ORCID Profile
0000-0003-1460-5572
Current Organisations
Alfred Health
,
Monash Health
,
Monash University
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Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.PRP.2010.07.002
Abstract: Tularemia is a rare zoonotic disease caused by Francisella tularensis, a Gram-negative bacteria. The clinical manifestations of pulmonary tularemia resemble those of other airways infections. Recently, a case of pulmonary tularemia was diagnosed at Tufts Medical Center. The purpose of the current report is to document the utility of applying several diagnostic tools, including immunohistochemistry, electron microscopy, microbiology and molecular biology in confirming the diagnosis of pulmonary tularemia, particularly in convalescing cases (up to 3 weeks postpresentation) and after antibiotic therapy. Our study demonstrates the usefulness of microbiological studies followed by morphological evaluation and the limitation of the molecular biology analysis of posttherapy s les.
Publisher: Cold Spring Harbor Laboratory
Date: 20-11-2020
DOI: 10.1101/2020.11.17.20233544
Abstract: Lasting immunity to SARS-CoV-2 following infection is questioned because serum antibodies decline in convalescence. However, functional immunity is mediated by long-lived memory T and B (Bmem) cells. To determine the longevity and immunophenotype of SARS-CoV-2-specific Bmem cells in COVID-19 patients. Recombinant spike receptor binding domain (RBD) and nucleocapsid protein (NCP) were produced for ELISA-based serology, and biotinylated for fluorescent tetramer generation to identify SARS-CoV-2-specific Bmem cells by flow cytometry with a panel of 13 mAbs. 36 blood s les were obtained from 25 COVID-19 patients (11 paired) between 4-242 days post-symptom onset for detection of neutralizing antibodies, IgG serology and flow cytometry. The recombinant RBD and NCP were specifically recognized by serum IgG in all patients and reactivity declined days post-symptom onset. All patients had detectable RBD- and NCP-specific Bmem cells at 8.23-267.6 cells/ml of blood (0.004-0.13% of B cells) regardless of s ling time. RBD- and NCP-specific Bmem cells predominantly expressed IgM or IgG1, with the latter formed slightly later than the former. RBD-specific IgG + Bmem were predominantly CD27 + , and numbers significantly correlated with circulating follicular helper T cell numbers. RBD- and NCP-specific Bmem cells persisted for 8 months, indicating that the decline in serum antibodies after 1 month does not indicate waning of immunity but a contraction of the immune response. Flowcytometric detection of SARS-CoV-2-specific Bmem cells enables detection of long-term functional immunity following infection or vaccination for COVID-19.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
Publisher: Massachusetts Medical Society
Date: 10-08-2023
DOI: 10.1056/NEJMC2307375
Publisher: Public Library of Science (PLoS)
Date: 13-11-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2017
Publisher: Elsevier BV
Date: 05-0006
Publisher: Elsevier BV
Date: 03-2021
Publisher: Informa UK Limited
Date: 2008
DOI: 10.1080/00365540701522942
Abstract: Although serious infections such as bacterial endocarditis (BE) are being increasingly treated with parenteral antibiotics via Hospital-in-the-Home (HITH) programmes in Australia, there are few published data to confirm the safety and efficacy of this treatment modality, especially among patients with BE due to pathogens other than streptococci. In a 12-month prospective, multi-site study we assessed HITH treatment outcomes for all cases of BE. Among the 40 BE cases (29 'definite', 11 'possible' Duke criteria) caused by a range of pathogens (16 staphylococci spp., 11 streptococci, 4 other, 9 culture-negative), cure was achieved in 37 (93%) cases. BE due to Staphylococcus aureus was significantly associated with an inferior outcome (p =0.046). Adverse events were relatively common (9/40), but most were not severe and were managed with continuation of HITH care. BE can be safely managed via HITH, but particular care in patient selection is necessary, especially for cases due to S. aureus.
Publisher: WHO Press
Date: 21-02-2013
Publisher: Elsevier BV
Date: 2003
DOI: 10.2139/SSRN.1030470
Publisher: Public Library of Science (PLoS)
Date: 28-02-2020
Publisher: Springer Science and Business Media LLC
Date: 15-07-2011
Publisher: Oxford University Press (OUP)
Date: 08-07-2015
DOI: 10.1093/CID/CIV556
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-12-2020
DOI: 10.1126/SCIIMMUNOL.ABF8891
Abstract: Memory B cells specific for SARS-CoV-2 spike and nucleocapsid proteins persist in peripheral blood after recovery from COVID-19.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.BIOS.2017.01.018
Abstract: Molecularly imprinted polymers (MIPs) are biomimetics which can selectively bind to analytes of interest. One of the most interesting areas where MIPs have shown the biggest potential is food analysis. MIPs have found use as sorbents in s le preparation attributed to the high selectivity and high loading capacity. MIPs have been intensively employed in classical solid-phase extraction and solid-phase microextraction. More recently, MIPs have been combined with magnetic bead extraction, which greatly simplifies s le handling procedures. Studies have consistently shown that MIPs can effectively minimize complex food matrix effects, and improve recoveries and detection limits. In addition to s le preparation, MIPs have also been viewed as promising alternatives to bio-receptors due to the inherent molecular recognition abilities and the high stability in harsh chemical and physical conditions. MIPs have been utilized as receptors in biosensing platforms such as electrochemical, optical and mass biosensors to detect various analytes in food. In this review, we will discuss the current state-of-the-art of MIP synthesis and applications in the context of food analysis. We will highlight the imprinting methods which are applicable for imprinting food templates, summarize the recent progress in using MIPs for preparing and analysing food s les, and discuss the current limitations in the commercialisation of MIPs technology. Finally, future perspectives will be given.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Oxford University Press (OUP)
Date: 20-01-2020
Publisher: Oxford University Press (OUP)
Date: 17-12-2021
DOI: 10.1093/JAC/DKAA506
Abstract: The urgent need to develop effective therapeutics and disseminate information from clinical studies has led to data from clinical trials being made available by alternate methods prior to peer-reviewed publication, including press releases, social media and pre-print papers. While this allows clinicians more open access to these data, a trust has to be placed with the investigators releasing these data without the availability of scientifically rigorous peer review. The ex les of results from trials studying dexamethasone and hydroxychloroquine for treatment of COVID-19 have had contrasting outcomes, including the potential for significant numbers of lives saved with the early release of results from the RECOVERY trial studying dexamethasone contrasting with unsubstantiated data being presented from trials studying hydroxychloroquine. Clinicians and researchers must maintain a healthy scepticism when reviewing results prior to peer-reviewed publication, but also consider when these opportunities may allow for early implementation of potentially lifesaving interventions for people infected with COVID-19.
