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1. Simvastatin in Critically Ill Patients with Covid-19.

Author

Hills, Thomas, Lorenzi, Elizabeth, Berry, Lindsay, Shyamsundar, Murali, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Aryal, Diptesh, Au, Carly, Beane, Abigail, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Burrell, Aidan, Buxton, Meredith, Calfee, Carolyn, Cecconi, Maurizio, Cheng, Allen, Cove, Matthew, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goligher, Ewan, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Harrison, David, Hashmi, Madiha, Higgins, Alisa, Huang, David, Ichihara, Nao, Jayakumar, Deva, Kruger, Peter, Lamontagne, François, Lampro, Lamprini, Lawler, Patrick, Marshall, John, Mason, Alexina, McGlothlin, Anna, McGuinness, Shay, McQuilten, Zoe, McVerry, Bryan, Mouncey, Paul, Murthy, Srinivas, Neal, Matthew, Nichol, Alistair, OKane, Cecilia, Parke, Rachael, Parker, Jane, Rabindrarajan, Ebenezer, Reyes, Luis, Rowan, Kathryn, Saito, Hiroki, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Shankar-Hari, Manu, Sinha, Pratik, Thompson, B, Turgeon, Alexis, Turner, Anne, van de Veerdonk, Frank, Weis, Sebastian, Young, Ian, Zarychanski, Ryan, McArthur, Colin, Angus, Derek, Berry, Scott, Derde, Lennie, Webb, Steve, Gordon, Anthony, McAuley, Daniel, and Lewis, Roger

Subjects
Humans, Bayes Theorem, COVID-19, COVID-19 Drug Treatment, Critical Illness, Hospital Mortality, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Treatment Outcome
Abstract

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was

Published
2023

3. Artificial intelligence-based epigenomic, transcriptomic and histologic signatures of tobacco use in oral squamous cell carcinoma

Author

Viet, Chi T., Asam, Kesava R., Yu, Gary, Dyer, Emma C., Kochanny, Sara, Thomas, Carissa M., Callahan, Nicholas F., Morlandt, Anthony B., Cheng, Allen C., Patel, Ashish A., Roden, Dylan F., Young, Simon, Melville, James, Shum, Jonathan, Walker, Paul C., Nguyen, Khanh K., Kidd, Stephanie N., Lee, Steve C., Folk, Gretchen S., Viet, Dan T., Grandhi, Anupama, Deisch, Jeremy, Ye, Yi, Momen-Heravi, Fatemeh, Pearson, Alexander T., and Aouizerat, Bradley E.

Published
2024
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6. Associations between COVID-19 and hospitalisation with respiratory and non-respiratory conditions: a record linkage study.

Author

Rowe, Stacey, Leder, Karin, Dyson, Kylie, Sundaresan, Lalitha, Wollersheim, Dennis, Lynch, Brigid, Abdullahi, Ifrah, Cowie, Benjamin, Stephens, Nicola, Nolan, Terence, Sullivan, Sheena, Sutton, Brett, and Cheng, Allen

Subjects
COVID-19, Epidemiology, Hospitals, Public health, SARS-COV-2, Humans, COVID-19, COVID-19 Vaccines, SARS-CoV-2, Hospitalization, Myocardial Infarction
Abstract

OBJECTIVES: To assess associations between SARS-CoV-2 infection and the incidence of hospitalisation with selected respiratory and non-respiratory conditions in a largely SARS-CoV-2 vaccine-naïve population . DESIGN, SETTING, PARTICIPANTS: Self-control case series; analysis of population-wide surveillance and administrative data for all laboratory-confirmed COVID-19 cases notified to the Victorian Department of Health (onset, 23 January 2020 - 31 May 2021; ie, prior to widespread vaccination rollout) and linked hospital admissions data (admission dates to 30 September 2021). MAIN OUTCOME MEASURES: Hospitalisation of people with acute COVID-19; incidence rate ratios (IRRs) comparing incidence of hospitalisations with defined conditions (including cardiac, cerebrovascular, venous thrombo-embolic, coagulative, and renal disorders) from three days before to within 89 days of onset of COVID-19 with incidence during baseline period (60-365 days prior to COVID-19 onset). RESULTS: A total of 20 594 COVID-19 cases were notified; 2992 people (14.5%) were hospitalised with COVID-19. The incidence of hospitalisation within 89 days of onset of COVID-19 was higher than during the baseline period for several conditions, including myocarditis and pericarditis (IRR, 14.8; 95% CI, 3.2-68.3), thrombocytopenia (IRR, 7.4; 95% CI, 4.4-12.5), pulmonary embolism (IRR, 6.4; 95% CI, 3.6-11.4), acute myocardial infarction (IRR, 3.9; 95% CI, 2.6-5.8), and cerebral infarction (IRR, 2.3; 95% CI, 1.4-3.9). CONCLUSION: SARS-CoV-2 infection is associated with higher incidence of hospitalisation with several respiratory and non-respiratory conditions. Our findings reinforce the value of COVID-19 mitigation measures such as vaccination, and awareness of these associations should assist the clinical management of people with histories of SARS-CoV-2 infection.

