Review of cannabis use among Aboriginal and Torres Strait Islander people

The health effects of cannabis use may not always be seen as a high priority for Aboriginal and Torres Strait Islander communities. However, the impact of cannabis use on physical and mental health can have significant consequences. It is known that the use of high potency cannabis has increased over the last two decades, with a corresponding increased risk to health. In particular, young people are at increased risk of experiencing harms to mental health. Physical harms to health include effects on the respiratory system, cardiovascular system, an increased risk of cancer, and in-utero effects from maternal use. The review notes concern that in countries where there has been commercialisation of cannabis use, there has been an increase in the rate and use of high potency products. While generalising findings about cannabis use for Aboriginal and Torres Strait Islander people is problematic due to limited data, high rates of cannabis use have been found in some remote communities. The review highlights the protective factors that reduce harms from cannabis use and suggests future directions for a collaborative approach to addressing cannabis related harms in communities. This review is part of a suite of knowledge exchange products that includes a summary, a video, and a fact sheet

Seroepidemiology of Streptococcus gallolyticus subspecies gallolyticus and Fusobacterium nucleatum with colorectal cancer

Colorectal cancer (CRC) is among the most frequently diagnosed cancers worldwide. Recent research focused on the association of CRC with an altered microbiome. More specifically, two bacteria, Fusobacterium nucleatum (F. nucleatum) and Streptococcus gallolyticus subspecies gallolyticus (S. gallolyticus) were individually brought in context with CRC. F. nucleatum is predominantly present in oral plaques and was found to be abundant in stool and tumor tissue of CRC patients. S. gallolyticus is a rare commensal in the human intestine and inducer of infective endocarditis that is associated with presence of CRC. The aim of this thesis was to explore potential serological associations of F. nucleatum and S. gallolyticus with CRC using multiplex serology, a high-throughput technology that allows the analysis of large seroepidemiological studies. Multiplex serology was to be developed for F. nucleatum and S. gallolyticus and applied in a retrospective case-control study to analyze potential serological associations with CRC. Prospective studies were to be analyzed to give information on temporality of the association: if serological associations are present prior to diagnosis, these antibodies might serve as early marker for risk of developing CRC. Eleven proteins for each, F. nucleatum and S. gallolyticus, were selected, recombinantly expressed and applied in multiplex serology. Serological validation of the assays was possible only to a limited extent due to a lack of a gold standard assay for comparison. Cut-offs for antibody-positivity to the individual proteins were arbitrarily defined to allow for 10% of controls as positive. Antibody responses to F. nucleatum and S. gallolyticus were analyzed in a retrospective case-control study conducted in Germany and two independent case-control studies nested within multi-center prospective cohorts from Europe and southern United States. Positivity to any of the F. nucleatum proteins was not associated with CRC, neither retro- nor prospectively. In contrast, odds for prevalent and incident CRC in the German case-control study as well as the European prospective study were significantly 2-fold increased with positivity to two or more proteins of a S. gallolyticus 6-marker panel. However, this association was not found in the southern United States study. In conclusion, antibody responses to S. gallolyticus, but not F. nucleatum, were significantly associated with CRC prior to diagnosis and might serve as marker for CRC development. A causal relationship of S. gallolyticus with CRC cannot be inferred from the generated data, however, results of this thesis might stimulate research on the involvement of S. gallolyticus in CRC development as well as risk factors leading to S. gallolyticus colonization

‘Even though you hate everything that\u27s going on, you know they are safer at home’: The role of Aboriginal and Torres Strait Islander families in methamphetamine use harm reduction and their own support needs

Introduction: First Nations people who use methamphetamine are overrepresented in regional and remote Australia and more likely to turn to family for support. This can place strain on families. The support needs of family members of individuals using methamphetamine are poorly understood. Methods: We conducted 19 focus groups and seven interviews with mostly First Nations community, family members and service providers. In total, 147 participants across six sites participated as part of a larger study investigating First Nations perspectives of how to address methamphetamine use and associated harms. We applied a social and emotional wellbeing framework to examine support needs and role of family in mitigating methamphetamine harms. Results: Findings highlighted the importance of families in providing support to people using methamphetamine and in reducing associated harms, often without external support. The support provided encompassed practical, social, emotional, financial, access to services and maintaining cultural connection. Providing support took a toll on family and negatively impacted their own social and emotional wellbeing. Discussion and Conclusions: First Nations families play an important and under-recognised role in reducing methamphetamine-related harms and greater efforts are required to support them. Professional resources are needed to deal with impacts of methamphetamine on families; these should be pragmatic, accessible, targeted and culturally appropriate. Support for families and communities should be developed using the social and emotional wellbeing framework that recognises wellbeing and healing as intrinsically connected to holistic health, kinship, community, culture and ancestry, and socioeconomic and historical influences on peoples\u27 lives

