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206 results on '"Rowlands J"'

1. Noise Correlations in a 1D Silicon Spin Qubit Array

Author

Donnelly, M. B., Rowlands, J., Kranz, L., Hsueh, Y. L., Chung, Y., Timofeev, A. V., Geng, H., Singh-Gregory, P., Gorman, S. K., Keizer, J. G., Rahman, R., and Simmons, M. Y.

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics
Abstract

Correlated noise across multi-qubit architectures is known to be highly detrimental to the operation of error correcting codes and the long-term feasibility of quantum processors. The recent discovery of spatially dependent correlated noise in multi-qubit architectures of superconducting qubits arising from the impact of cosmic radiation and high-energy particles giving rise to quasiparticle poisoning within the substrate has led to intense investigations of mitigation strategies to address this. In contrast correlated noise in semiconductor spin qubits as a function of distance has not been reported to date. Here we report the magnitude, frequency and spatial dependence of noise correlations between four silicon quantum dot pairs as a function of inter-dot distance at frequencies from 0.3mHz to 1mHz. We find the magnitude of charge noise correlations, quantified by the magnitude square coherence $C_{xy}$, are significantly suppressed from $>0.5$ to $<0.1$ as the inter-dot distance increases from 75nm to 300nm. Using an analytical model we confirm that, in contrast to superconducting qubits, the dominant source of correlated noise arises from low frequency charge noise from the presence of two level fluctuators (TLFs) at the native silicon-silicon dioxide surface. Knowing this, we conclude with an important and timely discussion of charge noise mitigation strategies., Comment: 9 pages, 4 figures, 1 table

Published
2024

2. A high-resolution CMOS imaging detector for the search of neutrinoless double $\beta$ decay in $^{82}$Se

Author

Chavarria, A. E., Galbiati, C., Li, X., and Rowlands, J. A.

Subjects
Physics - Instrumentation and Detectors, High Energy Physics - Experiment, High Energy Physics - Phenomenology, Nuclear Experiment
Abstract

We introduce high-resolution solid-state imaging detectors for the search of neutrinoless double $\beta$ decay. Based on the present literature, imaging devices from amorphous $^{82}$Se evaporated on a complementary metal-oxide-semiconductor (CMOS) active pixel array could have the energy and spatial resolution to produce two-dimensional images of ionizing tracks of utmost quality, effectively akin to an electronic bubble chamber in the double $\beta$ decay energy regime. Still to be experimentally demonstrated, a detector consisting of a large array of these devices could have very low backgrounds, possibly reaching $10^{-7}$/(kg y) in the neutrinoless decay region of interest (ROI), as it may be required for the full exploration of the neutrinoless double $\beta$ decay parameter space in the most unfavorable condition of a strongly quenched nucleon axial coupling constant., Comment: 13 pages, 5 figures

Published
2016
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3. An epistemic case for democracy : analysing the performance of voting groups

Author

Rowlands, J. J. and Wolff, Jonathan

Subjects
100
Abstract

This thesis argues that, given certain assumptions, democracies are epistemically superior to other forms of government. Using quantitative results calculated with Condorcet's Jury Theorem, it will assess the performance of different voting groups. These groups will be models of current systems of governance or those that could feasibly be adopted. To achieve this it will have to argue for the plausibility of two main claims. Firstly that there is a true choice open to voters in political decisions and secondly that democracies are better able to identify correct choices than alternative forms of government.

Published
2015

4. Origin of n- and p-type conductivity in undoped $\alpha$-PbO: role of defects

Author

Berashevich, J., Rowlands, J. A., and Reznik, A.

Subjects
Condensed Matter - Materials Science
Abstract

The first principles calculations (GGA) have been applied to study the crystallographic defects in $\alpha$-PbO in order to understand an origin of $n$- and $p$-type conductivity in otherwise undoped $\alpha$-PbO. It was found that deposition in the oxygen-deficient environment to be defined in our simulations by the Pb-rich/O-poor limit stimulates a formation of the O vacancies and the Pb interstitials both to be characterized by quite low formation energies $\sim$ 1.0 eV. The O vacancy being occupied by two electrons shifts a balance of electrons and holes between these two defects to excess of electrons (four electrons against two holes) that causes the $n$-type doping. For the Pb-poor/O-rich limit, an excess of oxygen triggers a formation of the O interstitials characterized by such a low formation energy that spontaneous appearance of this defect is predicted. It is shown that the concentration of the O interstitials is able to reach the extreme magnitude equal to number of the possible defect sites ($\sim 10^{22}$cm$^{-3}$). The localized state formed by the O interstitial is occupied by two holes and because there are no other defects in reasonable concentration to balance the hole redundancy, $p$-type doping is induced., Comment: 5 pages, 3 figures

Published
2013
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5. Self-passivation of vacancies in \alpha-PbO

Author

Berashevich, J., Rowlands, J. A., and Reznik, A.

Subjects
Condensed Matter - Materials Science
Abstract

We introduce a self-passivation of single lead (Pb) and oxygen (O) vacancies in the \alpha-PbO compound through formation of a Pb-O vacancy pair. The preferential mechanism for pair formation involves initial development of the single Pb vacancy which, by weakening the covalent bonding, sets up the crystal lattice for an appearance of the O vacancy. Binding of the Pb and O vacancies occurs through the ionization interactions. Since no dangling bonds appear at the Pb-O pair site, this defect has a minor effect on the electronic properties. In such, vacancy self-passivation offers a practical way to improve the transport properties in thermally grown PbO layers., Comment: 4 pages, 4 figures

Published
2013
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6. Lead monoxide $\alpha$-PbO: electronic properties and point defect formation

Author

Berashevich, J., Semeniuk, O., Rubel, O., Rowlands, J. A., and Reznik, A.

Subjects
Condensed Matter - Materials Science, Physics - Computational Physics
Abstract

The electronic properties of polycrystalline lead oxide consisting of a network of single-crystalline $\alpha$-PbO platelets and the formation of the native point defects in $\alpha$-PbO crystal lattice are studied using first principles calculations. The $\alpha$-PbO lattice consists of coupled layers interaction between which is too low to produce high efficiency interlayer charge transfer. In practice, the polycrystalline nature of $\alpha$-PbO causes the formation of lattice defects in such a high concentration that defect-related conductivity becomes the dominant factor in the interlayer charge transition. We found that the formation energy for the O vacancies is low, such vacancies are occupied by two electrons in the zero charge state and tend to donate their electrons to the Pb vacancies that leads to ionization of both vacancies.The vacancies introduce localized states in the band gap which can affect charge transport. The O vacancy forms a defect state at 1.03 eV above the valence band which can act as a deep trap for electrons, while the Pb vacancy forms a shallow trap for holes located just 0.1 eV above the valence band. Charge de-trapping from O vacancies can be accounted for the experimentally found dark current decay in ITO/PbO/Au structures., Comment: 7 pages, 5 figures

Published
2012
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7. Unipolar Time-Differential Pulse Response with a Solid-State Charpak Photoconductor

Author

Goldan, A. H., Tousignant, O., Karim, K. S., and Rowlands, J. A.

Subjects
Physics - Instrumentation and Detectors, Physics - Medical Physics
Abstract

We demonstrate, for the first time, a high granularity multi-well solid-state detector (MWSD) with the unipolar time-differential property for ultrafast pulse response. Results show a speed improvement factor of up to ~400 for amorphous selenium MWSD. The significance of the results presented here is the ability to reach the intrinsic physical limit for detector pulse speed by transitioning from the slow transit-time-limited response which depends on the bulk carrier transport mechanism, to the ultrafast dispersion-limited response which depends on the spatial spreading of the collected carrier packet. Furthermore, the proposed structure is the practical approach for achieving stable avalanche multiplication gain in large-area direct radiation detectors., Comment: 14 pages, 4 figures

Published
2012
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8. Solid-State Charpak Detector with Unipolar and Ultrafast Time-Differential Pulse Response

Author

Goldan, A. H., Tousignant, O., Rowlands, J. A., and Karim, K. S.

