Search

Background: Dengue virus (DENV) is endemic to many parts of the world and has serious health and socioeconomic effects even in high-income countries, especially with rapid changes in the climate globally. We explored the literature on dengue vector control methods used in high-income, city settings and associations with dengue incidence, dengue prevalence, or mosquito vector densities. Methods: Studies of any design or year were included if they reported effects on human DENV infection or Aedes vector indices of dengue-specific vector control interventions in high-income, city settings. Results: Of 24 eligible sources, most reported research in the United States (n = 8) or Australia (n = 5). Biocontrol (n = 12) and chemical control (n = 13) were the most frequently discussed vector control methods. Only 6 sources reported data on the effectiveness of a given method in reducing human DENV incidence or prevalence, 2 described effects of larval and adult control on Aedes DENV positivity, 20 reported effectiveness in reducing vector density, using insecticide, larvicide, source reduction, auto-dissemination of pyriproxyfen and Wolbachia, and only 1 described effects on human-vector contact. Conclusions: As most studies reported reductions in vector densities, rather than any effects on human DENV incidence or prevalence, we can draw no clear conclusions on which interventions might be most effective in reducing dengue in high-income, city areas. More research is needed linking evidence on the effects of different DENV vector control methods with dengue incidence/prevalence or mosquito vector densities in high-income, city settings as this is likely to differ from low-income settings. This is a significant evidence gap as climate changes increase the global reach of DENV. The importance of community involvement was clear in several studies, although it is impossible to tease out the relative contributions of this from other control methods used. Author summary: Dengue virus is present in many parts of the world and has serious health and socioeconomic effects even in high-income countries, especially with rapid changes in the climate globally. In this study, we explored the literature on dengue vector control methods used in high-income, city settings and associations with number of human dengue infections, and the density of mosquitoes. We found 24 papers with relevant results. Most of these described studies in the United States or Australia. Most were about various forms of biological or chemical control of the mosquitoes. Few papers discussed effects on human dengue infection. We were unable to draw any clear conclusions on how effective mosquito control methods were as we could identify little research on this subject in this specific setting. More research is needed on this topic, particularly as climate change will make more areas of the world vulnerable to dengue infection. [ABSTRACT FROM AUTHOR]

Background: Dengue (DENV), Ross River (RRV) and Barmah Forest viruses (BFV) are the most common human arboviral infections in Australia and the Pacific Island Countries and Territories (PICTs) and are associated with debilitating symptoms. All are nationally notifiable in Australia, but routine surveillance is limited to a few locations in the PICTs. Understanding the level of human exposure to these viruses can inform disease management and mitigation strategies. To assess the historic and current seroprevalence of DENV, RRV and BFV in Australia and the PICTs we conducted a systematic literature review of all published quantitative serosurveys. Methodology and principal findings: The Preferred Reporting of Items for Systematic Reviews and Meta-Analyses procedures were adopted to produce a protocol to systematically search for published studies reporting the seroprevalence of DENV, RRV and BFV in Australia and the PICTs. Data for author, research year, location, study population, serosurvey methods and positive tests were extracted. A total of 41 papers, reporting 78 serosurveys of DENV, RRV and BFV including 62,327 samples met the inclusion criteria for this review. Seroprevalence varied depending on the assay used, strategy of sample collection and location of the study population. Significant differences were observed in reported seropositivity depending on the sample collection strategy with clinically targeted sampling reporting the highest seroprevalence across all three viruses. Non-stratified seroprevalence showed wide ranges in reported positivity with DENV 0.0% -95.6%, RRV 0.0%-100.0%, and BFV 0.3% to 12.5%. We discuss some of the causes of variation including serological methods used, selection bias in sample collection including clinical or environmental associations, and location of study site. We consider the extent to which serosurveys reflect the epidemiology of the viruses and provide broad recommendations regarding the conduct and reporting of arbovirus serosurveys. Conclusions and significance: Human serosurveys provide important information on the extent of human exposure to arboviruses across: (1) time, (2) place, and (3) person (e.g., age, gender, clinical presentation etc). Interpreting results obtained at these scales has the potential to inform us about transmission cycles, improve diagnostic surveillance, and mitigate future outbreaks. Future research should streamline methods and reduce bias to allow a better understanding of the burden of these diseases and the factors associated with seroprevalence. Greater consideration should be given to the interpretation of seroprevalence in studies, and increased rigour applied in linking seroprevalence to transmission dynamics. Author summary: Mosquito-borne viruses contribute significantly to the global burden of diseases. Understanding infection rates in human populations is important for informing management of disease burden and public health policy. Serosurveys measure population exposure and immunity after arbovirus infections. We systematically reviewed serosurveys conducted for dengue virus (DENV), Ross River virus (RRV), and Barmah Forest virus (BFV) in Australia and the PICTs. We identified 41 studies reporting 78 serosurveys published between 1966 and 2020. For DENV we found the highest seroprevalence, greater than 95.0%, was reported in American Samoa. For RRV we found early evidence (1960–1969) of circulation outside Australia. There were three studies of BFV reporting 16 serosurveys within Australia and reporting low seroprevalence (<13%). Researchers used different serological methods so study comparisons must be nuanced. [ABSTRACT FROM AUTHOR]

Background: Melioidosis, a life-threatening infection caused by the gram negative bacterium Burkholderia pseudomallei, can involve almost any organ. Bone and joint infections (BJI) are a recognised, but incompletely defined, manifestation of melioidosis that are associated with significant morbidity and mortality in resource-limited settings. Methodology/principal findings: We identified all individuals with BJI due to B. pseudomallei managed at Cairns Hospital in tropical Australia between January 1998 and June 2023. The patients' demographics, their clinical findings and their treatment were correlated with their subsequent course. Of 477 culture-confirmed cases of melioidosis managed at the hospital during the study period, 39 (8%) had confirmed BJI; predisposing risk factors for melioidosis were present in 37/39 (95%). However, in multivariable analysis only diabetes mellitus was independently associated with the presence of BJI (odds ratio (95% confidence interval): 4.04 (1.81–9.00), p = 0.001). BJI was frequently only one component of multi-organ involvement: 29/39 (74%) had infection involving other organs and bacteraemia was present in 31/39 (79%). Of the 39 individuals with BJI, 14 (36%) had osteomyelitis, 8 (20%) had septic arthritis and 17 (44%) had both osteomyelitis and septic arthritis; in 32/39 (83%) the lower limb was involved. Surgery was performed in 30/39 (77%). Readmission after the initial hospitalisation was necessary in 11/39 (28%), 5/39 (13%) had disease recrudescence and 3/39 (8%) had relapse; 4/39 (10%) developed pathological fractures. ICU admission was necessary in 11/39 (28%) but all 11 of these patients survived. Only 1/39 (3%) died, 138 days after admission, due to his significant underlying comorbidity. Conclusions: The case-fatality rate from melioidosis BJI in Australia's well-resourced health system is very low. However, recrudescence, relapse and orthopaedic complications are relatively common and emphasise the importance of collaborative multidisciplinary care that includes early surgical review, aggressive source control, prolonged antibiotic therapy, and thorough, extended follow-up. Author summary: Bone and joint infections (BJI) are a recognised and life-threatening manifestation of melioidosis but frequently only one component of multi-organ involvement. Almost all patients with BJI due to Burkholderia pseudomallei have risk factors that predispose them to developing melioidosis, but diabetes appears to be the most closely associated with BJI. The vasculopathy, neuropathy, structural deformity and decreased immunity that is seen in many individuals with diabetes increases their risk of lower limb infection and these factors–combined with greater exposure to B. pseudomallei in the soil and surface water–might explain the lower limb predominance that is seen in many series of melioidosis-related BJI. Patients require early multimodal imaging, appropriate microbiological sampling, early surgical review, prompt source control and an adequate duration of antibiotic therapy–and, in many cases, critical care support–to ensure optimal outcomes. Collaborative, multidisciplinary care reduces the case-fatality rate of melioidosis BJI, but recrudescence, relapse and orthopaedic complications are common in survivors and therefore extended patient follow up is essential. [ABSTRACT FROM AUTHOR]

Background: The Wolbachia strategy aims to manipulate mosquito populations to make them incapable of transmitting dengue viruses between people. To test its efficacy, this strategy requires field trials. Public consultation and engagement are recognized as critical to the future success of these programs, but questions remain regarding how to proceed. This paper reports on a case study where social research was used to design a community engagement framework for a new dengue control method, at a potential release site in central Vietnam. Methodology/Principal Findings: The approach described here, draws on an anthropological methodology and uses both qualitative and quantitative methods to design an engagement framework tailored to the concerns, expectations, and socio-political setting of a potential trial release site for Wolbachia-infected Aedes aegypti mosquitoes. The process, research activities, key findings and how these were responded to are described. Safety of the method to humans and the environment was the most common and significant concern, followed by efficacy and impact on local lives. Residents expected to be fully informed and engaged about the science, the project, its safety, the release and who would be responsible should something go wrong. They desired a level of engagement that included regular updates and authorization from government and at least one member of every household at the release site. Conclusions/Significance: Results demonstrate that social research can provide important and reliable insights into public concerns and expectations at a potential release site, as well as guidance on how these might be addressed. Findings support the argument that using research to develop more targeted, engagement frameworks can lead to more sensitive, thorough, culturally comprehensible and therefore ethical consultation processes. This approach has now been used successfully to seek public input and eventually support for releases Wolbachia-infected mosquitoes, in two different international settings - Australia and Vietnam. Author Summary: In recent years, a number of new strategies using novel technologies for the control of dengue fever control have emerged. These strategies are notably different from their predecessors and not without controversy. Many also require open release field trials to test their efficacy. Public consultation and engagement are recognized as critical to the future success of these programs, but questions remain regarding how to proceed. In this paper we describe an approach to public engagement that uses social research to design an engagement framework and communication materials tailored to the concerns, expectations, and socio-political setting of potential trial release sites. This approach was developed and implemented in Australia (2008–2010) where the first publicly supported field trials occurred January 2011. We report here on the implementation of this approach in Vietnam (2009–2010) where the second release will occur in 2014. This paper describes the process, research activities, outcomes and key findings from the Vietnamese field site. It highlights key public concerns and expectations about engagement and authorization and shows how these were used to develop a more targeted, culturally appropriate and comprehensible engagement framework and communication materials. The paper demonstrates the viability of this approach to community engagement for new dengue control strategies, in a 'developing' country context. [ABSTRACT FROM AUTHOR]

Background: The clinical and genomic epidemiology of melioidosis varies across regions. Aim: To describe the clinical and genetic diversity of B. pseudomallei across Queensland, Australia. Methods: Whole genome sequencing of clinical isolates stored at the melioidosis reference lab from 1996–2020 was performed and analysed in conjunction with available clinical data. Results: Isolates from 292 patients were analysed. Bacteraemia was present in 71% and pneumonia in 65%. The case-fatality rate was 25%. Novel sequence types (ST) accounted for 51% of all isolates. No association was identified between the variable virulence factors assessed and patient outcome. Over time, the proportion of First Nation's patients declined from 59% to 26%, and the proportion of patients aged >70 years rose from 13% to 38%. Conclusion: This study describes a genomically diverse and comparatively distinct collection of B. pseudomallei clinical isolates from across Queensland, Australia. An increasing incidence of melioidosis in elderly patients may be an important factor in the persistently high case-fatality in this region and warrants further investigation and directed intervention. Author summary: Burkholderia pseudomallei is an environmental bacteria found in the soil and water of tropical and subtropical regions. This organism causes melioidosis, an infectious disease that often results in pneumonia and bloodstream infections. Previous studies have suggested a relationship between specific bacterial genetic factors and disease outcomes. This study reports on the clinical and bacterial genetic factors associated with disease outcomes in Queensland, Australia. A total of 292 patients and the associated bacterial isolates obtained from them during their hospital admission were analysed. The majority of patients presented with pneumonia and had a bloodstream infection. The case-fatality rate improved slightly over time but remains higher than other regions in Australia. Over the period of the study the proportion of First Nation's people affected decreased significantly. Notably, for reasons yet to be determined, the proportion of patients aged over 70 years increased over time. The bacterial genetic data demonstrate a high level of diversity across the region, however there was no association between previously described virulence genes and clinical outcomes in our cohort. This study creates a platform for further state-wide melioidosis research in Queensland. [ABSTRACT FROM AUTHOR]

Background: Strongyloides stercoralis infects human hosts mainly through skin contact with contaminated soil. The result is strongyloidiasis, a parasitic disease, with a unique cycle of auto-infection causing a variety of symptoms and signs, with possible fatality from hyper-infection. Australian Indigenous community members, often living in rural and remote settings, are exposed to and infected with S. stercoralis. The aim of this review is to determine barriers to control of strongyloidiasis. The purpose is to contribute to the development of initiatives for prevention, early detection and effective treatment of strongyloidiasis. Methodology/Principle Findings: Systematic search reviewing research published 2012 and earlier was conducted. Research articles discussing aspects of strongyloidiasis, context of infection and overall health in Indigenous Australians were reviewed. Based on the PRISMA statement, the systematic search of health databases, Academic Search Premier, Informit, Medline, PubMed, AMED, CINAHL, Health Source Nursing and Academic was conducted. Key search terms included strongyloidiasis, Indigenous, Australia, health, and community. 340 articles were retrieved with 16 original research articles published between 1969 and 2006 meeting criteria. Review found barriers to control defined across three key themes, (1) health status, (2) socioeconomic status, and (3) health care literacy and procedures. Conclusions/Significance: This study identifies five points of intervention: (1) develop reporting protocols between health care system and communities; (2) test all Indigenous Australian patients, immunocompromised patients and those exposed to areas with S. stercoralis; (3) health professionals require detailed information on strongyloidiasis and potential for exposure to Indigenous Australian people; (4) to establish testing and treatment initiatives within communities; and (5) to measure and report prevalence rates specific to communities and to act with initiatives based on these results. By defining barriers to control of strongyloidiasis in Australian Indigenous people, improved outcomes of prevention, treatment of strongyloidiasis and increased health overall are attainable. Author Summary: Strongyloides stercoralis, a nematode parasite, has a well-documented history of infecting human hosts in tropic and subtropic regions mainly through skin contact with inhabited soil. The result is strongyloidiasis, a human parasitic disease, with a unique cycle of auto-infection contributing to a variety of symptoms, of which, hyper-infection causing fatality may occur. In Australia, Indigenous community members often located in rural and remote settings, are exposed to and infected with strongyloides. Previous researchers report strongyloidiasis as a recurrent health issue for Indigenous Australians. This is a systematic review to determine the barriers to control for this pernicious pathogen. Barriers to control can be defined across three key themes: (1) health status, (2) socioeconomic status, and (3) health care literacy and procedure. By conceptualizing these barriers and addressing steps to control as outlined in this study, there is potential for improvement in prevention and treatment outcomes of strongyloidiasis and subsequently, overall health for Australian Indigenous people. This study contributes to furthering prevention and treatment of strongyloidiasis, increasing exposure to the issue of strongyloidiasis in Australian Indigenous people. It is the intent of this paper to express the need to have continued research and further health policy directed specifically to eradicate strongyloidiasis in Australian Indigenous communities. [ABSTRACT FROM AUTHOR]

