Infectious Diseases - Research Publications
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ItemImpact of chemically defined culture media formulations on extracellular vesicle production by amniotic epithelial cells(WILEY, 2021-07)The therapeutic properties of cell derived extracellular vesicles (EVs) make them promising cell-free alternative to regenerative medicine. However, clinical translation of this technology relies on the ability to manufacture EVs in a scalable, reproducible, and cGMP-compliant manner. To generate EVs in sufficient quantity, a critical step is the selection and development of culture media, where differences in formulation may influence the EV manufacturing process. In this study, we used human amniotic epithelial cells (hAECs) as a model system to explore the effect of different formulations of chemically defined, commercially sourced media on EV production. Here, we determined that cell viability and proliferation rate are not reliable quality indicators for EV manufacturing. The levels of tetraspanins and epitope makers of EVs were significantly impacted by culture media formulations. Mass spectrometry-based proteomic profiling revealed proteome composition of hAEC-EVs and the influence of media formulations on composition of EV proteome. This study has revealed critical aspects including cell viability and proliferation rate, EV yield, and tetraspanins, surface epitopes and proteome composition of EVs influenced by media formulations, and further insight into standardised EV production culture media that should be considered in clinical-grade scalable EV manufacture for generation of therapeutic EVs.
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ItemAssessment of the cobas® HBV RNA investigational assay in the setting of nucleoside analog therapy cessation(WILEY, 2022-12)HBV RNA is used as a marker of cccDNA transcription and is applicable in the setting of nucleos(t)ide analog (NA) treatment, which suppresses HBV DNA. Traditional assays for quantification of HBV RNA rely on labor-intensive 3'RACE assays targeting the polyA tail. In this study, the high-throughput Roche cobas®HBV RNA investigational assay was assessed on the Roche cobas® 6800 automated platform. Of 969 samples collected for a NA treatment cessation trial, and tested on the cobas assay, 249 were analyzed for sensitivity, reproducibility, sample type applicability, and results were compared to a RACE-based assay. Results of 97 paired serum and plasma samples demonstrated an excellent correlation of 0.98. However, 14.5% of plasma samples yielded detectable (below the limit of quantification) results, when the paired serum was undetectable, and plasma was shown to yield a statistically significant (p < 0.001) greater mean 0.119 log10 copies/ml. Quantification of 152 samples showed good correlation (0.91) between the cobas and RACE assays. The cobas assay demonstrated superior lower limit of quantification, 10 copies/ml, which resulted in detection of 13.2% more samples than the RACE assay. Reproducibility and linear range of the automated assay were also confirmed. The Roche cobas assay for HBV RNA is sensitive and highly recommended.
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ItemThe impact of point-of-care hepatitis C testing in needle and syringe exchange programs on linkage to care and treatment uptake among people who inject drugs: An Australian pilot study(WILEY, 2022-05)Point-of-care (POC) diagnostics overcome barriers to conventional hepatitis C (HCV) testing in people who inject drugs. This study assessed impact on hepatitis C treatment uptake of POC HCV testing in needle and syringe exchange programs (NSPs). Rapid EC was a single-arm interventional pilot study of HCV POC testing conducted in three inner-city community clinics with NSPs. Twelve months after the POC testing, a retrospective medical record and Pharmaceutical Benefits Scheme audit was performed to determine the number of HCV RNA-positive participants who were prescribed HCV treatment. 70 HCV RNA-positive Rapid EC study participants were included. 44 (63%) were prescribed DAAs; 26 (59%) completed treatment and 15 (34%) had SVR testing, all of whom were cured. Age ≥ 40 years (aOR 3.45, 95% CI 1.10-11.05, p = .03) and secondary school education (aOR 5.8, 95% CI 1.54-21.80, p = .009) had higher likelihood of being prescribed DAAs, whereas homelessness was inversely associated with prescription of DAAs (aOR 0.30, 95% CI 0.09-1.04, p = .057). Median time to receive a DAA script from date of diagnosis was seven days (IQR 0 to 14 days), and time to filling the DAA prescription was 2 days (IQR 0-12 days). In conclusion, provision of POC testing through NSPs was effective for linking new clients to HCV treatment and reduced the time to treatment. Further studies are needed to define the most cost-effective use of POC testing in models of care for people who inject drugs to increase HCV treatment uptake.