Published
2023

7. Comparison of baseline characteristics, treatment and clinical outcomes of critically ill COVID-19 patients admitted in the first and second waves in Australia

Author

Burrell, Aidan JC, Neto, Ary Serpa, Broadley, Tessa, Trapani, Tony, Begum, Husna, Campbell, Lewis T, Cheng, Allen C, Cheung, Winston, Cooper, D James, Erickson, Simon J, French, Craig J, Kaldor, John M, Litton, Edward, Murthy, Srinivas, McAllister, Richard E, Nichol, Alistair D, Palermo, Annamaria, Plummer, Mark P, Ramanan, Mahesh, Reddi, Benjamin AJ, Reynolds, Claire, Webb, Steve A, and Udy, Andrew A

Published
2021

8. Oral care practices and hospital-acquired pneumonia prevention: A national survey of Australian nurses

Author

Tehan, Peta Ellen, Browne, Katrina, Matterson, Georgia, Cheng, Allen C., Dawson, Sonja, Graves, Nicholas, Johnson, Douglas, Kiernan, Martin, Madhuvu, Auxillia, Marshall, Caroline, McDonagh, Julee, Northcote, Maria, O'Connor, Jayne, Orr, Liz, Rawson, Helen, Russo, Philip, Sim, Jenny, Stewardson, Andrew J., Wallace, Janet, White, Nicole, Wilson, Rhonda, and Mitchell, Brett G.

Published
2024
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9. Towards integrated cross-sectoral surveillance of pathogens and antimicrobial resistance: Needs, approaches, and considerations for linking surveillance to action

Author

Lappan, Rachael, Chown, Steven L., French, Matthew, Perlaza-Jiménez, Laura, Macesic, Nenad, Davis, Mark, Brown, Rebekah, Cheng, Allen, Clasen, Thomas, Conlan, Lindus, Goddard, Frederick, Henry, Rebekah, Knight, Daniel R., Li, Fuyi, Luby, Stephen, Lyras, Dena, Ni, Gaofeng, Rice, Scott A., Short, Francesca, Song, Jiangning, Whittaker, Andrea, Leder, Karin, Lithgow, Trevor, and Greening, Chris

Published
2024
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12. Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities

Author

Zhang, Wuji, Kedzierski, Lukasz, Chua, Brendon Y., Mayo, Mark, Lonzi, Claire, Rigas, Vanessa, Middleton, Bianca F., McQuilten, Hayley A., Rowntree, Louise C., Allen, Lilith F., Purcell, Ruth A., Tan, Hyon-Xhi, Petersen, Jan, Chaurasia, Priyanka, Mordant, Francesca, Pogorelyy, Mikhail V., Minervina, Anastasia A., Crawford, Jeremy Chase, Perkins, Griffith B., Zhang, Eva, Gras, Stephanie, Clemens, E. Bridie, Juno, Jennifer A., Audsley, Jennifer, Khoury, David S., Holmes, Natasha E., Thevarajan, Irani, Subbarao, Kanta, Krammer, Florian, Cheng, Allen C., Davenport, Miles P., Grubor-Bauk, Branka, Coates, P. Toby, Christensen, Britt, Thomas, Paul G., Wheatley, Adam K., Kent, Stephen J., Rossjohn, Jamie, Chung, Amy W., Boffa, John, Miller, Adrian, Lynar, Sarah, Nelson, Jane, Nguyen, Thi H. O., Davies, Jane, and Kedzierska, Katherine

Published
2023
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15. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, de Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, and Le Gal, Grégoire

Subjects
Clinical Trials and Supportive Activities, Clinical Research, Comparative Effectiveness Research, Cardiovascular, Good Health and Well Being, Aged, Anticoagulants, COVID-19, Critical Illness, Female, Hemorrhage, Heparin, Hospital Mortality, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Respiration, Artificial, Thrombosis, Treatment Failure, COVID-19 Drug Treatment, REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.MethodsIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.ResultsThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