Murray Valley encephalitis virus (MVEV) is the most serious of the endemic arboviruses in Australia. It was responsible for six known large outbreaks of encephalitis in south-eastern Australia in the 1900s, with the last comprising 58 cases in 1974. Since then MVEV clinical cases have been largely confined to the western and central parts of northern Australia. In 2011, high-level MVEV activity occurred in south-eastern Australia for the first time since 1974, accompanied by unusually heavy seasonal MVEV activity in northern Australia. This resulted in 17 confirmed cases of MVEV disease across Australia. Record wet season rainfall was recorded in many areas of Australia in the summer and autumn of 2011. This was associated with significant flooding and increased numbers of the mosquito vector and subsequent MVEV activity. This paper documents the outbreak and adds to our knowledge about disease outcomes, epidemiology of disease and the link between the MVEV activity and environmental factors. Clinical and demographic information from the 17 reported cases was obtained. Cases or family members were interviewed about their activities and location during the incubation period. In contrast to outbreaks prior to 2000, the majority of cases were non-Aboriginal adults, and almost half (40%) of the cases acquired MVEV outside their area of residence. All but two cases occurred in areas of known MVEV activity. This outbreak continues to reflect a change in the demographic pattern of human cases of encephalitic MVEV over the last 20 years. In northern Australia, this is associated with the increasing numbers of non-Aboriginal workers and tourists living and travelling in endemic and epidemic areas, and also identifies an association with activities that lead to high mosquito exposure. This outbreak demonstrates that there is an ongoing risk of MVEV encephalitis to the heavily populated areas of south-eastern Australia. Author Summary: An outbreak of Murray Valley encephalitis with 17 confirmed cases occurred across Australia in 2011. This outbreak involved parts of Australia where cases had not occurred for many decades. The epidemiology in this outbreak reflects a change that has occurred over the past 15 years, with more non-Aboriginal cases, fewer children and more cases that were not resident where they acquired the infection than had been observed prior to 2000. The outbreak was associated with significant flooding in many parts of Australia and most cases reported either outdoor activities where mosquito exposure was highly likely or significant mosquito exposure. [ABSTRACT FROM AUTHOR]

Background: Cryptococcus gattii is a globally endemic pathogen causing disease in apparently immune-competent hosts. We describe a 22-year cohort study from Australia's Northern Territory to evaluate trends in epidemiology and management, and outcome predictors. Methods: A retrospective cohort study of all C. gattii infections at the northern Australian referral hospital 1996–2018 was conducted. Cases were defined as confirmed (culture-positive) or probable. Demographic, clinical and outcome data were extracted from medical records. Results: 45 individuals with C. gattii infection were included: 44 Aboriginal Australians; 35 with confirmed infection; none HIV positive out of 38 tested. Multifocal disease (pulmonary and central nervous system) occurred in 20/45 (44%). Nine people (20%) died within 12 months of diagnosis, five attributed directly to C. gattii. Significant residual disability was evident in 4/36 (11%) survivors. Predictors of mortality included: treatment before the year 2002 (4/11 versus 1/34); interruption to induction therapy (2/8 versus 3/37) and end-stage kidney disease (2/5 versus 3/40). Prolonged antifungal therapy was the standard approach in this cohort, with median treatment duration being 425 days (IQR 166–715). Ten individuals had adjunctive lung resection surgery for large pulmonary cryptococcomas (median diameter 6cm [range 2.2-10cm], versus 2.8cm [1.2-9cm] in those managed non-operatively). One died post-operatively, and 7 had thoracic surgical complications, but ultimately 9/10 (90%) treated surgically were cured compared with 10/15 (67%) who did not have lung surgery. Four patients were diagnosed with immune reconstitution inflammatory syndrome which was associated with age <40 years, brain cryptococcomas, high cerebrospinal fluid pressure, and serum cryptococcal antigen titre >1:512. Conclusion: C. gattii infection remains a challenging condition but treatment outcomes have significantly improved over 2 decades, with eradication of infection the norm. Adjunctive surgery for the management of bulky pulmonary C. gattii infection appears to increase the likelihood of durable cure and likely reduces the required duration of antifungal therapy. Author summary: Cryptococcus gattii is an environmental fungus responsible for invasive infection, predominately in the central nervous system (CNS) and lungs. There is little evidence to guide its management. We have found First Nations Australians in this region have one of the highest incidences of Cryptococcus gattii infection in the world, with rates possibly increasing. Mortality was associated with end stage kidney disease, diagnosis in earlier years of the study, and unplanned interruptions to intravenous treatment. Whilst mortality improved through the study, neurological disability such as visual or hearing impairment following cure continues to be seen and is associated with brain cryptococcomas and high cerebral spinal fluid (CSF) pressure at diagnosis or during treatment. Blocked CSF shunts are uncommon and concerns of such potential complications should not preclude necessary surgical intervention for persisting increased CSF opening pressures or hydrocephalus which has been associated with poor outcome. Infection recurrence or persistence was associated with large pulmonary cryptococcomas (over 3cm diameter) not undergoing pulmonary surgery and we recommend that surgery be considered for any pulmonary cryptococcoma with a diameter over 2 to 3cm. Eradication of infection can be expected provided there is adequate therapy but may require very prolonged antifungal treatment. [ABSTRACT FROM AUTHOR]

Background: A fatal case of Japanese encephalitis (JE) occurred in a resident of the Tiwi Islands, in the Northern Territory of Australia in February 2021, preceding the large JE outbreak in south-eastern Australia in 2022. This study reports the detection, whole genome sequencing and analysis of the virus responsible (designated JEV/Australia/NT_Tiwi Islands/2021). Methods: Reverse transcription quantitative PCR (RT-qPCR) testing was performed on post-mortem brain specimens using a range of JE virus (JEV)-specific assays. Virus isolation from brain specimens was attempted by inoculation of mosquito and mammalian cells or embryonated chicken eggs. Whole genome sequencing was undertaken using a combination of Illumina next generation sequencing methodologies, including a tiling amplicon approach. Phylogenetic and selection analyses were performed using alignments of the Tiwi Islands JEV genome and envelope (E) protein gene sequences and publicly available JEV sequences. Results: Virus isolation was unsuccessful and JEV RNA was detected only by RT-qPCR assays capable of detecting all JEV genotypes. Phylogenetic analysis revealed that the Tiwi Islands strain is a divergent member of genotype IV (GIV) and is closely related to the 2022 Australian outbreak virus (99.8% nucleotide identity). The Australian strains share highest levels of nucleotide identity with Indonesian viruses from 2017 and 2019 (96.7–96.8%). The most recent common ancestor of this Australian-Indonesian clade was estimated to have emerged in 2007 (95% HPD range: 1998–2014). Positive selection was detected using two methods (MEME and FEL) at several sites in the E and non-structural protein genes, including a single site in the E protein (S194N) unique to the Australian GIV strains. Conclusion: This case represents the first detection of GIV JEV acquired in Australia, and only the second confirmed fatal human infection with a GIV JEV strain. The close phylogenetic relationship between the Tiwi Islands strain and recent Indonesian viruses is indicative of the origin of this novel GIV lineage, which we estimate has circulated in the region for several years prior to the Tiwi Islands case. Author summary: A fatal human case of Japanese encephalitis (JE) occurred in a patient from the Tiwi Islands of northern Australia in February 2021. The Tiwi Islands are 80km north of Darwin in the Timor Sea. Attempts to culture the virus from post-mortem brain tissue were unsuccessful. However, the whole genome was successfully sequenced and compared phylogenetically to other JE viruses. The Tiwi Islands strain was shown to belong to the rarely detected genotype IV (GIV) of the JE virus (JEV), together with the Australian 2022 outbreak strain, and is only the second fatal case of JE associated with a GIV virus. JEV strains isolated from Indonesia in 2017 and 2019 were shown to be the most-closely-related to the Australian GIV strain providing evidence for the geographic origins of the emergent Australian virus. From evolutionary analysis, the clade containing the Australian and recent Indonesian viruses was estimated to have emerged between 1998 and 2014, suggesting that this lineage of GIV viruses has been circulating for several years before the Tiwi Islands case. This is the third JE virus genotype to be detected in Australia and demonstrates the ease with which new genotypes can spread and unexpectedly cause disease in new areas. The possible origin and risks of further incursions into Australia are discussed. [ABSTRACT FROM AUTHOR]

Background: Crusted scabies is a debilitating dermatological condition. Although still relatively rare in the urban areas of Australia, rates of crusted scabies in remote Aboriginal communities in the Northern Territory (NT) are reported to be among the highest in the world. Objective: To estimate the health system costs associated with diagnosing, treating and managing crusted scabies. Methods: A disease pathway model was developed to identify the major phases of managing crusted scabies. In recognition of the higher resource use required to treat more severe cases, the pathway differentiates between crusted scabies severity grades. The disease pathway model was populated with data from a clinical audit of 42 crusted scabies patients diagnosed in the Top-End of Australia's Northern Territory between July 1, 2016 and May 1, 2018. These data were combined with standard Australian unit costs to calculate the expected costs per patient over a 12-month period, as well as the overall population cost for treating crusted scabies. Findings: The expected health care cost per patient diagnosed with crusted scabies is $35,418 Australian dollars (AUD) (95% CI: $27,000 to $43,800), resulting in an overall cost of $1,558,392AUD (95% CI: $1,188,000 to $1,927,200) for managing all patients diagnosed in the Northern Territory in a given year (2018). By far, the biggest component of the health care costs falls on the hospital system. Discussion: This is the first cost-of-illness analysis for treating crusted scabies. Such analysis will be of value to policy makers and researchers by informing future evaluations of crusted scabies prevention programs and resource allocation decisions. Further research is needed on the wider costs of crusted scabies including non-financial impacts such as the loss in quality of life as well as the burden of care and loss of well-being for patients, families and communities. Author summary: Crusted scabies is characterised by thick skin crusting and fissuring and can lead to serious secondary infections and death from complications. Rates of crusted scabies in remote Aboriginal communities in the Northern Territory (NT) are among the highest in the world. Efforts are on the way in Australia to prevent, if not eliminate, crusted scabies. We use data from a clinical audit of 42 patients diagnosed with crusted scabies in the Top-End of the NT to estimate the health system costs associated with diagnosing, treating and managing crusted scabies for patients and their households. This cost of illness study can provide a valuable starting point for policy makers and evaluators in estimating the potential economic impact of crusted scabies prevention programs on health care service use and costs. [ABSTRACT FROM AUTHOR]

Background: Leptospirosis is a zoonotic disease with a worldwide distribution, caused by pathogenic serovars in the genus Leptospira. Feral pigs are known carriers of Leptospira species and pig hunting using dogs is a common recreational activity in Queensland, Australia. Methodology and principal findings: This study aimed to determine the seroprevalence of Leptospira spp. serovars in pig-hunting dogs above the Tropic of Capricorn in Queensland and by establishing the geographic distribution, serovars and incidence of human cases of leptospirosis in Queensland, identify potential overlap between human and canine exposure. We also explored the knowledge and risk-taking behaviours of pig-hunting dog owners towards zoonotic diseases. Ninety-eight pig-hunting dogs deemed healthy by physical examination and owned by 41 people from Queensland had serum submitted for Microscopic Agglutination Testing (MAT) to determine antibody titres against Leptospira serovars, while 40/41 dog owners completed a survey on their knowledge of diseases relating to pig hunting. Human leptospirosis cases (n = 330) notified to Queensland Health between 2015–2018 were analysed. Approximately one quarter (23/87; 26%) of unvaccinated pig-hunting dogs were seropositive to Leptospira spp. Although harder to interpret, 8/11 (73%) vaccinated dogs were seropositive to Leptospira spp. Pig hunters may be more likely to contract leptospirosis compared with the general Queensland population, based on responses from surveyed hunters. The highest concentration of human leptospirosis was in the wet tropics region of Far North Queensland. There was little overlap between the serovars dogs were exposed to and those infecting humans. The dominant serovar identified in unvaccinated dogs was Australis (13/23; 57%), with serovar Arborea (36/330; 10.9%) responsible for the highest number of human leptospirosis cases. Topaz was the second most common serovar in both humans and dogs and was previously unrecorded in Australian dogs. Most hunters surveyed used hand washing as a zoonotic disease risk reduction technique. Conclusions: Leptospirosis is an emerging disease of growing significance. The infection requires a 'one health' approach to understand its epidemiology. With shifting climatic patterns influencing human-animal-environment interactions, ongoing monitoring of diseases like leptospirosis is critical to helping prevent infection of individuals and disease outbreaks. Author summary: Leptospirosis is a disease caused by pathogenic Leptospira serovars. Leptospira can infect both humans and animals depending on the species and serovar, with disease resulting from direct or indirect exposure to infected urine. In Australia, the highest number of human cases recorded annually occur in the state of Queensland. Feral pig hunting is a popular recreational activity in this state and hunters often use dogs to 'flush out' pigs. This study investigated whether dogs used to hunt feral pigs were exposed to Leptospira serovars, the geographic distribution of human leptospirosis cases and canine exposure to Leptospira serovars in Queensland, and the knowledge of this disease amongst owners of pig-hunting dogs. We found that roughly one quarter of unvaccinated pig-hunting dogs had been exposed to Leptospira spp. The wet tropics region of Far North Queensland was found to be the location of highest risk for exposure to Leptospira for humans. There was little overlap between the serovars dogs had been exposed to and those reported to have caused disease in humans, except for the serovars Topaz, Australis, and Pomona. Finally, pig hunters were found to be at increased risk of being diagnosed with leptospirosis compared to the Queensland public and engaged in risky hunting practices such as not wearing personal protective equipment (PPE). Our findings reinforce the emerging significance of leptospirosis for physicians and veterinarians in Australia. [ABSTRACT FROM AUTHOR]