Subjects
Physics - Instrumentation and Detectors
Abstract

For the first time we have fabricated a high granularity micropattern solid-state detector (MSSD) with the unipolar time-differential property for ultrafast pulse response. Optical, x-ray, and gamma-ray photoconductivity measurements prove the unipolar time-differential response with a speed improvement factor of ~400 for amorphous selenium MSSD. The significance of the results presented here is the ability to reach the intrinsic physical limit for detector pulse speed by transitioning from the transit-time-limited response, which depends on the bulk carrier transport mechanism, to range-limited response set by the spatial dispersion of the photo-induced carrier cloud. Furthermore, the combination of the time-differential and the avalanche-multiplication properties of the proposed micropattern solid-state detector can yield another great leap forward in the field of radiation detectors with applications ranging from high-energy, nuclear, and astro- physics, to industrial and medical diagnostics, and crystallography., Comment: This paper has been withdrawn by the author due to a crucial error in the discussion. Also, a newer version has been uploaded with a new title

Published
2012

9. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

Author

Meng, B., Abdullahi, A., Ferreira, I. A. T. M., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P. P., Fatihi, S., Rathore, S., Zepeda, S. K., Papa, G., Kemp, S. A., Ikeda, T., Toyoda, M., Tan, T. S., Kuramochi, J., Mitsunaga, S., Ueno, T., Shirakawa, K., Takaori-Kondo, A., Brevini, T., Mallery, D. L., Charles, O. J., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Ouwehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Maxwell, P., Shaw, A., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Fawke, S., Gleadall, N., Grenfell, R., Hinch, A., Jackson, S., Jarvis, I., Krishna, B., Nice, F., Omarjee, O., Perera, M., Potts, M., Richoz, N., Romashova, V., Stefanucci, L., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Butcher, H., Caputo, D., Chandler, M., Chinnery, P., Clapham-Riley, D., Dewhurst, E., Fernandez, C., Furlong, A., Graves, B., Gray, J., Hein, S., Ivers, T., Le Gresley, E., Linger, R., Kasanicki, M., King, R., Meloy, S., Moulton, A., Muldoon, F., Ovington, N., Papadia, S., Penkett, C. J., Phelan, I., Ranganath, V., Paraschiv, R., Sage, A., Sambrook, J., Scholtes, I., Schon, K., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Butlertanaka, E. P., Tanaka, Y. L., Ito, J., Uriu, K., Kosugi, Y., Suganami, M., Oide, A., Yokoyama, M., Chiba, M., Motozono, C., Nasser, H., Shimizu, R., Kitazato, K., Hasebe, H., Irie, T., Nakagawa, S., Wu, J., Takahashi, M., Fukuhara, T., Shimizu, K., Tsushima, K., Kubo, H., Kazuma, Y., Nomura, R., Horisawa, Y., Nagata, K., Kawai, Y., Yanagida, Y., Tashiro, Y., Tokunaga, K., Ozono, S., Kawabata, R., Morizako, N., Sadamasu, K., Asakura, H., Nagashima, M., Yoshimura, K., Cardenas, P., Munoz, E., Barragan, V., Marquez, S., Prado-Vivar, B., Becerra-Wong, M., Caravajal, M., Trueba, G., Rojas-Silva, P., Grunauer, M., Gutierrez, B., Guadalupe, J. J., Fernandez-Cadena, J. C., Andrade-Molina, D., Baldeon, M., Pinos, A., Bowen, J. E., Joshi, A., Walls, A. C., Jackson, L., Martin, D., Smith, K. G. C., Bradley, J., Briggs, J. A. G., Choi, J., Madissoon, E., Meyer, K. B., Mlcochova, P., Ceron-Gutierrez, L., Doffinger, R., Teichmann, S. A., Fisher, A. J., Pizzuto, M. S., de Marco, A., Corti, D., Hosmillo, M., Lee, J. H., James, L. C., Thukral, L., Veesler, D., Sigal, A., Sampaziotis, F., Goodfellow, I. G., Sato, K., and Gupta, R. K.

Subjects
Adult, Male, COVID-19 Vaccines, Virus Replication, Membrane Fusion, Antibodies, Cell Line, Tissue Culture Techniques, Chlorocebus aethiops, 80 and over, Animals, Humans, Viral, Neutralizing, Lung, Aged, Multidisciplinary, Virulence, SARS-CoV-2, Immune Sera, Cell Membrane, Serine Endopeptidases, COVID-19, Convalescence, Middle Aged, Virus Internalization, Spike Glycoprotein, Intestines, Coronavirus, Nasal Mucosa, Mutation, Female, Angiotensin-Converting Enzyme 2, Aged, 80 and over, Antibodies, Neutralizing, Antibodies, Viral, Spike Glycoprotein, Coronavirus
Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.

Published
2022
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11. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Author

Collier, D. A., Ferreira, I. A. T. M., Kotagiri, P., Datir, R. P., Lim, E. Y., Touizer, E., Meng, B., Abdullahi, A., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Maxwell, P., Shaw, A., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Gleadall, N., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Krishna, B., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Potts, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., D. D. De Bie E. M., Bunclark, K., Josipovic, M., Mackay, M., Michael, A., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Smith, K. G. C., Bradley, J. R., Ceron-Gutierrez, L., Cortes-Acevedo, P., Barcenas-Morales, G., Linterman, M. A., Mccoy, L. E., Davis, C., Thomson, E., Mckinney, E., Doffinger, R., Wills, M., Gupta, R. K., Collier, Dami A [0000-0001-5446-4423], Datir, Rawlings P [0000-0003-0521-2144], Smith, Kenneth GC [0000-0003-3829-4326], Linterman, Michelle A [0000-0001-6047-1996], McCoy, Laura E [0000-0001-9503-7946], Thomson, Emma [0000-0003-1482-0889], Lyons, Paul A [0000-0001-7035-8997], Gupta, Ravindra K [0000-0001-9751-1808], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, Aging, Secondary, T-Lymphocytes, Antibodies, Viral, Neutralization, 0302 clinical medicine, 80 and over, Medicine, Viral, Neutralizing, Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing, Autoantibodies, B-Lymphocytes, BNT162 Vaccine, COVID-19 Vaccines, Female, Health Personnel, Humans, Immunization, Secondary, Immunoglobulin A, Immunoglobulin Class Switching, Immunoglobulin G, Immunologic Memory, Inflammation, Interferon-gamma, Interleukin-2, Middle Aged, SARS-CoV-2, Somatic Hypermutation, Immunoglobulin, Spike Glycoprotein, Coronavirus, Vaccination, Vaccines, Synthetic, Immunity, Sars-Cov-2, Vaccines, education.field_of_study, Multidisciplinary, biology, Spike Glycoprotein, 030220 oncology & carcinogenesis, Antibody, Population, Article, Antibodies, 03 medical and health sciences, Immune system, Immunoglobulin, education, business.industry, Synthetic, Somatic Hypermutation, Vaccine efficacy, Coronavirus, 030104 developmental biology, Immunization, Immunology, biology.protein, business
Abstract

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating., Nature, 596 (7872), ISSN:0028-0836, ISSN:1476-4687

Published
2021
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12. SARS-CoV-2 evolution during treatment of chronic infection