Publisher: Wiley
Date: 25-03-2023
DOI: 10.1002/JPPR.1859
Abstract: Invasive candidiasis (IC) surveillance demonstrates an increasing incidence of resistance to azole‐based therapy. Consequently, echinocandins are often considered first‐line treatment for IC in critically ill patients. To better understand the complexities of decision‐making around echinocandin initiation, an evidence‐based audit tool was developed. To describe echinocandin initiation and compliance with current guidelines. A retrospective audit of echinocandin initiation was conducted between 1 January 2020 and 31 December 2020 at a quaternary referral hospital. An audit tool was developed by infectious diseases physicians and antimicrobial stewardship pharmacists, capturing patient demographics, microbiological results, indication for therapy, and risk factors for invasive fungal disease (IFD). Local guideline compliance was determined. This project was determined to be a quality improvement project and was not required to undergo ethical review according to the Alfred Hospital Ethics Committee procedures. One hundred sixty‐seven patients were initiated on 214 courses of echinocandin therapy. Caspofungin was most commonly prescribed ( n = 172, 80%). Of the 167 patients, most ( n = 119, 71%) were in the intensive care unit at the time of initiation. Empiric therapy for sepsis or infection of unclear source was the most commonly documented indication ( n = 117, 55%) 71% ( n = 153) of all courses were deemed empiric therapy, followed by directed therapy ( n = 55, 26%). The most common risk factors for IFD were recent exposure to broad‐spectrum antimicrobial therapy ( n = 165, 99%) and the presence of a urinary catheter ( n = 141, 84%). Most first doses were compliant with local guidelines ( n = 144, 67%). Echinocandin therapy was commonly prescribed in critically ill patients with risk factors for IFD. Although the majority of prescriptions were empiric and compliant with local guidelines, improved guidelines incorporating additional patient factors should be included in future antifungal stewardship initiatives.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 19-05-2022
DOI: 10.1038/S41467-022-30088-Y
Abstract: Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory s les from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory s les correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory s les and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory s les, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory s les and blood, and shows how drug therapy affects immune responses during COVID-19.
Publisher: Elsevier BV
Date: 10-2022
Publisher: The American Association of Immunologists
Date: 15-05-2022
Abstract: Understanding the generation of immunity to SARS-CoV-2 in lymphoid tissues draining the site of infection has implications for immunity to SARS-CoV-2. We performed tonsil biopsies under local anesthesia in 19 subjects who had recovered from SARS-CoV-2 infection 24–225 d previously. The biopsies yielded & million cells for flow cytometric analysis in 17 subjects. Total and SARS-CoV-2 spike-specific germinal center B cells, and T follicular helper cells, were readily detectable in human tonsils early after SARS-CoV-2 infection, as assessed by flow cytometry. Responses were higher in s les within 2 mo of infection but still detectable in some subjects out to 7 mo following infection. We conclude the tonsils are a secondary lymphoid organ that develop germinal center responses to SARS-CoV-2 infection and could play a role in the long-term development of immunity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-07-2021
Publisher: Elsevier BV
Date: 05-2018
Publisher: CSIRO Publishing
Date: 2019
DOI: 10.1071/SH18130
Abstract: Background Recruitment of people to randomised trials of online interventions presents particular challenges and opportunities. The aim of this study was to evaluate factors associated with the recruitment of people with HIV (PWHIV) and their doctors to the HealthMap trial, a cluster randomised trial of an online self-management program. Methods: Recruitment involved a three-step process. Study sites were recruited, followed by doctors caring for PWHIV at study sites and finally PWHIV. Data were collected from study sites, doctors and patient participants. Factors associated with site enrolment and patient participant recruitment were investigated using regression models. Results: Thirteen study sites, 63 doctor participants and 728 patient participants were recruited to the study. Doctors having a prior relationship with the study investigators (odds ratio (OR) 13.3 95% confidence interval (CI) 3.0, 58.7 P = 0.001) was positively associated with becoming a HealthMap site. Most patient participants successfully recruited to HealthMap (80%) had heard about the study from their HIV doctor. Patient enrolment was associated with the number of people with HIV receiving care at the site (β coefficient 0.10 95% CI 0.04, 0.16 P = 0.004), but not with employing a clinic or research nurse to help recruit patients (β coefficient 55.9 95% CI –2.55, 114.25 P = 0.06). Conclusion: Despite substantial investment in online promotion, a previous relationship with doctors was important for doctor recruitment, and doctors themselves were the most important source of patient recruitment to the HealthMap trial. Clinic-based recruitment strategies remain a critical component of trial recruitment, despite expanding opportunities to engage with online communities.
