133 results on '"Knight, GM"'
Search Results
2. Growth-Dependent Predation and Generalized Transduction of Antimicrobial Resistance by Bacteriophage
- Author
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Leclerc, QJ, Wildfire, J, Gupta, A, Lindsay, JA, and Knight, GM
- Abstract
Bacteriophage (phage) are both predators and evolutionary drivers for bacteria, notably contributing to the spread of antimicrobial resistance (AMR) genes by generalized transduction. Our current understanding of this complex relationship is limited. We used an interdisciplinary approach to quantify how these interacting dynamics can lead to the evolution of multidrug-resistant bacteria. We cocultured two strains of methicillin-resistant Staphylococcus aureus, each harboring a different antibiotic resistance gene, with generalized transducing phage. After a growth phase of 8 h, bacteria and phage surprisingly coexisted at a stable equilibrium in our culture, the level of which was dependent on the starting concentration of phage. We detected double-resistant bacteria as early as 7 h, indicating that transduction of AMR genes had occurred. We developed multiple mathematical models of the bacteria and phage relationship and found that phage-bacteria dynamics were best captured by a model in which phage burst size decreases as the bacteria population reaches stationary phase and where phage predation is frequency-dependent. We estimated that one in every 108 new phage generated was a transducing phage carrying an AMR gene and that double-resistant bacteria were always predominantly generated by transduction rather than by growth. Our results suggest a shift in how we understand and model phage-bacteria dynamics. Although rates of generalized transduction could be interpreted as too rare to be significant, they are sufficient in our system to consistently lead to the evolution of multidrug-resistant bacteria. Currently, the potential of phage to contribute to the growing burden of AMR is likely underestimated. IMPORTANCE Bacteriophage (phage), viruses that can infect and kill bacteria, are being investigated through phage therapy as a potential solution to the threat of antimicrobial resistance (AMR). In reality, however, phage are also natural drivers of bacterial evolution by transduction when they accidentally carry nonphage DNA between bacteria. Using laboratory work and mathematical models, we show that transduction leads to evolution of multidrug-resistant bacteria in less than 8 h and that phage production decreases when bacterial growth decreases, allowing bacteria and phage to coexist at stable equilibria. The joint dynamics of phage predation and transduction lead to complex interactions with bacteria, which must be clarified to prevent phage from contributing to the spread of AMR.
- Published
- 2022
3. Importance of patient bed pathways and length of stay differences in predicting COVID-19 hospital bed occupancy in England
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Leclerc, QJ, Fuller, NM, Keogh, RH, Diaz-Ordaz, K, Sekula, R, Semple, MG, Baillie, JK, Openshaw, PJM, Carson, G, Alex, B, Bach, B, Barclay, WS, Bogaert, D, Chand, M, Cooke, GS, Docherty, AB, Dunning, J, da Silva Filipe, A, Fletcher, T, Green, CA, Harrison, EM, Hiscox, JA, Ho, AYW, Horby, PW, Ijaz, S, Khoo, S, Klenerman, P, Law, A, Lim, WS, Mentzer, AJ, Merson, L, Meynert, AM, Noursadeghi, M, Moore, SC, Palmarini, M, Paxton, WA, Pollakis, G, Price, N, Rambaut, A, Robertson, DL, Russell, CD, Sancho-Shimizu, V, Scott, JT, de Silva, T, Sigfrid, L, Solomon, T, Sriskandan, S, Stuart, D, Summers, C, Tedder, RS, Thomson, EC, Thompson, AAR, Thwaites, RS, Turtle, LCW, Zambon, M, Hardwick, H, Donohue, C, Lyons, R, Griffiths, F, Oosthuyzen, W, Norman, L, Pius, R, Drake, TM, Fairfield, CJ, Knight, S, Mclean, KA, Murphy, D, Shaw, CA, Dalton, J, Lee, J, Plotkin, D, Girvan, M, Saviciute, E, Roberts, S, Harrison, J, Marsh, L, Connor, M, Halpin, S, Jackson, C, Gamble, C, Petersen, C, Mullaney, S, Leeming, G, Wham, M, Clohisey, S, Hendry, R, Scott-Brown, J, Greenhalf, W, Shaw, V, McDonald, S, Keating, S, Ahmed, KA, Armstrong, JA, Ashworth, M, Asiimwe, IG, Bakshi, S, Barlow, SL, Booth, L, Brennan, B, Bullock, K, Catterall, BWA, Clark, JJ, Clarke, EA, Cole, S, Cooper, L, Cox, H, Davis, C, Dincarslan, O, Dunn, C, Dyer, P, Elliott, A, Evans, A, Finch, L, Fisher, LWS, Foster, T, Garcia-Dorival, I, Gunning, P, Hartley, C, Ho, A, Jensen, RL, Jones, CB, Jones, TR, Khandaker, S, King, K, Kiy, RT, Koukorava, C, Lake, A, Lant, S, Latawiec, D, Lavelle-Langham, L, Lefteri, D, Lett, L, Livoti, LA, Mancini, M, McEvoy, L, McLauchlan, J, Metelmann, S, Miah, NS, Middleton, J, Mitchell, J, Murphy, EG, Penrice-Randal, R, Pilgrim, J, Prince, T, Reynolds, W, Ridley, PM, Sales, D, Shaw, VE, Shears, RK, Small, B, Subramaniam, KS, Szemiel, A, Taggart, A, Tanianis-Hughes, J, Thomas, J, Trochu, E, van Tonder, L, Wilcock, E, Zhang, JE, Adeniji, K, Agranoff, D, Agwuh, K, Ail, D, Alegria, A, Angus, B, Ashish, A, Atkinson, D, Bari, S, Barlow, G, Barnass, S, Barrett, N, Bassford, C, Baxter, D, Beadsworth, M, Bernatoniene, J, Berridge, J, Best, N, Bothma, P, Brealey, D, Brittain-Long, R, Bulteel, N, Burden, T, Burtenshaw, A, Caruth, V, Chadwick, D, Chambler, D, Chee, N, Child, J, Chukkambotla, S, Clark, T, Collini, P, Cosgrove, C, Cupitt, J, Cutino-Moguel, M-T, Dark, P, Dawson, C, Dervisevic, S, Donnison, P, Douthwaite, S, DuRand, I, Dushianthan, A, Dyer, T, Evans, C, Eziefula, C, Fegan, C, Finn, A, Fullerton, D, Garg, S, Garg, A, Gkrania-Klotsas, E, Godden, J, Goldsmith, A, Graham, C, Hardy, E, Hartshorn, S, Harvey, D, Havalda, P, Hawcutt, DB, Hobrok, M, Hodgson, L, Hormis, A, Jacobs, M, Jain, S, Jennings, P, Kaliappan, A, Kasipandian, V, Kegg, S, Kelsey, M, Kendall, J, Kerrison, C, Kerslake, I, Koch, O, Koduri, G, Koshy, G, Laha, S, Laird, S, Larkin, S, Leiner, T, Lillie, P, Limb, J, Linnett, V, Little, J, MacMahon, M, MacNaughton, E, Mankregod, R, Masson, H, Matovu, E, McCullough, K, McEwen, R, Meda, M, Mills, G, Minton, J, Mirfenderesky, M, Mohandas, K, Mok, Q, Moon, J, Moore, E, Morgan, P, Morris, C, Mortimore, K, Moses, S, Mpenge, M, Mulla, R, Murphy, M, Nagel, M, Nagarajan, T, Nelson, M, Otahal, I, Pais, M, Panchatsharam, S, Paraiso, H, Patel, B, Pattison, N, Pepperell, J, Peters, M, Phull, M, Pintus, S, Pooni, JS, Post, F, Price, D, Prout, R, Rae, N, Reschreiter, H, Reynolds, T, Richardson, N, Roberts, M, Roberts, D, Rose, A, Rousseau, G, Ryan, B, Saluja, T, Shah, A, Shanmuga, P, Sharma, A, Shawcross, A, Sizer, J, Shankar-Hari, M, Smith, R, Snelson, C, Spittle, N, Staines, N, Stambach, T, Stewart, R, Subudhi, P, Szakmany, T, Tatham, K, Thompson, C, Thompson, R, Tridente, A, Tupper-Carey, D, Twagira, M, Ustianowski, A, Vallotton, N, Vincent-Smith, L, Visuvanathan, S, Vuylsteke, A, Waddy, S, Wake, R, Walden, A, Welters, I, Whitehouse, T, Whittaker, P, Whittington, A, Wijesinghe, M, Williams, M, Wilson, L, Wilson, S, Winchester, S, Wiselka, M, Wolverson, A, Wooton, DG, Workman, A, Yates, B, Young, P, Quaife, M, Jarvis, CI, Meakin, SR, Quilty, BJ, Prem, K, Villabona-Arenas, CJ, Sun, FY, Abbas, K, Auzenbergs, M, Gimma, A, Tully, DC, Sherratt, K, Rosello, A, Davies, NG, Liu, Y, Lowe, R, Gibbs, HP, Waterlow, NR, Edmunds, WJ, Simons, D, Medley, G, Munday, JD, Flasche, S, Sandmann, FG, Showering, A, Eggo, RM, Chan, Y-WD, Pearson, CAB, Kucharski, AJ, Foss, AM, Russell, TW, Bosse, NI, Jit, M, Abbott, S, Williams, J, Endo, A, Clifford, S, Gore-Langton, GR, Klepac, P, Brady, O, Hellewell, J, Funk, S, van Zandvoort, K, Barnard, RC, Nightingale, ES, Jombart, T, Atkins, KE, Procter, SR, and Knight, GM
- Abstract
Background\ud \ud Predicting bed occupancy for hospitalised patients with COVID-19 requires understanding of length of stay (LoS) in particular bed types. LoS can vary depending on the patient’s “bed pathway” - the sequence of transfers of individual patients between bed types during a hospital stay. In this study, we characterise these pathways, and their impact on predicted hospital bed occupancy.\ud \ud \ud \ud Methods\ud \ud We obtained data from University College Hospital (UCH) and the ISARIC4C COVID-19 Clinical Information Network (CO-CIN) on hospitalised patients with COVID-19 who required care in general ward or critical care (CC) beds to determine possible bed pathways and LoS. We developed a discrete-time model to examine the implications of using either bed pathways or only average LoS by bed type to forecast bed occupancy. We compared model-predicted bed occupancy to publicly available bed occupancy data on COVID-19 in England between March and August 2020.\ud \ud \ud \ud Results\ud \ud In both the UCH and CO-CIN datasets, 82% of hospitalised patients with COVID-19 only received care in general ward beds. We identified four other bed pathways, present in both datasets: “Ward, CC, Ward”, “Ward, CC”, “CC” and “CC, Ward”. Mean LoS varied by bed type, pathway, and dataset, between 1.78 and 13.53 days.\ud \ud \ud \ud For UCH, we found that using bed pathways improved the accuracy of bed occupancy predictions, while only using an average LoS for each bed type underestimated true bed occupancy. However, using the CO-CIN LoS dataset we were not able to replicate past data on bed occupancy in England, suggesting regional LoS heterogeneities.\ud \ud \ud \ud Conclusions\ud \ud We identified five bed pathways, with substantial variation in LoS by bed type, pathway, and geography. This might be caused by local differences in patient characteristics, clinical care strategies, or resource availability, and suggests that national LoS averages may not be appropriate for local forecasts of bed occupancy for COVID-19.\ud \ud \ud \ud Trial registration\ud \ud The ISARIC WHO CCP-UK study ISRCTN66726260 was retrospectively registered on 21/04/2020 and designated an Urgent Public Health Research Study by NIHR.