Author

Kemp, S. A., Collier, D. A., Datir, R. P., Ferreira, I. A. T. M., Gayed, S., Jahun, A., Hosmillo, M., Rees-Spear, C., Mlcochova, P., Lumb, I. U., Roberts, D. J., Chandra, A., Temperton, N., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Gleadall, N., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Estee Torok, M., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Abnizova, I., Aigrain, L., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Betteridge, E., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Bonfield, J., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Goodwin, S., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Liddle, J., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Makunin, A., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mccarthy, S., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Puethe, C., Quail, M., Rajan, D., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Scott, C., Seekings, P., Shirley, L., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Jansen Van, P., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Whitwham, A., Widaa, S., Williams, M., Wilson, M., Wright, S., Farr, B. W., Quail, M. A., Thurston, S. A. J., Bronner, I. F., Redshaw, N. M., Lensing, S. V., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Sharrocks, K., Blane, E., Modis, Y., Leigh, K. E., Briggs, J. A. G., van Gils, M. J., Smith, K. G. C., Bradley, J. R., Doffinger, R., Ceron-Gutierrez, L., Barcenas-Morales, G., Pollock, D. D., Goldstein, R. A., Smielewska, A., Skittrall, J. P., Gouliouris, T., Goodfellow, I. G., Gkrania-Klotsas, E., Illingworth, C. J. R., Mccoy, L. E., Gupta, R. K., Medical Microbiology and Infection Prevention, AII - Infectious diseases, Collier, Dami A [0000-0001-5446-4423], Jahun, Aminu [0000-0002-4585-1701], Temperton, Nigel [0000-0002-7978-3815], Modis, Yorgo [0000-0002-6084-0429], Briggs, John AG [0000-0003-3990-6910], Goldstein, Richard A [0000-0001-5148-4672], Skittrall, Jordan P [0000-0002-8228-3758], Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], McCoy, Laura E [0000-0001-9503-7946], Gupta, Ravindra K [0000-0001-9751-1808], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Time Factors, viruses, Passive, Antibodies, Viral, CITIID-NIHR BioResource COVID-19 Collaboration, 2.1 Biological and endogenous factors, Viral, Aetiology, Neutralizing, Lung, Phylogeny, neutralising antibodies, Infectivity, education.field_of_study, Genome, Multidisciplinary, Alanine, biology, High-Throughput Nucleotide Sequencing, Viral Load, Spike Glycoprotein, Virus Shedding, Adenosine Monophosphate, Aged, Antibodies, Neutralizing, COVID-19, Chronic Disease, Genome, Viral, Humans, Immune Evasion, Immune Tolerance, Immunization, Passive, Immunosuppression Therapy, Mutagenesis, Mutant Proteins, Mutation, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Evolution, Molecular, Infectious Diseases, Pneumonia & Influenza, Antibody, Infection, Viral load, Biotechnology, Evolution, General Science & Technology, antibody escape, Convalescent plasma, 030106 microbiology, Population, evasion, Antibodies, Virus, Article, Vaccine Related, resistance, 03 medical and health sciences, Immune system, COVID-19 Genomics UK (COG-UK) Consortium, Biodefense, Genetics, Viral shedding, education, COVID-19 Serotherapy, QR355, Prevention, Wild type, Molecular, Pneumonia, Virology, COVID-19 Drug Treatment, Coronavirus, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, biology.protein, Immunization, immune suppression, mutation
Abstract

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Published
2021

13. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

Author

Bergamaschi, L., Mescia, F., Turner, L., Hanson, A. L., Kotagiri, P., Dunmore, B. J., Ruffieux, H., de Sa, A., Huhn, O., Morgan, M. D., Gerber, P. P., Wills, M. R., Baker, S., Calero-Nieto, F. J., Doffinger, R., Dougan, G., Elmer, A., Goodfellow, I. G., Gupta, R. K., Hosmillo, M., Hunter, K., Kingston, N., Lehner, P. J., Matheson, N. J., Nicholson, J. K., Petrunkina, A. M., Richardson, S., Saunders, C., Thaventhiran, J. E. D., Toonen, E. J. M., Weekes, M. P., Gottgens, B., Toshner, M., Hess, C., Bradley, J. R., Lyons, P. A., Smith, K. G. C., Allison, J., Ansaripour, A., Betancourt, A., Bong, S. -H., Bower, G., Bucke, A., Bullman, B., Bunclark, K., Butcher, H., Calder, J., Canna, L., Caputo, D., Clapham-Riley, D., Cossetti, C., Coudert, J. D., de Bie, E. M. D. D., Dewhurst, E., di Stefano, G., Domingo, J., Epping, M., Fahey, C., Fawke, S., Fuller, S., Furlong, A., Gleadall, N., Graf, S., Graves, B., Gray, J., Grenfell, R., Harris, J., Hewitt, S., Hinch, A., Hodgson, J., Holmes, E., Huang, C., Ivers, T., Jackson, S., Jarvis, I., Jones, E., Kennet, J., Jose, S., Josipovic, M., Kasanicki, M., Kourampa, J., Laurenti, E., Legchenko, E., Le Gresley, E., Lewis, D., Linger, R., Mackay, M., Marioni, J. C., Marsden, J., Martin, J., Matara, C., Meadows, A., Meloy, S., Mende, N., Michael, A., Michel, R., Mwaura, L., Muldoon, F., Nice, F., O'Brien, C., O'Donnell, C., Okecha, G., Omarjee, O., Ovington, N., Owehand, W. H., Papadia, S., Patterson, C., Perera, M., Phelan, I., Pointon, L., Polgarova, P., Polwarth, G., Pond, N., Price, J., Publico, C., Rastall, R., Ribeiro, C., Richoz, N., Romashova, V., Rossi, S., Rowlands, J., Ruffolo, V., Yarkoni, N. S., Sharma, R., Shih, J., Selvan, M., Spencer, S., Stefanucci, L., Stark, H., Stephens, J., Stirrups, K. E., Strezlecki, M., Summers, C., Sutcliffe, R., Tilly, T., Tong, Z., Tordesillas, H., Treacy, C., Townsend, P., Walker, N., Webster, J., Wilson, N. K., Wood, J., Wylot, M., Yong, C., Mescia, Federica [0000-0002-2759-4027], Hanson, Aimee [0000-0002-0231-8771], Ruffieux, Helene [0000-0002-7113-2540], Morgan, Michael [0000-0003-0757-0711], Wills, Mark [0000-0001-8548-5729], Baker, Stephen [0000-0003-1308-5755], Dougan, Gordon [0000-0003-0022-965X], Gupta, Ravindra [0000-0001-9751-1808], Hosmillo, Myra [0000-0002-3514-7681], Kingston, Nathalie [0000-0002-9190-2231], Lehner, Paul [0000-0001-9383-1054], Matheson, Nicholas [0000-0002-3318-1851], Richardson, Sylvia [0000-0003-1998-492X], Thaventhiran, James [0000-0001-8616-074X], Weekes, Michael [0000-0003-3196-5545], Gottgens, Berthold [0000-0001-6302-5705], Toshner, Mark [0000-0002-3969-6143], Bradley, John [0000-0002-7774-8805], Lyons, Paul [0000-0001-7035-8997], Smith, Kenneth [0000-0003-3829-4326], Apollo - University of Cambridge Repository, and Collaboration, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Immunology, Disease, macromolecular substances, immune pathology, Biology, CD8-Positive T-Lymphocytes, Systemic inflammation, Lymphocyte Activation, Severity of Illness Index, Article, Oxidative Phosphorylation, 03 medical and health sciences, recovery, 0302 clinical medicine, Immunophenotyping, Immune system, Immunopathology, Bystander effect, medicine, Immunology and Allergy, Humans, complement, Longitudinal Studies, systemic inflammation, bystander CD8+ T cell, SARS-CoV-2, Gene Expression Profiling, Interleukin, COVID-19, interferon, Prognosis, TNF-α, Biomarkers, Cytokines, Disease Susceptibility, Host-Pathogen Interactions, Inflammation Mediators, Phenotype, Reactive Oxygen Species, Transcriptome, 030104 developmental biology, Infectious Diseases, 030220 oncology & carcinogenesis, Tumor necrosis factor alpha, medicine.symptom
Abstract

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications., Graphical abstract, The immune changes that underlie COVID-19 severity have not been fully defined. By analyzing a longitudinal cohort of COVID-19 patients and integrating inflammatory factors, immunophenotyping, and transcriptome data, Bergamaschi et al. identify both early and persistent immune changes that distinguish mild and/or asymptomatic from more severe disease.

Published
2021

15. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies

Author

Collier, D. A., De Marco, A., Ferreira, I. A. T. M., Meng, B., Datir, R. P., Walls, A. C., Kemp, S. A., Bassi, J., Pinto, D., Silacci-Fregni, C., Bianchi, S., Tortorici, M. A., Bowen, J., Culap, K., Jaconi, S., Cameroni, E., Snell, G., Pizzuto, M. S., Pellanda, A. F., Garzoni, C., Riva, A., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Mccoy, L. E., Smith, K. G. C., Bradley, J. R., Temperton, N., Ceron-Gutierrez, L., Barcenas-Morales, G., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Torok, M. E., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., Hosmillo, M., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Betteridge, E., Farr, B. W., Goodwin, S., Quail, M. A., Scott, C., Shirley, L., Thurston, S. A. J., Rajan, D., Bronner, I. F., Aigrain, L., Redshaw, N. M., Lensing, S. V., Mccarthy, S., Makunin, A., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Bonfield, J., Puethe, C., Whitwham, A., Liddle, J., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Abnizova, I., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Quail, M., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Seekings, P., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Van, P. J., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Widaa, S., Williams, M., Wilson, M., Wright, S., Harvey, W., Virgin, H. W., Lanzavecchia, A., Piccoli, L., Doffinger, R., Wills, M., Veesler, D., Corti, D., and Gupta, R. K.