Publisher: Elsevier BV
Date: 2020
Publisher: Oxford University Press (OUP)
Date: 04-2008
DOI: 10.2146/AJHP070203
Abstract: A case of torsades de pointes associated with fluconazole use is described. A 68-year-old woman with a history of hypertension treated with 2.5 mg of indapamide for 16 months sought medical treatment after having two falls 1 month apart. A computed tomography scan and subsequent magnetic resonance imaging of the brain revealed a lesion in the left pons and middle cerebellar peduncle. Biopsy of the pontine lesion revealed large yeast forms and subsequently revealed Cryptococcus neoformans var. gattii. The patient was initially treated with conventional hotericin B and flucytosine for six weeks. The first week of therapy was complicated by hypokalemia, hypomagnesemia, and an episode of atrial fibrillation that was managed with electrolyte replacement, commencement of metoprolol, and switching from conventional hotericin B to hotericin B lipid complex. After six weeks, liposomal hotericin was discontinued and high-dose oral fluconazole was initiated. Six days after beginning fluconazole therapy, the patient had a generalized tonic-clonic seizure and suffered cardiopulmonary arrest. Postresuscitation, an electrocardiogram demonstrated a corrected Q-T interval of 556 msec. Recurrent episodes of torsades de pointes were also recorded postarrest. Fluconazole was discontinued at this time, and liposomal hotericin B was resumed. Neurologic and electroencephalographic assessment conducted 48 hours postarrest revealed that significant neurologic damage had been sustained. Supportive care was withdrawn, and the patient died two days later. A postmortem examination revealed no coronary artery disease or hemorrhagic transformation of the pontine cryptococcoma. Treatment with high-dose fluconazole was the probable cause of torsades de pointes in a patient with risk factors for this condition. The benefits and risks of using fluconazole should be carefully weighed for patients with risk factors for Q-T interval prolongation.
Publisher: Wiley
Date: 2015
Publisher: Elsevier BV
Date: 03-2021
Publisher: Wiley
Date: 02-11-2020
DOI: 10.1111/ANS.16423
Publisher: American Chemical Society (ACS)
Date: 11-04-2019
DOI: 10.1021/ACS.JMEDCHEM.9B00462
Abstract: The persistent reservoir of cells latently infected with human immunodeficiency virus (HIV)-integrated proviral DNA necessitates lifelong suppressive antiretroviral therapy (ART). Epigenetic targeted compounds have shown promise as potential latency-reversing agents however, these drugs have undesirable toxicity and lack specificity for HIV. We utilized a novel HEK293-derived FlpIn dual-reporter cell line, which quantifies specific HIV provirus reactivation (LTR promoter) relative to nonspecific host cell gene expression (CMV promoter), to identify the 5-substituted 2-acylaminothiazole hit class. Here, we describe the optimization of the hit class, defining the functionality necessary for HIV gene activation and for improving in vitro metabolism and solubility. The optimized compounds displayed enhanced HIV gene expression in HEK293 and Jurkat 10.6 latency cellular models and increased unspliced HIV RNA in resting CD4+ T cells isolated from HIV-infected in iduals on ART, demonstrating the potential of the 2-acylaminothiazole class as latency-reversing agents.