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ItemCOVID-19 pandemic 2020: a tertiary Melbourne hospital's experience(WILEY, 2022-07)BACKGROUND: The COVID-19 pandemic has affected different parts of Australia in distinct ways across 2020 and 2021. In 2020, Melbourne was the epicentre of COVID-19. As one of the key tertiary centres caring for the patients affected by the outbreaks, the Royal Melbourne Hospital (RMH) managed the majority of the Victorian inpatient caseload. AIMS: To review the demographics, management and outcomes of patients with COVID-19 cared for by the RMH services in 2020. METHODS: A single health service retrospective cohort analysis of demographics, interventions and outcomes was conducted to characterise the RMH experience in 2020. RESULTS: From January to December 2020, 433 patients required admission more than 24 h. The demographics of affected patients and outcomes changed over the course of the study. Overall, 47% (203/433) required oxygen, most frequently (36%; 154/433) with low-flow devices (nasal prongs or hudson mask), and 11% (47/433) of patients required admission to intensive care. We recorded a 30-day mortality of 24% (104/433) mortality overall, rising to over 50% in patients aged over 80 years. CONCLUSIONS: The experience of this health service in 2020 demonstrated changing demographics over time, with associated differences in outcomes; notably marked mortality in older populations, frequent complications and limited inter-site transfer possible with mobilised resources.
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ItemNo fever, no worries? A retrospective audit of bacteraemic patients in the emergency department(WILEY, 2022-02)BACKGROUND: Early identification and treatment of serious infections improve clinical outcomes. Previous studies have found that septic patients without fever are more likely to die than those with fever, due to delay in antibiotic administration. AIM: To determine whether antibiotic treatment and mortality differed in afebrile adult patients presenting to the emergency department (ED) with bacteraemia, compared with those with a history of fever. METHODS: Retrospective 6-month audit of all adult patients with positive blood cultures taken in the ED of a single tertiary hospital. Outcomes included the receipt of antibiotics within 4 and 24 h of ED arrival, in-hospital mortality and 30-day mortality. RESULTS: A total of 227 patients with clinically significant bacteraemia was identified, of which 38 (16.7%) were afebrile in the ED. There was no statistically significant difference in the proportion of afebrile or febrile patients receiving antibiotics within 4 h (44.7% vs 55.6%, P = 0.222) or 24 h (89.5% vs 95.2%, P = 0.163) of arrival at the ED. Inpatient mortality was not statistically different in the afebrile and febrile groups 15.8% vs 6.9%, P = 0.070), but 30-day mortality was higher among afebrile patients (27.6% vs 10.1%, P = 0.010). CONCLUSIONS: There was no significant difference in receipt of antibiotics within 4 h or 24 h ED arrival between the febrile and afebrile groups. However, afebrile patients experienced higher 30-day mortality. While most bacteraemic patients received antibiotics within 24 h, only half received antibiotics within 4 h, representing a key area for improvement.
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ItemCytomegalovirus DNAemia and disease: current-era epidemiology, clinical characteristics and outcomes in cancer patients other than allogeneic haemopoietic transplantation(WILEY, 2022-10)BACKGROUND: High-intensity chemotherapy and advances in novel immunotherapies have seen the emergence of cytomegalovirus (CMV) infections in cancer patients other than allogeneic haemopoietic cell transplantation (HCT). Aim To evaluate the epidemiology, clinical characteristics and outcomes of CMV infection in this population. METHODS: A retrospective review of cancer patients other than allogeneic HCT who had CMV DNAemia and/or disease from July 2013 till May 2020 at a quaternary cancer centre was performed. RESULTS: Of 11 485 cancer patients who underwent treatment during this period, 953 patients had CMV DNA testing performed and 238 of them had CMV DNAemia. After excluding patients with allogeneic HCT, 62 patients with CMV DNAemia were identified, of whom 10 had concurrent CMV disease. The most frequent underlying malignancies were B-cell lymphoproliferative disease (LPD) (31%; 19/62), T-cell LPD (21%; 13/62), chronic lymphocytic leukaemia (11%; 7/62) and multiple myeloma (10%; 6/62). Most patients had lymphopenia (77%; 48/62), multiple cancer therapies (63%; 39/62 received ≥2 previous therapies), co-infection (56%; 35/62 had ≥1 co-infection) and corticosteroid therapy (48%; 30/62) within 1 month before CMV diagnosis. CMV DNAemia and disease were observed in patients receiving novel immunotherapies, including bispecific antibody therapy, chimeric-antigen receptor T-cell therapy and immune checkpoint inhibitors. CONCLUSION: Patients with haematological malignancy, particularly B-cell LPD, T-cell LPD, chronic lymphocytic leukaemia and multiple myeloma, were frequently identified to have CMV DNAemia and disease. Lymphopenia, multiple cancer therapies, co-infection and recent receipt of systemic corticosteroids were also commonly observed. Future studies are necessary to determine optimal identification and management of CMV in these patients.