Background: Crusted scabies is endemic in some remote Aboriginal communities in the Northern Territory (NT) of Australia and carries a high mortality risk. Improvement in active case detection (ACD) for crusted scabies is hampered by a lack of evidence about best practice. We therefore conducted a systematic review of ACD methods for leprosy, a condition with similar ACD requirements, to consider how findings could be informative to crusted scabies detection. Methods and principle findings: We conducted systematic searches in MEDLINE, CINAHL, Scopus and the Cochrane Database for Systematic Reviews for studies published since 1999 that reported at least one comparison rate (detection or prevalence rate) against which the yield of the ACD method could be assessed. The search yielded 15 eligible studies from 511. Study heterogeneity precluded meta-analysis. Contact tracing and community screening of marginalised ethnic groups yielded the highest new case detection rates. Rapid community screening campaigns, and those using less experienced screening personnel, were associated with lower suspect confirmation rates. There is insufficient data to assess whether ACD campaigns improve treatment outcomes or disease control. Conclusion: This review demonstrates the importance of ACD campaigns in communities facing the highest barriers to healthcare access and within neighbourhoods of index cases. The potential benefit of ACD for crusted scabies is not quantified, however, lessons from leprosy suggest value in follow-up with previously identified cases and their close contacts to support for scabies control and to reduce the likelihood of reinfection in the crusted scabies case. Skilled screening personnel and appropriate community engagement strategies are needed to maximise screening uptake. More research is needed to assess ACD cost effectiveness, impact on disease control, and to explore ACD methods capable of capturing the homeless and highly mobile who may be missed in household centric models. Author summary: Crusted scabies is a severely debilitating skin disease with potentially fatal consequences that is endemic in some remote Aboriginal communities in the Northern Territory (NT) of Australia. Early detection is essential to maximise the chance of recovery and help prevent transmission of scabies to others. There is little knowledge about how to actively detect crusted scabies, so we sought relevant knowledge about a disease with many similarities: leprosy. The review demonstrates the importance of ACD campaigns in communities facing the highest barriers to healthcare access and within neighbourhoods of index cases. Lessons for crusted scabies in the NT include the importance of skilled screening personnel and appropriate community engagement strategies to maximise screening uptake. More research is needed to assess ACD cost effectiveness, impact on disease control, and to explore ACD methods capable of capturing the homeless and highly mobile who may be missed in household centric models. [ABSTRACT FROM AUTHOR]

Background: There are no national prevalence studies of Strongyloides stercoralis infection in Australia, although it is known to be endemic in northern Australia and is reported in high risk groups such as immigrants and returned travellers. We aimed to determine the seropositivity (number positive per 100,000 of population and percent positive of those tested) and geographical distribution of S. stercoralis by using data from pathology laboratories. Methodology: We contacted all seven Australian laboratories that undertake Strongyloides serological (ELISA antibody) testing to request de-identified data from 2012–2016 inclusive. Six responded. One provided positive data only. The number of people positive, number negative and number tested per 100,000 of population (Australian Bureau of Statistics data) were calculated including for each state/territory, each Australian Bureau of Statistics Statistical Area Level 3 (region), and each suburb/town/community/locality. The data was summarized and expressed as maps of Australia and Greater Capital Cities. Principal findings: We obtained data for 81,777 people who underwent serological testing for Strongyloides infection, 631 of whom were from a laboratory that provided positive data only. Overall, 32 (95% CI: 31, 33) people per 100,000 of population were seropositive, ranging between 23/100,000 (95% CI: 19, 29) (Tasmania) and 489/100,000 population (95%CI: 462, 517) (Northern Territory). Positive cases were detected across all states and territories, with the highest (260-996/100,000 and 17–40% of those tested) in regions across northern Australia, north-east New South Wales and north-west South Australia. Some regions in Greater Capital Cities also had a high seropositivity (112-188/100,000 and 17–20% of those tested). Relatively more males than females tested positive. Relatively more adults than children tested positive. Children were under-represented in the data. Conclusions/Significance: The study confirms that substantial numbers of S. stercoralis infections occur in Australia and provides data to inform public health planning. Author summary: Strongyloides stercoralis, a parasitic roundworm, is endemic in many countries world-wide. In Australia, groups at risk for strongyloidiasis include Aboriginal and/or Torres Strait Islander people, who acquired this parasite locally, and immigrants and returned travellers who acquired the infection outside Australia. We obtained deidentified results of ELISA IgG antibody tests for Strongyloides from diagnostic pathology laboratories during 2012 to 2016 and calculated the number of people who were positive at least once and the number who never had a positive result. We drew maps showing the number positive per 100,000 of population, the percent positive of those tested, and the number tested/100,000 for each region and the number positive in each suburb of residence according to the Australian Bureau of Statistics. The highest seropositivity (260-996/100,000 of population) was in Northern Australia, north-west South Australia and north-east New South Wales where many Aboriginal and Torres Strait Islander people live in remote communities. There were also some regions in Greater Capital Cities with a high number of people positive per 100,000 of population (112-188/100,000), likely reflecting higher populations of immigrants and returned travellers who were infected outside Australia. [ABSTRACT FROM AUTHOR]

Australia, home to the iconic dingo, is currently free from canine rabies. However northern Australia, including Indigenous communities with large free-roaming domestic dog populations, is at increased risk of rabies incursion from nearby Indonesia. We developed a novel agent-based stochastic spatial rabies spread model to evaluate the potential spread of rabies within the dingo population of the Northern Peninsula Area (NPA) region of northern Australia. The model incorporated spatio-temporal features specific to this host-environment system, including landscape heterogeneity, demographic fluctuations, dispersal movements and dingo ecological parameters—such as home range size and density—derived from NPA field studies. Rabies spread between dingo packs in nearly 60% of simulations. In such situations rabies would affect a median of 22 dingoes (approximately 14% of the population; 2.5–97.5 percentiles: 2–101 dingoes) within the study area which covered 1,131 km2, and spread 0.52 km/week for 191 days. Larger outbreaks occurred in scenarios in which an incursion was introduced during the dry season (vs. wet season), and close to communities (vs. areas with high risk of interaction between dingoes and hunting community dogs). Sensitivity analyses revealed that home range size and duration of infectious clinical period contributed most to the variance of outputs. Although conditions in the NPA would most likely not support a sustained propagation of the disease in the dingo population, due to the predicted number of infected dingoes following a rabies incursion and the proximity of Indigenous communities to dingo habitat, we conclude that the risk for human transmission could be substantial. Author summary: Although Australia is free from canine rabies, an incursion from nearby rabies-infected Indonesian islands is a realistic threat. The ubiquitous presence of dingoes in the wild, in association with large populations of free-roaming domestic dogs from northern Australian Indigenous communities, increases the risk of a rabies outbreak. Using a newly developed simulation model, we investigated the potential spread of rabies in a northern Australian dingo population. Nearly 60% of model simulations resulted in more than one pack infected. When spread did occur, outbreaks affected a median of 22 dingoes (an estimated 14% of the population in this area). The duration of infection, proportion of the population infected and spatial spread of the outbreak was greatest when rabies was introduced during the dry season and close to communities. Our results demonstrate that an incursion of rabies into the northern Australian dingo population would likely lead to a rabies outbreak, which would in turn pose a substantial threat to Indigenous communities in northern Australia. [ABSTRACT FROM AUTHOR]

Background: Scabies is listed as a neglected tropical disease by the World Health Organization. Crusted scabies affects vulnerable and immunosuppressed individuals and is highly contagious because of the enormous number of Sarcoptes scabiei mites present in the hyperkeratotic skin. Undiagnosed and untreated crusted scabies cases can result in outbreaks of scabies in residential facilities and can also undermine the success of scabies mass drug administration programs. Methods and principal findings: Crusted scabies became a formally notifiable disease in the Northern Territory of Australia in 2016. We conducted a 2-year prospective study of crusted scabies cases notified between March 2016 and February 2018, with subsequent follow up for 22 months. Demographics, clinical and laboratory data, treatment and outcomes were analysed, with cases classified by severity of disease. Over the 2-year study period, 80 patients had 92 episodes of crusted scabies; 35 (38%) were Grade 1 crusted scabies, 36 (39%) Grade 2 and 21 (23%) Grade 3. Median age was 47 years, 47 (59%) were female, 76 (95%) Indigenous Australians and 57 (71%) from remote Indigenous communities. Half the patients were diabetic and 18 (23%) were on dialysis for end-stage kidney failure. Thirteen (16%) patients had no comorbidities, and these were more likely to have Grade 3 disease. Eosinophilia was present in 60% and high immunoglobulin E in 94%. Bacteremia occurred in 11 episodes resulting in one fatality with methicillin-susceptible Staphylococcus aureus bacteremia. Two other deaths occurred during admission and 10 others died subsequent to discharge consequent to comorbidities. Treatment generally followed the recommended guidelines, with 3, 5 or 7 doses of oral ivermectin depending on the documented grade of crusted scabies, together with daily alternating topical scabicides and topical keratolytic cream. While response to this therapy was usually excellent, there were 33 episodes of recurrent crusted scabies with the majority attributed to new infection subsequent to return to a scabies-endemic community. Conclusions: Crusted scabies can be successfully treated with aggressive guideline-based therapy, but high mortality remains from underlying comorbidities. Reinfection on return to community is common while scabies remains endemic. Author summary: Undiagnosed crusted scabies patients can be index cases in outbreaks of scabies in residential facilities such as nursing homes and can undermine the success of scabies mass drug administration programs, but literature about this debilitating disease is very limited. The study describes a large cohort of patients with crusted scabies who have been treated according to established local guidelines. While the success of the initial clinical response supports the guideline-based treatment regimen for crusted scabies, with only one patient dying with scabies-related sepsis, the subsequent mortality remains high, reflecting the large burden of comorbidities in the cohort. In addition, there was a high rate of recurrent crusted scabies, attributed to new infection with scabies once the cured patients return to their scabies-endemic communities. Crusted scabies can be successfully treated using robust guidelines including multiple doses of ivermectin together with topical therapy. However, community-based initiatives such as support for 'scabies free zones' are needed to prevent re-infection and recurrent disease in those individuals who are susceptible to developing crusted scabies. Undiagnosed crusted scabies is a threat to the success of scabies mass drug administration programs and will continue to drive scabies outbreaks in residential facilities. [ABSTRACT FROM AUTHOR]

Scrub typhus and spotted fever rickettsioses (SFR) are understudied, vector-borne diseases of global significance. Over 1 billion individuals are at risk for scrub typhus alone in an endemic region, spanning across eastern and southern Asia to Northern Australia. While highly treatable, diagnostic challenges make timely antibiotic intervention difficult for these diseases. Delayed therapy may lead to severe outcomes affecting multiple organs, including the central nervous system (CNS), where infection and associated neuroinflammation may be lethal or lead to lasting sequelae. Meningitis and encephalitis are prevalent in both scrub typhus and SFR. Additionally, case reports detailing focal neurological deficits have come to light, with attention to both acute and chronic sequelae of infection. Despite the increasing number of clinical reports outlining neurologic consequences of these diseases, relatively little research has examined underlying mechanisms of neuroinflammation. Animal models of scrub typhus have identified cerebral T-cell infiltration and vascular damage associated with endothelial infection and neuropathogenesis. Differential gene expression analysis of brain tissues during murine scrub typhus have revealed selective increases in CXCR3 ligands, proinflammatory and type-1 cytokines and chemokines, and cytotoxicity molecules, as well as alterations in the complement pathway. In SFR, microglial expansion and macrophage infiltration contribute to neurological disease progression. This narrative Review highlights clinical neurologic features of scrub typhus and SFR and evaluates our current understanding of basic research into neuroinflammation for both diseases in animal models. Further investigation into key mediators of neuropathogenesis may yield prognostic markers and treatment regimens for severe patients. [ABSTRACT FROM AUTHOR]

Ross River virus (RRV) is the most common and widespread arbovirus in Australia. Epidemiological models of RRV increase understanding of RRV transmission and help provide early warning of outbreaks to reduce incidence. However, RRV predictive models have not been systematically reviewed, analysed, and compared. The hypothesis of this systematic review was that summarising the epidemiological models applied to predict RRV disease and analysing model performance could elucidate drivers of RRV incidence and transmission patterns. We performed a systematic literature search in PubMed, EMBASE, Web of Science, Cochrane Library, and Scopus for studies of RRV using population-based data, incorporating at least one epidemiological model and analysing the association between exposures and RRV disease. Forty-three articles, all of high or medium quality, were included. Twenty-two (51.2%) used generalised linear models and 11 (25.6%) used time-series models. Climate and weather data were used in 27 (62.8%) and mosquito abundance or related data were used in 14 (32.6%) articles as model covariates. A total of 140 models were included across the articles. Rainfall (69 models, 49.3%), temperature (66, 47.1%) and tide height (45, 32.1%) were the three most commonly used exposures. Ten (23.3%) studies published data related to model performance. This review summarises current knowledge of RRV modelling and reveals a research gap in comparing predictive methods. To improve predictive accuracy, new methods for forecasting, such as non-linear mixed models and machine learning approaches, warrant investigation. Author summary: As the most common human arbovirus infection in Australia, Ross River virus exerts a significant public health and economic burden on the population. Because the virus is transmitted by mosquitoes, incidence is influenced by climate, environment, and socio-economic factors. Using epidemiological models to predict incidence or outbreaks of RRV fully utilises these data to inform decision-making. In this systematic review, we summarised models and their predictive performance, and highlighted significant exposures in order to increase understanding of transmission. [ABSTRACT FROM AUTHOR]