Publisher: Informa UK Limited
Date: 06-10-2023
DOI: 10.1080/09540121.2022.2129562
Abstract: In 2014, UNAIDS outlined the 90-90-90 treatment targets. The "fourth 90" reflects the need to focus on optimising quality of life (HRQoL) in people living with HIV. Using a s le of non-heterosexual males in Melbourne, Australia, we aimed to assess HRQoL differences between HIV-positive and HIV-negative in iduals, and identify factors that predict HRQoL both at baseline and after three years of follow up. Clinical information and patient-reported outcomes incorporating the Assessing Quality of Life-6D scale were collected at baseline and at three years. Sixty-two HIV-positive cases (antiretroviral therapy naïve at baseline) and 48 controls were enrolled. Results were compared between cases and controls at baseline, three-year follow-up, and between timepoints. HRQoL was significantly lower in cases compared to controls (83.5 (IQR 77.2-88.6) vs 87.3 (IQR 82.1-91.8),
Publisher: Elsevier BV
Date: 12-2022
Publisher: Elsevier BV
Date: 12-2020
Publisher: Springer Science and Business Media LLC
Date: 10-11-2020
DOI: 10.1186/S12981-020-00321-Z
Abstract: Analytical treatment interruptions (ATI) are commonly used clinical endpoints to assess interventions aimed at curing HIV or achieving antiretroviral therapy (ART)-free HIV remission. Understanding the acceptability of ATI amongst people living with HIV (PLHIV) and their HIV healthcare providers (HHP) is limited. Two online surveys for PLHIV and HHP assessed awareness and acceptability of ATI, and understanding of the prospect for HIV cure in the future. Responses were collected from July 2017–January 2018. A descriptive analysis was performed and similar questions across the two surveys were compared using χ squared test. 442 PLHIV and 144 HHP completed the survey. 105/400 (26%) PLHIV had ever interrupted ART, 8% of which were in a clinical trial. Altruistic motivations were drivers of participation of PLHIV in cure related research. 81/135 (60%) HHP would support their patients wishing to enrol in an HIV cure-focused trial, but fewer would promote and allow such participation (25% and 31% respectively). Compared to HHP, PLHIV were more likely to believe that an HIV cure would be achievable within 10 years (55% vs. 19%, p 0.001), had less awareness of ATI (46% vs. 62%, p 0.001) and were less likely to have had experience of either participation or enrolment in an ATI study (5% vs. 18%, p 0.001) PLHIV were more optimistic about the potential for HIV cure. HHP had more direct experience with HIV cure-focused studies. Educational strategies are required for both groups to increase understanding around ATIs in HIV cure research but should be tailored specifically to each group.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-09-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2021
Publisher: European Respiratory Society (ERS)
Date: 2023
Publisher: Frontiers Media SA
Date: 28-04-2022
DOI: 10.3389/FCIMB.2022.855290
Abstract: Latent HIV-1 provirus in infected in iduals on suppressive therapy does not always remain transcriptionally silent. Both HIV-1 LTR and human gene promoter derived transcriptional events can contribute HIV-1 sequences to the mRNA produced in the cell. In addition, chimeric cellular:HIV mRNA can arise through readthrough transcription and aberrant splicing. Using target enrichment coupled to the Illumina Mi-Seq and PacBio RS II platforms, we show that 3’ LTR activation is frequent in latently infected cells from both the CCL19-induced primary cell model of HIV-1 latency as well as ex vivo s les. In both systems of latent HIV-1 infection, we detected several chimeric species that were generated via activation of a cryptic splice donor site in the 5’ LTR of HIV-1. Aberrant splicing involving the major HIV-1 splice donor sites, SD1 and SD4 disrupts post-transcriptional processing of the gene in which HIV-1 is integrated. In the primary cell model of HIV-1 latency, Tat-encoding sequences are incorporated into the chimeric mRNA transcripts through the use of SD4. Our study unravels clues to the characteristics of HIV-1 integrants that promote formation of chimeric cellular:HIV mRNA and improves the understanding of the HIV-1 RNA footprint in latently infected cells.
Publisher: European Centre for Disease Control and Prevention (ECDC)
Date: 02-06-2022
DOI: 10.2807/1560-7917.ES.2022.27.22.2200411
Abstract: Rapid diagnosis and whole genome sequencing confirmed a case of monkeypox in an HIV-positive in idual receiving antiretroviral therapy. The patient had a normal CD4+ T-cell count and suppressed HIV viral load and presented with a genital rash in Melbourne, Australia after return from Europe in May 2022. He subsequently developed systemic illness and disseminated rash and 11 days after symptom onset, he was hospitalised to manage painful bacterial cellulitis of the genital area.
Publisher: Mary Ann Liebert Inc
Date: 04-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2015
Publisher: Elsevier BV
Date: 09-2014
Publisher: Elsevier BV
Date: 04-2021
Publisher: Wiley
Date: 18-08-2023
DOI: 10.1111/IMCB.12682
Abstract: Current serological tests cannot differentiate between total immunoglobulin A (IgA) and dimeric IgA (dIgA) associated with mucosal immunity. Here, we describe two new assays, dIgA‐ELISA and dIgA‐multiplex bead assay (MBA), that utilize the preferential binding of dIgA to a chimeric form of secretory component, allowing the differentiation between dIgA and monomeric IgA. dIgA responses elicited through severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection were measured in (i) a longitudinal panel, consisting of 74 s les ( n = 20 in iduals) from hospitalized cases of coronavirus disease 2019 (COVID‐19) (ii) a longitudinal panel, consisting of 96 s les ( n = 10 in iduals) from in iduals with mild COVID‐19 (iii) a cross‐sectional panel with PCR‐confirmed SARS‐CoV‐2 infection with mild COVID‐19 ( n = 199) and (iv) pre–COVID‐19 s les ( n = 200). The dIgA‐ELISA and dIgA‐MBA demonstrated a specificity for dIgA of 99% and 98.5%, respectively. Analysis of dIgA responses in the longitudinal panels revealed that 70% (ELISA) and 50% (MBA) of patients elicited a dIgA response by day 20 after PCR diagnosis with a SARS‐CoV‐2 infection. In iduals with mild COVID‐19 displayed increased levels of dIgA within the first 3 weeks after diagnosis but responses appeared to be short lived, compared with sustained IgA levels. However, in s les from hospitalized patients with COVID‐19 we observed high and sustained levels of dIgA, up to 245 days after PCR diagnosis. Our results suggest that severe COVID‐19 infections are associated with sustained levels of plasma dIgA compared with mild cases.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1186/S13063-020-04576-9
Abstract: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. Participants will be recruited from hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently. Participants will be randomised 1:1:1:1 to: Group 1 : standard of care Group 2 : lopinavir (400mg) / ritonavir (100mg) twice daily for 10 days in tablet form Group 3 : hydroxychloroquine (800mg) 4x200mg administered 12 hours apart on Day 1, followed by 400mg twice a day for 6 days Group 4 : lopinavir /ritonavir plus hydroxychloroquine. Proportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation) at 15 days after enrolment. A range of clinical and virological secondary outcomes will also be evaluated. The randomisation schedule will be generated by an independent statistician. Randomisation will be stratified by site and will be in permuted blocks of variable block size. The randomised sequence allocation will only be accessible to the data management group, and site investigators will have in idual participant allocation provided through a web-based trial enrolment platform. This is an open-label study, with researchers assessing the laboratory outcomes blinded to treatment allocation. No unblinding procedures relating to potential adverse effects are therefore required. We assumed that 5% of participants receiving standard of care would meet the primary outcome, aimed to evaluate whether interventions could lead to a relative risk of 0.5, assuming no interaction between intervention arms. This corresponds to a required s le size of 610 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total s le size therefore is planned to be 2440. ASCOT protocol version 3, May 5, 2020. Recruitment opened April 4, 2020 and is ongoing, with planned completion of enrolment July 31, 2021. Australian New Zealand Clinical Trials Registry ( ACTRN12620000445976 ). Prospectively registered April 6, 2020. The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated this Letter serves as a summary of the key elements of the full protocol.