Subjects
0301 basic medicine, Male, Models, Molecular, Passive, Antibodies, Viral, Neutralization, 0302 clinical medicine, Models, Monoclonal, 80 and over, Viral, Neutralizing antibody, Neutralizing, Aged, 80 and over, Vaccines, Vaccines, Synthetic, Multidisciplinary, biology, Antibodies, Monoclonal, C500, Middle Aged, C700, Spike Glycoprotein, Vaccination, Spike Glycoprotein, Coronavirus, Female, Angiotensin-Converting Enzyme 2, Antibody, Aged, Antibodies, Neutralizing, COVID-19, COVID-19 Vaccines, HEK293 Cells, Humans, Immune Evasion, Immunization, Passive, Mutation, Neutralization Tests, SARS-CoV-2, medicine.drug_class, B100, Monoclonal antibody, Antibodies, Virus, 03 medical and health sciences, Immune system, medicine, COVID-19 Serotherapy, QR355, Synthetic, Molecular, Virology, Coronavirus, 030104 developmental biology, Immunization, biology.protein, 030217 neurology & neurosurgery
Abstract

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.

Published
2021

16. Intersectionality and Invisible Victims: Reflections on Data Challenges and Vicarious Trauma in Femicide, Family and Intimate Partner Homicide Research

Author

Cullen, P, Dawson, M, Price, J, Rowlands, J, Cullen, P, Dawson, M, Price, J, and Rowlands, J

Abstract

Rigorous, comprehensive and timely research are the cornerstone of social and transformative change. For researchers responding to femicide, family and intimate partner homicide, there are substantial challenges around accessing robust data that is complete and fully representative of the experiences and social identities of those affected. This raises questions of how certain social identities are privileged and how the lens of intersectionality may be constrained or enabled through research. Further, there is limited insight into the emotional labour and safety for researchers, and how they experience and mitigate vicarious trauma. We examine these issues through a shared critical reflection and conclude with key recommendations to address the challenges and issues identified. Four researchers examining and responding to femicide, family and intimate partner homicide in Australia, Canada and the United Kingdom shared and evaluated their critical reflection. We drew on our experiences and offer insights into processes, impacts and unintended consequences of fatality reviews and research initiatives. There are substantial limitations in accessibility and completeness of data, which has unintended consequences for the construction of social identities of those affected, including how multiple forms of exclusion and structural oppression are represented. Our experiences as researchers are complex and have driven us to implement strategies to mitigate vicarious trauma. We assert that these issues can be addressed by reconceptualizing the goals of data collection and fostering collaborative discussions among those involved in data collection and violence prevention to strengthen research, prevention efforts and safety for all involved.

Published
2021

23. Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19

Author

Jones, N. K., Rivett, L., Sparkes, D., Forrest, S., Sridhar, S., Young, J., Pereira-Dias, J., Cormie, C., Gill, H., Reynolds, N., Wantoch, M., Routledge, M., Warne, B., Levy, J., Jimenez, W. D. C., Samad, F. N. B., Mcnicholas, C., Ferris, M., Gray, J., Gill, M., Curran, M. D., Fuller, S., Chaudhry, A., Shaw, A., Bradley, J. R., Hannon, G. J., Goodfellow, I. G., Dougan, G., Smith, K. G. C., Lehner, P. J., Wright, G., Matheson, N. J., Baker, S., Weekes, M. P., Bradley, J., Goodfellow, I., Gupta, R., Lyons, P. A., Torok, M. E., Toshner, M., Kean, I., Caddy, S., Caller, L., Feltwell, T., Hall, G., Hamilton, W., Hosmillo, M., Houldcroft, C., Jahun, A., Khokhar, F., Meredith, L., Yakovleva, A., Butcher, H., Caputo, D., Clapham-Riley, D., Dolling, H., Furlong, A., Graves, B., Gresley, E. L., Kingston, N., Papadia, S., Stark, H., Stirrups, K. E., Webster, J., Calder, J., Harris, J., Hewitt, S., Kennet, J., Meadows, A., Rastall, R., Brien, C. O., Price, J., Publico, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Hannon, G., Brookes, K., Canna, L., Cruz, I., Dempsey, K., Elmer, A., Escoffery, N., Jones, H., Ribeiro, C., Saunders, C., Wright, A., Nyagumbo, R., Roberts, A., Bucke, A., Hargreaves, S., Johnson, D., Narcorda, A., Read, D., Sparke, C., Worboys, L., Lagadu, K., Mactavous, L., Gould, T., Raine, T., Mather, C., Ramenatte, N., Vallier, A. -L., Kasanicki, M., Eames, P. -J., Thake, L., Bartholomew, N., Brown, N., Curran, M., Parmar, S., Zhang, H., Bowring, A., Martell, G., Quinnell, N., Wright, J., Murphy, H., Dunmore, B. J., Legchenko, E., Graf, S., Huang, C., Hodgson, J., Hunter, K., Martin, J., Mescia, F., Odonnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Tong, Z., Treacy, C., Wood, J., Bergamaschi, L., Betancourt, A., Bowyer, G., De Sa, A., Epping, M., Hinch, A., Huhn, O., Jarvis, I., Lewis, D., Marsden, J., Mccallum, S., Nice, F., Omarjee, O., Perera, M., Romashova, N., Strezlecki, M., Yarkoni, N. S., Turner, L., Bailey, B., Doughton, R., Workman, C., Trotter, C., David, W., Jimenez, C., Jones, Nick K [0000-0003-4475-7761], Sridhar, Sushmita [0000-0001-7453-7482], Hannon, Gregory J [0000-0003-4021-3898], Goodfellow, Ian G [0000-0002-9483-510X], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], Weekes, Michael P [0000-0003-3196-5545], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Infectious Disease Transmission, global health, Occupational safety and health, Hospitals, University, Patient-to-Professional, 0302 clinical medicine, COVID-19 Testing, Patient Admission, Nasopharynx, Pandemic, Epidemiology, Prevalence, Medicine, Infection control, Mass Screening, 030212 general & internal medicine, Viral, Biology (General), Family Characteristics, General Neuroscience, Infectious, human biology, virus diseases, General Medicine, Middle Aged, Hospitals, 3. Good health, virology, Community-Acquired Infections, Occupational Diseases, England, epidemiology, Female, medicine.symptom, Symptom Assessment, Coronavirus Infections, Hospital Units, Adult, medicine.medical_specialty, Infectious Disease Transmission, Patient-to-Professional, QH301-705.5, Health Personnel, infectious disease, Science, Pneumonia, Viral, Real-Time Polymerase Chain Reaction, Asymptomatic, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Betacoronavirus, Disease Transmission, Disease Transmission, Infectious, Humans, human, Human Biology and Medicine, Hospitals, Teaching, Pandemics, Mass screening, Asymptomatic Diseases, emerging pathogens, University, Infection Control, General Immunology and Microbiology, business.industry, Clinical Laboratory Techniques, SARS-CoV-2, Teaching, COVID-19, Pneumonia, medicine, occupational health, Contact Tracing, Program Evaluation, 030104 developmental biology, Epidemiology and Global Health, Emergency medicine, business, Research Advance, Contact tracing
Abstract

Previously, we showed that 3% (31/1032)of asymptomatic healthcare workers (HCWs) from a large teaching hospital in Cambridge, UK, tested positive for SARS-CoV-2 in April 2020. About 15% (26/169) HCWs with symptoms of coronavirus disease 2019 (COVID-19) also tested positive for SARS-CoV-2 (Rivett et al., 2020). Here, we show that the proportion of both asymptomatic and symptomatic HCWs testing positive for SARS-CoV-2 rapidly declined to near-zero between 25th April and 24th May 2020, corresponding to a decline in patient admissions with COVID-19 during the ongoing UK ‘lockdown’. These data demonstrate how infection prevention and control measures including staff testing may help prevent hospitals from becoming independent ‘hubs’ of SARS-CoV-2 transmission, and illustrate how, with appropriate precautions, organizations in other sectors may be able to resume on-site work safely.