- Published
- 2021
4. Clinical evaluation of diamine silver fluoride/potassium iodide as a dentine desensitizing agent. A pilot study
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Craig, GG, Knight, GM, and McIntyre, JM
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- 2012
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5. Differences between normal and demineralized dentine pretreated with silver fluoride and potassium iodide after an in vitro challenge by Streptococcus mutans
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Knight, GM, McIntyre, JM, Craig, GG, Mulyani, Zilm, PS, and Gully, NJ
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- 2007
6. An in vitro model to measure the effect of a silver fluoride and potassium iodide treatment on the permeability of demineralized dentine to Streptococcus mutans
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Knight, GM, McIntyre, JM, Craig, GG, Mulyani, Zilm, PS, and Gully, NJ
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- 2005
7. Predicting IFN-γ responses after BCG vaccination in humans from macaques: A proof-of-concept study of Immunostimulation/Immunodynamic modelling methods
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Rhodes, SJ, Sarfas, C, Knight, GM, White, A, Pathan, AA, McShane, H, Evans, TG, Fletcher, H, Sharpe, S, and White, RG
- Abstract
Introduction Macaques play a central role in human tuberculosis(TB) vaccine development. Immune and challenge responses differ across macaque and human subpopulations. We determined which macaque subpopulations best predicted immune responses in different human subpopulations, using novel immunostimulation/immunodynamic modelling methods in a proof of concept study. Methods Data on IFN-γ secreting CD4+ T cells over time after recent BCG vaccination were available for 55 humans and 81 macaques. Human population covariates were: baseline BCG vaccination status, time since BCG vaccination, gender and monocyte/lymphocyte cell count ratio. The macaque population covariate was colony of origin. A two-compartment mathematical model describing the dynamics of the post-BCG IFN-γ T cell response was calibrated to these data using nonlinear mixed effects methods. The model was calibrated to macaque and human data separately. The association between subpopulations and BCG immune response in each species was assessed. Which macaque subpopulations best predicted immune responses in different human subpopulations was identified using Bayesian Information Criteria. Results Macaque colony and human baseline-BCG status were significantly (p Conclusion The work suggests that the immune responses of different human populations may be best modelled by different macaque colonies, and demonstrates the potential utility of immunostimulation/immunodynamic modelling to accelerate TB vaccine development.
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- 2017
8. Role of pyrazinamide in the emergence of extensively drug-resistant tuberculosis: a multi-strain mathematical model
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Fofana, MO, Shrestha, S, Knight, GM, Cohen, T, White, RG, Cobelens, F, and Dowdy, DW
- Abstract
Several infectious diseases of global importance-e.g., HIV infection and tuberculosis (TB)-require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model of Mycobacterium tuberculosis transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB-defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)-exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.
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- 2016
9. Inability to form a biofilm of Streptococcus mutans on silver fluoride -- and potassium iodide -- treated demineralized dentin.
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Knight GM, McIntyre JM, Craig GG, Zilm PS, and Gully NJ
- Abstract
Objective: The presence of a biofilm is necessary for both initiation and progression of dental caries. Silver-based preparations incorporated into, or applied onto, various materials designed for medical use have been shown to be effective in inhibiting biofilm formation. The purpose of this in vitro study was to measure whether a topical application of diamine silver fluoride (AgF) followed by potassium iodide (KI) on partially demineralized dentin affected the formation of a Streptococcus mutans biofilm. Method and Materials: Forty partially demineralized dentin disks were divided into 4 groups as follows: 10 disks as a control, 10 disks treated with AgF followed by KI, 10 disks treated with KI, and 10 disks treated with AgF. The outer surfaces of the disks were examined with a scanning electron microscope. Cross sections of the disks were subjected to electron probe microanalysis (EPMA) to determine the levels of calcium, phosphorous, silver, and fluoride in the dentin. Results: An S mutans biofilm covered the entire exposed surfaces of all control and KI-treated disks. No discernible bacterial biofilm was detected on disks treated with AgF or AgF/KI. Detectable amounts of silver and fluoride were found up to 450 µm in the AgF and AgF/KI sections. Conclusions: Demineralized dentin disks treated with AgF and AgF/KI prevented the formation of an S mutans biofilm and were significantly more resistant to further demineralization than the control and KI-treated disks over the experimental period. The presence of silver and fluoride in the outer layers of the disks treated with AgF and AgF/KI was the likely cause of the prevention of biofilm formation. Additional studies are required before any clinical recommendations can be made. (Quintessence Int 2009;40:155DS161) [ABSTRACT FROM AUTHOR]
- Published
- 2009
10. Behaviour of steel–concrete–steel sandwich composite beams with lacing subjected to reversed cyclic loads
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Anandavalli, N, primary, Lakshmanan, N, additional, Rajasankar, J, additional, and Knight, GM Samuel, additional
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- 2017
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11. A National Estimate of the Health and Cost Burden of Escherichia coli Bacteraemia in the Hospital Setting: The Importance of Antibiotic Resistance
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Naylor, NR, primary, Pouwels, KB, additional, Hope, R, additional, Green, N, additional, Henderson, KL, additional, Knight, GM, additional, Atun, R, additional, Robotham, JV, additional, and Deeny, SR, additional
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- 2017
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12. Behaviour of steel–concrete–steel sandwich composite beams with lacing subjected to reversed cyclic loads.
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Anandavalli, N, Lakshmanan, N, Rajasankar, J, and Knight, GM Samuel
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IRON & steel plates ,BLAST effect ,CYCLIC loads ,COMPOSITE construction ,STEEL-concrete composites - Abstract
Steel–concrete–steel (SCS) sandwich composite system consists of steel plates covering both sides of the concrete core and connected by mechanical means such as shear connectors. In conventional steel–concrete–steel system, shear connectors are welded to the steel cover plates. Laced steel–concrete composite (LSCC) system is a new form of steel–concrete–steel, proposed earlier by the authors. In LSCC system, steel cover plates are connected in a novel way using lacings and cross rods and hence is devoid of welding. Proposed sandwich composite system is being evaluated systematically for its structural behaviour under various modes of loading for use in special structures under severe loading such as blast loading. Damage under cyclic loading and energy absorption are extremely important, which are highlighted in this paper. An experimental investigation on the cyclic response behaviour of two LSCC beams is carried out. Angle of lacing is the parameter that is varied between the two beams. Both the beams are found to exhibit similar behaviour on most of the aspects. The envelope of hysteretic response indicates mild softening behaviour after reaching peak value. Maximum load resisted under both sagging and hogging moment conditions is found to be nearly equal, thus making the LSCC system suitable for situations where reversal of loads are encountered. Dissipated energy is observed to be nearly the same for the load applied in the upward as well as in the downward direction. Analytical prediction on energy absorption capacity is carried out by adopting a hysteretic model with strength deterioration. Cyclic ductility factor is evaluated to be about 20 for LSCC beams, while support rotation is calculated to be about 8° and 10° for beams with 45° and 60° angles of lacing, respectively. Spalling of concrete is prevented in LSCC beams by the steel cover plates. [ABSTRACT FROM AUTHOR]
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- 2019
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13. Behavior of Steel Fibre Reinforced Concrete Beams and Plates Under Static Load
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Elavenil, S, primary and Knight, GM Samuel, additional
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- 2008
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14. An in vitro investigation of marginal dentine caries abutting composite resin and glass ionomer cement restorations
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Knight, GM, primary, McIntyre, JM, additional, Craig, GG, additional, Zilm, PS, additional, and Gully, NJ, additional
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- 2007
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15. Electron probe microanalysis of ion exchange of selected elements between dentine and adhesive restorative materials
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Knight, GM, primary, McIntyre, JM, additional, and Craig, GG, additional
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- 2007
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16. Impact Response of Plates Under Drop Weight Impact Testing
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Elavenil, S, primary and Knight, GM Samuel, primary
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- 1970
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17. The development of a mathematical modelling framework to translate TB vaccine responses between species and predict the most immunogenic dose in humans using animal data
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Rhodes, SJ, White, RG, Fletcher, HA, and Knight, GM
- Abstract
Background: Preclinical animal experiments measuring vaccine immunogenicity and safety are essential, not only to establish if the vaccine should progress further, but to generate information on how the vaccine should be administered in humans. Animal models that represent human vaccine responses well are vital to translate information about vaccine dose to clinical phases. Vaccine dose is a key aspect in creating an effective vaccine. However, if the wrong dose is chosen, vaccine candidates may be mistakenly discarded and considerable resources wasted. Current methods of finding optimal vaccine dose are mostly empirically based, which may be leading to sub-optimal doses progressing into later clinical trials. A current example of this is in the tuberculosis (TB) vaccine developmental pipeline, where a series of adjuvanted subunit vaccines, the H-series, have progressed through to later stages of clinical development with a high dose that has been shown to less immunogenic than lower doses. In drug development, mathematical model-based methods are routinely used alongside empirical evaluations, to inform dose-finding. I hypothesised that vaccine development may benefit from the application of similar quantitative methods. As such, I launched the new field of vaccine immunostimulation/immunodynamic (IS/ID) mathematical modelling. My aims for this thesis were 1) to establish differences in Bacillus Calmette–Guérin (BCG) Interferon-Gamma (IFN-γ) response by human subpopulation, then develop a IS/ID model to represent these response dynamics and identify the most representative macaque subpopulation for human BCG responses. Aim 2) was to predict human H-series vaccine IFN-γ response using IS/ID model calibrated to mouse multi-dose IFN-γ data and allometric scaling. Methods: For aim 1, longitudinal data on IFN-γ emitting CD4+ T cells following vaccination BCG were available in humans and macaques. Human (sub)population covariates were: baseline BCG vaccination status, time since BCG vaccination, gender and monocyte/lymphocyte cell count ratio. The macaque (sub)population covariate was colony of origin. I developed a two-compartmental mathematical model describing the post-BCG IFN-γ immune response dynamics. The model was calibrated to the human and macaque data using 4 Nonlinear Mixed Effects Modelling (NLMEM) to establish if there were differences in IFN-γ dynamics for both species subpopulations. I then established which macaque subpopulation best described human data. For aim 2, longitudinal data on IFN-γ emitting CD4+ T cells following two vaccinations with five doses of novel TB vaccine H56+IC31 in mice were generated. I then assessed the shape of the dose response curve at early and late time points. I calibrated the T cell model to the mouse data and established the change in key model parameters across dose. Using the change in model parameters across dose found in the mice, I predicted the immune response dynamics in humans for different doses and which dose was most immunogenic. Results: In aim 1, I found that BCG status in humans (baseline BCG-naïve or baseline BCG-vaccinated) was associated with differences in the peak and end IFN-γ response after vaccination with BCG. When the mathematical model was calibrated to the BCG data for both macaques and humans, significant differences (p
18. Modelling the implementation of narrow versus broader spectrum antibiotics in the empiric treatment of E. coli bacteraemia.