Publisher: Wiley
Date: 29-10-2020
DOI: 10.1111/AJO.13270
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-01-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2017
Publisher: Public Library of Science (PLoS)
Date: 12-02-2013
Publisher: Springer Science and Business Media LLC
Date: 11-07-2016
Publisher: Elsevier BV
Date: 10-2014
Publisher: Elsevier BV
Date: 04-2016
Publisher: SAGE Publications
Date: 16-08-2018
Abstract: Disseminated histoplasmosis (DH), an endemic mycosis caused by the dimorphic fungus Histoplasma capsulatum, is a life-threatening infection in immunocompromised hosts. A patient with newly-diagnosed human immunodeficiency virus (HIV) infection presented with a violaceous, raised, indurated, pruritic rash over the face, arms and trunk on a background of significant weight loss, fevers with sweats, diarrhoea and worsening shortness of breath. His CD4+ T cell count was 14 cells/µl (12%). Histoplasmosis was diagnosed from histology, fungal stain and culture of skin biopsy. In addition to DH, he was found to have Pneumocystis jiroveci pneumonia and multi-resistant Salmonella choleraesuis bacteraemia. He improved with treatment with antibiotics and was commenced on conventional itraconazole, orally. Antiretroviral therapy was commenced soon after. He was unable to achieve therapeutic levels with the conventional formulation due to gastrointestinal side effects and had ongoing fevers. A newer formulation of oral itraconazole with improved bioavailability was commenced. He achieved therapeutic drug levels and had no further intolerance. His fevers settled and the rash improved. He has now completed one year of treatment and is well. To our knowledge this is the first case of moderate DH in an advanced HIV patient treated successfully with oral itraconazole with improved bioavailability.
Publisher: Cold Spring Harbor Laboratory
Date: 07-2021
DOI: 10.1101/2021.06.28.21259671
Abstract: Current tests for SARS-CoV-2 antibodies (IgG, IgM, IgA) cannot differentiate recent and past infections. We describe a point of care, lateral flow assay for SARS-CoV-2 dIgA based on the highly selective binding of dIgA to a chimeric form of secretory component (CSC), that distinguishes dIgA from monomeric IgA. Detection of specific dIgA uses a complex of biotinylated SARS-CoV-2 receptor binding domain and streptavidin-colloidal gold. SARS-CoV-2-specific dIgA was measured both in 112 cross-sectional s les and a longitudinal panel of 362 plasma s les from 45 patients with PCR-confirmed SARS-CoV-2 infection, and 193 discrete pre-COVID-19 or PCR-negative patient s les. The assay demonstrated 100% sensitivity from 11 days post-symptom onset, and a specificity of 98.2%. With an estimated half-life of 6.3 days, dIgA provides a unique biomarker for the detection of recent SARS-CoV-2 infections with potential to enhance diagnosis and management of COVID-19 at point-of-care.