Aedes aegypti is the primary vector of dengue, chikungunya, Zika, and urban yellow fever. Insecticides are often the most effective tools to rapidly decrease the density of vector populations, especially during arbovirus disease outbreaks. However, the intense use of insecticides, particularly pyrethroids, has selected for resistant mosquito populations worldwide. Mutations in the voltage gated sodium channel (NaV) are among the principal mechanisms of resistance to pyrethroids and DDT, also known as "knockdown resistance," kdr. Here we report studies on the origin and dispersion of kdr haplotypes in samples of Ae. aegypti from its worldwide distribution. We amplified the IIS6 and IIIS6 NaV segments from pools of Ae. aegypti populations from 15 countries, in South and North America, Africa, Asia, Pacific, and Australia. The amplicons were barcoded and sequenced using NGS Ion Torrent. Output data were filtered and analyzed using the bioinformatic pipeline Seekdeep to determine frequencies of the IIS6 and IIIS6 haplotypes per population. Phylogenetic relationships among the haplotypes were used to infer whether the kdr mutations have a single or multiple origin. We found 26 and 18 haplotypes, respectively for the IIS6 and IIIS6 segments, among which were the known kdr mutations 989P, 1011M, 1016I and 1016G (IIS6), 1520I, and 1534C (IIIS6). The highest diversity of haplotypes was found in African samples. Kdr mutations 1011M and 1016I were found only in American and African populations, 989P + 1016G and 1520I + 1534C in Asia, while 1534C was present in samples from all continents, except Australia. Based primarily on the intron sequence, IIS6 haplotypes were subdivided into two well-defined clades (A and B). Subsequent phasing of the IIS6 + IIIS6 haplotypes indicates two distinct origins for the 1534C kdr mutation. These results provide evidence of kdr mutations arising de novo at specific locations within the Ae. aegypti geographic distribution. In addition, our results suggest that the 1534C kdr mutation had at least two independent origins. We can thus conclude that insecticide selection pressure with DDT and more recently with pyrethroids is selecting for independent convergent mutations in NaV. Author summary: Insecticide resistance is a global threat for the control of Aedes aegypti, the mosquito vector of aboviruses such as dengue, chikungunya and Zika. Mutations in the voltage gated sodium channel (NaV), known as kdr, are one of the principal mechanisms related to resistance to pyrethroids, the class of insecticide most employed worldwide inside and around residences. We investigate whether the same kdr mutations found in Ae. aegypti populations from distinct regions of the world have a common origin and subsequently dispersed or if they emerged in unrelated populations at distinct moments. By evaluating the sequences of two fragments of the NaV gene, obtained from DNA collections of Ae. aegypti from several countries, we found at least two independent origins for the F1534C kdr mutation in American, African and Asian populations. There was no evidence for multiple origins of the common kdr mutations V1016I and P989S + V1016G, which were exclusive to American and Asian populations. Our results increase our knowledge of insecticide resistance evolution in one of the main arboviral mosquito vectors of major global diseases. [ABSTRACT FROM AUTHOR]

Aedes aegypti mosquitoes infected with the wMel strain of Wolbachia are being released into natural mosquito populations in the tropics as a way of reducing dengue transmission. High temperatures adversely affect wMel, reducing Wolbachia density and cytoplasmic incompatibility in some larval habitats that experience large temperature fluctuations. We monitored the impact of a 43.6°C heatwave on the wMel infection in a natural population in Cairns, Australia, where wMel was first released in 2011 and has persisted at a high frequency. Wolbachia infection frequencies in the month following the heatwave were reduced to 83% in larvae sampled directly from field habitats and 88% in eggs collected from ovitraps, but recovered to be near 100% four months later. Effects of the heatwave on wMel appeared to be stage-specific and delayed, with reduced frequencies and densities in field-collected larvae and adults reared from ovitraps but higher frequencies in field-collected adults. Laboratory experiments showed that the effects of heatwaves on cytoplasmic incompatibility and density are life stage-specific, with first instar larvae being the most vulnerable to temperature effects. Our results indicate that heatwaves in wMel-infected populations will have only temporary effects on Wolbachia frequencies and density once the infection has established in the population. Our results are relevant to ongoing releases of wMel-infected Ae. aegypti in several tropical countries. Author summary: Mosquitoes infected with Wolbachia bacteria are being released in the tropics to replace natural mosquito populations and suppress dengue transmission. Aedes aegypti mosquitoes with the wMel strain of Wolbachia were first released in Cairns, Australia in 2011 and releases were then expanded to the entire city and surrounding suburbs. Today, wMel is at a high frequency within the Ae. aegypti population and local dengue transmission in Cairns has declined to nearly zero. Wolbachia infections are vulnerable to high temperatures and the ability of wMel to persist in populations and block dengue may be constrained by climate. Cairns experienced a record heatwave of 43.6°C in November 2018 and we wanted to see whether this affected the wMel-infected Ae. aegypti population. Our results show that the frequency and density of wMel declined after the heatwave, with effects depending on the mosquito life stage tested. When we monitored the population again in April 2019, wMel had returned to a high frequency. We suggest that heatwaves of the magnitude experienced in Cairns will not have long-term impacts on the wMel infection but may affect invasion during releases or interfere with dengue blockage. Heatwaves may affect interventions with wMel-infected Ae. aegypti that are being deployed in several countries. Effects may depend on the proportion of larval habitats that are protected from extreme temperature fluctuations. [ABSTRACT FROM AUTHOR]

Strongyloidiasis is a neglected tropical disease caused by the human infective nematodes Strongyloides stercoralis, Strongyloides fuelleborni fuelleborni and Strongyloides fuelleborni kellyi. Previous large-scale studies exploring the genetic diversity of this important genus have focused on Southeast Asia, with a small number of isolates from the USA, Switzerland, Australia and several African countries having been genotyped. Consequently, little is known about the global distribution of geographic sub-variants of these nematodes and the genetic diversity that exists within the genus Strongyloides generally. We extracted DNA from human, dog and primate feces containing Strongyloides, collected from several countries representing all inhabited continents. Using a genotyping assay adapted for deep amplicon sequencing on the Illumina MiSeq platform, we sequenced the hyper-variable I and hyper-variable IV regions of the Strongyloides 18S rRNA gene and a fragment of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene from these specimens. We report several novel findings including unique S. stercoralis and S. fuelleborni genotypes, and the first identifications of a previously unknown S. fuelleborni infecting humans within Australia. We expand on an existing Strongyloides genotyping scheme to accommodate S. fuelleborni and these novel genotypes. In doing so, we compare our data to all 18S and cox1 sequences of S. fuelleborni and S. stercoralis available in GenBank (to our knowledge), that overlap with the sequences generated using our approach. As this analysis represents more than 1,000 sequences collected from diverse hosts and locations, representing all inhabited continents, it allows a truly global understanding of the population genetic structure of the Strongyloides species infecting humans, non-human primates, and domestic dogs. [ABSTRACT FROM AUTHOR]

Australia is currently canine rabies free. However, communities located on the northern coastline–such as the Northern Peninsula Area (NPA), Queensland–are at risk of an incursion due to their large populations of susceptible free-roaming dogs and proximity to rabies-infected Indonesian islands. A rabies-spread model was used to simulate potential outbreaks and evaluate various disease control strategies. A heterogeneous contact structure previously described in the population of interest–explorer dogs, roamer dogs and stay-at-home dogs–was incorporated into the model using six spatial kernels describing contacts between dog roaming categories. Twenty-seven vaccination strategies were investigated based on a complete block design of 50%, 70% and 90% coverage for each of the three roaming categories to simulate various targeted vaccination strategies. The 27 strategies were implemented in four population structures in which the proportion of dogs in each category varied–explorer dominant, roamer dominant, stay-at-home dominant and a field population (based on field estimates of population structure). The overall vaccination coverage varied depending on the subpopulation targeted for vaccination and the population structure modelled. A total of 108 scenarios were simulated 2000 times and the model outputs (outbreak size and duration) were compared to Strategy 14 (a standard recommended overall 70% vaccination coverage). In general, targeting explorer dogs–and to a lesser extent roamer dogs–produced similar outbreaks to Strategy 14 but with a lower overall vaccination coverage. Similarly, strategies that targeted stay-at-home dogs required a higher vaccination coverage to produce significantly smaller and shorter outbreaks. This study provides some theoretical evidence that targeting subpopulations of dogs for vaccination based on their roaming behaviours (and therefore risk of rabies transmission) could be more efficient than blanket 70% vaccination campaigns. Such information can be used in preparedness planning to help improve control of a potential rabies incursion in Australia. [ABSTRACT FROM AUTHOR]

The 2018 outbreak of Nipah virus in Kerala, India, highlights the need for global surveillance of henipaviruses in bats, which are the reservoir hosts for this and other viruses. Nipah virus, an emerging paramyxovirus in the genus Henipavirus, causes severe disease and stuttering chains of transmission in humans and is considered a potential pandemic threat. In May 2018, an outbreak of Nipah virus began in Kerala, > 1800 km from the sites of previous outbreaks in eastern India in 2001 and 2007. Twenty-three people were infected and 21 people died (16 deaths and 18 cases were laboratory confirmed). Initial surveillance focused on insectivorous bats (Megaderma spasma), whereas follow-up surveys within Kerala found evidence of Nipah virus in fruit bats (Pteropus medius). P. medius is the confirmed host in Bangladesh and is now a confirmed host in India. However, other bat species may also serve as reservoir hosts of henipaviruses. To inform surveillance of Nipah virus in bats, we reviewed and analyzed the published records of Nipah virus surveillance globally. We applied a trait-based machine learning approach to a subset of species that occur in Asia, Australia, and Oceana. In addition to seven species in Kerala that were previously identified as Nipah virus seropositive, we identified at least four bat species that, on the basis of trait similarity with known Nipah virus-seropositive species, have a relatively high likelihood of exposure to Nipah or Nipah-like viruses in India. These machine-learning approaches provide the first step in the sequence of studies required to assess the risk of Nipah virus spillover in India. Nipah virus surveillance not only within Kerala but also elsewhere in India would benefit from a research pipeline that included surveys of known and predicted reservoirs for serological evidence of past infection with Nipah virus (or cross reacting henipaviruses). Serosurveys should then be followed by longitudinal spatial and temporal studies to detect shedding and isolate virus from species with evidence of infection. Ecological studies will then be required to understand the dynamics governing prevalence and shedding in bats and the contacts that could pose a risk to public health. [ABSTRACT FROM AUTHOR]

Burkholderia pseudomallei causes melioidosis, a common source of pneumonia and sepsis in Southeast Asia and Northern Australia that results in high mortality rates. A caprine melioidosis model of aerosol infection that leads to a systemic infection has the potential to characterize the humoral immune response. This could help identify immunogenic proteins for new diagnostics and vaccine candidates. Outbred goats may more accurately mimic human infection, in contrast to the inbred mouse models used to date. B. pseudomallei infection was delivered as an intratracheal aerosol. Antigenic protein profiling was generated from the infecting strain MSHR511. Humoral immune responses were analyzed by ELISA and western blot, and the antigenic proteins were identified by mass spectrometry. Throughout the course of the infection the assay results demonstrated a much greater humoral response with IgG antibodies, in both breadth and quantity, compared to IgM antibodies. Pre-infection sera showed multiple immunogenic proteins already reactive for IgG (7–20) and IgM (0–12) in most of the goats despite no previous exposure to B. pseudomallei. After infection, the number of IgG reactive proteins showed a marked increase as the disease progressed. Early stage infection (day 7) showed immune reaction to chaperone proteins (GroEL, EF-Tu, and DnaK). These three proteins were detected in all serum samples after infection, with GroEL immunogenically dominant. Seven common reactive antigens were selected for further analysis using ELISA. The heat shock protein GroEL1 elicited the strongest goat antibody immune response compared to the other six antigens. Most of the six antigens showed the peak IgM reactivity at day 14, whereas the IgG reactivity increased further as the disease progressed. An overall MSHR511 proteomic comparison between the goat model and human sera showed that many immune reactive proteins are common between humans and goats with melioidosis. [ABSTRACT FROM AUTHOR]

Background: Buruli ulcer (BU), caused by Mycobacterium ulcerans, is increasing in incidence in Victoria, Australia. To improve understanding of disease transmission, we aimed to map the location of BU lesions on the human body. Methods: Using notification data and clinical records review, we conducted a retrospective observational study of patients diagnosed with BU in Victoria from 1998–2015. We created electronic density maps of lesion locations using spatial analysis software and compared lesion distribution by age, gender, presence of multiple lesions and month of infection. Findings: We examined 579 patients with 649 lesions; 32 (5.5%) patients had multiple lesions. Lesions were predominantly located on lower (70.0%) and upper (27.1%) limbs, and showed a non-random distribution with strong predilection for the ankles, elbows and calves. When stratified by gender, upper limb lesions were more common (OR 1·97, 95% CI 1·38–2·82, p<0·001) while lower limb lesions were less common in men than in women (OR 0·48, 95% CI 0·34–0·68, p<0·001). Patients aged ≥ 65 years (OR 3·13, 95% CI 1·52–6·43, p = 0·001) and those with a lesion on the ankle (OR 2·49, 95% CI 1·14–5·43, p = 0·02) were more likely to have multiple lesions. Most infections (71.3%) were likely acquired in the warmer 6 months of the year. Interpretation: Comparison with published work in Cameroon, Africa, showed similar lesion distribution and suggests the mode of M. ulcerans transmission may be the same across the globe. Our findings also aid clinical diagnosis and provide quantitative background information for further research investigating disease transmission. [ABSTRACT FROM AUTHOR]

Background: Globally, trachoma is the leading cause of infectious blindness and Australia is the only developed country with endemic trachoma. It is found in remote Indigenous communities burdened with poverty, overcrowding and poor hygiene. Lack of culturally appropriate health promotion, a small trachoma workforce and lack of awareness and support for trachoma elimination in general, were early barriers. Methods: A cross-sectional pre-post study using a convenience sample, was conducted in clinics, schools and community work-settings from 63 of the 82 remote Aboriginal communities identified as being at risk of trachoma in the Northern Territory (NT). The study assessed the effect of a multi-component health promotion strategy aimed at increasing knowledge, attitude and practice amongst health, education and community support settings staff. Data were collected between 2010 and 2012. The health promotion initiatives were introduced in communities in staggered delivery over a one-year period; 272 participants were surveyed at baseline and 261 at follow-up. Results: Trachoma related knowledge, attitudes and practice increased across all settings and for all primary outcome measures. Across all settings, there was a significant increase in the proportion of participants reporting the most important thing to do if a child has a ‘dirty’ face is to ‘wash it every time its dirty’ (61.6% cf 69.7%; X2p = 0.047), a significant reduction in the proportion of respondents answering ‘no’ to the question “Is it normal for kids to have dirty faces in your community’ (40.5% cf 29.6%; X2p = 0.009) and a significant increase in reported capacity to teach others about trachoma prevention (70.8% cf 83.3%; X2p <0.001). Conclusion: Health promotion was associated with increased trachoma knowledge, attitude and practice amongst health, education and community support staff working with children and in remote NT communities. In the early stages of the trachoma health promotion program, this increased trachoma awareness and improved local workforce capacity and support for trachoma elimination in three health promotion settings in remote communities in the NT. [ABSTRACT FROM AUTHOR]