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Khurana MP, Curran-Sebastian J, Bhatt S, and Knight GM
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- Humans, Antimicrobial Stewardship methods, Drug Resistance, Bacterial drug effects, Models, Theoretical, Bacteremia drug therapy, Bacteremia microbiology, Bacteremia mortality, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents pharmacology, Escherichia coli Infections drug therapy, Escherichia coli Infections microbiology, Escherichia coli drug effects
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The implementation of new antimicrobial resistance stewardship programs is crucial in optimizing antibiotic use. However, prescription choices can be difficult during empiric therapy; clinicians must balance the survival benefits of broader spectrum antibiotics with associated increases in resistance. The aim of this study was to evaluate the overall feasibility of switching to narrow spectrum antibiotics during the empiric treatment of E. coli bacteraemia by quantifying changes in resistance rates, antibiotic usage, and mortality using a deterministic state-transition model. Three unique model scenarios (A, B, and C), each representing a progressively broader spectrum empiric treatment regimen, were used to compare outcomes at 5 years. We show that the empiric use of the narrowest spectrum (first-line) antibiotics can lead to reductions in resistance to second-line antibiotics and the use of third-line antibiotics, but they also lead to increases in resistance to first-line therapy and higher mortality. Crucially, we find that shortening the duration of empiric and overall treatment, as well as reducing the baseline mortality rate, are important for increasing the feasibility of switching to narrow spectrum antibiotics in the empiric treatment of E. coli bacteraemia. We provide a flexible model design to investigate optimal treatment approaches for other bacterial infections., (© 2024. The Author(s).)
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- 2024
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19. MIC distribution analysis identifies differences in AMR between population sub-groups.
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Wildfire J, Waterlow NR, Clements A, Fuller NM, and Knight GM
- Abstract
Background: Phenotypic data, such as the minimum inhibitory concentrations (MICs) of bacterial isolates from clinical samples, are widely available through routine surveillance. MIC distributions inform antibiotic dosing in clinical care by determining cutoffs to define isolates as susceptible or resistant. However, differences in MIC distributions between patient sub-populations could indicate strain variation and hence differences in transmission, infection, or selection., Methods: The Vivli AMR register contains a wealth of MIC and metadata for a vast range of bacteria-antibiotic combinations. Using a generalisable methodology followed by multivariate regression, we explored MIC distribution variations across 4 bacteria, covering 7,135,070 samples, by key population sub-groups such as age, sex and infection type, and over time., Results: We found clear differences between MIC distributions across various patient sub-groups for a subset of bacteria-antibiotic pairings. For example, within Staphylococcus aureus , MIC distributions by age group and infection site displayed clear trends, especially for levofloxacin with higher resistance levels in older age groups (odds of 2.17 in those aged 85+ compared to 19-64), which appeared more often in men. This trend could reflect greater use of fluoroquinolones in adults than children but also reveals an increasing MIC level with age, suggesting either transmission differences or accumulation of resistance effects. We also observed high variations by WHO region, and over time, with the latter likely linked to changes in surveillance., Conclusions: We found that MIC distributions can be used to identify differences in AMR levels between population sub-groups. Our methodology could be used more widely to unveil hidden transmission sources and effects of antibiotic use in different patient sub-groups, highlighting opportunities to improve stewardship programmes and interventions, particularly at local scales., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Wildfire J et al.)
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- 2024
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20. Mathematical models of drug-resistant tuberculosis lack bacterial heterogeneity: A systematic review.
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Fuller NM, McQuaid CF, Harker MJ, Weerasuriya CK, McHugh TD, and Knight GM
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- Humans, Mycobacterium tuberculosis drug effects, Tuberculosis, Multidrug-Resistant drug therapy, Tuberculosis, Multidrug-Resistant microbiology, Models, Theoretical, Antitubercular Agents pharmacology, Antitubercular Agents therapeutic use
- Abstract
Drug-resistant tuberculosis (DR-TB) threatens progress in the control of TB. Mathematical models are increasingly being used to guide public health decisions on managing both antimicrobial resistance (AMR) and TB. It is important to consider bacterial heterogeneity in models as it can have consequences for predictions of resistance prevalence, which may affect decision-making. We conducted a systematic review of published mathematical models to determine the modelling landscape and to explore methods for including bacterial heterogeneity. Our first objective was to identify and analyse the general characteristics of mathematical models of DR-mycobacteria, including M. tuberculosis. The second objective was to analyse methods of including bacterial heterogeneity in these models. We had different definitions of heterogeneity depending on the model level. For between-host models of mycobacterium, heterogeneity was defined as any model where bacteria of the same resistance level were further differentiated. For bacterial population models, heterogeneity was defined as having multiple distinct resistant populations. The search was conducted following PRISMA guidelines in five databases, with studies included if they were mechanistic or simulation models of DR-mycobacteria. We identified 195 studies modelling DR-mycobacteria, with most being dynamic transmission models of non-treatment intervention impact in M. tuberculosis (n = 58). Studies were set in a limited number of specific countries, and 44% of models (n = 85) included only a single level of "multidrug-resistance (MDR)". Only 23 models (8 between-host) included any bacterial heterogeneity. Most of these also captured multiple antibiotic-resistant classes (n = 17), but six models included heterogeneity in bacterial populations resistant to a single antibiotic. Heterogeneity was usually represented by different fitness values for bacteria resistant to the same antibiotic (61%, n = 14). A large and growing body of mathematical models of DR-mycobacterium is being used to explore intervention impact to support policy as well as theoretical explorations of resistance dynamics. However, the majority lack bacterial heterogeneity, suggesting that important evolutionary effects may be missed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fuller et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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21. Antimicrobial resistance prevalence in bloodstream infection in 29 European countries by age and sex: An observational study.
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Waterlow NR, Cooper BS, Robotham JV, and Knight GM
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- Male, Female, Humans, Adolescent, Young Adult, Adult, Aged, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Escherichia coli, Prevalence, Bayes Theorem, Drug Resistance, Bacterial, Bacteria, Penicillins pharmacology, Microbial Sensitivity Tests, Methicillin-Resistant Staphylococcus aureus, Sepsis drug therapy
- Abstract
Background: Antibiotic usage, contact with high transmission healthcare settings as well as changes in immune system function all vary by a patient's age and sex. Yet, most analyses of antimicrobial resistance (AMR) ignore demographic indicators and provide only country-level resistance prevalence values. This study aimed to address this knowledge gap by quantifying how resistance prevalence and incidence of bloodstream infection (BSI) varied by age and sex across bacteria and antibiotics in Europe., Methods and Findings: We used patient-level data collected as part of routine surveillance between 2015 and 2019 on BSIs in 29 European countries from the European Antimicrobial Resistance Surveillance Network (EARS-Net). A total of 6,862,577 susceptibility results from isolates with age, sex, and spatial information from 944,520 individuals were used to characterise resistance prevalence patterns for 38 different bacterial species and antibiotic combinations, and 47% of these susceptibility results were from females, with a similar age distribution in both sexes (mean of 66 years old). A total of 349,448 isolates from 2019 with age and sex metadata were used to calculate incidence. We fit Bayesian multilevel regression models by country, laboratory code, sex, age, and year of sample to quantify resistant prevalence and provide estimates of country-, bacteria-, and drug-family effect variation. We explore our results in greater depths for 2 of the most clinically important bacteria-antibiotic combinations (aminopenicillin resistance in Escherichia coli and methicillin resistance in Staphylococcus aureus) and present a simplifying indicative index of the difference in predicted resistance between old (aged 100) and young (aged 1). At the European level, we find distinct patterns in resistance prevalence by age. Trends often vary more within an antibiotic family, such as fluroquinolones, than within a bacterial species, such as Pseudomonas aeruginosa. Clear resistance increases by age for methicillin-resistant Staphylococcus aureus (MRSA) contrast with a peak in resistance to several antibiotics at approximately 30 years of age for P. aeruginosa. For most bacterial species, there was a u-shaped pattern of infection incidence with age, which was higher in males. An important exception was E. coli, for which there was an elevated incidence in females between the ages of 15 and 40. At the country-level, subnational differences account for a large amount of resistance variation (approximately 38%), and there are a range of functional forms for the associations between age and resistance prevalence. For MRSA, age trends were mostly positive, with 72% (n = 21) of countries seeing an increased resistance between males aged 1 and 100 years and a greater change in resistance in males. This compares to age trends for aminopenicillin resistance in E. coli which were mostly negative (males: 93% (n = 27) of countries see decreased resistance between those aged 1 and 100 years) with a smaller change in resistance in females. A change in resistance prevalence between those aged 1 and 100 years ranged up to 0.51 (median, 95% quantile of model simulated prevalence using posterior parameter ranges 0.48, 0.55 in males) for MRSA in one country but varied between 0.16 (95% quantile 0.12, 0.21 in females) to -0.27 (95% quantile -0.4, -0.15 in males) across individual countries for aminopenicillin resistance in E. coli. Limitations include potential bias due to the nature of routine surveillance and dependency of results on model structure., Conclusions: In this study, we found that the prevalence of resistance in BSIs in Europe varies substantially by bacteria and antibiotic over the age and sex of the patient shedding new light on gaps in our understanding of AMR epidemiology. Future work is needed to determine the drivers of these associations in order to more effectively target transmission and antibiotic stewardship interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Waterlow et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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22. Why local antibiotic resistance data matters - Informing empiric prescribing through local data collation, app design and engagement in Zambia.
