Epidemiology of foodborne and emerging infectious diseases in Australia, 2014 to 2015

My placement was with the Zoonoses, Foodborne and Emerging Infectious Diseases section in the Office of Health Protection at the Australian Government Department of Health during 2014-2015. I focused on the following five projects. I described the epidemiology of bacterial toxin mediated foodborne outbreaks in Australia and identified risk factors and risk groups, from an analysis of outbreak data recorded from 2001 to 2013. The main risk factor for bacterial toxin mediated foodborne outbreaks is temperature abuse (storage between 4C and 60 C) of solid masses of foods, such as lasagna. Residents of aged care facilities were the group at highest risk of illness and death from bacterial toxin mediated foodborne outbreaks. Few outbreaks were identified with food prepared at home. As part of the national response to the large outbreak of Ebola virus disease (EVD) in West Africa (2014-2015), a national surveillance system was established to enable reporting and to provide information to jurisdictions to assist monitoring of travellers at risk of contracting EVD. I conducted an evaluation of this system. The system was considered useful and achieved its aims; however a coordinated central, online database would improve reporting and ease of use. Culture independent diagnostic testing (CIDT) for bacterial causes of gastroenteritis is becoming commonly used in pathology laboratories in Australia. These tests are rapid, cheap and require less technical expertise than traditional culture based laboratory tests. However, these tests do not provide the subtyping information required for public health surveillance, including outbreak detection. For the time being, laboratories are continuing culture in addition to CIDT. My project documents this transition in Queensland. In May 2014, three cases of bacteraemia caused by Ralstonia species were diagnosed in South Australia. The only common exposure was propofol, a sedative. An investigation into the cause of this cluster of cases was led by the Therapeutic Goods Administration (TGA) as the agency responsible for the regulation of propofol. Additional cases were identified from Queensland (four cases), and Victoria (one case). I was part of the epidemiology team assisting and advising the TGA. The investigation incorporated evidence from the case series, molecular analysis of isolates (including whole genome sequencing), assessment of causal association and expert consultation through the Delphi method. The cases of Ralstonia bacteraemia were determined to be associated with at least two separate exposures. Cases in Queensland were linked to contaminated bottled water, while cases in South Australia and Victoria were associated with propofol. The mechanism of contamination of the propofol was unable to be determined. During a multi-jurisdictional investigation into an outbreak of hepatitis A associated with consumption of frozen mixed berries in 2015, a national case control study was conducted. I assisted OzFoodNet Queensland with interviewing controls and conducted a sub-analysis of cases and controls from Queensland. Frozen mixed berries were the only food exposure with a statistically significant association with illness, supporting the implication of frozen mixed berries as the source of the outbreak, as indicated by traceback and microbiological evidence

Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition

ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure. Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs. Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine

Molecular characterization of adipose tissue in the African elephant (Loxodonta africana)

Adipose tissue (AT) is a dynamic and flexible organ with regulatory roles in physiological functions including metabolism, reproduction and inflammation; secreted adipokines, including leptin, and fatty acids facilitate many of these roles. The African elephant (Loxodonta africana) is experiencing serious challenges to optimal reproduction in captivity. The physiological and molecular basis of this impaired fertility remains unknown. AT production of leptin is a crucial molecular link between nutritional status, adiposity and fertility in many species. We propose that leptin has a similar function in the African elephant. African elephant visceral and subcutaneous adipose tissue (AT) was obtained from both sexes and a range of ages including females with known pregnancy status. RNA was extracted and histological sections created and analyzed by microarray, PCR and immunohistochemistry respectively. Gas-chromatography was used to determine the fatty acid composition of AT. Microarray expression profiling was used to compare gene expression profiles of AT from pre-pubertal versus reproductively competent adult African elephants. This study demonstrates, for the first time, leptin mRNA and protein expression in African elephant AT. The derived protein sequence of the elephant leptin protein was exploited to determine its relationship within the class I helical cytokine superfamily, which indicates that elephant leptin is most closely related to the leptin orthologs of Oryctolagus cuniculus (European rabbit), Lepus oiostolus (woolly hare), and members of the Ochotonidae (Pika). Immunohistological analysis identified considerable leptin staining within the cytoplasm of adipocytes. Significant differences in fatty acid profiles between pregnant and non-pregnant animals were revealed, most notably a reduction in both linoleic and α linoleic acid in pregnant animals. This report forms the basis for future studies to address the effect of nutrient composition and body condition on reproduction in captive and wild elephants