Modelling disease dynamics is most useful when data are limited. We present a spatial transmission model for the spread of canine rabies in the currently rabies-free wild dog population of Australia. The introduction of a sub-clinically infected dog from Indonesia is a distinct possibility, as is the spillover infection of wild dogs. Ranges for parameters were estimated from the literature and expert opinion, or set to span an order of magnitude. Rabies was judged to have spread spatially if a new infectious case appeared 120 km from the index case. We found 21% of initial value settings resulted in canine rabies spreading 120km, and on doing so at a median speed of 67 km/year. Parameters governing dog movements and behaviour, around which there is a paucity of knowledge, explained most of the variance in model outcomes. Dog density, especially when interactions with other parameters were included, explained some of the variance in whether rabies spread 120km, but dog demography (mean lifespan and mean replacement period) had minimal impact. These results provide a clear research direction if Australia is to improve its preparedness for rabies. [ABSTRACT FROM AUTHOR]

West Nile virus is globally wide-spread and causes significant disease in humans and animals. The evolution of West Nile virus Kunjin subtype in Australia (WNVKUN) was investigated using archival samples collected over a period of 50 years. Based on the pattern of fixed amino acid substitutions and time-stamped molecular clock analyses, a single long-term lineage (or topotype) was inferred. This implies that a bottleneck exists such that regional strains eventually die out and are replaced with strains from a single source. This was consistent with current hypotheses regarding the distribution of WNVKUN, whereby the virus is enzootic in northern Australia and is disseminated to southern states by water-birds or mosquitoes after flooding associated with above average rainfall. In addition, two previous amino acid changes associated with pathogenicity, an N-Y-S glycosylation motif in the envelope protein and a phenylalanine at amino acid 653 in the RNA polymerase, were both detected in all isolates collected since the 1980s. Changes primarily occurred due to stochastic drift. One fixed substitution each in NS3 and NS5, subtly changed the chemical environment of important functional groups, and may be involved in fine-tuning RNA synthesis. Understanding these evolutionary changes will help us to better understand events such as the emergence of the virulent strain in 2011. [ABSTRACT FROM AUTHOR]

Background: Within the last 10 years Zika virus (ZIKV) has caused unprecedented epidemics of human disease in the nations and territories of the western Pacific and South America, and continues to escalate in both endemic and non-endemic regions. We evaluated the vector competence of Australian mosquitoes for ZIKV to assess their potential role in virus transmission. Methodology/Principal Findings: Mosquitoes were exposed to infectious blood meals containing the prototype African ZIKV strain. After 14 days incubation at 28°C and high relative humidity, infection, dissemination and transmission rates were assessed. Infection in Culex annulirostris and Cx. sitiens could not be detected. 8% of Cx. quinquefasciatus were infected, but the virus did not disseminate in this species. Despite having infection rates > 50%, Aedes notoscriptus and Ae. vigilax did not transmit ZIKV. In contrast, Ae. aegypti had infection and transmission rates of 57% and 27%, respectively. In susceptibility trials, the virus dose required to infect 50% (ID50) of Ae. aegypti was106.4 tissue culture infectious dose50 (TCID50)/mL. Additionally, a threshold viral load within the mosquito of at least 105.1 TCID50 equivalents/mL had to be reached before virus transmission occurred. Conclusions/Significance: We confirmed Ae. aegypti to be the most likely mosquito vector of ZIKV in Australia, although the restricted distribution of this species will limit the receptive zone to northern Queensland where this species occurs. Importantly, the role in ZIKV transmission of Culex and other Aedes spp. tested will be negligible. Despite being the implicated vector, the relatively high ID50 and need for a high titer disseminated infection in Ae. aegypti suggest that high mosquito population densities will be required to facilitate epidemic ZIKV transmission among the currently immunologically naïve human population in Australia. [ABSTRACT FROM AUTHOR]

Background: Australia is the only high income country with persisting endemic trachoma. A national control program involving mass drug administration with oral azithromycin, in place since 2006, has some characteristics which differ from programs in low income settings, particularly in regard to the use of a wider range of treatment strategies, and more regular assessments of community prevalence. We aimed to examine the association between treatment strategies and trachoma prevalence. Methods: Through the national surveillance program, annual data from 2007–2013 were collected on trachoma prevalence and treatment with oral azithromycin in children aged 5–9 years from three Australian regions with endemic trachoma. Communities were classified for each year according to one of four trachoma treatment strategies implemented (no treatment, active cases only, household and community-wide). We estimated the change in trachoma prevalence between sequential pairs of years and across multiple years according to treatment strategy using random-effects meta-analyses. Findings: Over the study period, 182 unique remote Aboriginal communities had 881 annual records of both trachoma prevalence and treatment. From the analysis of pairs of years, the greatest annual fall in trachoma prevalence was in communities implementing community-wide strategies, with yearly absolute reductions ranging from -8% (95%CI -17% to 1%) to -31% (-26% to -37%); these communities also had the highest baseline trachoma prevalence (15.4%-43.9%). Restricting analyses to communities with moderate trachoma prevalence (5–19%) at initial measurement, and comparing community trachoma prevalence from the first to the last year of available data for the community, both community-wide and more targeted treatment strategies were associated with similar absolute reductions (-11% [-8% to -13%] and -7% [-5% to -10%] respectively). Results were similar stratified by region. Interpretation: Consistent with previous research, community-wide administration of azithromycin reduces trachoma prevalence. Our observation that less intensive treatment with a ‘household’ strategy in moderate prevalence communities (5-<20%) is associated with similar reductions in prevalence over time, will require confirmation in other settings if it is to be used as a basis for changes in control strategies. [ABSTRACT FROM AUTHOR]

Cryptosporidiosis causes gastroenteritis and is transmitted to humans via contaminated water and food, and contact with infected animals and people. We analyse long-term cryptosporidiosis patterns across Australia (2001–2012) and review published Australian studies and jurisdictional health bulletins to identify high risk populations and potential risk factors for disease. Using national data on reported cryptosporidiosis, the average annual rate of reported illness was 12.8 cases per 100 000 population, with cycles of high and low reporting years. Reports of illness peak in summer, similar to other infectious gastrointestinal diseases. States with high livestock densities like New South Wales and Queensland also record a spring peak in illnesses. Children aged less than four years have the highest rates of disease, along with adult females. Rates of reported cryptosporidiosis are highest in the warmer, remote regions and in Aboriginal and Torres Strait Islander populations. Our review of 34 published studies and seven health department reports on cryptosporidiosis in Australia highlights a lack of long term, non-outbreak studies in these regions and populations, with an emphasis on outbreaks and risk factors in urban areas. The high disease rates in remote, tropical and subtropical areas and in Aboriginal and Torres Strait Islander populations underscore the need to develop interventions that target the sources of infection, seasonal exposures and risk factors for cryptosporidiosis in these settings. Spatial epidemiology can provide an evidence base to identify priorities for intervention to prevent and control cryptosporidiosis in high risk populations. [ABSTRACT FROM AUTHOR]

Objective: To explore the efficacy of ivermectin in the treatment of serologically diagnosed cases of Strongyloides stercoralis (S. stercoralis) infection in an Aboriginal community and to describe factors that may influence the outcome of treatment. Methods: Longitudinal study of a group of 92 individuals with serologically diagnosed S. stercoralis treated with ivermectin and followed up over a period of approximately 6 months. Main outcomes were serological titers pre and post treatment, diabetic status, and duration of follow up. Findings: Treatment success was achieved in 62% to 79% of cases dependent on the methods employed for the diagnosis of infection and assessment of treatment outcome. Type 2 Diabetes Mellitus (T2DM) was found to be significantly associated with treatment failure in this group for two of the three methods employed. Interpretation: Ivermectin has been confirmed as an effective treatment for S stercoralis infection in this setting. T2DM appears to be an independent risk factor for treatment failure in this population, and plausible mechanisms to explain this observation are presented. [ABSTRACT FROM AUTHOR]

Identification and characterization of near-neighbor species are critical to the development of robust molecular diagnostic tools for biothreat agents. One such agent, Burkholderia pseudomallei, a soil bacterium and the causative agent of melioidosis, is lacking in this area because of its genomic diversity and widespread geographic distribution. The Burkholderia genus contains over 60 species and occupies a large range of environments including soil, plants, rhizospheres, water, animals and humans. The identification of novel species in new locations necessitates the need to identify the true global distribution of Burkholderia species, especially the members that are closely related to B. pseudomallei. In our current study, we used the Burkholderia-specific recA sequencing assay to analyze environmental samples from the Darwin region in the Northern Territory of Australia where melioidosis is endemic. Burkholderia recA PCR negative samples were further characterized using 16s rRNA sequencing for species identification. Phylogenetic analysis demonstrated that over 70% of the bacterial isolates were identified as B. ubonensis indicating that this species is common in the soil where B. pseudomallei is endemic. Bayesian phylogenetic analysis reveals many novel branches within the B. cepacia complex, one novel B. oklahomensis-like species, and one novel branch containing one isolate that is distinct from all other samples on the phylogenetic tree. During the analysis with recA sequencing, we discovered 2 single nucleotide polymorphisms in the reverse priming region of B. oklahomensis. A degenerate primer was developed and is proposed for future use. We conclude that the recA sequencing technique is an effective tool to classify Burkholderia and identify soil organisms in a melioidosis endemic area. Author Summary: Burkholderia is a widespread genus of bacteria that contains over 60 species. The species within Burkholderia range from environmentally important, such as isolates that breakdown pollutants, to human pathogens. Burkholderia pseudomallei, the causative agent of melioidosis, is endemic to Northern Australia and is a major public health concern in that region. We characterized 152 unknown environmental isolates using recA sequencing to identify the presence of Burkholderia bacteria in the region. The majority of bacteria identified in this study belonged to the B. ubonensis species and various species were found to inhabit the same environmental sample as the human pathogen, B. pseudomallei. The role of B. ubonensis and other Burkholderia species identified in this endemic region and how they interact with B. pseudomallei are important questions to address in order to understand the evolution of this important human pathogen. While they are occupying a similar geographic range, they must be exist in different niche in order to remain distinct species. [ABSTRACT FROM AUTHOR]

Domestic dog rabies is an endemic disease in large parts of the developing world and also epidemic in previously free regions. For example, it continues to spread in eastern Indonesia and currently threatens adjacent rabies-free regions with high densities of free-roaming dogs, including remote northern Australia. Mathematical and simulation disease models are useful tools to provide insights on the most effective control strategies and to inform policy decisions. Existing rabies models typically focus on long-term control programs in endemic countries. However, simulation models describing the dog rabies incursion scenario in regions where rabies is still exotic are lacking. We here describe such a stochastic, spatially explicit rabies simulation model that is based on individual dog information collected in two remote regions in northern Australia. Illustrative simulations produced plausible results with epidemic characteristics expected for rabies outbreaks in disease free regions (mean R0 1.7, epidemic peak 97 days post-incursion, vaccination as the most effective response strategy). Systematic sensitivity analysis identified that model outcomes were most sensitive to seven of the 30 model parameters tested. This model is suitable for exploring rabies spread and control before an incursion in populations of largely free-roaming dogs that live close together with their owners. It can be used for ad-hoc contingency or response planning prior to and shortly after incursion of dog rabies in previously free regions. One challenge that remains is model parameterisation, particularly how dogs' roaming and contacts and biting behaviours change following a rabies incursion in a previously rabies free population. Author Summary: Rabies in domestic dog populations still causes >50,000 human deaths worldwide each year. While its eradication by vaccination of the reservoir population (dogs and wildlife) was successful in many parts of the world, it is still present in the developing world and continues to spread to new regions. Theoretical rabies models supporting control plans do exist for rabies endemic regions; however these models usually provide information for long-term programs. Here, we describe a novel rabies simulation model for application in rabies-free regions experiencing an incursion. The model simulates a rabies outbreak in the free-ranging dog population in remote indigenous communities in northern Australia. Vaccination, dog density reduction and dog confinement are implemented as control strategies. Model outputs suggest that the outbreak lasts for an average of 7 months and typically spreads through all communities of the region. Dog vaccination was found to be the most effective response strategy. The model produces plausible results and can be used to provide information for ad-hoc response planning before and shortly after rabies incursion. [ABSTRACT FROM AUTHOR]