Publisher: Oxford University Press (OUP)
Date: 18-01-2011
DOI: 10.1093/CID/CIQ167
Publisher: Frontiers Media SA
Date: 28-03-2023
DOI: 10.3389/FIMMU.2023.1123342
Abstract: In people with HIV (PWH) both off and on antiretroviral therapy (ART), the expression of immune checkpoint (IC) proteins is elevated on the surface of total and HIV-specific T-cells, indicating T-cell exhaustion. Soluble IC proteins and their ligands can also be detected in plasma, but have not been systematically examined in PWH. Since T-cell exhaustion is associated with HIV persistence on ART, we aimed to determine if soluble IC proteins and their ligands also correlated with the size of the HIV reservoir and HIV-specific T-cell function. We used multiplex bead-based immunoassay to quantify soluble programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin domain and mucin domain 3 (TIM-3), PD-1 Ligand 1 (PD-L1) and PD-1 Ligand 2 (PD-L2) in plasma from PWH off ART (n=20), on suppressive ART (n=75) and uninfected controls (n=20). We also quantified expression of membrane-bound IC and frequencies of functional T-cells to Gag and Nef peptide stimulation on CD4+ and CD8+ T-cells using flow cytometry. The HIV reservoir was quantified in circulating CD4+ T-cells using qPCR for total and integrated HIV DNA, cell-associated unspliced HIV RNA and 2LTR circles. Soluble (s) PD-L2 level was higher in PWH off and on ART compared to uninfected controls. Higher levels of sPD-L2 correlated with lower levels of HIV total DNA and higher frequencies of gag-specific CD8+ T-cells expressing CD107a, IFNγ or TNFα. In contrast, the concentration of sLAG-3 was similar in uninfected in iduals and PWH on ART, but was significantly elevated in PWH off ART. Higher levels of sLAG-3 correlated with higher levels of HIV total and integrated DNA, and lower frequency of gag-specific CD4+ T cells expressing CD107a. Similar to sLAG-3, levels of sPD-1 were elevated in PWH off ART and normalized in PWH on ART. sPD-1 was positively correlated with the frequency of gag-specific CD4+ T cells expressing TNF-a and the expression of membrane-bound PD-1 on total CD8+ T-cells in PWH on ART. Plasma soluble IC proteins and their ligands correlate with markers of the HIV reservoir and HIV-specific T-cell function and should be investigated further in in large population-based studies of the HIV reservoir or cure interventions in PWH on ART.
Publisher: Elsevier BV
Date: 12-2015
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/SH14144
Abstract: Background An estimated 25 700 people live with diagnosed HIV (PLWH) in Australia and ~1200 newly diagnosed cases were notified in 2012. New HIV prevention strategies focus on in idual uptake of treatment however, a potential barrier is the financial burden of antiretroviral treatment (ART). We describe HIV ART dispensed and the estimated associated costs for PLWH in Victoria. Methods: A retrospective cross-sectional study of pharmacy data on ART dispensed between January 2012 and November 2013 from a hospital network, including Victoria’s largest sexual health clinic was conducted. Estimated annual patient costs of ART were calculated by the number of items dispensed per year, concession status, dispensing site and applicable co-payment. Results: A total of 60 225 dispensing records from 3903 in iduals were included this represented 83.8% of pharmaceutical benefits scheme-recorded ART dispensed in Victoria over this period. The estimated annual co-payment costs for patients without a concession card and who were collecting two medications was $433.20. One-fifth of patients (21.3%) collected four or more items, equating to an estimated annual cost of at least $866.40 without a concession card and $141.60 with a concession card. Of those dispensed four or more items, 40.4% were concession card holders. Conclusions: There may be meaningful patient costs associated with accessing ART for some PLWH. New HIV treatment-based prevention strategies need to consider financial vulnerabilities and appropriately targeted initiatives to alleviate patient costs associated with ART, ensuring they do not act as a barrier to commencement of and adherence to HIV treatment.
Publisher: Public Library of Science (PLoS)
Date: 16-05-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2021
Publisher: Elsevier BV
Date: 10-2021
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 06-2017
Publisher: Mary Ann Liebert Inc
Date: 04-2021
Publisher: Springer Science and Business Media LLC
Date: 11-09-2023
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/00365540500504158
Abstract: Lactococcus lactis is an uncommon cause of invasive disease in humans. We present a case of L. lactis liver abscess in an immunocompetent adult, apparently related to consumption of live culture yoghurt.
Publisher: Springer Science and Business Media LLC
Date: 05-12-2022
DOI: 10.1186/S12981-022-00476-X
Abstract: There are more than 7,800 people living with human immunodeficiency virus (HIV) in Victoria, Australia. Crucial in maximising the in idual and population level benefits from antiretroviral therapy (ART) is understanding how to achieve patient retention in care and the factors that drive it. This study was an expansion of a 2015 assessment of HIV-care retention in Victoria, which sought out to determine whether the inclusion of a broader range of HIV-healthcare sites would yield more accurate estimates of retention in HIV-care. We aimed to improve our understanding of HIV-care retention in Victoria, Australia, identify people living with HIV (PLHIV) with unknown outcomes, and attempt to re-engage PLHIV in care. A network of 15 HIV-care sites was established in Victoria, Australia across erse care settings which ranged from low-caseload rural sites to high-caseload metropolitan GP clinics and hospitals. In iduals who had an HIV viral load (VL) performed in both calendar years of 2016 and 2017 were classified as retained in care. In iduals with a VL test in 2016 but not in 2017 were considered to potentially have unknown outcomes as they may have been receiving care elsewhere, have disengaged from care or died. For this group, an intervention of cross-referencing partially de-identified data between healthcare sites, and contact tracing in iduals who still had unknown outcomes was performed. For 5223 in iduals considered to be retained in care across 15 healthcare sites in the study period, 49 had