Published
2020

24. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission

Author

Rivett, L., Sridhar, S., Sparkes, D., Routledge, M., Jones, N. K., Forrest, S., Young, J., Pereira-Dias, J., Hamilton, W. L., Ferris, M., Torok, M. E., Meredith, L., Curran, M. D., Fuller, S., Chaudhry, A., Shaw, A., Samworth, R. J., Bradley, J. R., Dougan, G., Smith, K. G. C., Lehner, P. J., Matheson, N. J., Wright, G., Goodfellow, I. G., Baker, S., Weekes, M. P., Lyons, P. A., Toshner, M., Warne, B., Scott, J. B., Cormie, C., Gill, H., Kean, I., Maes, M., Reynolds, N., Wantoch, M., Caddy, S., Caller, L., Feltwell, T., Hall, G., Hosmillo, M., Houldcroft, C., Jahun, A., Khokhar, F., Yakovleva, A., Butcher, H., Caputo, D., Clapham-Riley, D., Dolling, H., Furlong, A., Graves, B., Gresley, E. L., Kingston, N., Papadia, S., Stark, H., Stirrups, K. E., Webster, J., Calder, J., Harris, J., Hewitt, S., Kennet, J., Meadows, A., Rastall, R., Brien, C. O., Price, J., Publico, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Brookes, K., Canna, L., Cruz, I., Dempsey, K., Elmer, A., Escoffery, N., Jones, H., Ribeiro, C., Saunders, C., Wright, A., Nyagumbo, R., Roberts, A., Bucke, A., Hargreaves, S., Johnson, D., Narcorda, A., Read, D., Sparke, C., Warboys, L., Lagadu, K., Mactavous, L., Gould, T., Raine, T., Mather, C., Ramenatte, N., Vallier, A. -L., Kasanicki, M., Eames, P. -J., Mcnicholas, C., Thake, L., Bartholomew, N., Brown, N., Parmar, S., Zhang, H., Bowring, A., Martell, G., Quinnell, N., Wright, J., Murphy, H., Dunmore, B. J., Legchenko, E., Graf, S., Huang, C., Hodgson, J., Hunter, K., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Tong, Z., Treacy, C., Wood, J., Bergamaschi, L., Betancourt, A., Bowyer, G., A. D., Sa, Epping, M., Hinch, A., Huhn, O., Jarvis, I., Lewis, D., Marsden, J., Mccallum, S., Nice, F., Rivett, Lucy [0000-0002-2781-9345], Lehner, Paul J [0000-0001-9383-1054], Matheson, Nicholas J [0000-0002-3318-1851], Goodfellow, Ian G [0000-0002-9483-510X], Weekes, Michael P [0000-0003-3196-5545], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, medicine, global health, 0302 clinical medicine, COVID-19 Testing, Epidemiology, Pandemic, Health care, Infection control, 030212 general & internal medicine, Viral, Biology (General), Asymptomatic Infections, Nose, 0303 health sciences, Transmission (medicine), COVID-19, SARS-CoV-2, emerging pathogens, epidemiology, human, human biology, infectious disease, occupational health, virology, virus, Betacoronavirus, COVID-19 Vaccines, Coronavirus Infections, Female, Humans, Infection Control, Pandemics, Pneumonia, Viral, Real-Time Polymerase Chain Reaction, United Kingdom, Clinical Laboratory Techniques, Health Personnel, General Neuroscience, virus diseases, General Medicine, 3. Good health, medicine.anatomical_structure, medicine.symptom, Research Article, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), QH301-705.5, Science, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, Asymptomatic, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Throat, Infectious disease (athletes), Human Biology and Medicine, 030304 developmental biology, General Immunology and Microbiology, business.industry, Pneumonia, 030104 developmental biology, Epidemiology and Global Health, Carriage, business
Abstract

Significant differences exist in the availability of healthcare worker (HCW) SARS-CoV-2 testing between countries, and existing programmes focus on screening symptomatic rather than asymptomatic staff. Over a 3 week period (April 2020), 1032 asymptomatic HCWs were screened for SARS-CoV-2 in a large UK teaching hospital. Symptomatic staff and symptomatic household contacts were additionally tested. Real-time RT-PCR was used to detect viral RNA from a throat+nose self-swab. 3% of HCWs in the asymptomatic screening group tested positive for SARS-CoV-2. 17/30 (57%) were truly asymptomatic/pauci-symptomatic. 12/30 (40%) had experienced symptoms compatible with coronavirus disease 2019 (COVID-19)>7 days prior to testing, most self-isolating, returning well. Clusters of HCW infection were discovered on two independent wards. Viral genome sequencing showed that the majority of HCWs had the dominant lineage B∙1. Our data demonstrates the utility of comprehensive screening of HCWs with minimal or no symptoms. This approach will be critical for protecting patients and hospital staff., eLife digest Patients admitted to NHS hospitals are now routinely screened for SARS-CoV-2 (the virus that causes COVID-19), and isolated from other patients if necessary. Yet healthcare workers, including frontline patient-facing staff such as doctors, nurses and physiotherapists, are only tested and excluded from work if they develop symptoms of the illness. However, there is emerging evidence that many people infected with SARS-CoV-2 never develop significant symptoms: these people will therefore be missed by ‘symptomatic-only’ testing. There is also important data showing that around half of all transmissions of SARS-CoV-2 happen before the infected individual even develops symptoms. This means that much broader testing programs are required to spot people when they are most infectious. Rivett, Sridhar, Sparkes, Routledge et al. set out to determine what proportion of healthcare workers was infected with SARS-CoV-2 while also feeling generally healthy at the time of testing. Over 1,000 staff members at a large UK hospital who felt they were well enough to work, and did not fit the government criteria for COVID-19 infection, were tested. Amongst these, 3% were positive for SARS-CoV-2. On closer questioning, around one in five reported no symptoms, two in five very mild symptoms that they had dismissed as inconsequential, and a further two in five reported COVID-19 symptoms that had stopped more than a week previously. In parallel, healthcare workers with symptoms of COVID-19 (and their household contacts) who were self-isolating were also tested, in order to allow those without the virus to quickly return to work and bolster a stretched workforce. Finally, the rates of infection were examined to probe how the virus could have spread through the hospital and among staff – and in particular, to understand whether rates of infection were greater among staff working in areas devoted to COVID-19 patients. Despite wearing appropriate personal protective equipment, healthcare workers in these areas were almost three times more likely to test positive than those working in areas without COVID-19 patients. However, it is not clear whether this genuinely reflects greater rates of patients passing the infection to staff. Staff may give the virus to each other, or even acquire it at home. Overall, this work implies that hospitals need to be vigilant and introduce broad screening programmes across their workforces. It will be vital to establish such approaches before ‘lockdown’ is fully lifted, so healthcare institutions are prepared for any second peak of infections.

Published
2020

25. The Effect of Aspect Ratio on Wall Pressure Fluctuations at a Wing-Plate Junction

Author

Awasthi, M, Rowlands, J, Moreau, DJ, Doolan, CJ, Awasthi, M, Rowlands, J, Moreau, DJ, and Doolan, CJ

Abstract

Measurements of the wall pressure fluctuations near a wing-plate junction were made for wings with three different aspect ratios (AR) of 0.2, 0.5, and 1.0 at several angles of attack. The chord-based Reynolds number for each wing was 274,000. The results show that the wall pressure fluctuations are a function of wing AR for cases where AR≤ 1.0. For each wing, the pressure fluctuations are highest upstream of the wing leading-edge due to three-dimensional flow separation; wings with AR = 1.0 and 0.5 show comparable levels, while those with AR = 0.2 show lower fluctuation levels over a wide frequency range. Downstream of the leading-edge, the pressure fluctuations decay rapidly on both sides of the wing until the maximum thickness location after which little variation is observed. The pressure fluctuations downstream of the leading-edge on the suction-side were observed to be comparable for AR = 0.2 and 0.5, while those for AR = 1.0 were higher in magnitude. On the pressure-side, the pressure fluctuations near the leading-edge are a weak function of AR; however, those further downstream remain independent of AR. The pressure fluctuations aft of the wing on the suction-side are more coherent for lower ARs and show higher convection velocity, possibly due to an interaction between the tip and the junction flows for lower ARs.