Background: Worldwide, more than 40% of the population is at risk from dengue and recent estimates suggest that up to 390 million dengue infections are acquired every year. The Eliminate Dengue (ED) Program is investigating the use of Wolbachia-infected, transmission-compromised, mosquitoes to reduce dengue transmission. Previous introductions of genetically-modified strategies for dengue vector control have generated controversy internationally by inadequately engaging host communities. Community Engagement (CE) was a key component of the ED Program's initial open release trials in Queensland Australia. Their approach to CE was perceived as effective by the ED team's senior leadership, members of its CE team, and by its funders, but if and why this was the case was unclear. We conducted a qualitative case study of the ED Program's approach to CE to identify and critically examine its components, and to explain whether and how these efforts contributed to the support received by stakeholders. Methodology/Principal Findings: In-depth semi-structured interviews were conducted with 24 participants with a range of experiences and perspectives related to the ED Program's CE activities. Our analytic approach combined techniques of grounded theory and qualitative description. The ED Program's approach to CE reflected four foundational features: 1) enabling conditions; 2) leadership; 3) core commitments and guiding values; and 4) formative social science research. These foundations informed five key operational practices: 1) building the CE team; 2) integrating CE into management practices; 3) discerning the community of stakeholders; 4) establishing and maintaining a presence in the community; and 5) socializing the technology and research strategy. We also demonstrate how these practices contributed to stakeholders' willingness to support the trials. Conclusions/Significance: Our case study has identified, and explained the functional relationships among, the critical features of the ED Program's approach to CE. It has also illuminated how these features were meaningful to stakeholders and contributed to garnering support within the host communities for the open-release trials. Our findings reveal how translating ethical intentions into effective action is more socially complex than is currently reflected in the CE literature. Because our case study delineates the critical features of the ED Program's approach to CE, it can serve as a framework for other programs to follow when designing their own strategies. And because the findings outline a theory of change for CE, it can also serve as a starting point for developing an evaluation framework for CE. Author Summary: Community Engagement (CE) is gaining increasing recognition as an important dimension of biomedical, public health and global health research, including neglected tropical disease research. Yet, there has been little agreement about the specific goals of CE and about the best ways to design, conduct, and evaluate it. CE was an integral component of the ED Program's initial open release trials in Queensland, Australia and our retrospective case study of their approach to CE in that setting helps explain why the ED program was well accepted in the host communities of the initial field trials. Our analysis has generated an empirically grounded framework for CE that explains the linkages between the foundational ethical and practical commitments made by the ED program and its funders and the specific operational practices adopted by the ED program, through which these commitments were realized. Our case study also identified how these practices were meaningful to stakeholders and contributed to their willingness to support the ED program, in general, and the open-release trials in particular. This framework provides research funders, investigators, implementation partners, policy makers, research ethics committees and host communities an example to follow when designing their CE strategies and assessing whether CE is being conducted to high ethical standards. [ABSTRACT FROM AUTHOR]

Background: Australia is the only high-income country in which endemic trachoma persists. In response, the Australian Government has recently invested heavily towards the nationwide control of the disease. Methodology/Principal Findings: A novel simulation model was developed to reflect the trachoma epidemic in Australian Aboriginal communities. The model, which incorporates demographic, migration, mixing, and biological heterogeneities, was used to evaluate recent intervention measures against counterfactual past scenarios, and also to assess the potential impact of a series of hypothesized future intervention measures relative to the current national strategy and intensity. The model simulations indicate that, under the current intervention strategy and intensity, the likelihood of controlling trachoma to less than 5% prevalence among 5–9 year-old children in hyperendemic communities by 2020 is 31% (19%–43%). By shifting intervention priorities such that large increases in the facial cleanliness of children are observed, this likelihood of controlling trachoma in hyperendemic communities is increased to 64% (53%–76%). The most effective intervention strategy incorporated large-scale antibiotic distribution programs whilst attaining ambitious yet feasible screening, treatment, facial cleanliness and housing construction targets. Accordingly, the estimated likelihood of controlling trachoma in these communities is increased to 86% (76%–95%). Conclusions/Significance: Maintaining the current intervention strategy and intensity is unlikely to be sufficient to control trachoma across Australia by 2020. However, by shifting the intervention strategy and increasing intensity, the likelihood of controlling trachoma nationwide can be significantly increased. Author Summary: Australia is the only remaining high-income country reporting endemic levels of trachoma, with infections occurring predominantly within rural and remote Indigenous communities. Although the Australian government has recently invested large sums of money to combat the disease, it remains unclear whether the national goal of controlling trachoma by 2020 will be achieved. Here, we use a novel individual-based simulation model to estimate the impact of numerous potential future invention strategies and intensities. Our model is the most sophisticated trachoma transmission model to date, and the first to specifically represent trachoma in Australian Indigenous communities. Model projections suggest that although the current intervention strategy and intensity are unlikely to achieve the target of national control by 2020, the likelihood of achieving this goal can be significantly increased by shifting the intervention strategy and increasing the intensity of key intervention components such as screening, treatment and facial cleanliness activities. Our findings that the most resource rich country with endemic trachoma may require a more intensive intervention effort to control the disease suggest that challenges may remain in the fight for the global control and eventual elimination and eradication of trachoma. [ABSTRACT FROM AUTHOR]

Background: International melioidosis treatment guidelines recommend a minimum 10 to 14 days' intravenous antibiotic therapy (intensive phase), followed by 3 to 6 months' oral therapy (eradication phase). This approach is associated with rates of relapse, defined as recurrence following the eradication phase, that can exceed 5%. Rates of recrudescence, defined as recurrence during the eradication phase, have not previously been reported. In response to low eradication phase completion rates in Australia, a local guideline has evolved over the last ten years recommending a longer minimum intensive phase duration for many cases of melioidosis. Methodology/ Principal Findings: This retrospective cohort study reviews antibiotic duration for the first episode of care for all patients diagnosed with melioidosis and surviving the intensive phase during a recent three year period in the tropical north of Australia's Northern Territory; we also review adherence to the current local guideline and treatment outcomes. Of 215 first episodes of melioidosis surviving the intensive phase, the median (interquartile range) intensive phase duration was 26 (14-34) days. One hundred and eight (50.2%) patients completed eradication therapy; 58 (27.0%) patients took no eradication therapy. At 28 months' follow-up, one (0.5%) relapse and eleven (5.1%) recrudescences had occurred. On exact logistic regression analysis, the only independent risk factors for recrudescence were self-discharge during the intensive phase (odds ratio 6.2 [95% confidence interval 1.2-30.0]) and septic shock (odds ratio 5.3 [95% confidence interval 1.1-25.7]). Conclusions/ Significance: Relapsed melioidosis is rare in patients who receive a minimum intensive phase duration specified by our guideline and extended according to clinical progress. Recrudescence rates may improve with reductions in rates of self-discharge. Given the low relapse rate despite a high rate of eradication therapy non-adherence, the duration and necessity of eradication therapy for different patients after guideline-concordant intensive therapy should be evaluated further. Author Summary: Melioidosis is an infection caused by the soil bacterium Burkholderia pseudomallei; patients usually present with pneumonia, blood-stream infection and/or skin or internal organ abscesses. Melioidosis occurs most commonly in northern Australia and parts of Southeast Asia. It has a high mortality rate and, with standard treatment, a relapse rate greater than 5%; patients who relapse often represent severely unwell. Treatment comprises an intensive (intravenous antibiotic) phase, followed by a prolonged eradication (oral antibiotic) phase. Previous studies have found that the intensive phase is important to prevent mortality, and the eradication phase is important to prevent relapse. However, these studies have not been designed to detect an effect of intensive therapy on relapse rate. We know that adherence to eradication therapy is poor, and many of our patients live remotely making follow-up difficult. In order to address this, we have developed a new treatment guideline which stipulates a longer intensive phase for most patients. We show that adherence to this guideline is associated with very low relapse rates despite poor adherence to eradication therapy. It is possible that for many patients the eradication phase could be shortened or avoided when this intensive phase guideline is followed; this requires further research. [ABSTRACT FROM AUTHOR]

Melioidosis is an often fatal infectious disease affecting humans and animals in tropical regions and is caused by the saprophytic environmental bacterium Burkholderia pseudomallei. Domestic gardens are not only a common source of exposure to soil and thus to B. pseudomallei, but they also have been found to contain more B. pseudomallei than other environments. In this study we addressed whether anthropogenic manipulations common to gardens such as irrigation or fertilizers change the occurrence of B. pseudomallei. We conducted a soil microcosm experiment with a range of fertilizers and soil types as well as a longitudinal interventional study over three years on an experimental fertilized field site in an area naturally positive for B. pseudomallei. Irrigation was the only consistent treatment to increase B. pseudomallei occurrence over time. The effects of fertilizers upon these bacteria depended on soil texture, physicochemical soil properties and biotic factors. Nitrates and urea increased B. pseudomallei load in sand while phosphates had a positive effect in clay. The high buffering and cation exchange capacities of organic material found in a commercial potting mix led to a marked increase in soil salinity with no survival of B. pseudomallei after four weeks in the potting mix sampled. Imported grasses were also associated with B. pseudomallei occurrence in a multivariate model. With increasing population density in endemic areas these findings inform the identification of areas in the anthropogenic environment with increased risk of exposure to B. pseudomallei. Author Summary: Melioidosis cases are on the rise in endemic areas of northern Australia and Thailand. This potentially severe infectious disease affecting humans and animals in the tropical belt is caused by the gram negative bacterium Burkholderia pseudomallei. Domestic gardens are a common point of exposure to these environmental bacteria and B. pseudomallei are more prevalent in the dry season in gardens when compared to other areas. This is why we analysed whether common gardening practices such as regular watering (irrigation) or soil fertilizing change the occurrence of B. pseudomallei. We conducted a soil microcosm experiment with a range of fertilizers and soil types as well as a longitudinal interventional study over three years on an experimental fertilized field site in an area naturally positive for B. pseudomallei. Irrigation was the only consistent treatment to increase B. pseudomallei occurrence over time. The effects of fertilizers upon these bacteria depended on soil texture, physicochemical properties such as pH or salinity and vegetation. B. pseudomallei occurrence was also associated with imported grasses. With increasing populations in endemic areas, these findings inform the identification of areas in the anthropogenic environment with increased risk of exposure to B. pseudomallei. [ABSTRACT FROM AUTHOR]

Mycobacterium ulcerans causes Buruli ulcer (BU), a debilitating infection of subcutaneous tissue. There is a WHO-recommended antibiotic treatment requiring an 8-week course of streptomycin and rifampicin. This regime has revolutionized the treatment of BU but there are problems that include reliance on daily streptomycin injections and side effects such as ototoxicity. Trials of all-oral treatments for BU show promise but additional drug combinations that make BU treatment safer and shorter would be welcome. Following on from reports that avermectins have activity against Mycobacterium tuberculosis, we tested the in-vitro efficacy of ivermectin and moxidectin on M. ulcerans. We observed minimum inhibitory concentrations of 4–8 μg/ml and time-kill assays using wild type and bioluminescent M. ulcerans showed a significant dose-dependent reduction in M. ulcerans viability over 8-weeks. A synergistic killing-effect with rifampicin was also observed. Avermectins are well tolerated, widely available and inexpensive. Based on our in vitro findings we suggest that avermectins should be further evaluated for the treatment of BU. Author Summary: Neglected tropical diseases such as Buruli ulcer predominantly afflict the poorest populations in the world and reduce quality of life. Buruli ulcer is a necrotising infection that destroys the skin and soft tissue, frequently presenting as nodules or open ulcers. Buruli ulcer is treated with antibiotics and sometimes surgery. Unfortunately the antibiotic treatment can have toxic side effects, such as hearing loss. Also, patients must either be hospitalized or report daily to a treatment centre to get their medicine as the treatment is delivered by injection. In laboratory experiments we tested the susceptibility of Mycobacterium ulcerans, which causes Buruli ulcer, to avermectins. Avermectins are drugs that are used to treat common parasite and worm infections, such as river blindness. These drugs are inexpensive, have few side effects and are widely available. Our findings show that two avermectins called ivermectin and moxidectin inhibit the growth and also kill Mycobacterium ulcerans strains from both Africa and Australia. If their efficacy and safety also can be proven in animal and human studies, these drugs will provide an inexpensive addition to the current treatment of Buruli ulcer. [ABSTRACT FROM AUTHOR]

Introduction: Mycobacterium ulcerans (M. ulcerans) is a necrotizing skin infection endemic to the Bellarine Peninsula, Australia. Current treatment recommendations include 8 weeks of combination antibiotics, with adjuvant surgery if necessary. However, antibiotic toxicity often results in early treatment cessation and local experience suggests that shorter antibiotic courses may be effective with concurrent surgery. We report the outcomes of patients in the Barwon Health M. ulcerans cohort who received shorter courses of antibiotic therapy than 8 weeks. Methodology / Principal findings: A retrospective analysis was performed of all M. ulcerans infections treated at Barwon Health from March 1, 1998 to July 31, 2013. Sixty-two patients, with a median age of 65 years, received < 56 days of antibiotics and 51 (82%) of these patients underwent concurrent surgical excision. Most received a two-drug regimen of rifampicin combined with either ciprofloxacin or clarithromycin for a median 29 days (IQR 21–41days). Cessation rates were 55% for adverse events and 36% based on clinician decision. The overall success rate was 95% (98% with concurrent surgery; 82% with antibiotics alone) with a 50% success rate for those who received < 14 days of antibiotics increasing to 94% if they received 14–27 days and 100% for 28–55 days (p<0.01). A 100% success rate was seen for concurrent surgery and 14–27 days of antibiotics versus 67% for concurrent surgery and < 14 days of antibiotics (p = 0.12). No previously identified risk factors for treatment failure with surgery alone were associated with reduced treatment success rates with < 56 days of antibiotics. Conclusion: In selected patients, antibiotic treatment durations for M. ulcerans shorter than the current WHO recommended 8 weeks duration may be associated with successful outcomes. Author Summary: Buruli ulcer is a necrotizing skin and subcutaneous tissue infection caused by Mycobacterium ulcerans and is the third most common mycobacterial infection, behind tuberculosis and leprosy, world-wide. In recent years, the World Health Organisation has modified its guidelines for M. ulcerans treatment, moving from predominantly surgical to predominantly medical based management. It now recommends the combination of oral rifampicin and intramuscular streptomycin for a period of eight weeks as first-line therapy, with surgery as adjunctive therapy if necessary. The Barwon Health experience from south-eastern Australia has demonstrated that the entirely oral combination of rifampicin with either ciprofloxacin or clarithromycin for eight weeks can be an effective treatment option. However, these antibiotics are often toxic leading to early cessation, especially in the elderly. In addition, clinicians have been using a shorter duration of therapy for smaller lesions that have also been surgically managed. This study reviews our experience treating M. ulcerans with antibiotic durations of less than 8 weeks and demonstrates that successful outcomes can be achieved in selected patients, with success rates influenced by the duration of treatment and the use of surgical excision. This finding needs confirmation in further studies, but could have significant benefits in terms of reducing toxicity and improving adherence associated with Buruli ulcer antibiotic treatment. [ABSTRACT FROM AUTHOR]