unconfirmed transfers of care to an alternative provider and 79 had unknown outcomes. After the intervention, the number of unconfirmed care transfers was reduced to 17 and unknown outcomes reduced to 51. These changes were largely attributed to people being reclassified as confirmed transfers of care. Retention in care estimates that did not include the patient outcome of confirmed transfer of care ranged from 76.2 to 95.8% and did not alter with the intervention. However, retention in care estimates which considered confirmed transfers and those that re-entered care at a new site as retained in care significantly increased across five of the sites with estimates ranging from 80.9 to 98.3% pre-intervention to 83.3–100% post-intervention. In iduals whose outcomes remained unknown post-intervention were more often men who have sex with men (MSM) when compared to other categories (person who injects drugs (PWID), combined PWID/MSM, men who identify as heterosexual or unknown) (74.5% vs. 53.5%, [p = 0.06]) and receiving ART at their last HIV-care visit (84.3% vs. 67.8% [p = 0.09]). This study confirmed high retention in HIV-care and low numbers of people disengaged from HIV-care in Victoria. This was demonstrated across a larger number of sites with varying models of care than a prior assessment in 2015. These data align with national and state targets aiming for 95% of PLHIV retained in HIV-care.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-02-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2021
Publisher: Frontiers Media SA
Date: 14-06-2021
DOI: 10.3389/FGENE.2021.680725
Abstract: HIV-1 Tat protein is essential for virus production. RNA-binding proteins that facilitate Tat production may be absent or downregulated in resting CD4 + T-cells, the main reservoir of latent HIV in people with HIV (PWH) on antiretroviral therapy (ART). In this study, we examined the role of Tat RNA-binding proteins on the expression of Tat and control of latent and productive infection. Affinity purification coupled with mass spectrometry analysis was used to detect binding partners of MS2-tagged tat mRNA in a T cell-line model of HIV latency. The effect of knockdown and overexpression of the proteins of interest on Tat transactivation and translation was assessed by luciferase-based reporter assays and infections with a dual color HIV reporter virus. Out of the 243 interactions identified, knockdown of SRP14 (Signal Recognition Particle 14) negatively affected tat mRNA processing and translation as well as Tat-mediated transactivation, which led to an increase in latent infection. On the other hand, knockdown of HMGB3 (High Mobility Group Box 3) resulted in an increase in Tat transactivation and translation as well as an increase in productive infection. Footprinting experiments revealed that SRP14 and HMGB3 proteins bind to TIM-TAM, a conserved RNA sequence-structure in tat mRNA that functions as a Tat IRES modulator of tat mRNA. Overexpression of SRP14 in resting CD4 + T-cells from patients on ART was sufficient to reverse HIV-1 latency and induce virus production. The role of SRP14 and HMGB3 proteins in controlling HIV Tat expression during latency will be further assessed as potential drug targets.
Publisher: Wiley
Date: 09-10-2018
DOI: 10.1002/CPT.1220
Publisher: Oxford University Press (OUP)
Date: 15-05-2012
DOI: 10.1093/CID/CIS207
Publisher: Oxford University Press (OUP)
Date: 27-04-2012
DOI: 10.1093/CID/CIS206
Publisher: The American Association of Immunologists
Date: 2022
Abstract: In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4+ and CD8+ T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART (n = 11) and expression of CD107a, IFN-γ, TNF-α, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-γ and TNF-α in response to Gag and Nef peptides 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8+ and CD107a and IL-2 production in HIV-specific CD4+ and CD8+ T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4+ and CD8+ T cells in PWH on ART. These combinations should be further explored for an HIV cure.
Publisher: American Society for Clinical Investigation
Date: 10-04-2023
Publisher: Springer Science and Business Media LLC
Date: 24-02-2013
Publisher: Public Library of Science (PLoS)
Date: 26-05-2015
Publisher: Cold Spring Harbor Laboratory
Date: 13-01-2022
DOI: 10.1101/2022.01.12.473243
Abstract: The mutated residues in the Omicron spike protein have led to its rapid classification as a new SARS-CoV-2 variant of concern. As a result, Omicron may escape from the immune system, decreasing the protection provided by COVID-19 vaccines. Preliminary data shows a weaker neutralizing antibody response to Omicron compared to the ancestral SARS-CoV-2 virus, which can be increased after a booster vaccine. Here, we report that CD8 + T cells can recognize Omicron variant epitopes presented by HLA-A*02:01 in both COVID-19 recovered and vaccinated in iduals, even 6 months after infection or vaccination. Additionally, the T cell response was stronger for Omicron variant epitopes after the vaccine booster. Altogether, T cells can recognize Omicron variants, especially in vaccinated in iduals after the vaccine booster. CD8 + T cells response against Omicron variant epitopes is stronger after the vaccine booster.
Publisher: Massachusetts Medical Society
Date: 03-09-2020
DOI: 10.1056/NEJMC2022236
Publisher: Springer Science and Business Media LLC
Date: 08-09-2016
DOI: 10.1038/NCOMMS12731
Abstract: The ‘shock and kill’ approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents (LRAs) with targeted immunotherapy to purge infected cells. The administration of LRAs (panobinostat or vorinostat) to HIV-1-infected in iduals on antiretroviral therapy induces a significant increase in cell-associated unspliced (CA-US) HIV-1 RNA from CD4 + T cells. However, it is important to discern whether the increases in CA-US HIV-1 RNA are due to limited or broad activation of HIV-1 proviruses. Here we use single-genome sequencing to find that the RNA transcripts observed following LRA administration are genetically erse, indicating activation of transcription from an extensive range of proviruses. Defective sequences are more frequently found in CA HIV-1 RNA than in HIV-1 DNA, which has implications for developing an accurate measure of HIV-1 reservoir size. Our findings provide insights into the effects of panobinostat and vorinostat as LRAs for latent HIV-1.