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Fwoloshi S, Chola U, Nakazwe R, Tatila T, Mateele T, Kabaso M, Muzyamba T, Mutwale I, Jones ASC, Islam J, Chikatula E, Mweemba A, Mbewe W, Mulenga L, Aiken AM, Anitha Menon J, Bailey SL, and Knight GM
- Subjects
- Adult, Humans, Zambia epidemiology, Drug Resistance, Microbial, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Health Personnel, Mobile Applications
- Abstract
Background: Control of antimicrobial resistance (AMR) relies on local knowledge and local intervention implementation. Effective antibiotic stewardship requires locally-suitable prescribing guidelines. We aimed to use a novel digital tool (the ZARIApp) and a participatory approach to help develop locally-relevant empiric antibiotic prescribing guidelines for two hospitals in Lusaka, Zambia., Methods: We produced an AMR report using samples collected locally and routinely from adults within the prior two years (April 2020 - April 2022). We developed the ZARIApp, which provides prescribing recommendations based on local resistance data and antibiotic prescribing practices. We used qualitative evaluation of focus group discussions among healthcare professionals to assess the feasibility and acceptability of using the ZARIApp and identify the barriers to and enablers of this stewardship approach., Results: Resistance prevalence was high for many key pathogens: for example, 73% of 41 Escherichia coli isolates were resistant to ceftriaxone. We identified that high resistance rates were likely due to low levels of requesting and processing of microbiology samples from patients leading to insufficient and unrepresentative microbiology data. This emerged as the major barrier to generating locally-relevant guidelines. Through active stakeholder engagement, we modified the ZARIApp to better support users to generate empirical antibiotic guidelines within this context of unrepresentative microbiology data. Qualitative evaluation of focus group discussions suggested that the resulting ZARIApp was useful and easy to use. New antibiotic guidelines for key syndromes are now in place in the two study hospitals, but these have substantial residual uncertainty., Conclusions: Tools such as the free online ZARIApp can empower local settings to better understand and optimise how sampling and prescribing can help to improve patient care and reduce future AMR. However, the usability of the ZARIApp is severely limited by unrepresentative microbiology data; improved routine microbiology surveillance is vitally needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)
- Published
- 2023
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23. Guiding pragmatic treatment choices for rifampicin-resistant tuberculosis in the absence of second-line drug susceptibility testing.
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Achar J, Seddon JA, Knight GM, Dodd PJ, Esmail H, Hughes J, and McQuaid CF
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- Humans, Rifampin therapeutic use, Microbial Sensitivity Tests, Isoniazid therapeutic use, Antitubercular Agents therapeutic use, Antitubercular Agents pharmacology, Drug Resistance, Bacterial, Mycobacterium tuberculosis, Tuberculosis, Multidrug-Resistant drug therapy
- Abstract
Competing Interests: Conflict of interest: J. Achar reports grants from the Swedish Research Council (2020-02336), outside the submitted work. H. Esmail has participated on advisory boards for Cepheid on the subject of novel molecular diagnostics with no financial or other form of compensation received. C.F. McQuaid reports grants from Bill and Melinda Gates Foundation, and the Unitaid Adherence Support Coalition to End TB (ASCENT) project, outside the submitted work. All other authors have no potential conflicts of interest to disclose.
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- 2023
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24. The burden and dynamics of hospital-acquired SARS-CoV-2 in England.
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Cooper BS, Evans S, Jafari Y, Pham TM, Mo Y, Lim C, Pritchard MG, Pople D, Hall V, Stimson J, Eyre DW, Read JM, Donnelly CA, Horby P, Watson C, Funk S, Robotham JV, and Knight GM
- Subjects
- Humans, Communicable Disease Control, England epidemiology, Hospitals, Quarantine statistics & numerical data, SARS-CoV-2, COVID-19 epidemiology, COVID-19 transmission, Cross Infection epidemiology, Cross Infection prevention & control, Cross Infection transmission, Disease Transmission, Infectious prevention & control, Disease Transmission, Infectious statistics & numerical data, Inpatients, Pandemics prevention & control, Pandemics statistics & numerical data
- Abstract
Hospital-based transmission had a dominant role in Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) epidemics
1,2 , but large-scale studies of its role in the SARS-CoV-2 pandemic are lacking. Such transmission risks spreading the virus to the most vulnerable individuals and can have wider-scale impacts through hospital-community interactions. Using data from acute hospitals in England, we quantify within-hospital transmission, evaluate likely pathways of spread and factors associated with heightened transmission risk, and explore the wider dynamical consequences. We estimate that between June 2020 and March 2021 between 95,000 and 167,000 inpatients acquired SARS-CoV-2 in hospitals (1% to 2% of all hospital admissions in this period). Analysis of time series data provided evidence that patients who themselves acquired SARS-CoV-2 infection in hospital were the main sources of transmission to other patients. Increased transmission to inpatients was associated with hospitals having fewer single rooms and lower heated volume per bed. Moreover, we show that reducing hospital transmission could substantially enhance the efficiency of punctuated lockdown measures in suppressing community transmission. These findings reveal the previously unrecognized scale of hospital transmission, have direct implications for targeting of hospital control measures and highlight the need to design hospitals better equipped to limit the transmission of future high-consequence pathogens., (© 2023. The Author(s).)- Published
- 2023
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25. Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis.
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Menzies NA, Allwood BW, Dean AS, Dodd PJ, Houben RMGJ, James LP, Knight GM, Meghji J, Nguyen LN, Rachow A, Schumacher SG, Mirzayev F, and Cohen T
- Subjects
- Humans, Rifampin pharmacology, Rifampin therapeutic use, Global Burden of Disease, Models, Theoretical, Antitubercular Agents pharmacology, Antitubercular Agents therapeutic use, Tuberculosis, Multidrug-Resistant drug therapy, Tuberculosis, Multidrug-Resistant epidemiology, Tuberculosis drug therapy, Tuberculosis epidemiology, Tuberculosis prevention & control
- Abstract
In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission., (© 2023. Springer Nature Limited.)
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- 2023
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26. AHHME: A model for estimating the holistic cost-effectiveness of antimicrobial resistance interventions in food animal production.
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Emes ET, Waage J, Knight GM, and Naylor NR
- Abstract
Antimicrobial resistance (AMR) is considered a global priority for human health, and reducing antimicrobial use in food animals has been suggested as a key area for interventions aiming to reduce resistant infections in humans. In addition to the effect on human health, such interventions may have effects across food animal productivity, healthcare sector costs, and the broader macroeconomy, but these effects are rarely captured in the AMR health economic literature. Without being able to estimate these effects, it is difficult to understand the true cost-effectiveness of antimicrobial stewardship interventions in food animal production, or to correctly design and prioritise such interventions. We explore and demonstrate the potential use of a novel compartment-based mathematical model to estimate the holistic cost-effectiveness of AMR-related interventions in food animal production from a One Health perspective. The Agriculture Human Health Micro-Economic model (AHHME) uses Markov state transition models to model the movement of humans and food animals between health states. It assigns values to these health states utilising empiric approaches, from the perspectives of human health, food animal productivity, labour productivity and healthcare sector costs. Providing AHHME open-source code and interactive online modelling tools allow for capacity building in AMR intervention modelling. This model represents a useful framework for capturing the cost-effectiveness of AMR-related interventions in food animal production in a more holistic way: it can allow us to capture the often-overlooked benefits of such interventions in like terms while considering distributional concerns. It also demonstrates that methodological assumptions such as willingness-to-pay thresholds and discount rates can be just as important to health decision models as epidemiological parameters, and allows these assumptions to be altered. We provide example outputs, and encourage researchers and policymakers to use and adapt our code to explore, design, and prioritise AMR-related interventions in their own country contexts., Competing Interests: The authors declare no conflicts of interest, (Crown Copyright © 2023 Published by Elsevier B.V.)
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- 2023
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27. Markers of epidemiological success of methicillin-resistant Staphylococcus aureus isolates in European populations.
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Baede VO, Gupta A, Knight GM, Schouls LM, Laing K, Tavakol M, Barray A, de Vlas SJ, de Vos AS, Hendrickx APA, Khan M, Kretzschmar ME, van Wamel WJB, Lina G, Vandenesch F, Vos MC, Witney AA, Rasigade JP, and Lindsay JA
- Subjects
- Humans, Phylogeny, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Fluoroquinolones, Microbial Sensitivity Tests, Methicillin-Resistant Staphylococcus aureus, Staphylococcal Infections microbiology
- Abstract
Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) infections impose a considerable burden on health systems, yet there is remarkable variation in the global incidence and epidemiology of MRSA. The MACOTRA consortium aimed to identify bacterial markers of epidemic success of MRSA isolates in Europe using a representative MRSA collection originating from France, the Netherlands and the United Kingdom., Methods: Operational definitions of success were defined in consortium meetings to compose a balanced strain collection of successful and sporadic MRSA isolates. Isolates were subjected to antimicrobial susceptibility testing and whole-genome sequencing; genes were identified and phylogenetic trees constructed. Markers of epidemiological success were identified using genome-based time-scaled haplotypic density analysis and linear regression. Antimicrobial usage data from ESAC-Net was compared with national MRSA incidence data., Results: Heterogeneity of MRSA isolate collections across countries hampered the use of a unified operational definition of success; therefore, country-specific approaches were used to establish the MACOTRA strain collection. Phenotypic antimicrobial resistance varied within related MRSA populations and across countries. In time-scaled haplotypic density analysis, fluoroquinolone, macrolide and mupirocin resistance were associated with MRSA success, whereas gentamicin, rifampicin and trimethoprim resistance were associated with sporadicity. Usage of antimicrobials across 29 European countries varied substantially, and β-lactam, fluoroquinolone, macrolide and aminoglycoside use correlated with MRSA incidence., Discussion: Our results are the strongest yet to associate MRSA antibiotic resistance profiles and antibiotic usage with the incidence of infection and successful clonal spread, which varied by country. Harmonized isolate collection, typing, resistance profiling and alignment with antimicrobial usage over time will aid comparisons and further support country-specific interventions to reduce MRSA burden., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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28. Evolution of Personalized Dosimetry for Radioembolization of Hepatocellular Carcinoma.