Arthropod-borne viruses are a major cause of emerging disease with significant public health and economic impacts. However, the factors that determine their activity and seasonality are not well understood. In Australia, a network of sentinel cattle herds is used to monitor the distribution of several such viruses and to define virus-free regions. Herein, we utilize these serological data to describe the seasonality, and its drivers, of three economically important animal arboviruses: bluetongue virus, Akabane virus and bovine ephemeral fever virus. Through epidemiological time-series analyses of sero-surveillance data of 180 sentinel herds between 2004–2012, we compared seasonal parameters across latitudes, ranging from the tropical north (−10°S) to the more temperate south (−40°S). This analysis revealed marked differences in seasonality between distinct geographic regions and climates: seasonality was most pronounced in southern regions and gradually decreased as latitude decreased toward the Equator. Further, we show that both the timing of epidemics and the average number of seroconversions have a strong geographical component, which likely reflect patterns of vector abundance through co-varying climatic factors, especially temperature and rainfall. Notably, despite their differences in biology, including insect vector species, all three viruses exhibited very similar seasonality. By revealing the factors that shape spatial and temporal distributions, our study provides a more complete understanding of arbovirus seasonality that will enable better risk predictions. Author Summary: Arthropod-borne viruses (arboviruses) are a group of viruses that can have major impacts on public health, animal health and agricultural trade, and appear to be increasing in both number and prevalence worldwide. Despite their importance as emerging pathogens, the spatial patterns, long-term seasonal characteristics and drivers of seasonality in many arboviruses are poorly understood. The island continent of Australia provides an ideal case study for the spatial analysis of emerging arboviruses, harboring diverse climatic conditions across a wide range of latitudes. Herein we utilize long-term serological data from a nationwide network of sentinel herds in Australia to describe the seasonality of three economically important animal arboviruses: bluetongue virus, Akabane virus and bovine ephemeral fever virus. Using epidemiological time series analysis, we demonstrate that these viruses exhibit a distinct spatial pattern in both the peak timing and intensity of annual epidemic cycles, with the strongest seasonality observed in southerly geographic regions. In addition, we reveal the climatic factors that drive patterns of arbovirus distribution and, by doing so, provide a more complete understanding of arbovirus seasonality, which in turn will improve the risk assessment of these viruses. [ABSTRACT FROM AUTHOR]

Infection of susceptible hosts by the encapsulated Gram-negative bacterium Burkholderia pseudomallei (Bp) causes melioidosis, with septic patients attaining mortality rates ≥40%. Due to its high infectivity through inhalation and limited effective therapies, Bp is considered a potential bioweapon. Thus, there is great interest in identifying immune effectors that effectively kill Bp. Our goal is to compare the relative abilities of murine macrophages and neutrophils to clear Bp, as well as determine the importance of serum opsonins and bacterial capsule. Our findings indicate that murine macrophages and neutrophils are inherently unable to clear either unopsonized Bp or the relatively-avirulent acapsular bacterium B. thailandensis (Bt). Opsonization of Bp and Bt with complement or pathogen-specific antibodies increases macrophage-uptake, but does not promote clearance, although antibody-binding enhances complement deposition. In contrast, complement opsonization of Bp and Bt causes enhanced uptake and killing by neutrophils, which is linked with rapid ROS induction against bacteria exhibiting a threshold level of complement deposition. Addition of bacteria-specific antibodies enhances complement deposition, but antibody-binding alone cannot elicit neutrophil clearance. Bp capsule provides some resistance to complement deposition, but is not anti-phagocytic or protective against reactive oxygen species (ROS)-killing. Macrophages were observed to efficiently clear Bp only after pre-activation with IFNγ, which is independent of serum- and/or antibody-opsonization. These studies indicate that antibody-enhanced complement activation is sufficient for neutrophil-clearance of Bp, whereas macrophages are ineffective at clearing serum-opsonized Bp unless pre-activated with IFNγ. This suggests that effective immune therapies would need to elicit both antibodies and Th1-adaptive responses for successful prevention/eradication of melioidosis. Author Summary: Burkholderia pseudomallei is the causative agent of melioidosis, which is a major cause of septic death in endemic areas of Southeast Asia and northern Australia. This range now appears to be expanding, and with the increased incidence of diabetes, which is a major predisposing factor for B. pseudomallei infections, it is believed these cases will continue to increase. This organism is also categorized as a Tier 1 select agent with great potential for misuse as a bioweapon. Thus, there is great interest in developing vaccines and other immunotherapies for melioidosis. To better design these treatments, it is essential to understand which immune cells are capable of controlling B. pseudomallei, particularly during early stages of infection, and which immune mediators are required for these cells to optimally eradicate these bacteria. In this work, we identified that both macrophages and neutrophils were capable of internalizing and killing B. pseudomallei, but required different immune mediators to allow these effects. Complement and antibody-mediated opsonization was sufficient to promote uptake and killing of B. pseudomallei by neutrophils, whereas these opsonins could only enhance uptake by macrophages; macrophage-mediated killing required IFNγ. These findings suggest that successful therapies must elicit complement-activating antibodies and IFNγ to eradicate/prevent melioidosis. [ABSTRACT FROM AUTHOR]

Scabies is an infectious skin disease caused by the mite Sarcoptes scabiei and has been classified as one of the six most prevalent epidermal parasitic skin diseases infecting populations living in poverty by the World Health Organisation. The role of the complement system, a pivotal component of human innate immunity, as an important defence against invading pathogens has been well documented and many parasites have an arsenal of anti-complement defences. We previously reported on a family of scabies mite proteolytically inactive serine protease paralogues (SMIPP-Ss) thought to be implicated in host defence evasion. We have since shown that two family members, SMIPP-S D1 and I1 have the ability to bind the human complement components C1q, mannose binding lectin (MBL) and properdin and are capable of inhibiting all three human complement pathways. This investigation focused on inhibition of the lectin pathway of complement activation as it is likely to be the primary pathway affecting scabies mites. Activation of the lectin pathway relies on the activation of MBL, and as SMIPP-S D1 and I1 have previously been shown to bind MBL, the nature of this interaction was examined using binding and mutagenesis studies. SMIPP-S D1 bound MBL in complex with MBL-associated serine proteases (MASPs) and released the MASP-2 enzyme from the complex. SMIPP-S I1 was also able to bind MBL in complex with MASPs, but MASP-1 and MASP-2 remained in the complex. Despite these differences in mechanism, both molecules inhibited activation of complement components downstream of MBL. Mutagenesis studies revealed that both SMIPP-Ss used an alternative site of the molecule from the residual active site region to inhibit the lectin pathway. We propose that SMIPP-Ss are potent lectin pathway inhibitors and that this mechanism represents an important tool in the immune evasion repertoire of the parasitic mite and a potential target for therapeutics. Author Summary: Scabies is a skin infection caused by parasitic scabies mites. There are an estimated 300 million cases globally, with the majority of infections occurring in the world's poorest communities. In Australia, scabies is common in remote Indigenous communities where the infection rate is 16 times higher than the non-Indigenous population. Current treatments have remained relatively unchanged for years and consequently treatment resistance has inevitability emerged. Despite scabies being a well known and frequent infectious skin disease, scabies research has been neglected, resulting in a lack of basic scabies mite biological data. As a result no new therapeutics have been developed. Our research seeks to understand the relationship between the parasite and the human host and one key area of interest is how mites avoid destruction and survive in human skin. We have determined that to survive an attack by the skin's immune defence system the mites release counter defensive proteins that inhibit the skin's defences from activating. This strategy allows the mites to survive in the skin, reproduce and to establish an infection. With this information we can design therapeutics that target these mite proteins, allow the skin to mount an attack and potentially reduce infection. [ABSTRACT FROM AUTHOR]

Background: Melioidosis is a problem in the developing tropical regions of Southeast Asia and Northern Australia where the the Gram negative saprophytic bacillus Burkholderia pseudomallei is endemic with the risk of fulminant septicaemia. While diabetes mellitus is a well-established risk factor for melioidiosis, little is known if specific hypoglycemic agents may differentially influence the susceptibility and clinical course of infection with B. pseudomallei (Bp). Methodology/Principal Findings: In this cohort study, patients with pre-existing diabetes and melioidosis were retrospectively studied. Outcome measures: mortality, length of stay and development of complications (namely hypotension, intubation, renal failure and septicaemia) were studied in relation to prior diabetic treatment regimen. Peripheral blood mononuclear cells (PBMC) from diabetic patients and healthy PBMC primed with metformin, glyburide and insulin were stimulated with purified Bp antigens in vitro. Immune response and specific immune pathway mediators were studied to relate to the clinical findings mechanistically. Of 74 subjects, 44 (57.9%) had sulphonylurea-containing diabetic regimens. Patient receiving sulphonylureas had more severe septic complications (47.7% versus 16.7% p = 0.006), in particular, hypotension requiring intropes (p = 0.005). There was also a trend towards increased mortality in sulphonylurea-users (15.9% versus 3.3% p = 0.08). In-vitro, glyburide suppressed inflammatory cytokine production in a dose-dependent manner. An effect of the drug was the induction of IL-1R-associated kinase-M at the level of mRNA transcription. Conclusion/Significance: Sulphonylurea treatment results in suppression of host inflammatory response and may put patients at higher risk for adverse outcomes in melioidosis. Author Summary: Melioidosis is a problem in the developing tropical regions of Southeast Asia and Northern Australia where the Gram negative bacillus Burkholderia pseudomallei can cause life-threatening infection. Diabetes mellitus is a recognised risk factor for melioidiosis; however little is known if commonly used anti-diabetic drugs may affect the clinical course of the disease. In this study, we found that patients who were receiving sulphonylureas for diabetic treatment had more severe septic complications requiring intensive care as well as increased risk of deaths. This may be attributable to the capacity of sulphonylureas in modulating the host immune response. We highlight caution in the prescription of this class of drug, which is popular due to its low cost and easy availability, especially in melioidosis-endemic tropical regions. [ABSTRACT FROM AUTHOR]

Burkholderia pseudomallei is a soil-dwelling bacterium and the causative agent of melioidosis. Isolation of B. pseudomallei from clinical samples is the "gold standard" for the diagnosis of melioidosis; results can take 3–7 days to produce. Alternatively, antibody-based tests have low specificity due to a high percentage of seropositive individuals in endemic areas. There is a clear need to develop a rapid point-of-care antigen detection assay for the diagnosis of melioidosis. Previously, we employed In vivo Microbial Antigen Discovery (InMAD) to identify potential B. pseudomallei diagnostic biomarkers. The B. pseudomallei capsular polysaccharide (CPS) and numerous protein antigens were identified as potential candidates. Here, we describe the development of a diagnostic immunoassay based on the detection of CPS. Following production of a CPS-specific monoclonal antibody (mAb), an antigen-capture immunoassay was developed to determine the concentration of CPS within a panel of melioidosis patient serum and urine samples. The same mAb was used to produce a prototype Active Melioidosis Detect Lateral Flow Immunoassay (AMD LFI); the limit of detection of the LFI for CPS is comparable to the antigen-capture immunoassay (∼0.2 ng/ml). The analytical reactivity (inclusivity) of the AMD LFI was 98.7% (76/77) when tested against a large panel of B. pseudomallei isolates. Analytical specificity (cross-reactivity) testing determined that 97.2% of B. pseudomallei near neighbor species (35/36) were not reactive. The non-reactive B. pseudomallei strain and the reactive near neighbor strain can be explained through genetic sequence analysis. Importantly, we show the AMD LFI is capable of detecting CPS in a variety of patient samples. The LFI is currently being evaluated in Thailand and Australia; the focus is to optimize and validate testing procedures on melioidosis patient samples prior to initiation of a large, multisite pre-clinical evaluation. Author Summary: Burkholderia pseudomallei is an environmental bacterium and the cause of melioidosis. Culture of patient samples is the "gold standard" diagnostic test, but may take up to 7 days to complete. Melioidosis has a 10–40% case fatality rate depending on the geographic location. Delays in diagnosis could lead to administration of ineffective antimicrobial therapy, since B. pseudomallei is resistant to empiric antibiotic regimens. Therefore, we have developed a lateral flow immunoassay that can be used in the clinical setting to diagnose melioidosis in 15 minutes. The test promises to provide improved management of patients with melioidosis. [ABSTRACT FROM AUTHOR]

Introduction: Dengue is one of the most widespread mosquito-borne diseases in the world. The causative agent, dengue virus (DENV), is primarily transmitted by the mosquito Aedes aegypti, a species that has proved difficult to control using conventional methods. The discovery that A. aegypti transinfected with the wMel strain of Wolbachia showed limited DENV replication led to trial field releases of these mosquitoes in Cairns, Australia as a biocontrol strategy for the virus. Methodology/Principal Findings: Field collected wMel mosquitoes that were challenged with three DENV serotypes displayed limited rates of body infection, viral replication and dissemination to the head compared to uninfected controls. Rates of dengue infection, replication and dissemination in field wMel mosquitoes were similar to those observed in the original transinfected wMel line that had been maintained in the laboratory. We found that wMel was distributed in similar body tissues in field mosquitoes as in laboratory ones, but, at seven days following blood-feeding, wMel densities increased to a greater extent in field mosquitoes. Conclusions/Significance: Our results indicate that virus-blocking is likely to persist in Wolbachia-infected mosquitoes after their release and establishment in wild populations, suggesting that Wolbachia biocontrol may be a successful strategy for reducing dengue transmission in the field. Author Summary: Almost half of the world's population is at risk of contracting dengue virus, particularly in the tropics and sub-tropics. The virus is transmitted by the mosquito Aedes aegypti, a cosmopolitan species that has proved difficult to control using traditional methods. A new biocontrol strategy has been developed involving the release of mosquitoes infected with Wolbachia bacteria. Mosquitoes with the wMel strain of Wolbachia show dramatically reduced replication and transmission of dengue virus in laboratory trials. Although promising, the utility of Wolbachia biocontrol depends on field wMel-infected mosquitoes retaining the phenotype of reduced viral replication. Mosquitoes with wMel were released in the field in Cairns, Australia in early 2011. We provide evidence that, one year later, field collected wMel mosquitoes showed reduced dengue virus replication in the body and limited dissemination to the head compared to controls. Wolbachia numbers in mosquitoes increased following blood meals, which may further decrease viral replication if the insects feed frequently. Our results indicate that Wolbachia-mediated dengue interference is sustained in field populations and shows no sign of attenuation after one year of deployment. [ABSTRACT FROM AUTHOR]

