Publications by authors named "J Newcombe"

221 Publications

Clinical Characteristics and Outcomes of COVID-19 in a low-prevalence, well-resourced setting, Sydney, Australia.

Intern Med J 2021 Jul 6. Epub 2021 Jul 6.

Staff Specialist Microbiology and Infectious Diseases , NSW Health Pathology, Northern Sydney Local Health District.

Background: The Northern Sydney Local Health District was one of the first health regions to be affected by COVID-19 in Australia.

Aim: To describe the clinical characteristics, risk factors and outcomes in our low-prevalence Australian population.

Methods: A retrospective analysis of 517 laboratory-confirmed COVID-19 cases between January and June 2020. Patient information was collected as part of routine care within the COVID-19 Virtual Hospital system. Outcomes examined were death, recovery at 30 days and intensive care unit (ICU) admission.

Results: The case fatality rate was 1.8%. Multivariate analysis showed factors independently associated with death, composite outcome of death/ICU admission or incomplete recovery at 30 days were age > 80 and presence of 2 or more comorbidities. Most cases acquired COVID-19 through international (50.9%) or cruise ship travel (9.1%). Health care workers comprised 12.8% of the cohort and represented a disproportionately high percentage of the "unknown" source group (27.6%). The median incubation period was 5 days (IQR 3-8); one patient had an incubation period of 15 days. Hospitalisation was required in 11.8%, ICU admission in 2.1% and ventilation in 1.4%. A RALE score on CXR of >10 was independently associated with death.

Conclusions: In this low prevalence, well-resourced Australian setting, we report an overall low mortality. Factors associated with adverse patient outcomes on multivariate analysis were age greater than 80 and the presence of 2 or more comorbidities. This data can assist in early risk stratification of COVID-19 patients, and in surge capacity planning for hospitals. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15445DOI Listing
July 2021

Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes.

Proc Natl Acad Sci U S A 2021 Jul;118(27)

Division of Neuroscience, Institute of Experimental Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132, Milan, Italy;

Demyelination is a key pathogenic feature of multiple sclerosis (MS). Here, we evaluated the astrocyte contribution to myelin loss and focused on the neurotrophin receptor TrkB, whose up-regulation on the astrocyte finely demarcated chronic demyelinated areas in MS and was paralleled by neurotrophin loss. Mice lacking astrocyte TrkB were resistant to demyelination induced by autoimmune or toxic insults, demonstrating that TrkB signaling in astrocytes fostered oligodendrocyte damage. In vitro and ex vivo approaches highlighted that astrocyte TrkB supported scar formation and glia proliferation even in the absence of neurotrophin binding, indicating TrkB transactivation in response to inflammatory or toxic mediators. Notably, our neuropathological studies demonstrated copper dysregulation in MS and model lesions and TrkB-dependent expression of copper transporter (CTR1) on glia cells during neuroinflammation. In vitro experiments evidenced that TrkB was critical for the generation of glial intracellular calcium flux and CTR1 up-regulation induced by stimuli distinct from neurotrophins. These events led to copper uptake and release by the astrocyte, and in turn resulted in oligodendrocyte loss. Collectively, these data demonstrate a pathogenic demyelination mechanism via the astrocyte release of copper and open up the possibility of restoring copper homeostasis in the white matter as a therapeutic target in MS.
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http://dx.doi.org/10.1073/pnas.2025804118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271600PMC
July 2021

Lactate-induced dispersal of microcolonies is mediated by changes in cell density and pilus retraction and is influenced by temperature change.

Infect Immun 2021 Jun 14:IAI0029621. Epub 2021 Jun 14.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.

is the etiologic agent of meningococcal meningitis and sepsis. Initial colonization of meningococci to the upper respiratory tract epithelium is crucial for disease development. The colonization occurs in several steps and expression of type IV pili (Tfp) is essential for both attachment and microcolony formation of encapsulated bacteria. Previously, we have shown that host-derived lactate induces synchronized dispersal of meningococcal microcolonies. In this study, we demonstrated that lactate-induced dispersal is dependent on bacterial concentration but not on the quorum sensing system autoinducer-2 or the two-component systems NarP/NarQ, PilR/PilS, NtrY/NtrX, and MisR/MisS. Further, there were no changes in expression of genes related to assembly, elongation, retraction, and modification of Tfp throughout the time course of lactate induction. By using and mutants, however, we found that lactate-induced dispersal was dependent on PilT-retraction but not on phosphoglycerol-modification of Tfp even though the PptB activity was important for preventing re-aggregation post-dispersal. Furthermore, protein synthesis was required for lactate-induced dispersal. Finally, we found that at a lower temperature, lactate-induced dispersal was delayed and unsynchronized, and bacteria reformed microcolonies. We conclude that lactate-induced microcolony dispersal is dependent on bacterial concentration, PilT-dependent Tfp retraction, and protein synthesis and influenced by environmental temperature.
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http://dx.doi.org/10.1128/IAI.00296-21DOI Listing
June 2021