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Knight GM, Gordon AC, Gates V, Talwar A, Riaz A, Salem R, and Lewandowski R
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- Humans, Treatment Outcome, Yttrium Radioisotopes adverse effects, Radiometry, Carcinoma, Hepatocellular diagnostic imaging, Carcinoma, Hepatocellular radiotherapy, Carcinoma, Hepatocellular pathology, Liver Neoplasms diagnostic imaging, Liver Neoplasms radiotherapy, Liver Neoplasms pathology, Embolization, Therapeutic adverse effects, Embolization, Therapeutic methods
- Abstract
Yttrium-90 transarterial radioembolization (TARE) has progressed from a salvage or palliative lobar or sequential bilobar regional liver therapy for patients with advanced disease to a versatile, potentially curative, and often highly selective local treatment for patients across Barcelona Clinic Liver Cancer stages. With this shift, radiation dosimetry has evolved to become more tailored to patients and target lesion(s), with treatment dose and distributions adapted for specific clinical goals (ie, palliation, bridging or downstaging to liver transplantation, converting to surgical resection candidacy, or ablative/curative intent). Data have confirmed that "personalizing" dosimetry yields real-world improvements in tumor response and overall survival while maintaining a favorable adverse event profile. In this review, imaging techniques used before, during, and after TARE have been reviewed. Historical algorithms and contemporary image-based dosimetry methods have been reviewed and compared. Finally, recent and upcoming developments in TARE methodologies and tools have been discussed., (Copyright © 2023 SIR. Published by Elsevier Inc. All rights reserved.)
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- 2023
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29. Quantifying patient- and hospital-level antimicrobial resistance dynamics in Staphylococcus aureus from routinely collected data.
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Leclerc Q, Clements A, Dunn H, Hatcher J, Lindsay JA, Grandjean L, and Knight GM
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- Child, Humans, Staphylococcus aureus genetics, Methicillin, Routinely Collected Health Data, Drug Resistance, Bacterial, Hospitals, Pediatric, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Staphylococcal Infections epidemiology
- Abstract
Introduction. Antimicrobial resistance (AMR) to all antibiotic classes has been found in the pathogen Staphylococcus aureus . The reported prevalence of these resistances varies, driven by within-host AMR evolution at the patient level, and between-host transmission at the hospital level. Without dense longitudinal sampling, pragmatic analysis of AMR dynamics at multiple levels using routine surveillance data is essential to inform control measures. Gap Statement. The value and limitations of routinely collected hospital data to gain insight into AMR dynamics at the hospital and individual levels simultaneously are unclear. Methodology. We explored S. aureus AMR diversity in 70 000 isolates from a UK paediatric hospital between 2000-2021, using electronic datasets containing multiple routinely collected isolates per patient with phenotypic antibiograms and information on hospitalization and antibiotic consumption. Results. At the hospital level, the proportion of isolates that were meticillin-resistant (MRSA) increased between 2014-2020 from 25-50 %, before sharply decreasing to 30%, likely due to a change in inpatient demographics. Temporal trends in the proportion of isolates resistant to different antibiotics were often correlated in MRSA, but independent in meticillin-susceptible S. aureus . Ciprofloxacin resistance in MRSA decreased from 70-40 % of tested isolates between 2007-2020, likely linked to a national policy to reduce fluoroquinolone usage in 2007. At the patient level, we identified frequent AMR diversity, with 4 % of patients ever positive for S. aureus simultaneously carrying, at some point, multiple isolates with different resistances. We detected changes over time in AMR diversity in 3 % of patients ever positive for S. aureus . These changes equally represented gain and loss of resistance. Conclusion. Within this routinely collected dataset, we found that 65 % of changes in resistance within a patient's S. aureus population could not be explained by antibiotic exposure or between-patient transmission of bacteria, suggesting that within-host evolution via frequent gain and loss of AMR genes may be responsible for these changing AMR profiles. Our study highlights the value of exploring existing routine surveillance data to determine underlying mechanisms of AMR. These insights may substantially improve our understanding of the importance of antibiotic exposure variation, and the success of single S. aureus clones.
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- 2023
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30. Reply: Discussing the place of TIPS in non-cirrhotic patients with chronic extra hepatic portal vein occlusion refractory to standard of care therapy.
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Knight GM, Thornburg B, and Salem R
- Subjects
- Humans, Standard of Care, Liver Cirrhosis pathology, Portal Vein pathology, Portasystemic Shunt, Transjugular Intrahepatic
- Published
- 2023
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31. Correction for Leclerc et al., "Growth-Dependent Predation and Generalized Transduction of Antimicrobial Resistance by Bacteriophage".
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Leclerc QJ, Wildfire J, Gupta A, Lindsay JA, and Knight GM
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- 2023
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32. Modelling the synergistic effect of bacteriophage and antibiotics on bacteria: Killers and drivers of resistance evolution.
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Leclerc QJ, Lindsay JA, and Knight GM
- Subjects
- Anti-Bacterial Agents pharmacology, Staphylococcus aureus, Bacteria, Tetracycline pharmacology, Erythromycin pharmacology, Bacteriophages genetics, Phage Therapy
- Abstract
Bacteriophage (phage) are bacterial predators that can also spread antimicrobial resistance (AMR) genes between bacteria by generalised transduction. Phage are often present alongside antibiotics in the environment, yet evidence of their joint killing effect on bacteria is conflicted, and the dynamics of transduction in such systems are unknown. Here, we combine in vitro data and mathematical modelling to identify conditions where phage and antibiotics act in synergy to remove bacteria or drive AMR evolution. We adapt a published model of phage-bacteria dynamics, including transduction, to add the pharmacodynamics of erythromycin and tetracycline, parameterised from new in vitro data. We simulate a system where two strains of Staphylococcus aureus are present at stationary phase, each carrying either an erythromycin or tetracycline resistance gene, and where multidrug-resistant bacteria can be generated by transduction only. We determine rates of bacterial clearance and multidrug-resistant bacteria appearance, when either or both antibiotics and phage are present at varying timings and concentrations. Although phage and antibiotics act in synergy to kill bacteria, by reducing bacterial growth antibiotics reduce phage production. A low concentration of phage introduced shortly after antibiotics fails to replicate and exert a strong killing pressure on bacteria, instead generating multidrug-resistant bacteria by transduction which are then selected for by the antibiotics. Multidrug-resistant bacteria numbers were highest when antibiotics and phage were introduced simultaneously. The interaction between phage and antibiotics leads to a trade-off between a slower clearing rate of bacteria (if antibiotics are added before phage), and a higher risk of multidrug-resistance evolution (if phage are added before antibiotics), exacerbated by low concentrations of phage or antibiotics. Our results form hypotheses to guide future experimental and clinical work on the impact of phage on AMR evolution, notably for studies of phage therapy which should investigate varying timings and concentrations of phage and antibiotics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Leclerc et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2022
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33. Dehydration Tolerance in Epidemic versus Nonepidemic MRSA Demonstrated by Isothermal Microcalorimetry.
- Author
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Baede VO, Tavakol M, Vos MC, Knight GM, and van Wamel WJB
- Subjects
- Humans, Staphylococcus aureus, Dehydration, France, Anti-Bacterial Agents pharmacology, Methicillin-Resistant Staphylococcus aureus, Staphylococcal Infections microbiology
- Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) clusters are considered epidemic or nonepidemic based on their ability to spread effectively. Successful transmission could be influenced by dehydration tolerance. Current methods for determination of dehydration tolerance lack accuracy. Here, a climate-controlled in vitro dehydration assay using isothermal microcalorimetry (IMC) was developed and linked with mathematical modeling to determine survival of 44 epidemic versus 54 nonepidemic MRSA strains from France, the United Kingdom, and the Netherlands after 1 week of dehydration. For each MRSA strain, the growth parameters time to end of first growth phase ( tmax [h]) and maximal exponential growth rate ( μ
m ) were deduced from IMC data for 3 experimental replicates, 3 different starting inocula, and before and after dehydration. If the maximal exponential growth rate was within predefined margins (±36% of the mean), a linear relationship between tmax and starting inoculum could be utilized to predict log reduction after dehydration for individual strains. With these criteria, 1,330 of 1,764 heat flow curves (data sets) (75%) could be analyzed to calculate the post-dehydration inoculum size, and thus the log reduction due to dehydration, for 90 of 98 strains (92%). Overall reduction was ~1 log after 1 week. No difference in dehydration tolerance was found between the epidemic and nonepidemic strains. Log reduction was negatively correlated with starting inoculum, indicating better survival of higher inocula. This study presents a framework to quantify bacterial survival. MRSA strains showed great capacity to persist in the environment, irrespective of epidemiological success. This finding strengthens the need for effective surface cleaning to contain MRSA transmission. IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of infections globally. While some MRSA clusters have spread worldwide, others are not able to disseminate successfully beyond certain regions despite frequent introduction. Dehydration tolerance facilitates transmission in hospital environments through enhanced survival on surfaces and fomites, potentially explaining differences in transmission success between MRSA clusters. Unfortunately, the currently available techniques to determine dehydration tolerance of cluster-forming bacteria like S. aureus are labor-intensive and unreliable due to their dependence on quantitative culturing. In this study, bacterial survival was assessed in a newly developed assay using isothermal microcalorimetry. With this technique, the effect of drying can be determined without the disadvantages of quantitative culturing. In combination with a newly developed mathematical algorithm, we determined dehydration tolerance of a large number of MRSA strains in a systematic, unbiased, and robust manner.- Published
- 2022
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34. Maternity service reconfigurations for intrapartum and postnatal midwifery staffing shortages: modelling of low-risk births in England.
- Author
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Grollman C, Daniele MAS, Brigante L, Knight GM, Latina L, Morgan AS, and Downe S
- Subjects
- England, Female, Humans, Pregnancy, Workforce, COVID-19 epidemiology, Home Childbirth, Midwifery methods
- Abstract
Introduction: Choice of birth setting is important and it is valuable to know how reconfiguring available settings may affect midwifery staffing needs. COVID-19-related health system pressures have meant restriction of community births. We aimed to model the potential of service reconfigurations to offset midwifery staffing shortages., Methods: We adapted the Birthrate Plus method to develop a tool that models the effects on intrapartum and postnatal midwifery staffing requirements of changing service configurations for low-risk births. We tested our tool on two hypothetical model trusts with different baseline configurations of hospital and community low-risk birth services, representing those most common in England, and applied it to scenarios with midwifery staffing shortages of 15%, 25% and 35%. In scenarios with midwifery staffing shortages above 15%, we modelled restricting community births in line with professional guidance on COVID-19 service reconfiguration. For shortages of 15%, we modelled expanding community births per the target of the Maternity Transformation programme., Results: Expanding community births with 15% shortages required 0.0 and 0.1 whole-time equivalent more midwives in our respective trusts compared with baseline, representing 0% and 0.1% of overall staffing requirements net of shortages. Restricting home births with 25% shortages reduced midwifery staffing need by 0.1 midwives (-0.1% of staffing) and 0.3 midwives (-0.3%). Suspending community births with 35% shortages meant changes of -0.3 midwives (-0.3%) and -0.5 midwives (-0.5%) in the two trusts. Sensitivity analysis showed that our results were robust even under extreme assumptions., Conclusion: Our model found that reconfiguring maternity services in response to shortages has a negligible effect on intrapartum and postnatal midwifery staffing needs. Given this, with lower degrees of shortage, managers can consider increasing community birth options where there is demand. In situations of severe shortage, reconfiguration cannot recoup the shortage and managers must decide how to modify service arrangements., Competing Interests: Competing interests: MD has consulted for and LB works for the Royal College of Midwives. CG, GK, LL, ASM and SD declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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35. Quantifying the primary and secondary effects of antimicrobial resistance on surgery patients: Methods and data sources for empirical estimation in England.
