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Article ; Online: Not Quite a Mono Spot Diagnosis. Splenic Infarction Complicating Infectious Mononucleosis.

Patruno, Jacqueline V / Milross, Luke / Javaid, Muhammad M

2020 Volume 134, Issue 5, Page(s) e306–e307

MeSH term(s)	Emergency Service, Hospital ; Female ; Humans ; Infectious Mononucleosis/complications ; Infectious Mononucleosis/diagnosis ; Splenic Infarction/diagnosis ; Splenic Infarction/diagnostic imaging ; Splenic Infarction/etiology ; Tomography, X-Ray Computed ; Young Adult
Language	English
Publishing date	2020-11-18
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	80015-6
ISSN	1555-7162 ; 1873-2178 ; 0002-9343 ; 1548-2766
ISSN (online)	1555-7162 ; 1873-2178
ISSN	0002-9343 ; 1548-2766
DOI	10.1016/j.amjmed.2020.10.025
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Article ; Online: Immune processes in the pathogenesis of chronic lung allograft dysfunction: identifying the missing pieces of the puzzle.

Bos, Saskia / Milross, Luke / Filby, Andrew J / Vos, Robin / Fisher, Andrew J

European respiratory review : an official journal of the European Respiratory Society

2022 Volume 31, Issue 165

Abstract: Lung transplantation is the optimal treatment for selected patients with end-stage chronic lung diseases. However, chronic lung allograft dysfunction remains the leading obstacle to improved long-term outcomes. Traditionally, lung allograft rejection has ...

Abstract	Lung transplantation is the optimal treatment for selected patients with end-stage chronic lung diseases. However, chronic lung allograft dysfunction remains the leading obstacle to improved long-term outcomes. Traditionally, lung allograft rejection has been considered primarily as a manifestation of cellular immune responses. However, in reality, an array of complex, interacting and multifactorial mechanisms contribute to its emergence. Alloimmune-dependent mechanisms, including T-cell-mediated rejection and antibody-mediated rejection, as well as non-alloimmune injuries, have been implicated. Moreover, a role has emerged for autoimmune responses to lung self-antigens in the development of chronic graft injury. The aim of this review is to summarise the immune processes involved in the pathogenesis of chronic lung allograft dysfunction, with advanced insights into the role of innate immune pathways and crosstalk between innate and adaptive immunity, and to identify gaps in current knowledge.
MeSH term(s)	Allografts ; Autoimmunity ; Graft Rejection/etiology ; Graft Rejection/pathology ; Humans ; Lung ; Lung Transplantation/adverse effects
Language	English
Publishing date	2022-07-27
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1077620-5
ISSN	1600-0617 ; 0905-9180
ISSN (online)	1600-0617
ISSN	0905-9180
DOI	10.1183/16000617.0060-2022
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Article ; Online: Downregulation of MALAT1 is a hallmark of tissue and peripheral proliferative T cells in COVID-19.

Dey, Shoumit / Ashwin, Helen / Milross, Luke / Hunter, Bethany / Majo, Joaquim / Filby, Andrew J / Fisher, Andrew J / Kaye, Paul M / Lagos, Dimitris

Clinical and experimental immunology

2023 Volume 212, Issue 3, Page(s) 262–275

Abstract: T cells play key protective but also pathogenic roles in COVID-19. We studied the expression of long non-coding RNAs (lncRNAs) in COVID-19 T-cell transcriptomes by integrating previously published single-cell RNA sequencing datasets. The long intergenic ... ...