An evaluation of 4 commercial assays for the detection of SARS-CoV-2 antibodies in a predominantly mildly symptomatic low prevalence Australian population.

J Clin Virol 2021 05 17;138:104797. Epub 2021 Mar 17.

Department of Microbiology, Sullivan Nicolaides Pathology, Queensland, Australia.

A total of 1080 individual patient samples (158 positive serology samples from confirmed, predominantly mildly symptomatic COVID-19 patients and 922 serology negative including 496 collected pre-COVID) from four states in Australia were analysed on four commercial SARS-CoV-2 serological assays targeting antibodies to different antigens (Roche Elecsys and Abbott Architect: nucleocapsid; Diasorin Liaison and Euroimmun: spike). A subset was compared to immunofluorescent antibody (IFA) and micro-neutralisation. Sensitivity and specificity of the Roche (n = 1033), Abbott (n = 806), Diasorin (n = 1034) and Euroimmun (n = 175) were 93.7 %/99.5 %, 90.2 %/99.4 %, 88.6 %/98.6 % and 91.3 %/98.8 %, respectively. ROC analysis with specificity held at 99 % increased the sensitivity for the Roche and Abbott assays from 93.7% to 98.7% (cut-off 0.21) and 90.2 % to 94.0 % (cut-off 0.91), respectively. Overall seropositivity of samples increased from a maximum of 23 % for samples 0-7 days-post-onset of symptoms (dpos), to 61 % from samples 8-14dpos and 93 % from those >14dpos. IFA and microneutralisation values correlated best with assays targeting antibodies to spike protein with values >80 AU/mL on the Diasorin assay associated with neutralising antibody. Detectable antibody was present in 22/23 (96 %), 20/23 (87 %), 15/23 (65 %) and 9/22 (41 %) patients with samples >180dpos on the Roche, Diasorin, Abbott and microneutralisation assays respectively. Given the low prevalence in this community, two-step algorithms on initial positive results saw an increase in the positive predictive value (PPV) of positive samples (39 %-65 % to ≥98 %) for all combinations. Similarly accuracy increased from a range of 98.5 %-99.4 % to ≥99.8 % assuming a 1 % seroprevalence. Negative predictive value (NPV) was high (≥99.8 %) regardless of which assay was used initially.
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http://dx.doi.org/10.1016/j.jcv.2021.104797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968170PMC
May 2021

Automated and unbiased discrimination of ALS from control tissue at single cell resolution.

Brain Pathol 2021 Jul 11;31(4):e12937. Epub 2021 Feb 11.

Idiap Research Institute, Martigny, Switzerland.

Histopathological analysis of tissue sections is invaluable in neurodegeneration research. However, cell-to-cell variation in both the presence and severity of a given phenotype is a key limitation of this approach, reducing the signal to noise ratio and leaving unresolved the potential of single-cell scoring for a given disease attribute. Here, we tested different machine learning methods to analyse high-content microscopy measurements of hundreds of motor neurons (MNs) from amyotrophic lateral sclerosis (ALS) post-mortem tissue sections. Furthermore, we automated the identification of phenotypically distinct MN subpopulations in VCP- and SOD1-mutant transgenic mice, revealing common morphological cellular phenotypes. Additionally we established scoring metrics to rank cells and tissue samples for both disease probability and severity. By adapting this paradigm to human post-mortem tissue, we validated our core finding that morphological descriptors robustly discriminate ALS from control healthy tissue at single cell resolution. Determining disease presence, severity and unbiased phenotypes at single cell resolution might prove transformational in our understanding of ALS and neurodegeneration more broadly.
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http://dx.doi.org/10.1111/bpa.12937DOI Listing
July 2021
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