Matt Keeling, Mike Tildesley, Louise Dyson publications
Modelling SARS-CoV-2 transmission in a UK university setting
Bringing together student communities during the COVID-19 pandemic may require strong interventions to control transmission. We constructed a network-based model to capture the interactions of a student population in different settings (housing, social and study). For a single academic term of a representative campus-based university, we ran a susceptible–latent–infectious–recovered type epidemic process, parameterised according to available estimates for SARS-CoV-2. We investigated the impact of: adherence to (or effectiveness of) isolation and test and trace . Our findings suggest SARS-CoV-2 may readily transmit in a university setting if there is limited adherence to nonpharmaceutical interventions and/or there are delays in receiving test results. Following isolation guidance and effective contact tracing curbed transmission and reduced the expected time an adhering student would spend in isolation
By mid-May 2020, cases of COVID-19 in the UK had been declining for over a month; a multi-phase emergence from lockdown was planned, including a scheduled partial reopening of schools on 1 June 2020. Although evidence suggests that children generally display mild symptoms, the size of the school-age population means the total impact of reopening schools is unclear. Here, we present work from mid-May 2020 that focused on the imminent opening of schools and consider what these results imply for future policy. We compared eight strategies for reopening primary and secondary schools in England. Modifying a transmission model fitted to UK SARS-CoV-2 data, we assessed how reopening schools affects contact patterns, anticipated secondary infections and the relative change in the reproduction number, R. We determined the associated public health impact and its sensitivity to changes in social distancing within the wider community. We predicted that reopening schools with half-sized classes or focused on younger children was unlikely to push R above one.
Mark Wall publications
CO2-sensitive connexin hemichannels in neurons and glia: three different modes of signallling?
Connexins can assemble into either gap junctions (between two cells) or hemichannels (from one cell to the extracellular space) and mediate cell-to-cell signalling. A subset of connexins (Cx26, Cx30, Cx32) are directly sensitive to CO2 and fluctuations in the level within a physiological range affect their open probability, and thus, change cell conductance. Recently, we have shown that dopaminergic neurons in the substantia nigra and GABAergic neurons in the VTA also express Cx26 hemichannels. An increase in the level of CO2 results in hemichannel opening, increasing whole-cell conductance, and decreasing neuronal excitability. We found that the expression of Cx26 in the dopaminergic neurons in the substantia nigra at P7-10 is transferred to glial cells by P17-21, displaying a shift from being inhibitory (to neuronal activity) in young mice, to potentially excitatory (via ATP release). Thus, Cx26 hemichannels could have three modes of signalling (release of ATP, excitatory flickering open and shut and inhibitory shunting) depending on where they are expressed (neurons or glia) and the stage of development.International Journal of Molecular Science July 21.
Group I metabotropic glutamate receptor-mediated long term depression is disrupted in the hippocampus of WAG/Rij rats modelling absence epilepsy
Gabriele di Cicco, Emmanuel Marzano, Luisa Lacovelli, Roberto Celli, Gillesvan Luijtelaar, Ferdinando Nicolette, Richard T Ngomba, Mark J Wall
Absence epilepsy is frequently associated with cognitive dysfunction, although the underlying mechanisms are not well understood. Here we report that some forms of hippocampal synaptic plasticity are abnormal in symptomatic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Our findings suggest that abnormalities in hippocampal mGlu5 receptor-dependent synaptic plasticity are associated with the pathological phenotype of WAG/Rij rats. This lays the groundwork for the study of mGlu5 receptors as a candidate drug target for the treatment of cognitive dysfunction linked to absence epilepsy. Neuropharmacology. June 2021
Matt Keeling publications
The population attributable fraction of cases due to gatherings and with relevance to COVID-19 mitigation strategies
Ellen Brooks-Pollock, Jonathan M Read, Thomas House, Graham F Medley, Matt J Keeling and Leon Danon
Many countries have banned groups and gatherings as part of their response to the pandemic caused by the coronavirus, SARS-CoV-2. Although there are outbreak reports involving mass gatherings, the contribution to overall transmission is unknown. We used data from a survey of social contact behaviour that specifically asked about contact with groups to estimate the population attributable fraction (PAF) due to groups as the relative change in the basic reproduction number when groups are prevented. Groups of 50+ individuals accounted for 0.5% of reported contact events, and we estimate that the PAF due to groups of 50+ people is 5.4% (95% confidence interval 1.4%, 11.5%). The PAF due to groups of 20+ people is 18.9% (12.7%, 25.7%) and the PAF due to groups of 10+ is 25.2% (19.4%, 31.4%). Under normal circumstances with pre-COVID-19 contact patterns, large groups of individuals have a relatively small epidemiological impact; small- and medium-sized groups between 10 and 50 people have a larger impact on an epidemic. Philosophical Transactions of the Royal Society B July 21.