Abstract	T cells play key protective but also pathogenic roles in COVID-19. We studied the expression of long non-coding RNAs (lncRNAs) in COVID-19 T-cell transcriptomes by integrating previously published single-cell RNA sequencing datasets. The long intergenic non-coding RNA MALAT1 was the most highly transcribed lncRNA in T cells, with Th1 cells demonstrating the lowest and CD8+ resident memory cells the highest MALAT1 expression, amongst CD4+ and CD8+ T-cells populations, respectively. We then identified gene signatures that covaried with MALAT1 in single T cells. A significantly higher number of transcripts correlated negatively with MALAT1 than those that correlated. Enriched functional annotations of the MALAT1- anti-correlating gene signature included processes associated with T-cell activation such as cell division, oxidative phosphorylation, and response to cytokine. The MALAT1 anti-correlating gene signature shared by both CD4+ and CD8+ T-cells marked dividing T cells in both the lung and blood of COVID-19 patients. Focussing on the tissue, we used an independent patient cohort of post-mortem COVID-19 lung samples and demonstrated that MALAT1 suppression was indeed a marker of MKI67+ proliferating CD8+ T cells. Our results reveal MALAT1 suppression and its associated gene signature are a hallmark of human proliferating T cells.
MeSH term(s)	Humans ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Down-Regulation ; Cell Proliferation/genetics ; COVID-19/genetics ; CD8-Positive T-Lymphocytes/metabolism
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2023-03-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxad034
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Article: The trajectory of COVID-19 cardiopulmonary disease: insights from an autopsy study of community-based, pre-hospital deaths.

Milross, Luke / Majo, Joaquim / Pulle, Julian / Hoggard, Sam / Cooper, Nigel / Hunter, Bethany / Duncan, Christopher J A / Filby, Andrew / Fisher, Andrew J

ERJ open research

2022 Volume 8, Issue 4

Abstract: Background: Post mortem: Methods: In this study we investigated patterns of lung and heart injury from 46 community-based, pre-hospital COVID-19-attributable deaths who underwent autopsy.: Results: The cohort comprised 22 females and 24 males, ... ...

Abstract	Background: Post mortem Methods: In this study we investigated patterns of lung and heart injury from 46 community-based, pre-hospital COVID-19-attributable deaths who underwent autopsy. Results: The cohort comprised 22 females and 24 males, median age 64 years (range 19-91) at time of death with illness duration range 0-23 days. Comorbidities associated with poor outcomes in COVID-19 included obesity (body mass index >30 kg·m Conclusions: Identifying such advanced acute lung injury in community-based deaths is extremely unusual and raises the question why some with severe COVID-19 pneumonitis were not hospitalised. Multiple factors including low symptom burden, rapidly progressive disease trajectories and psychosocial factors provide possible explanations.
Language	English
Publishing date	2022-12-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2827830-6
ISSN	2312-0541
ISSN	2312-0541
DOI	10.1183/23120541.00303-2022
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Article ; Online: Identification of a protein expression signature distinguishing early from organising diffuse alveolar damage in COVID-19 patients.

Ashwin, Helen / Milross, Luke / Wilson, Julie / Majo, Joaquim / Hang Lee, Jimmy Tsz / Calder, Grant / Hunter, Bethany / James, Sally / Lagos, Dimitris / Signoret, Nathalie / Filby, Andrew / Bayraktar, Omer Ali / Fisher, Andrew J / Kaye, Paul M

Journal of clinical pathology

2023 Volume 76, Issue 8, Page(s) 561–565

Abstract: Diffuse alveolar damage (DAD) is the histological expression of acute respiratory distress syndrome and characterises lung pathology due to infection with SARS-CoV-2, and other respiratory pathogens of clinical significance. DAD reflects a time-dependent ...