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Naylor NR, Evans S, Pouwels KB, Troughton R, Lamagni T, Muller-Pebody B, Knight GM, Atun R, and Robotham JV
- Subjects
- Anti-Bacterial Agents, England, Humans, Information Storage and Retrieval, Communicable Diseases, Drug Resistance, Bacterial
- Abstract
Antimicrobial resistance (AMR) may negatively impact surgery patients through reducing the efficacy of treatment of surgical site infections, also known as the "primary effects" of AMR. Previous estimates of the burden of AMR have largely ignored the potential "secondary effects," such as changes in surgical care pathways due to AMR, such as different infection prevention procedures or reduced access to surgical procedures altogether, with literature providing limited quantifications of this potential burden. Former conceptual models and approaches for quantifying such impacts are available, though they are often high-level and difficult to utilize in practice. We therefore expand on this earlier work to incorporate heterogeneity in antimicrobial usage, AMR, and causative organisms, providing a detailed decision-tree-Markov-hybrid conceptual model to estimate the burden of AMR on surgery patients. We collate available data sources in England and describe how routinely collected data could be used to parameterise such a model, providing a useful repository of data systems for future health economic evaluations. The wealth of national-level data available for England provides a case study in describing how current surveillance and administrative data capture systems could be used in the estimation of transition probability and cost parameters. However, it is recommended that such data are utilized in combination with expert opinion (for scope and scenario definitions) to robustly estimate both the primary and secondary effects of AMR over time. Though we focus on England, this discussion is useful in other settings with established and/or developing infectious diseases surveillance systems that feed into AMR National Action Plans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Naylor, Evans, Pouwels, Troughton, Lamagni, Muller-Pebody, Knight, Atun and Robotham.)
- Published
- 2022
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36. Preoperative portal vein recanalization-transjugular intrahepatic portosystemic shunt for chronic obliterative portal vein thrombosis: Outcomes following liver transplantation.
- Author
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Talwar A, Varghese J, Knight GM, Katariya N, Caicedo JC, Dietch Z, Borja-Cacho D, Ladner D, Christopher D, Baker T, Abecassis M, Mouli S, Desai K, Riaz A, Thornburg B, and Salem R
- Subjects
- Humans, Portal Vein surgery, Treatment Outcome, Hemangioma, Cavernous complications, Liver Transplantation adverse effects, Portasystemic Shunt, Transjugular Intrahepatic adverse effects, Venous Thrombosis surgery
- Abstract
High-grade portal vein thrombosis (PVT) is often considered to be a technically challenging scenario for liver transplantation (LT) and in some centers a relative contraindication. This study compares patients with chronic obliterative PVT who underwent portal vein recanalization-transjugular intrahepatic portosystemic shunt (PVR-TIPS) and subsequent LT to those with partial nonocclusive PVT who underwent LT without an intervention. This institutional review board-approved study analyzed 49 patients with cirrhosis with PVT from 2000 to 2020 at our institution. Patients were divided into two groups, those that received PVR-TIPS due to anticipated surgical challenges from chronic obliterative PVT and those who did not because of partial PVT. Demographic data and long-term outcomes were compared. A total of 35 patients received PVR-TIPS while 14 did not, with all receiving LT. Patients with PVR-TIPS had a higher Yerdel score and frequency of cavernoma than those that did not. PVR-TIPS was effective in decreasing portosystemic gradient (16 down to 8 mm HG; p < 0.05). Both groups allowed for end-to-end anastomoses in >90% of cases. However, veno-veno bypass was used significantly more in patients who did not receive PVR-TIPS. Additionally, patients without PVR-TIPS required significantly more intraoperative red blood cells. Overall survival was not different between groups. PVR-TIPS demonstrated efficacy in resolving PVT and allowed for end-to-end portal vein anastomoses. PVR-TIPS is a viable treatment option for chronic obliterative PVT with or without cavernoma that simplifies the surgical aspects of LT., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
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- 2022
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37. The contribution of hospital-acquired infections to the COVID-19 epidemic in England in the first half of 2020.
- Author
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Knight GM, Pham TM, Stimson J, Funk S, Jafari Y, Pople D, Evans S, Yin M, Brown CS, Bhattacharya A, Hope R, Semple MG, Read JM, Cooper BS, and Robotham JV
- Subjects
- Hospitalization, Hospitals, Humans, SARS-CoV-2, COVID-19 epidemiology, Cross Infection epidemiology
- Abstract
Background: SARS-CoV-2 is known to transmit in hospital settings, but the contribution of infections acquired in hospitals to the epidemic at a national scale is unknown., Methods: We used comprehensive national English datasets to determine the number of COVID-19 patients with identified hospital-acquired infections (with symptom onset > 7 days after admission and before discharge) in acute English hospitals up to August 2020. As patients may leave the hospital prior to detection of infection or have rapid symptom onset, we combined measures of the length of stay and the incubation period distribution to estimate how many hospital-acquired infections may have been missed. We used simulations to estimate the total number (identified and unidentified) of symptomatic hospital-acquired infections, as well as infections due to onward community transmission from missed hospital-acquired infections, to 31st July 2020., Results: In our dataset of hospitalised COVID-19 patients in acute English hospitals with a recorded symptom onset date (n = 65,028), 7% were classified as hospital-acquired. We estimated that only 30% (range across weeks and 200 simulations: 20-41%) of symptomatic hospital-acquired infections would be identified, with up to 15% (mean, 95% range over 200 simulations: 14.1-15.8%) of cases currently classified as community-acquired COVID-19 potentially linked to hospital transmission. We estimated that 26,600 (25,900 to 27,700) individuals acquired a symptomatic SARS-CoV-2 infection in an acute Trust in England before 31st July 2020, resulting in 15,900 (15,200-16,400) or 20.1% (19.2-20.7%) of all identified hospitalised COVID-19 cases., Conclusions: Transmission of SARS-CoV-2 to hospitalised patients likely caused approximately a fifth of identified cases of hospitalised COVID-19 in the "first wave" in England, but less than 1% of all infections in England. Using time to symptom onset from admission for inpatients as a detection method likely misses a substantial proportion (> 60%) of hospital-acquired infections., (© 2022. The Author(s).)
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- 2022
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38. Growth-Dependent Predation and Generalized Transduction of Antimicrobial Resistance by Bacteriophage.
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Leclerc QJ, Wildfire J, Gupta A, Lindsay JA, and Knight GM
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- Animals, Anti-Bacterial Agents pharmacology, Predatory Behavior, Drug Resistance, Bacterial, Bacteriophages, Methicillin-Resistant Staphylococcus aureus
- Abstract
Bacteriophage (phage) are both predators and evolutionary drivers for bacteria, notably contributing to the spread of antimicrobial resistance (AMR) genes by generalized transduction. Our current understanding of this complex relationship is limited. We used an interdisciplinary approach to quantify how these interacting dynamics can lead to the evolution of multidrug-resistant bacteria. We cocultured two strains of methicillin-resistant Staphylococcus aureus, each harboring a different antibiotic resistance gene, with generalized transducing phage. After a growth phase of 8 h, bacteria and phage surprisingly coexisted at a stable equilibrium in our culture, the level of which was dependent on the starting concentration of phage. We detected double-resistant bacteria as early as 7 h, indicating that transduction of AMR genes had occurred. We developed multiple mathematical models of the bacteria and phage relationship and found that phage-bacteria dynamics were best captured by a model in which phage burst size decreases as the bacteria population reaches stationary phase and where phage predation is frequency-dependent. We estimated that one in every 10
8 new phage generated was a transducing phage carrying an AMR gene and that double-resistant bacteria were always predominantly generated by transduction rather than by growth. Our results suggest a shift in how we understand and model phage-bacteria dynamics. Although rates of generalized transduction could be interpreted as too rare to be significant, they are sufficient in our system to consistently lead to the evolution of multidrug-resistant bacteria. Currently, the potential of phage to contribute to the growing burden of AMR is likely underestimated. IMPORTANCE Bacteriophage (phage), viruses that can infect and kill bacteria, are being investigated through phage therapy as a potential solution to the threat of antimicrobial resistance (AMR). In reality, however, phage are also natural drivers of bacterial evolution by transduction when they accidentally carry nonphage DNA between bacteria. Using laboratory work and mathematical models, we show that transduction leads to evolution of multidrug-resistant bacteria in less than 8 h and that phage production decreases when bacterial growth decreases, allowing bacteria and phage to coexist at stable equilibria. The joint dynamics of phage predation and transduction lead to complex interactions with bacteria, which must be clarified to prevent phage from contributing to the spread of AMR.- Published
- 2022
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39. Impact of non-pharmaceutical interventions on SARS-CoV-2 outbreaks in English care homes: a modelling study.
- Author
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Rosello A, Barnard RC, Smith DRM, Evans S, Grimm F, Davies NG, Deeny SR, Knight GM, and Edmunds WJ
- Subjects
- Disease Outbreaks prevention & control, Humans, Infection Control, Vaccination, COVID-19 epidemiology, COVID-19 prevention & control, SARS-CoV-2
- Abstract
Background: COVID-19 outbreaks still occur in English care homes despite the interventions in place., Methods: We developed a stochastic compartmental model to simulate the spread of SARS-CoV-2 within an English care home. We quantified the outbreak risk with baseline non-pharmaceutical interventions (NPIs) already in place, the role of community prevalence in driving outbreaks, and the relative contribution of all importation routes into a fully susceptible care home. We also considered the potential impact of additional control measures in care homes with and without immunity, namely: increasing staff and resident testing frequency, using lateral flow antigen testing (LFD) tests instead of polymerase chain reaction (PCR), enhancing infection prevention and control (IPC), increasing the proportion of residents isolated, shortening the delay to isolation, improving the effectiveness of isolation, restricting visitors and limiting staff to working in one care home. We additionally present a Shiny application for users to apply this model to their facility of interest, specifying care home, outbreak and intervention characteristics., Results: The model suggests that importation of SARS-CoV-2 by staff, from the community, is the main driver of outbreaks, that importation by visitors or from hospitals is rare, and that the past testing strategy (monthly testing of residents and daily testing of staff by PCR) likely provides negligible benefit in preventing outbreaks. Daily staff testing by LFD was 39% (95% 18-55%) effective in preventing outbreaks at 30 days compared to no testing., Conclusions: Increasing the frequency of testing in staff and enhancing IPC are important to preventing importations to the care home. Further work is needed to understand the impact of vaccination in this population, which is likely to be very effective in preventing outbreaks., (© 2022. The Author(s).)