Published
2020

27. The health consequences of early soy consumption

Author

Badger, Thomas M., Ronis, Martin J.J., Hakkak, Reza, Rowlands, J. Craig, and Korourian, Soheila

Subjects
Soyfoods -- Health aspects, Infant formulas -- Health aspects, Medicine, Preventive -- Planning, Food/cooking/nutrition
Abstract

Infants fed soy formula are the segment of the U. S. population that consumes the most soy. Before birth and after weaning, most Americans are not exposed to appreciable levels of soyfoods other than foods that have small amounts of processed soy components. The opposite scenario occurs in Asia, because Asians are more likely to consume relatively high levels of soyfoods throughout life, except between birth and weaning, when breastfeeding or milk-based formula are common. Soy formula is made with soy protein isolate containing isoflavones (SPI+) and supports normal growth and development in term infants. Recent data suggest that there are no long-term adverse effects of early exposure to soy formula through young adulthood. It is as yet unknown whether soy formula consumption by infants will result in health problems or benefits upon aging, but multigenerational animal studies with diets made with SPI+ have not revealed any problems. Soy isoflavones can function as estrogen agonists, antagonists or selective estrogen receptor modulators, depending on the conditions, and much research has focused on health effects of purified isoflavones. Results from several studies suggest that the effects of diets made with SPI+ differ significantly from those of diets to which purified soy isoflavones are added. Furthermore, it seems that soy protein processed to contain lower levels of isoflavones also provides significant health benefits. Further research is needed to confirm the results of the few studies that have been conducted and new studies are needed to investigate the more subtle effects that could occur during development or that could surface later in life. KEY WORDS: * soy * genistein * development * infant formula * disease prevention

Published
2002

28. Soy and whey proteins downregulate DMBA-induced liver and mammary gland CYP1 expression in female rats. (Nutrition and Cancer)

Author

Rowlands, J. Craig, He, Ling, Hakkak, Reza, Ronis, Martin J.J., and Badger, Thomas M.

Subjects
Protein metabolism -- Physiological aspects, Whey products -- Health aspects, Soyfoods -- Health aspects, Diet in disease -- Research, Cytochrome P-450 -- Health aspects, Cancer -- Health aspects, Food/cooking/nutrition
Abstract

One possible mechanism by which diet may reduce cancer risk is through enhancement of metabolic systems that prevent activation of carcinogens or accelerate carcinogen inactivation. We studied the effects of diet and 7,12-dimethylbenz-(a)anthracene (DMBA) on hepatic and mammary gland CYP1A1, CYP1A2 and CYP1B1 enzymes in female Sprague-Dawley rats. Diets (AIN-93G) were fed from conception to adulthood, and DMBA was given by oral gavage at age 48-50 d. The protein sources of diets were casein (CAS), soy protein isolate (SPI) or whey protein hydrolysate (WPH). The DMBA-induced hepatic ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase activities and CYP1A1 protein and mRNA expression were lower (P < 0.05) in SPI-fed rats compared with those fed casein. Differences in mammary gland CYP1 expression were also observed with decreased DMBA induction (P < 0.05) of all three CYP1 proteins and mRNAs in rats fed either SPI or WPH compared with those fed CAS. Most notable were the decreased constitutive and DMBA-induced mammary gland expression of CYP1B1 protein of 93 and 96%, respectively, in the SPI-fed rats relative to the CAS-fed controls. The diet-induced changes in CYP1 enzyme expression were consistent with changes in the AhR and ARNT transcription factors that regulate them. Decreased (P < 0.05) mammary constitutive AhR and ARNT proteins were measured in SPI-fed rats. There was also a 100% increase in constitutive AhR protein in the WPH-fed rats that paralleled a 100% increase in constitutive CYP1B1 protein in the mammary gland. These results demonstrate the importance of diet in regulation of phase I metabolism in liver and mammary gland, and suggest a potential mechanism by which soy or whey proteins reduce DMBA-induced mammary tumor incidence. KEY WORDS: * cytochrome P450 * rats * soy protein * whey protein * casein.

Published
2001

30. Vital Signs: Update on Zika Virus–Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure — U.S. Zika Pregnancy Registry, 2016

Author

Reynolds, M. R., Jones, A. M., Petersen, E. E., Lee, E. H., Rice, M. E., Bingham, A., Ellington, S. R., Evert, N., Reagan-Steiner, S., Oduyebo, T., Brown, C. M., Martin, S., Ahmad, N., Bhatnagar, J., Macdonald, J., Gould, C., Fine, A. D., Polen, K. D., Lake-Burger, H., Hillard, C. L., Hall, N., Mahsa Yazdy, Slaughter, K., Sommer, J. N., Adamski, A., Raycraft, M., Fleck-Derderian, S., Gupta, J., Newsome, K., Baez-Santiago, M., Slavinski, S., White, J. L., Moore, C. A., Shapiro-Mendoza, C. K., Petersen, L., Boyle, C., Jamieson, D. J., Meaney-Delman, D., Honein, M. A., Adair, J., Ruberto, I., Haselow, D. T., Im, L., Jilek, W., Lehmann, M. S., Olney, R., Porse, C. C., Ramstrom, K. C., Sowunmi, S., Marzec, N. S., Davis, K., Esponda-Morrison, B., Zachariah Fraser, M., O’connor, C. A., Chung, W., Richardson, F., Sexton, T., Stocks, M. E., Woldai, S., Bundek, A. M., Zambri, J., Goldberg, C., Eisenstein, L., Jackson, J., Kopit, R., Logue, T., Mendoza, R., Feldpausch, A., Graham, T., Mann, S., Park, S. Y., Carter, K. K., Potts, E. J., Stevens, T., Simonson, S., Tonzel, J. L., Davis, S., Robinson, S., Hyun, J. K., Jenkins, E. M., Piccardi, M., Reid, L. D., Dunn, J. E., Higgins, C. A., Lin, A. E., Munshi, G. S., Sandhu, K., Scotland, S. J., Soliva, S., Copeland, G., Signs, K. A., Schiffman, E., Byers, P., Hand, S., Mulgrew, C. L., Hamik, J., Koirala, S., Ludwig, L. A., Fredette, C. R., Garafalo, K., Worthington, K., Ropri, A., Ade, J. N., Alaali, Z. S., Blog, D., Brunt, S. J., Bryant, P., Burns, A. E., Carson, K., Dupuis, A. P., Sullivan-Frohm, A., Griffin, J., Hidalgo, C., Lance, L. A., Many, P. S., Naizby, B. E., Polfleit, M. J., Rahman, T., Rem, T., Robbins, A. E., Rowlands, J. V., Seaver, C., Seward, K. A., Smith, L., Sohi, I., Wester, R. E., Bush, S., Dean, A. B., Demarest, V., Dufort, E. M., Furuya, A. M., Fuschino, M., Kulas, K. E., Lamson, D. M., Lee, W. T., Limberger, R., Marchewka, M. J., Popowich, M., St George, K., Wong, S. J., Zeng, L., Glaze, V. H., Souto, M. I., Ackelsberg, J., Alex, B., Ballen, V., Baumgartner, J., Bloch, D., Clark, S., Conners, E., Cooper, H., Davidson, A., Dentinger, C., Deocharan, B., Vito, A., Fu, J., Hrusa, G., Iqbal, M., Iwamoto, M., Jones, L., Kubinson, H., Lash, M., Layton, M., Lee, C. T., Liu, D., Mcgibbon, E., Moy, M., Ngai, S., Parton, H. B., Peterson, E., Poy, J., Rakeman, J., Stoute, A., Thompson, C., Weiss, D., Westheimer, E., Winters, A., Younis, M., Chan, R. L., Cronquist, L. J., Caton, L., Lind, L., Nalluswami, K., Perella, D., Brady, D. S., Gosciminski, M., Mcauley, P., Drociuk, D., Leedom, V., Witrick, B., Bollock, J., Hartel, M. B., Lucinski, L. S., Mcdonald, M., Miller, A. M., Ponson, T. A., Price, L., Nance, A. E., Peterson, D., Cook, S., Martin, B., Oltean, H., Neary, J., Baker, M. A., Cummons, K., Bryan, K., Arnold, K. E., Arth, A. C., Bollweg, B. C., Cragan, J. D., Dawson, A. L., Denison, A. M., Dziuban, E. J., Estetter, L., Silva-Flannery, L., Free, R. J., Galang, R. R., Gary, J., Goldsmith, C. S., Green, C., Hale, G. L., Hayes, H. M., Igbinosa, I., Kelly Keating, M., Khan, S., Kim, S. Y., Lampe, M., Lewis, A., Mai, C., Martines, R. B., Miers, B., Moore, J., Muehlenbachs, A., Nahabedian, J., Panella, A., Parihar, V., Patel, M. M., Brett Rabeneck, D., Rasmussen, S. A., Ritter, J. M., Rollin, D. C., Sanders, J. H., Shieh, W. -J, Simeone, R. M., Simon, E. L., Sims, J. R., Spivey, P. J., Talley-Mcrae, H., Tshiwala, A. K., Maldeghem, K., Viens, L., Wainscott-Sargent, A., Williams, T., and Zaki, S.

