Minami, Atsushi, Fraley, Amy E., Adrover-Castellano, Maria L., Carney, Nolan A., Shende, Vikram V., Qi, Feifei, Oikawa, Hideaki, Kato, Hikaru, Tsukamoto, Sachiko, Paton, Robert S., Williams, Robert M., Sherman, David H., and Li, Shengying

Published
2020
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37. Intramolecular Diels–Alder Reactions of Cycloalkenones: Stereoselectivity, Lewis Acid Acceleration, and Halogen Substituent Effects

Author

Pham, Hung V, Paton, Robert S, Ross, Audrey G, Danishefsky, Samuel J, and Houk, KN

Subjects
Catalysis, Cycloparaffins, Halogens, Ketones, Lewis Acids, Models, Molecular, Thermodynamics, Chemical Sciences, General Chemistry
Abstract

The intramolecular Diels-Alder reactions of cycloalkenones and terminal dienes occur with high endo stereoselectivity, both thermally and under Lewis-acidic conditions. Through computations, we show that steric repulsion and tether conformation govern the selectivity of the reaction, and incorporation of either BF3 or α-halogenation increases the rate of cycloaddition. With a longer tether, isomerization from a terminal diene to the more stable internal diene results in a more facile cycloaddition.

Published
2014

39. Electrochemical Modification of Polypeptides at Selenocysteine

Author

Mackay, Angus S, primary, Maxwell, Joshua W. C., additional, Bedding, Max J., additional, Kulkarni, Sameer S., additional, Byrne, Stephen A., additional, Kambanis, Lucas, additional, Popescu, Mihai V., additional, Paton, Robert S., additional, Malins, Lara R., additional, Ashhurst, Anneliese S., additional, Corcilius, Leo, additional, and Payne, Richard J, additional

Published
2023
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48. Exploring Cuneanes as Potential Benzene Isosteres and Energetic Materials: Scope and Mechanistic Investigations into Regioselective Rearrangements from Cubanes

Author

Son, Jeong-Yu, primary, Aikonen, Santeri, additional, Morgan, Nathan, additional, Harmata, Alexander S., additional, Sabatini, Jesse J., additional, Sausa, Rosario C., additional, Byrd, Edward F. C., additional, Ess, Daniel H., additional, Paton, Robert S., additional, and Stephenson, Corey R. J., additional

Published
2023
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