Genetic Stasis of Dominant West Nile Virus Genotype, Houston, Texas

The accumulation and fixation of mutations in West Nile virus (WNV) led to the emergence of a dominant genotype throughout North America. Subsequent analysis of 44 isolates, including 19 new sequences, from Houston, Texas, suggests that WNV has reached relative genetic stasis at the local level in recent years

Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration

Background & Aims: Mouse models of lineage tracing have helped to describe the important subpopulations of hepatocytes responsible for liver regeneration. However, conflicting results have been obtained from different models. Herein, we aimed to reconcile these conflicting reports by repeating a key lineage-tracing study from pericentral hepatocytes and characterising this Axin2CreERT2 model in detail. Methods: We performed detailed characterisation of the labelled population in the Axin2CreERT2 model. We lineage traced this cell population, quantifying the labelled population over 1 year and performed in-depth phenotypic comparisons, including transcriptomics, metabolomics and analysis of proteins through immunohistochemistry, of Axin2CreERT2 mice to WT counterparts. Results: We found that after careful definition of a baseline population, there are marked differences in labelling between male and female mice. Upon induced lineage tracing there was no expansion of the labelled hepatocyte population in Axin2CreERT2 mice. We found substantial evidence of disrupted homeostasis in Axin2CreERT2 mice. Offspring are born with sub-Mendelian ratios and adult mice have perturbations of hepatic Wnt/β-catenin signalling and related metabolomic disturbance. Conclusions: We find no evidence of predominant expansion of the pericentral hepatocyte population during liver homeostatic regeneration. Our data highlight the importance of detailed preclinical model characterisation and the pitfalls which may occur when comparing across sexes and backgrounds of mice and the effects of genetic insertion into native loci. Impact and implications: Understanding the source of cells which regenerate the liver is crucial to harness their potential to regrow injured livers. Herein, we show that cells which were previously thought to repopulate the liver play only a limited role in physiological regeneration. Our data helps to reconcile differing conclusions drawn from results from a number of prior studies and highlights methodological challenges which are relevant to preclinical models more generally

Heterogeneity in outcomes of treated HIV-positive patients in Europe and North America: relation with patient and cohort characteristics

Background HIV cohort collaborations, which pool data from diverse patient cohorts, have provided key insights into outcomes of antiretroviral therapy (ART). However, the extent of, and reasons for, between-cohort heterogeneity in rates of AIDS and mortality are unclear. Methods We obtained data on adult HIV-positive patients who started ART from 1998 without a previous AIDS diagnosis from 17 cohorts in North America and Europe. Patients were followed up from 1 month to 2 years after starting ART. We examined between-cohort heterogeneity in crude and adjusted (age, sex, HIV transmission risk, year, CD4 count and HIV-1 RNA at start of ART) rates of AIDS and mortality using random-effects meta-analysis and meta-regression. Results During 61 520 person-years, 754/38 706 (1.9%) patients died and 1890 (4.9%) progressed to AIDS. Between-cohort variance in mortality rates was reduced from 0.84 to 0.24 (0.73 to 0.28 for AIDS rates) after adjustment for patient characteristics. Adjusted mortality rates were inversely associated with cohorts' estimated completeness of death ascertainment [excellent: 96-100%, good: 90-95%, average: 75-89%; mortality rate ratio 0.66 (95% confidence interval 0.46-0.94) per category]. Mortality rate ratios comparing Europe with North America were 0.42 (0.31-0.57) before and 0.47 (0.30-0.73) after adjusting for completeness of ascertainment. Conclusions Heterogeneity between settings in outcomes of HIV treatment has implications for collaborative analyses, policy and clinical care. Estimated mortality rates may require adjustment for completeness of ascertainment. Higher mortality rate in North American, compared with European, cohorts was not fully explained by completeness of ascertainment and may be because of the inclusion of more socially marginalized patients with higher mortality ris

Treatment Burden and Chronic Illness: Who is at Most Risk?

Background: There is a need to ascertain the type and level of treatment burden experienced by people with co-morbidities. This is important to identify the characteristics of participants who are at most risk of treatment burden.  Objective: The aim of this study is to identify the characteristics of participants who are at most risk of treatment burden.  Methods: This cross-sectional study was part of a larger project and recruitment was conducted across four Australian regions: rural, semi-rural and metropolitan. Participants were asked about their treatment burden using an adapted version of a measure, which included the following five dimensions: medication, time and administrative, lifestyle change, social life and financial burden.  Results: In total, 581 participants with various chronic health conditions reported a mean global treatment burden of 56.5 out of 150 (standard deviation = 34.5). Number of chronic conditions (β = .34, p < 0.01), age, (β = −.27, p < 0.01), the presence of an unpaid carer (β = .22, p < 0.001) and the presence of diabetes mellitus and other endocrine conditions (β = .13, p < 0.01) were significant predictors of overall treatment burden. For the five dimensions of treatment burden, social, medicine and administrative burden were predicted by the same cluster of variables: number of conditions, age, presence of an unpaid carer and diabetes. However, in addition to these variables, financial dimensions were also predicted by education level, ethnicity and health insurance. Educational level also influenced lifestyle burden.  Conclusion: A substantial proportion of community-dwelling adults with chronic conditions have considerable levels of treatment burden. Specifically, health professionals should provide greater focus on managing overall treatment burden for persons who are of young age, have an endocrine condition or an unpaid carer, or a combination of these factors