Published
2021

16. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Author

Lawler, Patrick R, Goligher, Ewan C, Berger, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kahn, Susan R, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Costantini, Todd W, de Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, García-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, and Krishnan, Vidya

Subjects
Cardiovascular, Clinical Trials and Supportive Activities, Clinical Research, Hematology, Transplantation, Good Health and Well Being, Adult, Aged, Anticoagulants, COVID-19, Female, Hemorrhage, Heparin, Heparin, Low-Molecular-Weight, Hospital Mortality, Humans, Male, Middle Aged, Survival Analysis, Thrombosis, COVID-19 Drug Treatment, ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.MethodsIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.ResultsThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Published
2021

17. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.

Author

REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, de Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, and Kutcher, Matthew E

Subjects
REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Humans, Thrombosis, Critical Illness, Hemorrhage, Heparin, Anticoagulants, Treatment Failure, Respiration, Artificial, Hospital Mortality, Logistic Models, Odds Ratio, Aged, Middle Aged, Female, Male, COVID-19, Clinical Research, Cardiovascular, Clinical Trials and Supportive Activities, Comparative Effectiveness Research, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.MethodsIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.ResultsThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

Published
2021

18. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.

Author

ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Lawler, Patrick R, Goligher, Ewan C, Berger, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kahn, Susan R, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Costantini, Todd W, de Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, García-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, and King, Andrew J

Subjects
ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Humans, Thrombosis, Hemorrhage, Heparin, Heparin, Low-Molecular-Weight, Anticoagulants, Hospital Mortality, Survival Analysis, Adult, Aged, Middle Aged, Female, Male, COVID-19, Hematology, Clinical Trials and Supportive Activities, Transplantation, Clinical Research, Cardiovascular, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.MethodsIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.ResultsThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Published
2021

19. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Author

Arabi, Yaseen M, Gordon, Anthony C, Derde, Lennie PG, Nichol, Alistair D, Murthy, Srinivas, Beidh, Farah Al, Annane, Djillali, Swaidan, Lolowa Al, Beane, Abi, Beasley, Richard, Berry, Lindsay R, Bhimani, Zahra, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen, De Jong, Menno, Detry, Michelle A, Duffy, Eamon J, Estcourt, Lise J, Fitzgerald, Mark, Fowler, Rob, Girard, Timothy D, Goligher, Ewan C, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa M, Hills, Thomas E, Horvat, Christopher M, Huang, David T, King, Andrew J, Lamontagne, Francois, Lawler, Patrick R, Lewis, Roger, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Malakouti, Salim, McAuley, Daniel F, McGlothlin, Anna, Mcguinness, Shay, McVerry, Bryan J, Montgomery, Stephanie K, Morpeth, Susan C, Mouncey, Paul R, Orr, Katrina, Parke, Rachael, Parker, Jane C, Patanwala, Asad E, Rowan, Kathryn M, Santos, Marlene S, Saunders, Christina T, Seymour, Christopher W, Shankar-Hari, Manu, Tong, Steven YC, Turgeon, Alexis F, Turner, Anne M, Van de Veerdonk, Frank Leo, Zarychanski, Ryan, Green, Cameron, Berry, Scott, Marshall, John C, McArthur, Colin, Angus, Derek C, and Webb, Steven A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Comparative Effectiveness Research, Clinical Research, Clinical Trials and Supportive Activities, Good Health and Well Being, Adult, Antiviral Agents, Bayes Theorem, Critical Illness, Drug Combinations, Humans, Hydroxychloroquine, Lopinavir, Ritonavir, SARS-CoV-2, COVID-19 Drug Treatment, Adaptive platform trial, Intensive care, Pneumonia, Pandemic, COVID-19, Lopinavir-ritonavir, REMAP-CAP Investigators, Public Health and Health Services, Emergency & Critical Care Medicine, Clinical sciences
Abstract

PurposeTo study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).MethodsCritically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.ResultsWe randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).ConclusionAmong critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