Abstract	Diffuse alveolar damage (DAD) is the histological expression of acute respiratory distress syndrome and characterises lung pathology due to infection with SARS-CoV-2, and other respiratory pathogens of clinical significance. DAD reflects a time-dependent immunopathological process, progressing from an early/exudative stage through to an organising/fibrotic stage, yet within an individual these different stages of DAD may coexist. Understanding the progression of DAD is central to the development of new therapeutics to limit progressive lung damage. Here, we applied highly multiplexed spatial protein profiling to autopsy lung tissues derived from 27 patients who died from COVID-19 and identified a protein signature (ARG1, CD127, GZMB, IDO1, Ki67, phospho-PRAS40 (T246) and VISTA) that distinguishes early DAD from late DAD with good predictive accuracy. These proteins warrant further investigation as potential regulators of DAD progression.
MeSH term(s)	Humans ; COVID-19/diagnosis ; COVID-19/pathology ; SARS-CoV-2 ; Lung/pathology ; Respiratory Distress Syndrome/pathology ; Autopsy
Language	English
Publishing date	2023-03-09
Publishing country	England
Document type	Journal Article
ZDB-ID	80261-x
ISSN	1472-4146 ; 0021-9746
ISSN (online)	1472-4146
ISSN	0021-9746
DOI	10.1136/jcp-2023-208771
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Article ; Online: Down-regulation of MALAT1 is a hallmark of tissue and peripheral proliferative T cells in COVID-19

Dey, Shoumit / Ashwin, Helen / Milross, Luke / Hunter, Bethany / Majo, Joaquim / Filby, Andrew J / Fisher, Andrew J / Kaye, Paul M. / Lagos, Dimitris

medRxiv

Abstract: T cells play key protective but also pathogenic roles in COVID-19. We studied expression of long non-coding RNAs (lncRNAs) in COVID-19 T cell transcriptomes by integrating previously published single-cell RNA sequencing datasets. The long intergenic non- ... ...

Abstract	T cells play key protective but also pathogenic roles in COVID-19. We studied expression of long non-coding RNAs (lncRNAs) in COVID-19 T cell transcriptomes by integrating previously published single-cell RNA sequencing datasets. The long intergenic non-coding RNA MALAT1 was the most highly transcribed lncRNA in T cells, with Th1 cells demonstrating the lowest and CD8+ resident memory cells the highest MALAT1 expression, amongst CD4+ and CD8+ T cells populations, respectively. We then identified gene signatures that covaried with MALAT1 in single T cells. A significantly higher number of transcripts correlated negatively with MALAT1 than those that correlated. Enriched functional annotations of the MALAT1- anti-correlating gene signature included processes associated with T cell activation such as cell division, oxidative phosphorylation and response to cytokine. The MALAT1 anti-correlating gene signature shared by both CD4+ and CD8+ T cells marked dividing T cells in both lung and blood of COVID-19 patients. Focussing on the tissue, we used an independent patient cohort of post-mortem COVID-19 lung samples and demonstrated that MALAT1 suppression was indeed a marker of MKI67+ proliferating CD8+ T cells. Our results reveal MALAT1 suppression and its associated gene signature are a hallmark of human proliferating T cells.
Keywords	covid19
Language	English
Publishing date	2023-01-07
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2023.01.06.23284229
Database	COVID19

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Article ; Online: Down-regulation of MALAT1 is a hallmark of tissue and peripheral proliferative T cells in COVID-19

Dey, Shoumit / Ashwin, Helen / Milross, Luke / Hunter, Bethany / Maho, Joaquim / Filby, Andrew J / Fisher, Andrew J / Kaye, Paul M / Lagos, Dimitris

medRxiv

Abstract	T cells play key protective but also pathogenic roles in COVID-19. We studied expression of long non-coding RNAs (lncRNAs) in COVID-19 T cell transcriptomes by integrating previously published single-cell RNA sequencing datasets. The long intergenic non-coding RNA MALAT1 was the most highly transcribed lncRNA in T cells, with Th1 cells demonstrating the lowest and CD8+ resident memory cells the highest MALAT1 expression, amongst CD4+ and CD8+ T cells populations, respectively. We then identified gene signatures that covaried with MALAT1 in single T cells. A significantly higher number of transcripts correlated negatively with MALAT1 than those that correlated. Enriched functional annotations of the MALAT1- anti-correlating gene signature included processes associated with T cell activation such as cell division, oxidative phosphorylation and response to cytokine. The MALAT1 anti-correlating gene signature shared by both CD4+ and CD8+ T cells marked dividing T cells in both lung and blood of COVID-19 patients. Focussing on the tissue, we used an independent patient cohort of post-mortem COVID-19 lung samples and demonstrated that MALAT1 suppression was indeed a marker of MKI67+ proliferating CD8+ T cells. Our results reveal MALAT1 suppression and its associated gene signature are a hallmark of human proliferating T cells.
Keywords	covid19
Language	English
Publishing date	2023-01-07
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2023.01.06.23284229
Database	COVID19

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Article ; Online: Post-mortem lung tissue: the fossil record of the pathophysiology and immunopathology of severe COVID-19.

