Infectious Diseases - Research Publications
Permanent URI for this collection
Search Results
1 - 10 of 1330
-
ItemDevelopment of Matrix-Embedded Bovine Tracheal Organoids to Study the Innate Immune Response against Bovine Respiratory Disease(MDPI, 2023)Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in feedlot cattle. Bovine herpesvirus-1 (BHV-1) is one of the main culprits of BRD; however, research on BHV-1 is hampered by the lack of suitable models for infection and drug testing. In this study, we established a novel bovine tracheal organoid culture grown in a basement membrane extract type 2 (BME2) matrix and compared it with the air–liquid interface (ALI) culture system. After differentiation, the matrix-embedded organoids developed beating cilia and demonstrated a transcriptomic profile similar to the ALI culture system. The matrix-embedded organoids were also highly susceptible to BHV-1 infection and immune stimulation by Pam2Cys, an immunomodulator, which resulted in robust cytokine production and tracheal antimicrobial peptide mRNA upregulation. However, treatment of bovine tracheal organoid cultures with Pam2Cys was not sufficient to inhibit viral infection or replication, suggesting a role of the non-epithelial cellular microenvironment in vivo.
-
ItemModelling mass drug administration strategies for reducing scabies burden in Monrovia, Liberia(CAMBRIDGE UNIV PRESS, 2023-08-18)Scabies is a parasitic infestation with high global burden. Mass drug administrations (MDAs) are recommended for communities with a scabies prevalence of >10%. Quantitative analyses are needed to demonstrate the likely effectiveness of MDA recommendations. In this study, we developed an agent-based model of scabies transmission calibrated to demographic and epidemiological data from Monrovia. We used this model to compare the effectiveness of MDA scenarios for achieving scabies elimination and reducing scabies burden, as measured by time until recrudescence following delivery of an MDA and disability-adjusted-life-years (DALYs) averted. Our model showed that three rounds of MDA delivered at six-month intervals and reaching 80% of the population could reduce prevalence below 2% for three years following the final round, before recrudescence. When MDAs were followed by increased treatment uptake, prevalence was maintained below 2% indefinitely. Increasing the number of and coverage of MDA rounds increased the probability of achieving elimination and the number of DALYs averted. Our results suggest that acute reduction of scabies prevalence by MDA can support a transition to improved treatment access. This study demonstrates how modelling can be used to estimate the expected impact of MDAs by projecting future epidemiological dynamics and health gains under alternative scenarios.
-
ItemNo Preview AvailableThe evolutionary mechanism of non-carbapenemase carbapenem-resistant phenotypes in Klebsiella spp(eLIFE SCIENCES PUBL LTD, 2023-07-06)Antibiotic resistance is driven by selection, but the degree to which a bacterial strain's evolutionary history shapes the mechanism and strength of resistance remains an open question. Here, we reconstruct the genetic and evolutionary mechanisms of carbapenem resistance in a clinical isolate of Klebsiella quasipneumoniae. A combination of short- and long-read sequencing, machine learning, and genetic and enzymatic analyses established that this carbapenem-resistant strain carries no carbapenemase-encoding genes. Genetic reconstruction of the resistance phenotype confirmed that two distinct genetic loci are necessary in order for the strain to acquire carbapenem resistance. Experimental evolution of the carbapenem-resistant strains in growth conditions without the antibiotic revealed that both loci confer a significant cost and are readily lost by de novo mutations resulting in the rapid evolution of a carbapenem-sensitive phenotype. To explain how carbapenem resistance evolves via multiple, low-fitness single-locus intermediates, we hypothesised that one of these loci had previously conferred adaptation to another antibiotic. Fitness assays in a range of drug concentrations show how selection in the antibiotic ceftazidime can select for one gene (blaDHA-1) potentiating the evolution of carbapenem resistance by a single mutation in a second gene (ompK36). These results show how a patient's treatment history might shape the evolution of antibiotic resistance and could explain the genetic basis of carbapenem-resistance found in many enteric-pathogens.
-
ItemNo Preview AvailableFirst Nations, Inuit and Métis Peoples Living in Urban Areas of Canada and Their Access to Healthcare: A Systematic Review.(MDPI AG, 2023-05-25)In Canada, approximately 52% of First Nations, Inuit and Métis (Indigenous) peoples live in urban areas. Although urban areas have some of the best health services in the world, little is known about the barriers or facilitators Indigenous peoples face when accessing these services. This review aims to fill these gaps in knowledge. Embase, Medline and Web of Science were searched from 1 January 1981 to 30 April 2020. A total of 41 studies identified barriers or facilitators of health service access for Indigenous peoples in urban areas. Barriers included difficult communication with health professionals, medication issues, dismissal by healthcare staff, wait times, mistrust and avoidance of healthcare, racial discrimination, poverty and transportation issues. Facilitators included access to culture, traditional healing, Indigenous-led health services and cultural safety. Policies and programs that remove barriers and implement the facilitators could improve health service access for Indigenous peoples living in urban and related homelands in Canada.