Publisher: Massachusetts Medical Society
Date: 24-01-2023
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 03-2019
DOI: 10.1002/JIA2.25258
Publisher: Springer Science and Business Media LLC
Date: 13-10-2020
DOI: 10.1186/S13063-020-04766-5
Abstract: Primary objective: To determine the efficacy of a candidate antiviral on time to virological cure compared to standard of care within 14 days of randomisation Secondary objectives: • To determine the safety of the antiviral • To determine the clinical benefit of the antiviral over placebo according to the WHO 7-point ordinal scale • To determine the clinical benefit of the antiviral over placebo on time to resolution of clinical symptoms • To determine the effect of the antiviral over placebo on biomarkers of inflammation and immune activation This is a multi-centre, triple-blind, randomised placebo controlled phase II, 2-arm trial with parallel-group design with allocation ratio 1:1. Inclusion Criteria: • Provision of informed consent by the participant • Age ≥18 years • Confirmed SARS-CoV-2 by nucleic acid testing in the past 5 days • COVID-19 related symptom initiation within 5 days • Female patients of childbearing potential must have a negative pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment. Exclusion criteria: • Known allergy to the study medication • Is on another clinical trial investigating an antiviral treatment for COVID-19 • Pregnancy • Patients with severe hepatic dysfunction equivalent to Grade C in the Child-Pugh classification • Patients with renal impairment requiring dialysis • Is deemed by the Investigator to be ineligible for any reason Participants will be recruited from, and the study visits will take place at Alfred Hospital, Monash Health, Austin Health in Victoria, Australia for hospitalised participants as well as recruitment in the community in participants homes for eligible people not requiring hospitalisation. The first candidate antiviral is favipiravir Arm 1: Favipiravir 1800 mg favipiravir BD on Day 1 followed by 800 mg BD favipiravir for the next 13 days. Arm 2: Placebo Primary outcome: Time to virological cure as defined by 2 successive throat (or combined nose/throat) swabs negative for SARS-CoV-2 by nucleic acid testing during the 14 days after enrolment. Randomisation performed at the Alfred Hospital Clinical Trials Pharmacy using computer generated block-randomisation lists with 6 participants per block. Within each block half of the participants will be randomised to the candidate antiviral and the other half to placebo. Randomisation is stratified by study site, with participants enrolled in the community considered as a study site. Study participants, study investigators and the study statistician will be blinded to treatment allocation. The study aims to recruit 190 people (95/arm) with the first candidate antiviral favipiravir Protocol version 2.0 Dated 31-Jul-2020. Recruitment will take place between July 2020 and December 2020. clinicaltrials.gov NCT04445467 First posted 24-Jun-2020 The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated this Letter serves as a summary of the key elements of the full protocol.
Publisher: Informa UK Limited
Date: 15-10-2014
DOI: 10.1080/09540121.2013.845282
Abstract: Operational research to identify factors predicting poor clinical outcomes is critical to maximize patient care and prolong first-line regimens for those receiving free antiretroviral therapy (ART) in India. We sought to identify social or clinical factors amenable to intervention that predict virological outcomes after 12 months of ART. We examined a retrospective cohort of consecutive adults initiating free nonnucleoside reverse transcriptase inhibitor-based regimens. In iduals remaining in care 12 months post-ART initiation were tested for HIV viral load and surveyed to identify barriers and facilitators to adherence, and to determine clinic travel times and associated costs. Uni- and multivariate logistic regression identified factors predicting HIV viral load >200 copies/mL after 12 months of ART. Of 230 adults initiating ART, 10% of patients died, 8% transferred out, 5% were lost to follow-up, and 174/230 (76%) completed 12 months of ART, the questionnaire, and viral load testing. HIV viral load was <200 copies/mL in 140/174 (80%) patients. In multivariate models, being busy with work or caring for others (OR 2.9, p 200 copies/mL after 12 months of ART. Clinical outcomes following ART are related to programmatic factors such as prolonged travel time and in idual factors such as being busy with family or using alcohol. Simple interventions that alter these factors should be evaluated to improve clinical outcomes for populations receiving free ART in similar settings.
Publisher: Oxford University Press (OUP)
Date: 04-02-2021
DOI: 10.1093/AJE/KWAB014
Abstract: Ambitious World Health Organization targets for disease elimination require monitoring of epidemics using routine health data in settings of decreasing and low incidence. We evaluated 2 methods commonly applied to routine testing results to estimate incidence rates that assume a uniform probability of infection between consecutive negative and positive tests based on 1) the midpoint of this interval and 2) a randomly selected point in this interval. We compared these with an approximation of the Poisson binomial distribution, which assigns partial incidence to time periods based on the uniform probability of occurrence in these intervals. We assessed bias, variance, and convergence of estimates using simulations of Weibull-distributed failure times with systematically varied baseline incidence and varying trend. We considered results for quarterly, half-yearly, and yearly incidence estimation frequencies. We applied the methods to assess human immunodeficiency virus (HIV) incidence in HIV-negative patients from the Treatment With Antiretrovirals and Their Impact on Positive and Negative Men (TAIPAN) Study, an Australian study of HIV incidence in men who have sex with men, between 2012 and 2018. The Poisson binomial method had reduced bias and variance at low levels of incidence and for increased estimation frequency, with increased consistency of estimation. Application of methods to real-world assessment of HIV incidence found decreased variance in Poisson binomial model estimates, with observed incidence declining to levels where simulation results had indicated bias in midpoint and random-point methods.
No related grants have been discovered for James McMahon.