Subjects
0301 basic medicine, Gerontology, medicine.medical_specialty, Microcephaly, Health (social science), Epidemiology, Health, Toxicology and Mutagenesis, Vital signs, Congenital Abnormalities, Zika virus, 03 medical and health sciences, Fetus, 0302 clinical medicine, Health Information Management, Central Nervous System Diseases, Pregnancy, Humans, Medicine, Eye Abnormalities, Neural Tube Defects, Registries, 030212 general & internal medicine, Pregnancy Complications, Infectious, Pregnancy registry, biology, Vital Signs, Zika Virus Infection, business.industry, Obstetrics, Public health, Infant, Newborn, Brain, Infant, Gestational age, Zika Virus, General Medicine, biology.organism_classification, medicine.disease, United States, 030104 developmental biology, Female, business
Abstract

Background In collaboration with state, tribal, local, and territorial health departments, CDC established the U.S. Zika Pregnancy Registry (USZPR) in early 2016 to monitor pregnant women with laboratory evidence of possible recent Zika virus infection and their infants. Methods This report includes an analysis of completed pregnancies (which include live births and pregnancy losses, regardless of gestational age) in the 50 U.S. states and the District of Columbia (DC) with laboratory evidence of possible recent Zika virus infection reported to the USZPR from January 15 to December 27, 2016. Birth defects potentially associated with Zika virus infection during pregnancy include brain abnormalities and/or microcephaly, eye abnormalities, other consequences of central nervous system dysfunction, and neural tube defects and other early brain malformations. Results During the analysis period, 1,297 pregnant women in 44 states were reported to the USZPR. Zika virus-associated birth defects were reported for 51 (5%) of the 972 fetuses/infants from completed pregnancies with laboratory evidence of possible recent Zika virus infection (95% confidence interval [CI] = 4%-7%); the proportion was higher when restricted to pregnancies with laboratory-confirmed Zika virus infection (24/250 completed pregnancies [10%, 95% CI = 7%-14%]). Birth defects were reported in 15% (95% CI = 8%-26%) of fetuses/infants of completed pregnancies with confirmed Zika virus infection in the first trimester. Among 895 liveborn infants from pregnancies with possible recent Zika virus infection, postnatal neuroimaging was reported for 221 (25%), and Zika virus testing of at least one infant specimen was reported for 585 (65%). Conclusions and implications for public health practice These findings highlight why pregnant women should avoid Zika virus exposure. Because the full clinical spectrum of congenital Zika virus infection is not yet known, all infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy should receive postnatal neuroimaging and Zika virus testing in addition to a comprehensive newborn physical exam and hearing screen. Identification and follow-up care of infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy and infants with possible congenital Zika virus infection can ensure that appropriate clinical services are available.

Published
2017
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31. Method Protocols for Metabolic and Functional Analysis of the BRIN-BD11 ß-Cell Line: A Preclinical Model for Type 2 Diabetes

Author

Rowlands, J., Walz, N., Rowles, J., Keane, Kevin, Carlessi, Rodrigo, Newsholme, P., Rowlands, J., Walz, N., Rowles, J., Keane, Kevin, Carlessi, Rodrigo, and Newsholme, P.

Abstract

In type 2 diabetes, prolonged dysregulation of signalling and ß-cell metabolic control leads to ß-cell dysfunction, and is increasingly associated with abnormal metabolic states which disrupt normal cellular physiology. Utilization of appropriate ß-cell models enables a systematic approach to understand the impact of perturbations to the biological system. The BRIN-BD11 ß-cell line is a useful, pre-clinical cell model for ß-cell dysfunction associated with type 2 diabetes, among other metabolic disorders. The present chapter describes detection and analysis of ß-cell dysfunction with respect to changes in bioenergetics and metabolism, generation of intracellular reactive oxygen species, and acute and chronic insulin secretion in the BRIN-BD11 cell line.

Published
2019

34. Two-step hybrid calibration of remote microphones

Author

Awasthi, M, Rowlands, J, Moreau, DJ, Doolan, CJ, Awasthi, M, Rowlands, J, Moreau, DJ, and Doolan, CJ

Abstract

A two-step, hybrid procedure to calibrate the remote microphones is presented. The calibration obtained in this manner can be directly applied to the measured pressure spectrum without resorting to any modeling or assumptions about the shape of the calibration curve. To demonstrate an application of the methodology, measurements of wall pressure fluctuations underneath a zero pressure gradient turbulent boundary layer were made. The calibrated pressure spectrum is shown to be qualitatively and quantitatively consistent with previous experimental studies and an empirical model, indicating the accuracy of the hybrid calibration technique.

Published
2018

38. GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation

Author

Carlessi, Rodrigo, Chen, Y., Rowlands, J., Cruzat, Vinicius, Keane, Kevin, Egan, L., Mamotte, Cyril, Stokes, R., Gunton, J., Bittencourt, P., Newsholme, Philip, Carlessi, Rodrigo, Chen, Y., Rowlands, J., Cruzat, Vinicius, Keane, Kevin, Egan, L., Mamotte, Cyril, Stokes, R., Gunton, J., Bittencourt, P., and Newsholme, Philip

Abstract

Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic ß-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in ß-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 ß-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of ß-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1a) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in ß-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated ß-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression.

Published
2017

39. GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation

Author

Carlessi, R, Chen, Y, Rowlands, J, Cruzat, VF, Keane, KN, Egan, L, Mamotte, C, Stokes, R, Gunton, JE, Bittencourt, PIHD, Newsholme, P, Carlessi, R, Chen, Y, Rowlands, J, Cruzat, VF, Keane, KN, Egan, L, Mamotte, C, Stokes, R, Gunton, JE, Bittencourt, PIHD, and Newsholme, P

Abstract

© 2017 The Author(s). Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in β-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 β-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of β-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1α) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in β-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated β-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression.

Published
2017

40. Winter to summer change in vitamin D status reduces systemic inflammation and bioenergetic activity of human peripheral blood mononuclear cells

Author

Calton, E., Keane, Kevin, Raizel, R., Rowlands, J., Soares, Mario, Newsholme, Philip, Calton, E., Keane, Kevin, Raizel, R., Rowlands, J., Soares, Mario, and Newsholme, Philip

Abstract

Background: Vitamin D status [25(OH)D] has recently been reported to be associated with altered cellular bioenergetic profiles of peripheral blood mononuclear cells (PBMCs). No study has tracked the seasonal variation of 25(OH)D and its putative influence on whole body energy metabolism, cellular bioenergetic profiles, inflammatory markers and clinical chemistry. Material and methods: Whole body energy metabolism and substrate utilisation were measured by indirect calorimetry. PBMCs obtained from the same subjects were isolated from whole blood, counted and freshly seeded. Bioenergetic analysis (mitochondrial stress test and glycolysis stress test) was performed using the Seahorse XFe96 flux analyser. 25(OH)D was assessed using the Architect immunoassay method. Results: 25(OH)D increased by a median (IQR) of 14.40 (20.13) nmol/L (<0.001) from winter to summer and was accompanied by significant improvements in indices of insulin sensitivity, McAuley's index (p=0.019) and quantitative insulin sensitivity check index (p=0.028). PBMC mitochondrial parameters basal respiration, non-mitochondrial respiration, ATP production, proton leak, and maximal respiration decreased in summer compared to winter. Similarly, PBMC glycolytic parameters glycolytic activity, glucose response, and glycolytic capacity were all reduced in summer compared to winter. There was also a trend for absolute resting metabolic rate (RMR) to decrease (p=0.066). Markers of systemic inflammation MCP-1, IL-6, IL-8, IL-10, and IL-12p70 decreased significantly in summer compared to winter. Participants who entered winter with a low 25(OH)D (<50 nmol/L), had the greatest alteration in bioenergetic parameters in summer, relative to those with winter 25(OH)D concentrations of 50–75 nmol/L or >75 nmol/L. The absolute change in 25(OH)D was not associated with altered bioenergetics. Conclusion: Seasonal improvements in 25(OH)D was associated with reduced systemic inflammation, PBMC bioenergetic profiles and whol