The last 20 years has seen a significant series of outbreaks of Buruli/Bairnsdale Ulcer (BU), caused by Mycobacterium ulcerans, in temperate south-eastern Australia (state of Victoria). Here, the prevailing view of M. ulcerans as an aquatic pathogen has been questioned by recent research identifying native wildlife as potential terrestrial reservoirs of infection; specifically, tree-dwelling common ringtail and brushtail possums. In that previous work, sampling of environmental possum faeces detected a high prevalence of M. ulcerans DNA in established endemic areas for human BU on the Bellarine Peninsula, compared with non-endemic areas. Here, we report research from an emergent BU focus recently identified on the Mornington Peninsula, confirming associations between human BU and the presence of the aetiological agent in possum faeces, detected by real-time PCR targeting M. ulcerans IS2404, IS2606 and KR. Mycobacterium ulcerans DNA was detected in 20/216 (9.3%) ground collected ringtail possum faecal samples and 4/6 (66.6%) brushtail possum faecal samples. The distribution of the PCR positive possum faecal samples and human BU cases was highly focal: there was a significant non-random cluster of 16 M. ulcerans positive possum faecal sample points detected by spatial scan statistics (P<0.0001) within a circle of radius 0.42 km, within which were located the addresses of 6/12 human cases reported from the area to date; moreover, the highest sample PCR signal strength (equivalent to ≥106 organisms per gram of faeces) was found in a sample point located within this cluster radius. Corresponding faecal samples collected from closely adjacent BU-free areas were predominantly negative. Possums may be useful sentinels to predict endemic spread of human BU in Victoria, for public health planning. Further research is needed to establish whether spatial associations represent evidence of direct or indirect transmission between possums and humans, and the mechanism by which this may occur. Author Summary: Mycobacterium ulcerans causes the disfiguring human skin disease Buruli ulcer (BU). The mechanism of transmission and reservoir for human infection remain unknown. In previous research, we reported the detection of M. ulcerans DNA in the faeces of possums (small tree-dwelling marsupials) in an area of South-East Australia (the Bellarine peninsula) where the largest recorded outbreak of human BU has been in progress for the last decade. The current study was carried out in a new outbreak area (the Mornington peninsula), and describes the detection of M. ulcerans DNA in possum faeces collected from the ground, in locations which correspond closely with the addresses of human BU cases. The association of new human BU cases with areas where M. ulcerans positive possum faeces are found contributes further evidence to the possible role of possums as an environmental reservoir of infection. Possums may be useful sentinel animals to monitor the spread of BU in Australia. [ABSTRACT FROM AUTHOR]

Background: Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans, with endemicity predominantly in sub-Saharan Africa and south-eastern Australia. The mode of transmission and the environmental reservoir(s) of the bacterium and remain elusive. Real-time PCR investigations have detected M. ulcerans DNA in a variety of Australian environmental samples, including the faeces of native possums with and without clinical evidence of infection. This report seeks to expand on previously published findings by the authors' investigative group with regards to clinical and subclinical disease in selected wild possum species in BU-endemic areas of Victoria, Australia. Methodology/Principal Findings: Twenty-seven clinical cases of M. ulcerans infection in free-ranging possums from southeastern Australia were identified retrospectively and prospectively between 1998–2011. Common ringtail possums (Pseudocheirus peregrinus), a common brushtail possum (Trichosurus vulpecula) and a mountain brushtail possum (Trichosurus cunninghami) were included in the clinically affected cohort. Most clinically apparent cases were adults with solitary or multiple ulcerative cutaneous lesions, generally confined to the face, limbs and/or tail. The disease was minor and self-limiting in the case of both Trichosurus spp. possums. In contrast, many of the common ringtail possums had cutaneous disease involving disparate anatomical sites, and in four cases there was evidence of systemic disease at post mortem examination. Where tested using real-time PCR targeted at IS2404, animals typically had significant levels of M. ulcerans DNA throughout the gut and/or faeces. A further 12 possums without cutaneous lesions were found to have PCR-positive gut contents and/or faeces (subclinical cases), and in one of these the organism was cultured from liver tissue. Comparisons were made between clinically and subclinically affected possums, and 61 PCR-negative, non-affected individuals, with regards to disease category and the categorical variables of species (common ringtail possums v others) and sex. Animals with clinical lesions were significantly more likely to be male common ringtail possums. Conclusions/Significance: There is significant disease burden in common ringtail possums (especially males) in some areas of Victoria endemic for M. ulcerans disease. The natural history of the disease generally remains unknown, however it appears that some mildly affected common brushtail and mountain brushtail possums can spontaneously overcome the infection, whereas some severely affected animals, especially common ringtail possums, may become systemically, and potentially fatally affected. Subclinical gut carriage of M. ulcerans DNA in possums is quite common and in some common brushtail and mountain brushtail possums this is transient. Further work is required to determine whether M. ulcerans infection poses a potential threat to possum populations, and whether these animals are acting as environmental reservoirs in certain geographical areas. Author Summary: Mycobacterium ulcerans causes skin disease predominantly in sub-Saharan Africa and southeastern Australia. The mode of transmission and the environmental reservoir(s) of the bacterium are unknown. Investigations have detected M. ulcerans DNA in a variety of Australian environmental samples, including the faeces of native possums. This report expands on these studies by detailing the clinical, pathological and microbiological findings in affected wild possum species in endemic areas. Twenty-seven clinically and 12 subclinically affected individuals were identified. Most clinical cases were adults with skin ulcers of the face, limbs and/or tail. The disease was mild and self-limiting in both Trichosurus spp. possums. In contrast, many of the common ringtail possums had multiple skin ulcers and in some there was evidence of internal disease. There were also significant levels of M. ulcerans DNA throughout the gut. Comparisons were made with regards to disease category, species and sex; with clinical cases more likely to be male common ringtail possums. Asymptomatic gut carriage of M. ulcerans DNA is quite common and may be transient in some individuals. Further work is needed to determine whether M. ulcerans infection poses a potential threat to possum populations, and whether these animals are acting as reservoirs in some areas. [ABSTRACT FROM AUTHOR]

Introduction: In resource-poor areas, infectious diseases may be important causes of morbidity among individuals infected with the Human T-Lymphotropic Virus type 1 (HTLV-1). We report the clinical associations of HTLV-1 infection among socially disadvantaged Indigenous adults in central Australia. Methodology and Principal Findings: HTLV-1 serological results for Indigenous adults admitted 1st January 2000 to 31st December 2010 were obtained from the Alice Springs Hospital pathology database. Infections, comorbid conditions and HTLV-1 related diseases were identified using ICD-10 AM discharge morbidity codes. Relevant pathology and imaging results were reviewed. Disease associations, admission rates and risk factors for death were compared according to HTLV-1 serostatus. HTLV-1 western blots were positive for 531 (33.3%) of 1595 Indigenous adults tested. Clinical associations of HTLV-1 infection included bronchiectasis (adjusted Risk Ratio, 1.35; 95% CI, 1.14–1.60), blood stream infections (BSI) with enteric organisms (aRR, 1.36; 95% CI, 1.05–1.77) and admission with strongyloidiasis (aRR 1.38; 95% CI, 1.16–1.64). After adjusting for covariates, HTLV-1 infection remained associated with increased numbers of BSI episodes (adjusted negative binomial regression, coefficient, 0.21; 95% CI, 0.02–0.41) and increased admission numbers with strongyloidiasis (coefficient, 0.563; 95% CI, 0.17–0.95) and respiratory conditions including asthma (coefficient, 0.99; 95% CI, 0.27–1.7), lower respiratory tract infections (coefficient, 0.19; 95% CI, 0.04–0.34) and bronchiectasis (coefficient, 0.60; 95% CI, 0.02–1.18). Two patients were admitted with adult T-cell Leukemia/Lymphoma, four with probable HTLV-1 associated myelopathy and another with infective dermatitis. Independent predictors of mortality included BSI with enteric organisms (aRR 1.78; 95% CI, 1.15–2.74) and bronchiectasis (aRR 2.07; 95% CI, 1.45–2.98). Conclusion: HTLV-1 infection contributes to morbidity among socially disadvantaged Indigenous adults in central Australia. This is largely due to an increased risk of other infections and respiratory disease. The spectrum of HTLV-1 related diseases may vary according to the social circumstances of the affected population. Author Summary: The Human T-Lymphotropic Virus type 1 (HTLV-1) infects at least 5–10 million people worldwide. In developed countries, the most frequently reported HTLV-1 associated diseases include a fatal hematological malignancy, Adult T-cell Leukemia/Lymphoma (ATLL), and the neurological disorder, HTLV-1 associated myelopathy (HAM), which arise in <10% of HTLV-1 carriers during their lifetime. However, most HTLV-1 carriers live in resource-poor areas where infectious diseases, such as strongyloidiasis, could be more important causes of morbidity. Demonstrating such an effect is difficult due to the resource constraints experienced by developing countries in which populations with a substantial burden of infectious diseases reside in areas that are highly endemic for HTLV-1. This is not the case in HTLV-1 endemic central Australia where Indigenous Australians have, for example, among the highest reported blood stream infection rates worldwide in a setting in which sophisticated medical facilities are readily available. We report that bronchiectasis, blood stream infections and admissions with lower respiratory tract infections and strongyloidiasis are associated with HTLV-1 infection. These conditions were far more common than HTLV-1 associated malignancies or neurological conditions in this socially disadvantaged Indigenous population. The spectrum of HTLV-1 related diseases therefore varies according to the social circumstances of the affected population. [ABSTRACT FROM AUTHOR]

Leptospirosis is a globally important, neglected zoonotic infection caused by spirochetes of the genus Leptospira. Since genetic transformation remains technically limited for pathogenic Leptospira, a systems biology pathogenomic approach was used to infer leptospiral virulence genes by whole genome comparison of culture-attenuated Leptospira interrogans serovar Lai with its virulent, isogenic parent. Among the 11 pathogen-specific protein-coding genes in which non-synonymous mutations were found, a putative soluble adenylate cyclase with host cell cAMP-elevating activity, and two members of a previously unstudied ∼15 member paralogous gene family of unknown function were identified. This gene family was also uniquely found in the alpha-proteobacteria Bartonella bacilliformis and Bartonella australis that are geographically restricted to the Andes and Australia, respectively. How the pathogenic Leptospira and these two Bartonella species came to share this expanded gene family remains an evolutionary mystery. In vivo expression analyses demonstrated up-regulation of 10/11 Leptospira genes identified in the attenuation screen, and profound in vivo, tissue-specific up-regulation by members of the paralogous gene family, suggesting a direct role in virulence and host-pathogen interactions. The pathogenomic experimental design here is generalizable as a functional systems biology approach to studying bacterial pathogenesis and virulence and should encourage similar experimental studies of other pathogens. Author Summary: Leptospirosis is one of the most common diseases transmitted by animals worldwide. It is important because it causes an often lethal febrile illnesses in tropical and subtropical areas associated with poor sanitation and agriculture. Leptospirosis may be epidemic, associated with natural disasters and flooding, or endemic in tropical regions. It is unknown how Leptospira cause disease and why different strains cause different severity of illness. In this study we attenuated (weakened) a highly virulent strain of L. interrogans by culturing it in vitro over several months. Comparison of the whole genome sequence before and after the attenuation process revealed a small set of genes that were mutated, and therefore associated with virulence. We discovered a putative soluble adenylate cyclase with host cell cAMP elevating activity, with implications for immune evasion and a new gene family that is upregulated in vivo during acute hamster infection. Interestingly, both Bartonella bacilliformis and Bartonella australis also have this unique gene family we describe in pathogenic Leptospira. This information aids in our understanding of Leptospira evolution and pathogenesis. [ABSTRACT FROM AUTHOR]

Background: HTLV-1 infection is endemic among people of Melanesian descent in Papua New Guinea, the Solomon Islands and Vanuatu. Molecular studies reveal that these Melanesian strains belong to the highly divergent HTLV-1c subtype. In Australia, HTLV-1 is also endemic among the Indigenous people of central Australia; however, the molecular epidemiology of HTLV-1 infection in this population remains poorly documented. Findings: Studying a series of 23 HTLV-1 strains from Indigenous residents of central Australia, we analyzed coding (gag, pol, env, tax) and non-coding (LTR) genomic proviral regions. Four complete HTLV-1 proviral sequences were also characterized. Phylogenetic analyses implemented with both Neighbor-Joining and Maximum Likelihood methods revealed that all proviral strains belong to the HTLV-1c subtype with a high genetic diversity, which varied with the geographic origin of the infected individuals. Two distinct Australians clades were found, the first including strains derived from most patients whose origins are in the North, and the second comprising a majority of those from the South of central Australia. Time divergence estimation suggests that the speciation of these two Australian clades probably occurred 9,120 years ago (38,000–4,500). Conclusions: The HTLV-1c subtype is endemic to central Australia where the Indigenous population is infected with diverse subtype c variants. At least two Australian clades exist, which cluster according to the geographic origin of the human hosts. These molecular variants are probably of very ancient origin. Further studies could provide new insights into the evolution and modes of dissemination of these retrovirus variants and the associated ancient migration events through which early human settlement of Australia and Melanesia was achieved. Author Summary: The Human T-lymphotropic virus type 1 (HTLV-1) infects at least 5–10 million persons worldwide. In Oceania, previous studies have shown that HTLV-1 is present in a few ancient populations from remote areas of Papua New Guinea, the Solomon Islands, the Vanuatu archipelago and central Australia. The latter comprise one of the most socio-economically disadvantaged groups within any developed country. Characterization of the few available HTLV-1 viruses from Oceania indicates that these belong to a specific HTLV-1 genotype, the Australo-Melanesian c-subtype. In this study, we provide details for 23 HTLV-1 viruses derived from the Indigenous population of central Australia, a vast remote area of 1,000,000 km2. We reveal considerable genetic diversity of HTLV-1c subtype viruses and the existence of two HTLV-1c clades within which a high degree of genetic diversity was also apparent. These newly described HTLV-1c clades clustered according to the geographic origin of their human hosts. Indigenous Australians from the North of central Australia harbor HTLV-1c subtype viruses that are distinct from those of individuals from regions to the South. These data suggest that HTLV-1 was probably introduced to Australia during ancient migration events and was then confined to isolated Indigenous communities in central Australia. [ABSTRACT FROM AUTHOR]