Published
2021

21. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

Author

Gordon, Anthony, Mouncey, Paul, Al-Beidh, Farah, Rowan, Kathryn, Nichol, Alistair, Arabi, Yaseen, Annane, Djillali, Beane, Abi, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buzgau, Adrian, Cheng, Allen, Detry, Michelle, Duffy, Eamon, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa, Hills, Thomas, Horvat, Christopher, Lamontagne, Francois, Lawler, Patrick, Leavis, Helen, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, Mayr, Florian, McAuley, Daniel, McGlothlin, Anna, McGuinness, Shay, McVerry, Bryan, Montgomery, Stephanie, Morpeth, Susan, Murthy, Srinivas, Orr, Katrina, Parke, Rachael, Parker, Jane, Patanwala, Asad, Pettilä, Ville, Rademaker, Emma, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Shankar-Hari, Manu, Sligl, Wendy, Turgeon, Alexis, Turner, Anne, van de Veerdonk, Frank, Zarychanski, Ryan, Green, Cameron, Lewis, Roger, Angus, Derek, McArthur, Colin, Berry, Scott, Webb, Steve, and Derde, Lennie

Subjects
Adult, Aged, Antibodies, Monoclonal, Humanized, COVID-19, Critical Illness, Female, Hospital Mortality, Humans, Intensive Care Units, Male, Middle Aged, Odds Ratio, Receptors, Interleukin-6, Respiration, Artificial, COVID-19 Drug Treatment
Abstract

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Published
2021

25. Diabetes mellitus, glycaemic control, and severe COVID-19 in the Australian critical care setting: A nested cohort study

Author

Visser, Adam, Mattke, Adrian, Regli, Adrian, Rashid, Alan, Tabah, Alexis, Walker, Alison, Cheng, Allen, Corley, Amanda, Udy, Andrew, Ramnani, Anil, Eidan, Anthony, DeKeulenaer, Bart, Reddi, Benjamin, Richards, Brent, Knott, Cameron, Moore, Cara, Delzoppo, Carmel, Boschert, Catherine, Tacon, Catherine, French, Craig, Austin, Danielle, Brewster, David, Cooper, David, Crosbie, David, Hawkins, David, Jessen, Edda, Martinez, Eduardo, Fysh, Edward, Litton, Edward, Oberender, Felix, McGain, Forbes, Salt, Gavin, Eastwood, Glenn, Taori, Gopal, White, Hayden, Buscher, Hergen, Seppelt, Ian, Leditschke, Isabel Anne, Young, Janelle, Lavana, Jayshree, Cohen, Jeremy, Lugsdin, Jessica, Botha, John, Santamaria, John, Barrett, Jonathan, Singh, Kasha, Laupland, Kevin, El-Khawas, Khaled, Estensen, Kristine, Deshpande, Kush, White, Kyle, Fitzpatrick, Leigh, Campbell, Lewis, Ramanan, Mahesh, Saxena, Manoj, Kainer, Marion, Kol, Mark, Page, Mark, Plummer, Mark, Sterba, Martin, Anstey, Matthew, Brain, Matthew, Maiden, Matthew, Kilminster, Myrene, Hammond, Naomi, Bhadange, Neeraj, Humphreys, Nicole, Jain, Paras, Azzi, Paul, Secombe, Paul, Lister, Paula, Chan, Peter, McCanny, Peter, Britton, Phillip, Janin, Pierre, Krishnamurthy, Ravi, Sonawane, Ravikiran, Tiruvoipati, Ravindranath, Totaro, Richard, Bellomo, Rinaldo, Sanghavi, Ritesh, Bates, Samantha, Peake, Sandra, Bihari, Shailesh, George, Shane, Erickson, Simon, Webb, Steve, Arora, Subhash, Ganu, Subodh, Rozen, Thomas, McKenna, Toni, Kadam, Umesh, Nayyar, Vineet, Choy, Wei Han, Albassam, Wisam, Plummer, Mark P., Rait, Louise, Finnis, Mark E., French, Craig J., Douglas, James, Bhurani, Mansi, Broadley, Tessa, Trapani, Tony, Deane, Adam M., Udy, Andrew A., and Burrell, Aidan J.C.

Published
2023
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26. Where has all the influenza gone? The impact of COVID-19 on the circulation of influenza and other respiratory viruses, Australia, March to September 2020.

Author

Sullivan, Sheena, Carlson, Sandra, Cheng, Allen, Chilver, Monique, Dwyer, Dominic, Irwin, Melissa, Kok, Jen, Macartney, Kristine, MacLachlan, Jennifer, Minney-Smith, Cara, Smith, David, Stocks, Nigel, Taylor, Janette, and Barr, Ian

Subjects
influenza, non-pharmaceutical interventions, respiratory syncytial virus, rhinoviruses, travel restrictions, Australia, COVID-19, Coronavirus, Coronavirus Infections, Disease Notification, Epidemiological Monitoring, Female, Humans, Influenza, Human, Male, Pandemics, Population Surveillance, Respiratory Tract Infections, SARS-CoV-2, Seasons, Sentinel Surveillance
Abstract

The coronavirus disease pandemic was declared in March 2020, as the southern hemispheres winter approached. Australia expected co-circulation of severe acute respiratory syndrome coronavirus 2, influenza and other seasonal respiratory viruses. However, influenza notifications were 7,029 (March-September) compared with an average 149,832 for the same period in 2015-2019 [corrected], despite substantial testing. Restrictions on movement within and into Australia may have temporarily eliminated influenza. Other respiratory pathogens also showed remarkably changed activity in 2020.