Published
2017

44. Long-Term Use of Dietary Soy Protein Isolates: Lack of Apparent Toxic Effects?

Author

Badger, Thomas M., Hakkak, Reza, Shelnutt, Susan R., Ronis, Martin J. J., and Rowlands, J. Craig

Subjects
Soybean -- Health aspects, Flavones -- Health aspects, Soyfoods -- Health aspects, Infant formulas -- Analysis, Food/cooking/nutrition
Abstract

Soybeans are considered a valuable source of protein and a health-promoting food source that has been consumed throughout the world for centuries. Soy protein isolate (SPI), first developed more than 50 years ago, is used in formulas for infants allergic to the milk products found in traditional milk-based formulas. Isoflavones are one class of several so-called phytochemicals that are bound to soy proteins in relatively high abundance. These estrogenic compounds are absorbed as aglycones and circulate mainly as glucuronide or sulfate conjugates within mammals. All three of these molecular forms have been reported to possess bioactivity. The circulating and tissue isoflavone concentrations of total isoflavones of infants fed soy-based formulas are high (1-10 [micro]mol/L), actually exceeding those typically reported for adult Asian soy consumers. These concentrations are sufficient to have both estrogen- and nonestrogenmediated effects inasmuch as nanomolar concentrations are reported to transactivate estrogen-dependent reporter genes, and many signal transduction effects occur at low micromolar concentrations. Because soy infant formulas result in high circulating concentrations of bioactive phytochemicals not found in breast milk or milk-based infant formula, we are interested in potential health consequences of soy-based formulas. We studied the SPI used in infant formula in cell culture, multigenerational rat studies, pigs and humans (infants and adults). In these studies, we observed no evidence of toxicity. Our data from chronic animal studies demonstrated that SPI-containing diets prevent incidence, multiplicity and growth of chemically induced mammary and colon tumors, increase activities of phase I and II detoxification systems, and support normal breeding, gestation, lactation, maternal behavior, and growth and development. However, too few studies have been conducted to enable us to determine the long-term consequences of exposure to high concentrations of estrogenic compounds during infancy, a period in which non-soy--consuming infants would not be exposed to such endocrine factors. Thus, even though we have not observed any toxic effects of diets containing high levels of isoflavones, subtle effects might not be readily obvious, or more serious effects might take years to become apparent. In addition, because these diets have been commercially available only since 1965, insufficient time has elapsed to determine the effects on such disorders as breast cancer. Several important facts are required, including target tissue isoflavone concentrations, identification of specific bioactive isoflavones molecules, estrogen receptor [Alpha] or [Beta] levels and functionality in infants, an understanding of target tissue isoflavone metabolism and mechanisms of isoflavone actions. Further basic and clinical studies are required. [Supported by the USDA-ARS Human Nutrition Research Program.]

Published
2000

45. Mode of action and dose-response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study

Author

Budinsky, R. A., Schrenk, D., Simon, T., Van Den Berg, M., Reichard, J. F., Silkworth, J. B., Aylward, L. L., Brix, A., Gasiewicz, T., Kaminski, N., Perdew, G., Starr, T. B., Walker, N. J., Rowlands, J. C., LS IRAS Tox Algemeen, Risk Assessment of Toxic and Immunomodulatory Agents, IRAS RATIA1, LS IRAS Tox Algemeen, Risk Assessment of Toxic and Immunomodulatory Agents, and IRAS RATIA1

Subjects
medicine.medical_specialty, TCDD, Polychlorinated Dibenzodioxins, Apoptosis, Toxicology, Modulating factors, Internal medicine, medicine, Animals, Humans, Mode of action, Receptor, Dose-response assessment, Cell Proliferation, Key events, Dioxin, Dose-Response Relationship, Drug, biology, Cell growth, Liver Neoplasms, Human relevance framework, medicine.disease, Aryl hydrocarbon receptor, Mitochondria, Oxidative Stress, Cell Transformation, Neoplastic, Endocrinology, Liver, Receptors, Aryl Hydrocarbon, Toxicity, Carcinogens, biology.protein, Cancer research, Tumor promotion, Liver cancer
Abstract

Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose-response behavior of key events, alteration of the dose-response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure.

Published
2014

48. A solid-state amorphous selenium avalanche technology for low photon flux imaging applications

Author

Wronski, M. M., Zhao, W., Reznik, A., Tanioka, K., DeCrescenzo, G., and Rowlands, J. A.

Subjects
Diagnostic Imaging, Medical Physics Letters, Photons, Selenium, Electric Conductivity, food and beverages, Electrodes
Abstract

The feasibility of a practical solid-state technology for low photon flux imaging applications was investigated. The technology is based on an amorphous selenium photoreceptor with a voltage-controlled avalanche multiplication gain. If this photoreceptor can provide sufficient internal gain, it will be useful for an extensive range of diagnostic imaging systems.The avalanche photoreceptor under investigation is referred to as HARP-DRL. This is a novel concept in which a high-gain avalanche rushing photoconductor (HARP) is integrated with a distributed resistance layer (DRL) and sandwiched between two electrodes. The avalanche gain and leakage current characteristics of this photoreceptor were measured.HARP-DRL has been found to sustain very high electric field strengths without electrical breakdown. It has shown avalanche multiplication gains as high as 10(4) and a very low leakage current (or = 20 pA/mm2).This is the first experimental demonstration of a solid-state amorphous photoreceptor which provides sufficient internal avalanche gain for photon counting and photon starved imaging applications.

Published
2010

50. Effect of repeated x-ray exposure on the resolution of amorphous selenium based x-ray imagers

Author

Kabir, M. Z., Chowdhury, L., DeCrescenzo, G., Tousignant, O., Kasap, S. O., and Rowlands, J. A.

Subjects
Equipment Failure Analysis, Selenium, Radiation Imaging Physics, Reproducibility of Results, Dose-Response Relationship, Radiation, X-Ray Intensifying Screens, sense organs, Equipment Design, skin and connective tissue diseases, Radiation Dosage, Sensitivity and Specificity
Abstract

A numerical model and the experimental methods to study the x-ray exposure dependent change in the modulation transfer function (MTF) of amorphous selenium (a-Se) based active matrix flat panel imagers (AMFPIs) are described. The physical mechanisms responsible for the x-ray exposure dependent change in MTF are also investigated.A numerical model for describing the x-ray exposure dependent MTF of a-Se based AMFPIs has been developed. The x-ray sensitivity and MTF of an a-Se AMFPI have been measured as a function of exposure. The instantaneous electric field and free and trapped carrier distributions in the photoconductor layer are obtained by numerically solving the Poisson's equation, continuity equations, and trapping rate equations using the backward Euler finite difference method. From the trapped carrier distributions, a method for calculating the MTF due to incomplete charge collection is proposed.The model developed in this work and the experimental data show a reasonably good agreement. The model is able to simultaneously predict the dependence of the sensitivity and MTF on accumulated exposure at different applied fields and bias polarities, with the same charge transport parameters that are typical of the particular a-Se photoconductive layer that is used in these AMFPIs. Under negative bias, the MTF actually improves with the accumulated x-ray exposure while the sensitivity decreases. The MTF enhancement with exposure decreases with increasing applied field.The most prevalent processes that control the MTF under negative bias are the recombination of drifting holes with previously trapped electrons (electrons remain in deep traps due to their long release times compared with the time scale of the experiments) and the deep trapping of drifting holes and electrons.

Published
2010

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