The epidemiology and outcomes of central nervous system infections in Far North Queensland, tropical Australia; 2000-2019

Background: The epidemiology of central nervous system (CNS) infections in tropical Australia is incompletely defined. Methods: A retrospective study of all individuals in Far North Queensland, tropical Australia, who were diagnosed with a CNS infection between January 1, 2000, and December 31, 2019. The microbiological aetiology of the infection was correlated with patients' demographic characteristics and their clinical course. Results: There were 725 cases of CNS infection during the study period, meningitis (77.4%) was the most common, followed by brain abscess (11.6%), encephalitis (9.9%) and spinal infection (1.1%). Infants (24.3%, p<0.0001) and Aboriginal and Torres Strait Islander Australians (175/666 local residents, 26.3%, p<0.0001) were over-represented in the cohort. A pathogen was identified in 513 cases (70.8%); this was viral in 299 (41.2%), bacterial in 175 (24.1%) and fungal in 35 (4.8%). Cryptococcal meningitis (24 cases) was diagnosed as frequently as pneumococcal meningitis (24 cases). There were only 2 CNS infections with a S. pneumoniae serotype in the 13-valent pneumococcal vaccine after its addition to the National Immunisation schedule in 2011. Tropical pathogens-including Cryptococcus species (9/84, 11%), Mycobacterium tuberculosis (7/84, 8%) and Burkholderia pseudomallei (5/ 84, 6%)-were among the most common causes of brain abscess. However, arboviral CNS infections were rare, with only one locally acquired case-a dengue infection in 2009-diagnosed in the entire study period. Intensive Care Unit admission was necessary in 14.3%; the overall case fatality rate was 4.4%. Conclusion: Tropical pathogens cause CNS infections as commonly as traditional bacterial pathogens in this region of tropical Australia. However, despite being highlighted in the national consensus guidelines, arboviruses were identified very rarely. Prompt access to sophisticated diagnostic and supportive care in Australia's well-resourced public health system is likely to have contributed to the cohort's low case-fatality rate

A complex increase in hepatitis C virus in a correctional facility: bumps in the road

Objective: The prevalence of hepatitis C virus (HCV) in correctional facilities in Australia among people who inject drugs is 60%, with disproportionate effects observed in Aboriginal and Torres Strait Islander people. Following the micro-elimination of HCV in a Queensland correctional facility (QCF), newly acquired cases began to increase in mid-2019. Here we discuss the public health response to increasing HCV in a QCF. Methods: Enhanced surveillance was performed to obtain contextual outbreak data on risk factors including injecting drug use, sharing of personal hygiene equipment and do-it-yourself-tattooing. Results: In the sixteen months, there were 250 notifications of new and re-infected HCV infections in prisoners in the QCF. Qualitative data revealed the leading factor in transmission to be injecting drug use. Conclusions: Drivers for increased HCV transmission in correctional facilities include boredom, waiting lists for opioid substitution programs, changes in injecting behaviours and sharing of injecting paraphernalia. Point-of-care testing combined with education and the development of a needle and syringe program may be promising ways forward for managing HCV in correctional facilities. Implications for public health: Correctional facilities are key locations to target sexually transmitted infection (STI) and blood-borne virus (BBV) testing and treatment as well as health promotion to improve the health of inmates and the communities they return to

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

Was infectious syphilis being misclassified in remote Australian outbreaks? Evidence that informed modification of the national case definition

Objective: To assess the ability of the national case definition to identify infectious syphilis during an outbreak affecting predominantly Aboriginal and Torres Strait Islander people in a remote Australian region. Methods: A retrospective case series study of all non-congenital syphilis cases in the region notified between 1 January 2009 and 31 December 2012 was performed. The national infectious syphilis case definition was compared with an expanded case definition derived from experienced clinician assessment and the definition proposed in the Interim Guidelines for the Public Health Management of Syphilis Outbreaks in Remote Populations in Australia from the Communicable Diseases Network Australia (CDNA). Results: Two hundred and forty syphilis cases were notified, of which 44 (18.3%) were symptomatic. The national case definition classified 106 (44.2%) cases as infectious, compared with 182 (75.8%) using the clinician-derived expanded case definition and 165 (68.8%) by the interim guidelines case definition. Seven confirmed and 6 probable cases were diagnosed as a result of contact tracing of probable infectious cases identified using the expanded case definition. Conclusions and implications: The national case definition for infectious syphilis applied in this remote Australian outbreak underestimated infectious cases when compared with experienced clinicians' evaluation by up to 76 cases (42%) and was inadequate to monitor the magnitude of a syphilis outbreak in such a setting. This may compromise surveillance and resource allocation decisions, and could reduce the capacity to interrupt transmission and contain an outbreak. A revised national case definition, informed by this analysis, was released by CDNA in July 2015