Published
2020

27. A minimal common outcome measure set for COVID-19 clinical research

Author

infection, WHO Working Group on the Clinical Characterisation and Management of COVID-19, Marshall, John C, Murthy, Srinivas, Diaz, Janet, Adhikari, NK, Angus, Derek C, Arabi, Yaseen M, Baillie, Kenneth, Bauer, Michael, Berry, Scott, Blackwood, Bronagh, Bonten, Marc, Bozza, Fernando, Brunkhorst, Frank, Cheng, Allen, Clarke, Mike, Dat, Vu Quoc, de Jong, Menno, Denholm, Justin, Derde, Lennie, Dunning, Jake, Feng, Xiaobin, Fletcher, Tom, Foster, Nadine, Fowler, Rob, Gobat, Nina, Gomersall, Charles, Gordon, Anthony, Glueck, Thomas, Harhay, Michael, Hodgson, Carol, Horby, Peter, Kim, YaeJean, Kojan, Richard, Kumar, Bharath, Laffey, John, Malvey, Denis, Martin-Loeches, Ignacio, McArthur, Colin, McAuley, Danny, McBride, Stephen, McGuinness, Shay, Merson, Laura, Morpeth, Susan, Needham, Dale, Netea, Mihai, Oh, Myoung-Don, Phyu, Sabai, Piva, Simone, Qiu, Ruijin, Salisu-Kabara, Halima, Shi, Lei, Shimizu, Naoki, Sinclair, Jorge, Tong, Steven, Turgeon, Alexis, Uyeki, Tim, van de Veerdonk, Frank, Webb, Steve, Williamson, Paula, Wolf, Timo, and Zhang, Junhua

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Infectious Diseases, Infection, Good Health and Well Being, Betacoronavirus, COVID-19, Clinical Trials as Topic, Coronavirus Infections, Humans, Outcome Assessment, Health Care, Pandemics, Patient Outcome Assessment, Pneumonia, Viral, SARS-CoV-2, Survival Analysis, Treatment Outcome, Viral Load, WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection, Medical Microbiology, Public Health and Health Services, Microbiology, Clinical sciences, Medical microbiology, Epidemiology
Abstract

Clinical research is necessary for an effective response to an emerging infectious disease outbreak. However, research efforts are often hastily organised and done using various research tools, with the result that pooling data across studies is challenging. In response to the needs of the rapidly evolving COVID-19 outbreak, the Clinical Characterisation and Management Working Group of the WHO Research and Development Blueprint programme, the International Forum for Acute Care Trialists, and the International Severe Acute Respiratory and Emerging Infections Consortium have developed a minimum set of common outcome measures for studies of COVID-19. This set includes three elements: a measure of viral burden (quantitative PCR or cycle threshold), a measure of patient survival (mortality at hospital discharge or at 60 days), and a measure of patient progression through the health-care system by use of the WHO Clinical Progression Scale, which reflects patient trajectory and resource use over the course of clinical illness. We urge investigators to include these key data elements in ongoing and future studies to expedite the pooling of data during this immediate threat, and to hone a tool for future needs.

Published
2020

28. The Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia (REMAP-CAP) Study: Rationale and Design

Author

Angus, Derek C, Berry, Scott, Lewis, Roger J, Al-Beidh, Farah, Arabi, Yaseen, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc, Broglio, Kristine, Brunkhorst, Frank, Cheng, Allen C, Chiche, Jean-Daniel, De Jong, Menno, Detry, Michelle, Goossens, Herman, Gordon, Anthony, Green, Cameron, Higgins, Alisa M, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Litton, Edward, Marshall, John, McGlothlin, Anna, McGuinness, Shay, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, O'Neill, Genevieve K, Parke, Rachael, Parker, Jane, Rohde, Gernot, Rowan, Kathryn, Turner, Anne, Young, Paul, Derde, Lennie, McArthur, Colin, and Webb, Steven A