Milross, Luke / Majo, Joaquim / Cooper, Nigel / Kaye, Paul M / Bayraktar, Omer / Filby, Andrew / Fisher, Andrew J

The Lancet. Respiratory medicine

2021 Volume 10, Issue 1, Page(s) 95–106

Abstract: The lungs are the main site that is affected in severe COVID-19, and post-mortem lung tissue provides crucial insights into the pathophysiology of severe disease. From basic histology to state-of-the-art multiparameter digital pathology technologies, ... ...

Abstract	The lungs are the main site that is affected in severe COVID-19, and post-mortem lung tissue provides crucial insights into the pathophysiology of severe disease. From basic histology to state-of-the-art multiparameter digital pathology technologies, post-mortem lung tissue provides snapshots of tissue architecture, and resident and inflammatory cell phenotypes and composition at the time of death. Contrary to early assumptions that COVID-19 in the lungs is a uniform disease, post-mortem findings have established a high degree of disease heterogeneity. Classic diffuse alveolar damage represents just one phenotype, with disease divisible by early and late progression as well as by pathophysiological process. A distinct lung tissue state occurs with secondary infection; extrapulmonary causes of death might also originate from a pathological process in the lungs linked to microthrombosis. This heterogeneity of COVID-19 lung disease must be recognised in the management of patients and in the development of novel treatment strategies.
MeSH term(s)	Autopsy ; COVID-19/immunology ; COVID-19/pathology ; Fossils ; Humans ; Lung/pathology ; Lung/physiopathology ; Lung/virology ; Patient Acuity ; SARS-CoV-2
Language	English
Publishing date	2021-12-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2686754-0
ISSN	2213-2619 ; 2213-2600
ISSN (online)	2213-2619
ISSN	2213-2600
DOI	10.1016/S2213-2600(21)00408-2
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Article: Perceptions held by healthcare professionals concerning organ donation after circulatory death in an Australian intensive care unit without a local thoracic transplant service: A descriptive exploratory study.

Milross, Luke / O'Donnell, Thomas / Bucknall, Tracey / Pilcher, David / Poole, Alexis / Reddi, Benjamin / Ihle, Joshua

Australian critical care : official journal of the Confederation of Australian Critical Care Nurses

2021 Volume 35, Issue 4, Page(s) 430–437

Abstract: Background and objective: Organ donation rates continue to be low in Australia compared with demand. Donation after circulatory death (DCD) has been an important strategy to increase donation rates, facilitated by advances in cardiopulmonary support in ... ...