Estimation of changes in the force of infection for intestinal and urogenital schistosomiasis in countries with Schistosomiasis Control Initiative-assisted programmes

The last decade has seen an expansion of national schistosomiasis control programmes in Africa based on large-scale preventative chemotherapy. In many areas this has resulted in considerable reductions in infection and morbidity levels in treated individuals. In this paper, we quantify changes in the force of infection (FOI), defined here as the per (human) host parasite establishment rate, to ascertain the impact on transmission of some of these programmes under the umbrella of the Schistosomiasis Control Initiative (SCI)

The effectiveness of interventions to change six health behaviours: a review of reviews

Background: Several World Health Organisation reports over recent years have highlighted the high incidence of chronic diseases such as diabetes, coronary heart disease and cancer. Contributory factors include unhealthy diets, alcohol and tobacco use and sedentary lifestyles. This paper reports the findings of a review of reviews of behavioural change interventions to reduce unhealthy behaviours or promote healthy behaviours. We included six different health-related behaviours in the review: healthy eating, physical exercise, smoking, alcohol misuse, sexual risk taking (in young people) and illicit drug use. We excluded reviews which focussed on pharmacological treatments or those which required intensive treatments (e. g. for drug or alcohol dependency). Methods: The Cochrane Library, Database of Abstracts of Reviews of Effectiveness (DARE) and several Ovid databases were searched for systematic reviews of interventions for the six behaviours (updated search 2008). Two reviewers applied the inclusion criteria, extracted data and assessed the quality of the reviews. The results were discussed in a narrative synthesis. Results: We included 103 reviews published between 1995 and 2008. The focus of interventions varied, but those targeting specific individuals were generally designed to change an existing behaviour (e. g. cigarette smoking, alcohol misuse), whilst those aimed at the general population or groups such as school children were designed to promote positive behaviours (e. g. healthy eating). Almost 50% (n = 48) of the reviews focussed on smoking (either prevention or cessation). Interventions that were most effective across a range of health behaviours included physician advice or individual counselling, and workplace- and school-based activities. Mass media campaigns and legislative interventions also showed small to moderate effects in changing health behaviours. Generally, the evidence related to short-term effects rather than sustained/longer-term impact and there was a relative lack of evidence on how best to address inequalities. Conclusions: Despite limitations of the review of reviews approach, it is encouraging that there are interventions that are effective in achieving behavioural change. Further emphasis in both primary studies and secondary analysis (e.g. systematic reviews) should be placed on assessing the differential effectiveness of interventions across different population subgroups to ensure that health inequalities are addressed.</p

Understanding the uptake of diagnostics for sustainable gastrointestinal nematode control by European dairy cattle farmers: a multi-country cross-sectional study

To mitigate emerging anthelmintic resistance (AR) in cattle, sustainable gastrointestinal nematode control strategies should be adopted. A multi-centre study was set up to understand the factors affecting European dairy cattle farmers’ adoption of diagnostics and to gauge for differences between regions. The data were collected through a multi-lingual survey by participating countries of the European Co-operation in Science and Technology (COST) action COMbatting Anthelmintic Resistance in ruminants (COMBAR). Four countries provided sufficient data to be included in the data analysis: Norway, Italy, Germany and Austria. Three models were estimated and validated through structural equation modelling. Norway, along with Germany and Austria (pooled dataset) showed similar trends that align with previous studies. AR risk perception had no influence on the adoption intention of diagnostics, a positive influence was found for attitude towards diagnostics and subjective norms (i.e., perceived opinion of others), and a negative influence of attitudes towards anthelminthics. Additionally, routine (i.e., perception of the current treatment) had an indirect effect on adoption intention through attitudes. Italy’s data deviated from these findings, presenting a positive effect of the perceived severity of AR, and perceived behavioural control (i.e., perceived ability to perform a specific behaviour) on adoption intention of diagnostics. Finally, Norway’s data set allowed for inclusion of a measurement of current behaviour in the model, identifying a direct positive effect of the perceived actual behaviour of other farmers on their own behaviour