Subjects
Influenza, Cancer, Clinical Research, Lung, Clinical Trials and Supportive Activities, Vaccine Related, Pneumonia & Influenza, Comparative Effectiveness Research, Patient Safety, Infectious Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Anti-Bacterial Agents, Antiviral Agents, Betacoronavirus, COVID-19, Community-Acquired Infections, Coronavirus Infections, Evidence-Based Medicine, Humans, Influenza, Human, Pandemics, Pneumonia, Pneumonia, Viral, Point-of-Care Systems, SARS-CoV-2, randomized clinical trial, Bayesian adaptive platform trial, master protocol, community-acquired pneumonia, coronavirus disease 2019, Bayesian adaptive, platform trial
Abstract

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Published
2020

29. The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design.

Author

Angus, Derek C, Berry, Scott, Lewis, Roger J, Al-Beidh, Farah, Arabi, Yaseen, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc, Broglio, Kristine, Brunkhorst, Frank, Cheng, Allen C, Chiche, Jean-Daniel, De Jong, Menno, Detry, Michelle, Goossens, Herman, Gordon, Anthony, Green, Cameron, Higgins, Alisa M, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Litton, Edward, Marshall, John, McGlothlin, Anna, McGuinness, Shay, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, O'Neill, Genevieve K, Parke, Rachael, Parker, Jane, Rohde, Gernot, Rowan, Kathryn, Turner, Anne, Young, Paul, Derde, Lennie, McArthur, Colin, and Webb, Steven A

Subjects
Humans, Community-Acquired Infections, Pneumonia, Viral, Coronavirus Infections, Pneumonia, Anti-Bacterial Agents, Antiviral Agents, Evidence-Based Medicine, Point-of-Care Systems, Influenza, Human, Pandemics, Betacoronavirus, COVID-19, SARS-CoV-2, Bayesian adaptive, community-acquired pneumonia, coronavirus disease 2019, master protocol, platform trial, randomized clinical trial, Bayesian adaptive platform trial, Respiratory System, Clinical Sciences
Abstract

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Published
2020

30. Antimicrobial susceptibility of bacterial isolates from clinical specimens in four Pacific Island countries, 2017–2021

Author

Loftus, Michael J., Everts, Richard J., Cheng, Allen C., Eti, Perenise, Fakasiieiki, Timote, Isaia, Lupeoletalelei, Isopo, Enita, Jenney, Adam W.J., Lameko, Viali, Leaupepe, Hinauri, Leavai, Folototo, Lee, Sue J., Moungaevalu, Mele, Stewardson, Andrew J., Tekoaua, Rosemary, Tou, Douglas, Wuatai, Geoffrey, and Peleg, Anton Y.

Published
2023
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31. Superior immunogenicity of mRNA over adenoviral vectored COVID-19 vaccines reflects B cell dynamics independent of anti-vector immunity: Implications for future pandemic vaccines

Author

Liu, Yi, Sánchez-Ovando, Stephany, Carolan, Louise, Dowson, Leslie, Khvorov, Arseniy, Jessica Hadiprodjo, A., Tseng, Yeu Yang, Delahunty, Catherine, Khatami, Ameneh, Macnish, Marion, Dougherty, Sonia, Hagenauer, Michelle, Riley, Kathryn E., Jadhav, Ajay, Harvey, Joanne, Kaiser, Marti, Mathew, Suja, Hodgson, David, Leung, Vivian, Subbarao, Kanta, Cheng, Allen C., Macartney, Kristine, Koirala, Archana, Marshall, Helen, Clark, Julia, Blyth, Christopher C., Wark, Peter, Kucharski, Adam J., Sullivan, Sheena G., and Fox, Annette

Published
2023
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33. NuSTAR Detection of a Hard X-ray Source in the Supernova Remnant - Molecular Cloud Interaction Site of IC 443

Author

Zhang, Shuo, Tang, Xiaping, Zhang, Xiao, Sun, Lei, Gotthelf, Eric V., Zhang, Zhi-Yu, Li, Hui, Cheng, Allen, Pasham, Dheeraj, Baganoff, Frederick K., Perez, Kerstin, Hailey, Charles J., and Mori, Kaya