-
ItemNo Preview AvailableComprehensive Case-Control Study of Protective and Risk Factors for Buruli Ulcer, Southeastern Australia.(Centers for Disease Control and Prevention (CDC), 2023-10)To examine protective and risk factors for Buruli ulcer (BU), we conducted a case-control study of 245 adult BU cases and 481 postcode-matched controls across BU-endemic areas of Victoria, Australia. We calculated age- and sex-adjusted odds ratios for socio-environmental, host, and behavioral factors associated with BU by using conditional logistic regression. Odds of BU were >2-fold for persons with diabetes mellitus and persons working outdoors who had soil contact in BU-endemic areas (compared with indoor work) but were lower among persons who had bacillus Calmette-Guérin vaccinations. BU was associated with increasing numbers of possums and with ponds and bore water use at residences. Using insect repellent, covering arms and legs outdoors, and immediately washing wounds were protective; undertaking multiple protective behaviors was associated with the lowest odds of BU. Skin hygiene/protection behaviors and previous bacillus Calmette-Guérin vaccination might provide protection against BU in BU-endemic areas.
-
ItemNo Preview AvailableA randomised controlled trial of email versus mailed invitation letter in a national longitudinal survey of physicians(PUBLIC LIBRARY SCIENCE, 2023-08-22)Despite their low cost, the use of email invitations to distribute surveys to medical practitioners have been associated with lower response rates. This research compares the difference in response rates from using email approach plus online completion rather than a mailed invitation letter plus a choice of online or paper completion. A parallel randomised controlled trial was conducted during the 11th annual wave of the nationally representative Medicine in Australia: Balancing Employment and Life (MABEL) longitudinal survey of doctors. The control group was invited using a mailed paper letter (including a paper survey plus instructions to complete online) and three mailed paper reminders. The intervention group was approached in the same way apart from the second reminder when they were approached by email only. The primary outcome is the response rate and the statistical analysis was blinded. 18,247 doctors were randomly allocated to the control (9,125) or intervention group (9,127), with 9,108 and 9,107 included in the analysis. Using intention to treat analysis, the response rate in the intervention group was 35.92% compared to 37.59% in the control group, a difference of -1.66 percentage points (95% CI: -3.06 to -0.26). The difference was larger for General Practitioners (-2.76 percentage points, 95% CI: -4.65 to -0.87) compared to other specialists (-0.47 percentage points, 95% CI: -2.53 to 1.60). For those who supplied an email address, the average treatment effect on the treated was higher at -2.63 percentage points (95% CI: -4.50 to -0.75) for all physicians, -3.17 percentage points (95% CI: -5.83 to -0.53) for General Practitioners, and -2.1 percentage points (95% CI: -4.75 to 0.56) for other specialists. For qualified physicians, using email to invite participants to complete a survey leads to lower response rates compared to a mailed letter. Lower response rates need to be traded off with the lower costs of using email rather than mailed letters.
-
ItemNo Preview AvailableVAR2CSA Ectodomain Labeling in Plasmodium falciparum Infected Red Blood Cells and Analysis via Flow Cytometry.(Bio-Protocol, LLC, 2023-08-05)Presentation of the variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (EMP1) at the surface of infected red blood cells (RBCs) underpins the malaria parasite's pathogenicity. The transport of EMP1 to the RBC surface is facilitated by a parasite-derived trafficking system, in which over 500 parasite proteins are exported into the host cell cytoplasm. To understand how genetic ablation of selected exported proteins affects EMP1 transport, several EMP1 surface presentation assays have been developed, including: 1) trypsinization of surface-exposed EMP1 and analysis by SDS-PAGE and immunoblotting; and 2) infected RBC binding assays, to determine binding efficiency to immobilized ligand under physiological flow conditions. Here, we describe a third EMP1 surface presentation assay, where antibodies to the ectodomain of EMP1 and flow cytometry are used to quantify surface-exposed EMP1 in live cells. The advantages of this assay include higher throughput capacity and data better suited for robust quantitative analysis. This protocol can also be applied to other cellular contexts where an antibody can be developed for the ectodomain of the protein of interest.