Contrasting factors associated with COVID-19-related ICU admission and death outcomes in hospitalised patients by means of Shapley values
Cavallaro, Massimo, Moiz, Haseeb, Keeling, Matt J. and McCarthy, Noel D
Identification of those at greatest risk of death due to the substantial threat of COVID-19 can benefit from novel approaches to epidemiology that leverage large datasets and complex machine-learning models, provide data-driven intelligence, and guide decisions such as intensive-care unit admission (ICUA). The objective of this study is two-fold: substantively to evaluate the association of demographic and health records with two related, yet different, outcomes of severe COVID-19 ; and methodologically to compare interpretations based on logistic regression and on gradient-boosted decision tree (GBDT) predictions interpreted by means of the Shapley impacts of covariates.. The results of this study are also relevant for the evaluation of complex automated clinical decision systems, which should optimise prediction scores whilst remaining interpretable to clinicians and mitigating potential biases.
Selective intra-carotid blood cooling in acute ischemic stroke: a safety and feasibility study in an ovine stroke model
Cattaneo G.F.M., Herrmann A.M., Eiden S.A., Wieser M., Kellner E., Doostkam S., Süß P., Kiefer S., Lutz L., Maurer C.J., Wolferz J., Nitzsche B., Büchert M., Jost T., Ihorst G., Haberstroh J., Mülling C., Strecker C., Niesen W.D., Shah M.J., Urbach H., Boltze J., Meckel
Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model.Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups.Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.
Switching Cytolytic Nanopores into Antimicrobial Fractal Ruptures by a Single Side Chain Mutation
Katharine Hammond, Flaviiu Cipcigan, Kareem Al Nahas, Valeria Losasso, Helen Lewis, Jehangir Cama, Fausto Martelli, Patrick Simcock, Marcus Fletcher, Jascindra Ravi, Phillip J Stansfeld, Stefano Pagliara, Bart W Hoogenboom, Ulrich F Keyser, Mark S P Sansom, Jason Crain, and Maxim G Ryadnov
Disruption of cell membranes is a fundamental host defense response found in virtually all forms of life. The molecular mechanisms vary but generally lead to energetically favored circular nanopores. Here, we report an elaborate fractal rupture pattern induced by a single side-chain mutation in ultrashort (8-11-mers) helical peptides, which otherwise form transmembrane pores. In contrast to known mechanisms, this mode of membrane disruption is restricted to the upper leaflet of the bilayer where it exhibits propagating fronts of peptide-lipid interfaces that are strikingly similar to viscous instabilities in fluid flow. The two distinct disruption modes, pores and fractal patterns, are both strongly antimicrobial, but only the fractal rupture is nonhemolytic. The results offer wide implications for elucidating differential membrane targeting phenomena defined at the nanoscale
Human immune response against salivary antigens of Simulium damnosum s.l.: a new epidemiological marker for exposure to blackfly bites in onchocerciasis endemic areas
Laura Willen, Maria-Gloria Basáñez, Vit Dvorak, Francis BD Veriegh, Frank T Aboagye , Bright Idun, Maha Elhadi Osman, Mike Y Osei-Atweneboana, Orin Courtenay, Petr Volf
Simulium damnosum sensu lato (s.l.) blackflies transmit Onchocerca volvulus, a filarial nematode that causes human onchocerciasis. Human landing catches (HLCs) is currently the sole method used to estimate blackfly biting rates but is labour-intensive and questionable on ethical grounds. A potential alternative is to measure host antibodies to vector saliva deposited during bloodfeeding. Here, immunoassays to quantify human antibody responses to S. damnosum s.l. saliva were developed, and the salivary proteome of S. damnosum s.l. was investigated. This study validated for the first time human immunoassays that quantify humoral immune responses as potential markers of exposure to blackfly bites. These assays have the potential to facilitate understanding patterns of exposure as well as evaluating the impact of vector control on biting rates. Future studies need to investigate seasonal fluctuations of these antibody responses, potential cross-reactions with other bloodsucking arthropods, and thoroughly identify the most immunogenic proteins.