Subjects
Astrophysics - High Energy Astrophysical Phenomena
Abstract

We report on a broadband study of a complex X-ray source (1SAX J0618.0+2227) associated with the interaction site of the supernova remnant (SNR) IC 443 and ambient molecular cloud (MC) using NuSTAR, XMM_Newton, and Chandra observations. Its X-ray spectrum is composed of both thermal and non-thermal components. The thermal component can be equally well represented by either a thin plasma model with kT=0.19 keV or a blackbody model with kT=0.11 keV. The non-thermal component can be fit with either a power-law with Gamma~1.7 or a cutoff power-law with Gamma~1.5 and a cutoff energy at E_cut~18 keV. Using the newly obtained NuSTAR dataset, we test three possible scenarios for isolated X-ray sources in the SNR-MC interaction site: 1) pulsar wind nebula (PWN); 2) SNR ejecta fragment; 3) shocked molecular clump. We conclude that this source is most likely composed of a SNR ejecta (or a PWN) and surrounding shocked molecular clumps. The nature of this hard X-ray source in the SNR-MC interaction site of IC 443 may shed light on unidentified X-ray sources with hard X-ray spectra in rich environments for star forming regions, such as the Galactic center., Comment: 10 pages, 6 figures. Accepted by ApJ

Published
2018
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34. Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial

Author

McMahon, James H., Lau, Jillian S.Y., Coldham, Anna, Roney, Janine, Hagenauer, Michelle, Price, Sally, Bryant, Mellissa, Garlick, Jill, Paterson, Anne, Lee, Sue J., O'Bryan, Jess, Hearps, Anna, Tachedjian, Gilda, Pinskier, Henry, Phillips, Cameron, Garrow, Stuart, Pinskier, Nathan, Melvin, Robert, Blakeway, Luke, Wisniewski, Jessica A., Byers, Sally, Badoordeen, Gnei Z., Pereira, Stephanie, Pragastis, Katherine, Trubiano, Jason A., Chua, Kyra Y.L., Kainer, Marion, Molton, James S., Gardiner, Bradley J., Pierce, Anna B., Cheng, Allen, Rogers, Benjamin A., and Peleg, Anton Y.

Published
2022
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35. Heterogeneity in influenza seasonality and vaccine effectiveness in Australia, Chile, New Zealand and South Africa: early estimates of the 2019 influenza season.

Author

Sullivan, Sheena, Arriola, Carmen, Bocacao, Judy, Burgos, Pamela, Bustos, Patricia, Carville, Kylie, Cheng, Allen, Chilver, Monique, Cohen, Cheryl, Deng, Yi-Mo, El Omeiri, Nathalie, Fasce, Rodrigo, Hellferscee, Orienka, Huang, Q, Gonzalez, Cecilia, Jelley, Lauren, Leung, Vivian, Lopez, Liza, McAnerney, Johanna, McNeill, Andrea, Olivares, Maria, Peck, Heidi, Sotomayor, Viviana, Tempia, Stefano, Vergara, Natalia, von Gottberg, Anne, Walaza, Sibongile, and Wood, Timothy

Subjects
influenza, influenza vaccines, sentinel surveillance, southern hemisphere, vaccine effectiveness, Adolescent, Adult, Australia, Child, Chile, Female, Humans, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H3N2 Subtype, Influenza B virus, Influenza Vaccines, Influenza, Human, Male, Middle Aged, New Zealand, Outcome Assessment, Health Care, Population Surveillance, Reverse Transcriptase Polymerase Chain Reaction, Seasons, Sentinel Surveillance, South Africa, Vaccination, Vaccine Potency
Abstract

We compared 2019 influenza seasonality and vaccine effectiveness (VE) in four southern hemisphere countries: Australia, Chile, New Zealand and South Africa. Influenza seasons differed in timing, duration, intensity and predominant circulating viruses. VE estimates were also heterogeneous, with all-ages point estimates ranging from 7-70% (I2: 33%) for A(H1N1)pdm09, 4-57% (I2: 49%) for A(H3N2) and 29-66% (I2: 0%) for B. Caution should be applied when attempting to use southern hemisphere data to predict the northern hemisphere influenza season.

Published
2019

36. Attributable mortality and excess length of stay associated with third-generation cephalosporin-resistant Enterobacterales bloodstream infections: a prospective cohort study in Suva, Fiji

Author

Loftus, Michael J., Young-Sharma, Tracey E.M.W., Lee, Sue J., Wati, Shitanjni, Badoordeen, Gnei Z., Blakeway, Luke V., Byers, Sally M.H., Cheng, Allen C., Cooper, Ben S., Cottingham, Hugh, Jenney, Adam W.J., Hawkey, Jane, Macesic, Nenad, Naidu, Ravi, Prasad, Amitesh, Prasad, Vinita, Tudravu, Litia, Vakatawa, Timoci, van Gorp, Elke, Wisniewski, Jessica A., Rafai, Eric, Peleg, Anton Y., and Stewardson, Andrew J.