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ItemShock and kill within the CNS: A promising HIV eradication approach?(Oxford University Press (OUP), 2022-11)The most studied HIV eradication approach is the "shock and kill" strategy, which aims to reactivate the latent reservoir by latency reversing agents (LRAs) and allowing elimination of these cells by immune-mediated clearance or viral cytopathic effects. The CNS is an anatomic compartment in which (persistent) HIV plays an important role in HIV-associated neurocognitive disorder. Restriction of the CNS by the blood-brain barrier is important for maintenance of homeostasis of the CNS microenvironment, which includes CNS-specific cell types, expression of transcription factors, and altered immune surveillance. Within the CNS predominantly myeloid cells such as microglia and perivascular macrophages are thought to be a reservoir of persistent HIV infection. Nevertheless, infection of T cells and astrocytes might also impact HIV infection in the CNS. Genetic adaptation to this microenvironment results in genetically distinct, compartmentalized viral populations with differences in transcription profiles. Because of these differences in transcription profiles, LRAs might have different effects within the CNS as compared with the periphery. Moreover, reactivation of HIV in the brain and elimination of cells within the CNS might be complex and could have detrimental consequences. Finally, independent of activity on latent HIV, LRAs themselves can have adverse neurologic effects. We provide an extensive overview of the current knowledge on compartmentalized (persistent) HIV infection in the CNS and on the "shock and kill" strategy. Subsequently, we reflect on the impact and promise of the "shock and kill" strategy on the elimination of persistent HIV in the CNS.
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ItemAssessment of the lifetime prevalence and incidence of induced abortion and correlates among female sex workers in Mombasa, Kenya: a secondary cohort analysis(BMJ PUBLISHING GROUP, 2022-10)INTRODUCTION: Prevalence of lifetime-induced abortion in female sex workers (FSWs) in Kenya was previously estimated between 43% and 86%. Our analysis aimed at assessing lifetime prevalence and correlates, and incidence and predictors of induced abortions among FSWs in Kenya. METHODS: This is a secondary prospective cohort analysis using data collected as part of the WHISPER or SHOUT cluster-randomised trial in Mombasa, assessing effectiveness of an SMS-intervention to reduce incidence of unintended pregnancy. Eligible participants were current FSWs, 16-34 years and not pregnant or planning pregnancy. Baseline data on self-reported lifetime abortion, correlates and predictors were collected between September 2016 and May 2017. Abortion incidence was measured at 6-month and 12-month follow-up. A multivariable logistic regression model was used to assess correlates of lifetime abortion and discrete-time survival analysis was used to assess predictors of abortions during follow-up. RESULTS: Among 866 eligible participants, lifetime abortion prevalence was 11.9%, while lifetime unintended pregnancy prevalence was 51.2%. Correlates of lifetime abortions were currently not using a highly effective contraceptive (adjusted OR (AOR)=1.76 (95% CI=1.11 to 2.79), p=0.017) and having ever-experienced intimate partner violence (IPV) (AOR=2.61 (95% CI=1.35 to 5.06), p=0.005). Incidence of unintended pregnancy and induced abortion were 15.5 and 3.9 per 100 women-years, respectively. No statistically significant associations were found between hazard of abortion and age, sex work duration, partner status, contraceptive use and IPV experience. CONCLUSION: Although experience of unintended pregnancy remains high, lifetime prevalence of abortion may have decreased among FSW in Kenya. Addressing IPV could further decrease induced abortions in this population. TRIAL REGISTRATION NUMBER: ACTRN12616000852459.
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ItemThe National COVID-19 Clinical Evidence Taskforce: pregnancy and perinatal guidelines(WILEY, 2022-11-06)INTRODUCTION: Pregnant women are at higher risk of severe illness from coronavirus disease 2019 (COVID-19) than non-pregnant women of a similar age. Early in the COVID-19 pandemic, it was clear that evidenced-based guidance was needed, and that it would need to be updated rapidly. The National COVID-19 Clinical Evidence Taskforce provided a resource to guide care for people with COVID-19, including during pregnancy. Care for pregnant and breastfeeding women and their babies was included as a priority when the Taskforce was set up, with a Pregnancy and Perinatal Care Panel convened to guide clinical practice. MAIN RECOMMENDATIONS: As of May 2022, the Taskforce has made seven specific recommendations on care for pregnant women and those who have recently given birth. This includes supporting usual practices for the mode of birth, umbilical cord clamping, skin-to-skin contact, breastfeeding, rooming-in, and using antenatal corticosteroids and magnesium sulfate as clinically indicated. There are 11 recommendations for COVID-19-specific treatments, including conditional recommendations for using remdesivir, tocilizumab and sotrovimab. Finally, there are recommendations not to use several disease-modifying treatments for the treatment of COVID-19, including hydroxychloroquine and ivermectin. The recommendations are continually updated to reflect new evidence, and the most up-to-date guidance is available online (https://covid19evidence.net.au). CHANGES IN MANAGEMENT RESULTING FROM THE GUIDELINES: The National COVID-19 Clinical Evidence Taskforce has been a critical component of the infrastructure to support Australian maternity care providers during the COVID-19 pandemic. The Taskforce has shown that a rapid living guidelines approach is feasible and acceptable.