Was infectious syphilis being misclassified in remote Australian outbreaks? Evidence that informed modification of the national case definition

Objective: To assess the ability of the national case definition to identify infectious syphilis during an outbreak affecting predominantly Aboriginal and Torres Strait Islander people in a remote Australian region. Methods: A retrospective case series study of all non-congenital syphilis cases in the region notified between 1 January 2009 and 31 December 2012 was performed. The national infectious syphilis case definition was compared with an expanded case definition derived from experienced clinician assessment and the definition proposed in the Interim Guidelines for the Public Health Management of Syphilis Outbreaks in Remote Populations in Australia from the Communicable Diseases Network Australia (CDNA). Results: Two hundred and forty syphilis cases were notified, of which 44 (18.3%) were symptomatic. The national case definition classified 106 (44.2%) cases as infectious, compared with 182 (75.8%) using the clinician-derived expanded case definition and 165 (68.8%) by the interim guidelines case definition. Seven confirmed and 6 probable cases were diagnosed as a result of contact tracing of probable infectious cases identified using the expanded case definition. Conclusions and implications: The national case definition for infectious syphilis applied in this remote Australian outbreak underestimated infectious cases when compared with experienced clinicians' evaluation by up to 76 cases (42%) and was inadequate to monitor the magnitude of a syphilis outbreak in such a setting. This may compromise surveillance and resource allocation decisions, and could reduce the capacity to interrupt transmission and contain an outbreak. A revised national case definition, informed by this analysis, was released by CDNA in July 2015

Chronic hepatitis B: care delivery and patient knowledge in the Torres Strait region of Australia

BACKGROUND: Chronic hepatitis B (CHB) disproportionately affects Indigenous Australians. This article reports the findings of two studies in the Torres Strait and Northern Peninsula area (T&NPA) of Queensland in Australia. The aim of the first study was to assess CHB care delivery, the second assessed CHB patient knowledge about the condition.\ud \ud METHODS: A pathology database search (1997-2009) identified a cohort of potential CHB patients in T&NPA. A file audit assessed care delivery for a random sample of 83 CHB patients. A survey assessed knowledge of 42 CHB patients.\ud \ud RESULTS: A total of 365 hepatitis B positive patients were identified. There are gaps in patient review, monitoring, follow up and specialist referral. Patients had limited knowledge about CHB and measures to reduce its health impact.\ud \ud DISCUSSION: Chronic hepatitis B affects a substantial number of Indigenous adults in the T&NPA. There is limited adherence to clinical guidelines. Improved uptake of clinical guidelines adapted for remote areas, incorporation of CHB into systematic chronic disease care, and culturally appropriate patient education resources and programs are needed

Fecal Microbiota Composition Drives Immune Activation in HIV-infected Individuals

The inflammatory properties of the enteric microbiota of Human Immunodeficiency Virus (HIV)-infected individuals are of considerable interest because of strong evidence that bacterial translocation contributes to chronic immune activation and disease progression. Altered enteric microbiota composition occurs with HIV infection but whether altered microbiota composition or increased intestinal permeability alone drives peripheral immune activation is controversial. To comprehensively assess the inflammatory properties of HIV-associated enteric microbiota and relate these to systemic immune activation, we developed methods to purify whole fecal bacterial communities (FBCs) from stool for use in in vitro immune stimulation assays with human cells. We show that the enteric microbiota of untreated HIV-infected subjects induce significantly higher levels of activated monocytes and T cells compared to seronegative subjects. FBCs from anti-retroviral therapy (ART)-treated HIV-infected individuals induced intermediate T cell activation, indicating an only partial correction of adaptive immune cell activation capacity of the microbiome with ART. In vitro activation levels correlated with activation levels and viral load in blood and were particularly high in individuals harboring specific gram-positive opportunistic pathogens. Blockade experiments implicated Tumor Necrosis Factor (TNF)-α and Toll-Like Receptor-2 (TLR2), which recognizes peptidoglycan, as strong mediators of T cell activation; This may contradict a previous focus on lipopolysaccharide as a primary mediator of chronic immune activation. These data support that increased inflammatory properties of the enteric microbiota and not increased permeability alone drives chronic inflammation in HIV. Keywords: Microbiome, HIV, Chronic inflammation, Immune activation, Fecal bacteria, TLR

Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability

Background Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease, however, its role in inflammation-induced hypercoagulability is poorly understood. Objective/Methods Using novel myeloid cell-based global haemostasis assays and murine models of immunometabolic disease, we evaluated the role of inflammation-associated metabolic reprogramming in regulating blood coagulation. Results Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity via reduced plasminogen activator inhibitor 1 (PAI-1)-activity. Macrophage polarisation or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and APC generation compared to macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice. Conclusion Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thrombo-inflammatory disease.</p

Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.status: publishe