Published
2022
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37. Creating Effective Interrupted Time Series Graphs: Review and Recommendations

Author

Turner, Simon L., Karahalios, Amalia, Forbes, Andrew B., Taljaard, Monica, Grimshaw, Jeremy M., Korevaar, Elizabeth, Cheng, Allen C., Bero, Lisa, and McKenzie, Joanne E.

Abstract

Introduction: Interrupted Time Series (ITS) studies may be used to assess the impact of an interruption, such as an intervention or exposure. The data from such studies are particularly amenable to visual display and, when clearly depicted, can readily show the short- and long-term impact of an interruption. Further, well-constructed graphs allow data to be extracted using digitizing software, which can facilitate their inclusion in systematic reviews and meta-analyses. Aim: We provide recommendations for graphing ITS data, examine the properties of plots presented in ITS studies, and provide examples employing our recommendations. Methods and results: Graphing recommendations from seminal data visualization resources were adapted for use with ITS studies. The adapted recommendations cover plotting of data points, trend lines, interruptions, additional lines and general graph components. We assessed whether 217 graphs from recently published (2013-2017) ITS studies met our recommendations and found that 130 graphs (60%) had clearly distinct data points, 100 (46%) had trend lines, and 161 (74%) had a clearly defined interruption. Accurate data extraction (requiring distinct points that align with axis tick marks and labels that allow the points to be interpreted) was possible in only 72 (33%) graphs. Conclusion: We found that many ITS graphs did not meet our recommendations and could be improved with simple changes. Our proposed recommendations aim to achieve greater standardization and improvement in the display of ITS data, and facilitate re-use of the data in systematic reviews and meta-analyses.

Published
2021
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41. Epidemiology, antimicrobial resistance and outcomes of Staphylococcus aureus bacteraemia in a tertiary hospital in Fiji: A prospective cohort study

Author

Loftus, Michael J., Young-Sharma, Tracey E.M.W., Wati, Shitanjni, Badoordeen, Gnei Z., Blakeway, Luke V., Byers, Sally M.H., Cheng, Allen C., Jenney, Adam W.J., Naidu, Ravi, Prasad, Amitesh, Prasad, Vinita, Tudravu, Litia, Vakatawa, Timoci, van Gorp, Elke, Wisniewski, Jessica A., Rafai, Eric, Stewardson, Andrew J., and Peleg, Anton Y.

Published
2022
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44. Suboptimal SARS-CoV-2−specific CD8⁺ T cell response associated with the prominent HLA-A*02 : 01 phenotype

Author

Habel, Jennifer R., Nguyen, Thi H. O., van de Sandt, Carolien E., Juno, Jennifer A., Chaurasia, Priyanka, Wragg, Kathleen, Koutsakos, Marios, Hensen, Luca, Jia, Xiaoxiao, Chua, Brendon, Zhang, Wuji, Tan, Hyon-Xhi, Flanagan, Katie L., Doolan, Denise L., Torresi, Joseph, Chen, Weisan, Wakim, Linda M., Cheng, Allen C., Doherty, Peter C., Petersen, Jan, Rossjohn, Jamie, Wheatley, Adam K., Kent, Stephen J., Rowntree, Louise C., and Kedzierska, Katherine

Published
2020

48. Integrated immune dynamics define correlates of COVID-19 severity and antibody responses

Author

Koutsakos, Marios, Rowntree, Louise C., Hensen, Luca, Chua, Brendon Y., van de Sandt, Carolien E., Habel, Jennifer R., Zhang, Wuji, Jia, Xiaoxiao, Kedzierski, Lukasz, Ashhurst, Thomas M., Putri, Givanna H., Marsh-Wakefield, Felix, Read, Mark N., Edwards, Davis N., Clemens, E. Bridie, Wong, Chinn Yi, Mordant, Francesca L., Juno, Jennifer A., Amanat, Fatima, Audsley, Jennifer, Holmes, Natasha E., Gordon, Claire L., Smibert, Olivia C., Trubiano, Jason A., Hughes, Carly M., Catton, Mike, Denholm, Justin T., Tong, Steven Y.C., Doolan, Denise L., Kotsimbos, Tom C., Jackson, David C., Krammer, Florian, Godfrey, Dale I., Chung, Amy W., King, Nicholas J.C., Lewin, Sharon R., Wheatley, Adam K., Kent, Stephen J., Subbarao, Kanta, McMahon, James, Thevarajan, Irani, Nguyen, Thi H.O., Cheng, Allen C., and Kedzierska, Katherine

Published
2021
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