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- 2022
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40. Effectiveness of infection prevention and control interventions, excluding personal protective equipment, to prevent nosocomial transmission of SARS-CoV-2: a systematic review and call for action.
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Jafari Y, Yin M, Lim C, Pople D, Evans S, Stimson J, Pham TM, Read JM, Robotham JV, Cooper BS, and Knight GM
- Abstract
Many infection prevention and control (IPC) interventions have been adopted by hospitals to limit nosocomial transmission of SARS-CoV-2. The aim of this systematic review is to identify evidence on the effectiveness of these interventions. We conducted a literature search of five databases (OVID MEDLINE, Embase, CENTRAL, COVID-19 Portfolio (pre-print), Web of Science). SWIFT ActiveScreener software was used to screen English titles and abstracts published between 1st January 2020 and 6th April 2021. Intervention studies, defined by Cochrane Effective Practice and Organisation of Care, that evaluated IPC interventions with an outcome of SARS-CoV-2 infection in either patients or healthcare workers were included. Personal protective equipment (PPE) was excluded as this intervention had been previously reviewed. Risks of bias were assessed using the Cochrane tool for randomised trials (RoB2) and non-randomized studies of interventions (ROBINS-I). From 23,156 screened articles, we identified seven articles that met the inclusion criteria, all of which evaluated interventions to prevent infections in healthcare workers and the majority of which were focused on effectiveness of prophylaxes. Due to heterogeneity in interventions, we did not conduct a meta-analysis. All agents used for prophylaxes have little to no evidence of effectiveness against SARS-CoV-2 infections. We did not find any studies evaluating the effectiveness of interventions including but not limited to screening, isolation and improved ventilation. There is limited evidence from interventional studies, excluding PPE, evaluating IPC measures for SARS-CoV-2. This review calls for urgent action to implement such studies to inform policies to protect our most vulnerable populations and healthcare workers., (© 2021 The Authors.)
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- 2022
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41. Understanding MRSA clonal competition within a UK hospital; the possible importance of density dependence.
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de Vos AS, de Vlas SJ, Lindsay JA, Kretzschmar MEE, and Knight GM
- Subjects
- Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Hospitals, Humans, Microbial Sensitivity Tests, United Kingdom epidemiology, Methicillin-Resistant Staphylococcus aureus genetics, Staphylococcal Infections drug therapy, Staphylococcal Infections epidemiology
- Abstract
Background: Methicillin resistant Staphylococcus aureus (MRSA) bacteria cause serious, often healthcare-associated infections and are frequently highly resistant to diverse antibiotics. Multiple MRSA clonal complexes (CCs) have evolved independently and countries have different prevalent CCs. It is unclear when and why the dominant CC in a region may switch., Methods: We developed a mathematical deterministic model of MRSA CC competing for limited resource. The model distinguishes 'standard MRSA' and multidrug resistant sub-populations within each CC, allowing for resistance loss and transfer between same CC bacteria. We first analysed how dynamics of this system depend on growth-rate and resistance-potential differences between CCs, and on their resistance gene accumulation. We then fit the model to capture the longitudinal CC dynamics observed at a single UK hospital, which exemplified the UK-wide switch from mainly CC30 to mainly CC22., Results: We find that within a CC, gain and loss of resistance can allow for co-existence of sensitive and resistant sub-populations. Due to more efficient transfer of resistance at higher CC density, more drug resistance can accumulate in the population of a more prevalent CC. We show how this process of density dependent competition, together with prevalence disruption, could explain the relatively sudden switch from mainly CC30 to mainly CC22 in the UK hospital setting. Alternatively, the observed hospital dynamics could be reproduced by assuming that multidrug resistant CC22 evolved only around 2004., Conclusions: We showed how higher prevalence may advantage a CC by allowing it to acquire antimicrobial resistances more easily. Due to this density dependence in competition, dominance in an area can depend on historic contingencies; the MRSA CC that happened to be first could stay dominant because of its high prevalence advantage. This then could help explain the stability, despite frequent stochastic introductions across borders, of geographic differences in MRSA CC., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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42. TIPS for Adults Without Cirrhosis With Chronic Mesenteric Venous Thrombosis and EHPVO Refractory to Standard-of-Care Therapy.
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Knight GM, Clark J, Boike JR, Maddur H, Ganger DR, Talwar A, Riaz A, Desai K, Mouli S, Hohlastos E, Garcia Pagan JC, Gabr A, Stein B, Lewandowski R, Thornburg B, and Salem R
- Subjects
- Adult, Aged, Chronic Disease therapy, Combined Modality Therapy methods, Feasibility Studies, Female, Humans, Male, Middle Aged, Portal Vein pathology, Retrospective Studies, Treatment Outcome, Vascular Patency, Anticoagulants administration & dosage, Mesenteric Ischemia therapy, Portal Vein surgery, Portasystemic Shunt, Transjugular Intrahepatic adverse effects, Venous Thrombosis therapy
- Abstract
Background and Aims: Extrahepatic portal vein occlusion (EHPVO) from portal vein thrombosis is a rare condition associated with substantial morbidity and mortality. The purpose of this study is to investigate the efficacy of transjugular intrahepatic portosystemic shunts (TIPS) for the treatment of chronic EHPVO, cavernomatosis, and mesenteric venous thrombosis in adults without cirrhosis who are refractory to standard-of-care therapy., Approach and Results: Thirty-nine patients with chronic EHPVO received TIPS. Laboratory parameters and follow-up were assessed at 1, 3, 6, 12, and 24 months, and every 6 months thereafter. Two hepatologists adjudicated symptom improvement attributable to mesenteric thrombosis and EHPVO before/after TIPS. Kaplan-Meier was used to assess primary and overall TIPS patency, assessing procedural success. Adverse events, radiation exposure, hospital length-of-stay and patency were recorded. Cavernoma was present in 100%, with TIPS being successful in all cases using splenic, mesenteric, and transhepatic approaches. Symptom improvement was noted in 26 of 30 (87%) at 6-month follow-up. Twelve patients (31%) experienced TIPS thrombosis. There were no significant long-term laboratory adverse events or deaths. At 36 months, freedom from primary TIPS thrombosis was 63%; following secondary interventions, overall patency was increased to 81%., Conclusions: TIPS in chronic, noncirrhotic EHPVO with cavernomas and mesenteric venous thrombosis is technically feasible and does not adversely affect liver function. Most patients demonstrate subjective and objective benefit from TIPS. Improvement in patency rates are needed with proper timing of adjuvant anticoagulation., (© 2021 by the American Association for the Study of Liver Diseases.)
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- 2021
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43. The effectiveness of biosecurity interventions in reducing the transmission of bacteria from livestock to humans at the farm level: A systematic literature review.
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Youssef DM, Wieland B, Knight GM, Lines J, and Naylor NR
- Subjects
- Animals, Bacterial Infections microbiology, Bacterial Infections transmission, Humans, Bacteria, Bacterial Infections veterinary, Bacterial Zoonoses prevention & control, Containment of Biohazards, Farms standards, Livestock microbiology
- Abstract
Zoonotic bacterial infections are a health hazard for people who are in regular contact with livestock at the farm level. Improved biosecurity can limit zoonotic pathogen transmission within farms. The aim of this review was to summarize the effectiveness of farm-level biosecurity interventions in reducing bacterial transmission from animals to people who lived, worked in or visited farms. A systematic literature review was conducted using Embase, Ovid Medline and Agris databases, which were searched on 7
th of July 2019, limited to English language papers but with no time exclusion criteria. A narrative synthesis was undertaken utilizing the Centre for Reviews and Dissemination approach, reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias within and across the included studies was performed using established checklists. Out of 869 studies retrieved through database searches, 11 studies were selected. In addition, three studies were found through study reference lists. Fourteen studies were therefore included in this review. Biosecurity interventions were grouped into five categories: hand washing, sanitization and hygienic measures (six studies); personal protective equipment (five studies); vaccination (two studies); other interventions (e.g. air ventilation flap) (four studies); and routine farm activities (two studies). Across studies that investigated odds of human colonization or infection (three studies), odds were seen to both be increased and decreased through use of tested biosecurity measures. Large confidence intervals that often crossed the threshold of an odds ratio equal to 1 were found. Most of the studies' overall risk of bias was 'medium risk' (11 studies), with selection bias domains generally being scored 'medium risk.' Biosecurity interventions are potentially beneficial in reducing bacterial transmission from animals to humans. However, more high-quality evidence is needed to increase certainty in which interventions, in which contexts, are most effective from the human health perspective., (© 2021 The Authors. Zoonoses and Public Health published by Wiley-VCH GmbH.)- Published
- 2021
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44. Importance of patient bed pathways and length of stay differences in predicting COVID-19 hospital bed occupancy in England.
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Leclerc QJ, Fuller NM, Keogh RH, Diaz-Ordaz K, Sekula R, Semple MG, Atkins KE, Procter SR, and Knight GM
- Subjects
- England, Humans, Length of Stay, SARS-CoV-2, Bed Occupancy, COVID-19
- Abstract
Background: Predicting bed occupancy for hospitalised patients with COVID-19 requires understanding of length of stay (LoS) in particular bed types. LoS can vary depending on the patient's "bed pathway" - the sequence of transfers of individual patients between bed types during a hospital stay. In this study, we characterise these pathways, and their impact on predicted hospital bed occupancy., Methods: We obtained data from University College Hospital (UCH) and the ISARIC4C COVID-19 Clinical Information Network (CO-CIN) on hospitalised patients with COVID-19 who required care in general ward or critical care (CC) beds to determine possible bed pathways and LoS. We developed a discrete-time model to examine the implications of using either bed pathways or only average LoS by bed type to forecast bed occupancy. We compared model-predicted bed occupancy to publicly available bed occupancy data on COVID-19 in England between March and August 2020., Results: In both the UCH and CO-CIN datasets, 82% of hospitalised patients with COVID-19 only received care in general ward beds. We identified four other bed pathways, present in both datasets: "Ward, CC, Ward", "Ward, CC", "CC" and "CC, Ward". Mean LoS varied by bed type, pathway, and dataset, between 1.78 and 13.53 days. For UCH, we found that using bed pathways improved the accuracy of bed occupancy predictions, while only using an average LoS for each bed type underestimated true bed occupancy. However, using the CO-CIN LoS dataset we were not able to replicate past data on bed occupancy in England, suggesting regional LoS heterogeneities., Conclusions: We identified five bed pathways, with substantial variation in LoS by bed type, pathway, and geography. This might be caused by local differences in patient characteristics, clinical care strategies, or resource availability, and suggests that national LoS averages may not be appropriate for local forecasts of bed occupancy for COVID-19., Trial Registration: The ISARIC WHO CCP-UK study ISRCTN66726260 was retrospectively registered on 21/04/2020 and designated an Urgent Public Health Research Study by NIHR.