-
ItemNo Preview AvailableWeekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency(PUBLIC LIBRARY SCIENCE, 2023-09)BACKGROUND: The World Health Organization recommends that primaquine should be given once weekly for 8-weeks to patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but data on its antirelapse efficacy and safety are limited. METHODS: Within the context of a multicentre, randomised clinical trial of two primaquine regimens in P. vivax malaria, patients with G6PD deficiency were excluded and enrolled into a separate 12-month observational study. They were treated with a weekly dose of 0.75 mg/kg primaquine for 8 weeks (PQ8W) plus dihydroartemisinin piperaquine (Indonesia) or chloroquine (Afghanistan, Ethiopia, Vietnam). G6PD status was diagnosed using the fluorescent spot test and confirmed by genotyping for locally prevalent G6PD variants. The risk of P. vivax recurrence following PQ8W and the consequent haematological recovery were characterized in all patients and in patients with genotypically confirmed G6PD variants, and compared with the patients enrolled in the main randomised control trial. RESULTS: Between July 2014 and November 2017, 42 male and 8 female patients were enrolled in Afghanistan (6), Ethiopia (5), Indonesia (19), and Vietnam (20). G6PD deficiency was confirmed by genotyping in 31 patients: Viangchan (14), Mediterranean (4), 357A-G (3), Canton (2), Kaiping (2), and one each for A-, Chatham, Gaohe, Ludhiana, Orissa, and Vanua Lava. Two patients had recurrent P. vivax parasitaemia (days 68 and 207). The overall 12-month cumulative risk of recurrent P. vivax malaria was 5.1% (95% CI: 1.3-18.9) and the incidence rate of recurrence was 46.8 per 1000 person-years (95% CI: 11.7-187.1). The risk of P. vivax recurrence was lower in G6PD deficient patients treated with PQ8W compared to G6PD normal patients in all treatment arms of the randomised controlled trial. Two of the 26 confirmed hemizygous males had a significant fall in haemoglobin (>5g/dl) after the first dose but were able to complete their 8 week regimen. CONCLUSIONS: PQ8W was highly effective in preventing P. vivax recurrences. Whilst PQ8W was well tolerated in most patients across a range of different G6PD variants, significant falls in haemoglobin may occur after the first dose and require clinical monitoring. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT01814683).
-
ItemNo Preview AvailableA human model of Buruli ulcer: The case for controlled human infection and considerations for selecting a Mycobacterium ulcerans challenge strain(PUBLIC LIBRARY SCIENCE, 2023-06)Critical knowledge gaps regarding infection with Mycobacterium ulcerans, the cause of Buruli ulcer (BU), have impeded development of new therapeutic approaches and vaccines for prevention of this neglected tropical disease. Here, we review the current understanding of host-pathogen interactions and correlates of immune protection to explore the case for establishing a controlled human infection model of M. ulcerans infection. We also summarise the overarching safety considerations and present a rationale for selecting a suitable challenge strain.
-
ItemNo Preview AvailableWHAM-A Prospective Study of Weight and Body Composition After Risk-Reducing Bilateral Salpingo-oophorectomy(ENDOCRINE SOC, 2023-07-06)CONTEXT: Body weight and composition may change over the natural menopause transition. Whether surgical menopause has similar effects, and the impact of HRT, are unknown. Understanding the metabolic effects of surgical menopause will inform clinical care. OBJECTIVE: To prospectively measure weight and body composition over 24-months following surgical menopause compared to a similar comparison group who retained their ovaries. METHODS: Prospective observational study of weight change from baseline to 24-months in 95 premenopausal women at elevated risk of ovarian cancer planning risk-reducing oophorectomy (RRSO) and 99 comparators who retained their ovaries. Change in body composition from baseline to 24-months was also assessed by DXA in a subgroup of 54 women who underwent RRSO and 81 comparators who retained their ovaries. In the sub-group, weight, fat mass, lean mass, and abdominal fat measures were compared between groups. RESULTS: At 24-months both groups had gained weight (RRSO 2760 ± 4860 g vs Comparators 1620 ± 4540 g) with no difference between groups (mean difference 730 g; 95% CI 920 g, 2380 g; p = 0.383). In the body composition subgroup, there was no difference in weight between groups at 24-months (mean difference 944 g; 95%CI -1120 g, 2614 g; p = 0.431). RRSO women may have gained slightly more abdominal visceral adipose tissue (mean difference 99.0 g; 95% CI 8.8 g, 189.2 g, p = 0.032) but there were no other differences in body composition. There were also no differences in weight or body composition between HRT users and non-users at 24-months. CONCLUSION: 24-months after RRSO, there was no difference in body weight compared with women who retained their ovaries. RRSO women gained more abdominal visceral adipose tissue than comparators, but there were no other differences in body composition. Use of HRT following RRSO had no effect on these outcomes.