Abstract	Background and objective: Organ donation rates continue to be low in Australia compared with demand. Donation after circulatory death (DCD) has been an important strategy to increase donation rates, facilitated by advances in cardiopulmonary support in intensive care units (ICUs). However, DCD may harbour greater logistical challenges and unfavourable perceptions amongst some ICU healthcare professionals. The aim of this study was to evaluate and understand DCD perceptions at an Australian tertiary hospital. Methods: This descriptive exploratory study was conducted at an Australian tertiary hospital. Participants were recruited voluntarily for interview via email and word-of-mouth through the hospital's ICU network. The study used a mixed-methods approach; five close-ended questions were included in the form of Likert scales followed by a semistructured interview with open-ended questions designed to understand participants' perceptions of DCD. Interviews were recorded, transcribed, and thematically analysed. Results: Sixteen participants were interviewed including eight intensive care doctors, four donation specialist nursing coordinators (DSNCs), and four bedside nurses. Likert responses demonstrated clinicians' support for both DCD and donation after brain death (DBD). Thematic analysis of the transcripts yielded three overarching themes including 'Contextual and environmental influences on DCD decision-making', 'Personal difficulties faced by clinicians in DCD decision-making', and 'Family influences on DCD decision-making'. Significant geographical separation between donation and organ retrieval teams, incurring significant resource utilisation, impacted the donation team's decision-making around DCD, as did a perceived disruption of ICU care to facilitate donation especially for cases where successful DCD was identified to be unlikely. Conclusions: Overall, DCD was as acceptable to participants as DBD. However, the geographical separation of this centre meant that logistical barriers potentially impacted the DCD process. Open lines of communication with transplant centres, local resourcing, and a culture of education, experience, and leadership may facilitate the DCD programs where distant retrieval is commonplace.
MeSH term(s)	Australia ; Brain Death ; Death ; Delivery of Health Care ; Humans ; Intensive Care Units ; Tissue and Organ Procurement
Language	English
Publishing date	2021-07-29
Publishing country	Australia
Document type	Journal Article
ZDB-ID	1159493-7
ISSN	1878-1721 ; 1036-7314
ISSN (online)	1878-1721
ISSN	1036-7314
DOI	10.1016/j.aucc.2021.06.013
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Article ; Online: Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19.

Milross, Luke / Hunter, Bethany / McDonald, David / Merces, George / Thomson, Amanda / Hilkens, Catharien M U / Wills, John / Rees, Paul / Jiwa, Kasim / Cooper, Nigel / Majo, Joaquim / Ashwin, Helen / Duncan, Christopher J A / Kaye, Paul M / Bayraktar, Omer Ali / Filby, Andrew / Fisher, Andrew J

EBioMedicine

2023 Volume 99, Page(s) 104945

Abstract: Background: Lung damage in severe COVID-19 is highly heterogeneous however studies with dedicated spatial distinction of discrete temporal phases of diffuse alveolar damage (DAD) and alternate lung injury patterns are lacking. Existing studies have also ...

Abstract	Background: Lung damage in severe COVID-19 is highly heterogeneous however studies with dedicated spatial distinction of discrete temporal phases of diffuse alveolar damage (DAD) and alternate lung injury patterns are lacking. Existing studies have also not accounted for progressive airspace obliteration in cellularity estimates. We used an imaging mass cytometry (IMC) analysis with an airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease. Methods: Lung tissue was obtained at post-mortem from severe COVID-19 deaths. Pathologist-selected regions of interest (ROIs) were chosen by light microscopy representing the patho-evolutionary spectrum of DAD and alternate disease phenotypes were selected for comparison. Architecturally normal SARS-CoV-2-positive lung tissue and tissue from SARS-CoV-2-negative donors served as controls. ROIs were stained for 40 cellular protein markers and ablated using IMC before segmented cells were classified. Cell populations corrected by ROI airspace and their spatial relationships were compared across lung injury patterns. Findings: Forty patients (32M:8F, age: 22-98), 345 ROIs and >900k single cells were analysed. DAD progression was marked by airspace obliteration and significant increases in mononuclear phagocytes (MnPs), T and B lymphocytes and significant decreases in alveolar epithelial and endothelial cells. Neutrophil populations proved stable overall although several interferon-responding subsets demonstrated expansion. Spatial analysis revealed immune cell interactions occur prior to microscopically appreciable tissue injury. Interpretation: The immunopathogenesis of severe DAD in COVID-19 lung disease is characterised by sustained increases in MnPs and lymphocytes with key interactions occurring even prior to lung injury is established. Funding: UK Research and Innovation/Medical Research Council through the UK Coronavirus Immunology Consortium, Barbour Foundation, General Sir John Monash Foundation, Newcastle University, JGW Patterson Foundation, Wellcome Trust.
MeSH term(s)	Humans ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; COVID-19/pathology ; Lung Injury/pathology ; Endothelial Cells ; SARS-CoV-2 ; Lung/pathology
Language	English
Publishing date	2023-12-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104945
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