- Published
- 2021
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45. Antimicrobial resistance at the G7.
- Author
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Glover RE, Knight GM, and Chandler CIR
- Subjects
- Humans, United Kingdom, Drug Resistance, Microbial, Global Health, International Cooperation
- Abstract
Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.
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- 2021
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46. Implication of backward contact tracing in the presence of overdispersed transmission in COVID-19 outbreaks.
- Author
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Endo A, Leclerc QJ, Knight GM, Medley GF, Atkins KE, Funk S, and Kucharski AJ
- Abstract
Introduction: Contact tracing has the potential to control outbreaks without the need for stringent physical distancing policies, e.g. civil lockdowns. Unlike forward contact tracing, backward contact tracing identifies the source of newly detected cases. This approach is particularly valuable when there is high individual-level variation in the number of secondary transmissions (overdispersion). Methods: By using a simple branching process model, we explored the potential of combining backward contact tracing with more conventional forward contact tracing for control of COVID-19. We estimated the typical size of clusters that can be reached by backward tracing and simulated the incremental effectiveness of combining backward tracing with conventional forward tracing. Results: Across ranges of parameter values consistent with dynamics of SARS-CoV-2, backward tracing is expected to identify a primary case generating 3-10 times more infections than a randomly chosen case, typically increasing the proportion of subsequent cases averted by a factor of 2-3. The estimated number of cases averted by backward tracing became greater with a higher degree of overdispersion. Conclusion: Backward contact tracing can be an effective tool for outbreak control, especially in the presence of overdispersion as is observed with SARS-CoV-2., Competing Interests: Competing interests: AE received a research grant from Taisho Pharmaceutical Co., Ltd., (Copyright: © 2021 Endo A et al.)
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- 2021
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47. Community transmission of multidrug-resistant tuberculosis is associated with activity space overlap in Lima, Peru.
- Author
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Bui DP, Chandran SS, Oren E, Brown HE, Harris RB, Knight GM, and Grandjean L
- Subjects
- Adult, Female, Geographic Information Systems, Humans, Male, Middle Aged, Peru epidemiology, Social Networking, Young Adult, Community-Acquired Infections epidemiology, Community-Acquired Infections transmission, Tuberculosis, Multidrug-Resistant epidemiology, Tuberculosis, Multidrug-Resistant transmission
- Abstract
Background: Transmission of multidrug-resistant tuberculosis (MDRTB) requires spatial proximity between infectious cases and susceptible persons. We assess activity space overlap among MDRTB cases and community controls to identify potential areas of transmission., Methods: We enrolled 35 MDRTB cases and 64 TB-free community controls in Lima, Peru. Cases were whole genome sequenced and strain clustering was used as a proxy for transmission. GPS data were gathered from participants over seven days. Kernel density estimation methods were used to construct activity spaces from GPS locations and the utilization distribution overlap index (UDOI) was used to quantify activity space overlap., Results: Activity spaces of controls (median = 35.6 km
2 , IQR = 25.1-54) were larger than cases (median = 21.3 km2 , IQR = 17.9-48.6) (P = 0.02). Activity space overlap was greatest among genetically clustered cases (mean UDOI = 0.63, sd = 0.67) and lowest between cases and controls (mean UDOI = 0.13, sd = 0.28). UDOI was positively associated with genetic similarity of MDRTB strains between case pairs (P < 0.001). The odds of two cases being genetically clustered increased by 22% per 0.10 increase in UDOI (OR = 1.22, CI = 1.09-1.36, P < 0.001)., Conclusions: Activity space overlap is associated with MDRTB clustering. MDRTB transmission may be occurring in small, overlapping activity spaces in community settings. GPS studies may be useful in identifying new areas of MDRTB transmission.- Published
- 2021
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48. Antimicrobial resistance and COVID-19: Intersections and implications.
- Author
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Knight GM, Glover RE, McQuaid CF, Olaru ID, Gallandat K, Leclerc QJ, Fuller NM, Willcocks SJ, Hasan R, van Kleef E, and Chandler CI
- Subjects
- Communicable Disease Control methods, Communicable Disease Control organization & administration, Humans, SARS-CoV-2, Anti-Bacterial Agents supply & distribution, Anti-Bacterial Agents therapeutic use, COVID-19 epidemiology, COVID-19 prevention & control, Critical Pathways organization & administration, Critical Pathways trends, Drug Resistance, Bacterial physiology, Global Health trends, COVID-19 Drug Treatment
- Abstract
Before the coronavirus 2019 (COVID-19) pandemic began, antimicrobial resistance (AMR) was among the top priorities for global public health. Already a complex challenge, AMR now needs to be addressed in a changing healthcare landscape. Here, we analyse how changes due to COVID-19 in terms of antimicrobial usage, infection prevention, and health systems affect the emergence, transmission, and burden of AMR. Increased hand hygiene, decreased international travel, and decreased elective hospital procedures may reduce AMR pathogen selection and spread in the short term. However, the opposite effects may be seen if antibiotics are more widely used as standard healthcare pathways break down. Over 6 months into the COVID-19 pandemic, the dynamics of AMR remain uncertain. We call for the AMR community to keep a global perspective while designing finely tuned surveillance and research to continue to improve our preparedness and response to these intersecting public health challenges., Competing Interests: GK, RG, CM, IO, KG, QL, NF, SW, RH, Ev, CC No competing interests declared, (© 2021, Knight et al.)
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- 2021
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49. Ongoing challenges to understanding multidrug- and rifampicin-resistant tuberculosis in children versus adults.
- Author
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McQuaid CF, Cohen T, Dean AS, Houben RMGJ, Knight GM, Zignol M, and White RG
- Subjects
- Adolescent, Adult, Antitubercular Agents therapeutic use, Child, Europe, Finland, Germany, Humans, Peru, Poland, Rifampin therapeutic use, United Kingdom, Mycobacterium tuberculosis, Tuberculosis, Multidrug-Resistant drug therapy, Tuberculosis, Multidrug-Resistant epidemiology
- Abstract
Previous analyses suggest that children with tuberculosis (TB) are no more or no less likely to have multidrug (MDR)- or rifampicin-resistant (RR)-TB than adults. However, the availability of new data, particularly for high MDR/RR-TB burden countries, suggest updates of country-specific estimates are warranted.We used data from population-representative surveys and surveillance collected between 2000 and 2018 to compare the odds ratio of MDR/RR-TB among children (aged <15 years) with TB, compared to the odds of MDR/RR-TB among adults (aged ≥15 years) with TB.In most settings (45 out of 55 countries), and globally as a whole, there is no evidence that age is associated with odds of MDR/RR-TB. However, in some settings, such as former Soviet Union countries in general, and Georgia, Kazakhstan, Lithuania, Tajikistan and Uzbekistan in particular, as well as Peru, MDR/RR-TB is positively associated with age ≥15 years. Meanwhile, in Western Europe in general, and the United Kingdom, Poland, Finland and Luxembourg in particular, MDR/RR-TB is positively associated with age <15 years. 16 countries had sufficient data to compare over time between 2000-2011 and 2012-2018, with evidence for decreases in the odds ratio in children compared to adults in Germany, Kazakhstan and the United States of America.Our results support findings that in most settings a child with TB is as likely as an adult with TB to have MDR/RR-TB. However, setting-specific heterogeneity requires further investigation. Furthermore, the odds ratio for MDR/RR-TB in children compared to adults is generally either stable or decreasing. There are important gaps in detection, recording and reporting of drug resistance among paediatric TB cases, limiting our understanding of transmission risks and measures needed to combat the global TB epidemic., Competing Interests: Conflict of interest: C.F. McQuaid has nothing to disclose. Conflict of interest: T. Cohen has nothing to disclose. Conflict of interest: A.S. Dean has nothing to disclose. Conflict of interest: R.M.G.J. Houben has nothing to disclose. Conflict of interest: G.M. Knight has nothing to disclose. Conflict of interest: M. Zignol has nothing to disclose. Conflict of interest: R.G. White has nothing to disclose., (Copyright ©ERS 2021.)
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- 2021
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50. Systematic Review and Meta-analysis Comparing Prostatic Artery Embolization to Gold-Standard Transurethral Resection of the Prostate for Benign Prostatic Hyperplasia.
- Author
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Knight GM, Talwar A, Salem R, and Mouli S
- Subjects
- Aged, Arteries, Humans, Male, Prostate surgery, Prostatic Hyperplasia surgery, Reference Standards, Treatment Outcome, Embolization, Therapeutic methods, Prostate blood supply, Prostatic Hyperplasia therapy, Transurethral Resection of Prostate methods
- Abstract
Purpose: To report a comparative systematic review and meta-analysis of prostatic artery embolization (PAE) and transurethral resection of the prostate (TURP) for the management of benign prostatic hyperplasia (BPH)., Materials and Methods: A multi-database search for relevant literature was conducted on 15 July 2020 to include studies published on or before that date. Search terms used were: (prostate embolization OR prostatic embolization OR prostate embolization OR prostatic embolization) AND (prostatic hyperplasia OR prostatic obstruction). Risk of bias was assessed using Cochrane Collaboration and ROBINS-I criteria. Random-effects meta-analysis was performed using RevMan 5.3., Results: Six studies with 598 patients were included. TURP was associated with significantly more improvement in maximum urinary flow rate (Q
max ) (mean difference = 5.02 mL/s; 95% CI [2.66,7.38]; p < 0.0001; I2 = 89%), prostate volume (mean difference = 15.59 mL; 95% CI [7.93,23.25]; p < 0.00001; I2 = 88%), and prostate-specific antigen (PSA) (mean difference = 1.02 ng/mL; 95% CI [0.14,1.89]; p = 0.02; I2 = 71%) compared to PAE. No significant difference between PAE and TURP was observed for changes in International Prostate Symptoms Score (IPSS), IPSS quality of life (IPSS-QoL), International Index of Erectile Function (IIEF-5), and post-void residual (PVR). PAE was associated with fewer adverse events (AEs) (39.0% vs. 77.7%; p < 0.00001) and shorter hospitalization times (mean difference = -1.94 days; p < 0.00001), but longer procedural times (mean difference = 51.43 min; p = 0.004)., Conclusion: Subjective symptom improvement was equivalent between TURP and PAE. While TURP demonstrated larger improvements for some objective parameters, PAE was associated with fewer AEs and shorter hospitalization times., Level of Evidence Ii: Level 2a, Systematic Review.- Published
- 2021
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