Epstein-Barr virus and human papillomavirus serum antibodies define the viral status of nasopharyngeal carcinoma in a low endemic country

Epstein-Barr virus (EBV) causes nasopharyngeal carcinoma (NPC) in endemic regions, where almost every tumor is EBV-positive. In Western populations, NPC is rare, and human papillomavirus infection (HPV) has been suggested as another viral cause. We validated multiplex serology with molecular tumor markers, to define EBV-positive, HPV-positive, and EBV-/HPV-negative NPCs in the United Kingdom, and analyzed survival differences between those groups. Sera from NPC cases (N = 98) and age- and sex-matched controls (N = 142) from the Head and Neck 5000 clinical cohort study were analyzed. IgA and IgG serum antibodies against 13 EBV antigens were measured and compared with EBER in situ hybridization (EBER-ISH) data of 41 NPC tumors (29 EBER-ISH positive, 12 negative). IgG antibodies to EBV LF2 correctly diagnosed EBV-positive NPCs in 28 of 29 cases, while all EBER-ISH negative NPCs were seronegative to LF2 IgG (specificity = 100%, sensitivity = 97%). HPV early antigen serology was compared to HPV molecular markers (p16 expression, HPV DNA and RNA) available for 41 NPCs (13 positive, 28 negative). Serology matched molecular HPV markers in all but one case (specificity = 100%, sensitivity = 92%). EBV and HPV infections were mutually exclusive. Overall, 67% of the analyzed NPCs were defined as EBV-positive, 18% as HPV-positive and 14% as EBV/HPV-negative. There was no statistical evidence of a difference in survival between the three groups. These data provide evidence that both, EBV-positive and HPV-positive NPCs are present in a low incidence country, and that EBV and HPV serum antibodies correlate with the viral status of the tumor.</p

Heme ligation and redox chemistry in two bacterial thiosulfate dehydrogenase (TsdA) enzyme

Thiosulfate dehydrogenases (TsdA) are bidirectional bacterial di-heme enzymes that catalyze the interconversion of tetrathionate and thiosulfate at measurable rates in both directions. In contrast to our knowledge of TsdA activities, information on the redox properties in the absence of substrates is rather scant. To address this deficit, we combined magnetic circular dichroism (MCD) spectroscopy and protein film electrochemistry (PFE) in a study to resolve heme ligation and redox chemistry in two representative TsdAs. We examined the TsdAs from Campylobacter jejuni, a micro-aerobe human pathogen, and from the purple sulfur bacterium Allochromatium vinosum. In these organisms, the enzyme functions as a tetrathionate reductase and a thiosulfate oxidase respectively. The active site Heme 1 in both enzymes has His/Cys− ligation in the ferric and ferrous states and the midpoint potentials (Em) of the corresponding redox transformations are similar, −185 mV versus standard hydrogen electrode (SHE). However, fundamental differences are observed in the properties of the second, electron transferring, Heme 2. In C. jejuni TsdA Heme 2 has His/Met ligation and an Em of +172 mV. In A. vinosum TsdA, Heme 2 reduction triggers a switch from His/Lys ligation (Em, −129 mV) to His/Met (Em,+266 mV) but the rates of interconversion are such that His/Lys ligation would be retained during turnover. In summary, our findings have unambiguously assigned Em values to defined axial ligand sets in TsdAs, specified the rates of Heme 2 ligand exchange in the A. vinosum enzyme, and provided information relevant to describing their catalytic mechanism(s)

Immunostimulatory Membrane Proteins Potentiate \u3cem\u3eH. pylori-\u3c/em\u3eInduced Carcinogenesis by Enabling CagA Translocation

Infection with Helicobacter pylori is the single greatest risk factor for developing gastric adenocarcinoma. In prospective, population-based studies, seropositivity to the uncharacterized H. pylori proteins Hp0305 and Hp1564 was significantly associated with cancer risk in East Asia. However, the mechanism underlying this observation has not been elucidated. Here, we show that Hp0305 and Hp1564 act in concert with previously ascribed H. pylori virulence mechanisms to orchestrate cellular alterations that promote gastric carcinogenesis. In samples from 546 patients exhibiting premalignant gastric lesions, seropositivity to Hp0305 and Hp1564 was significantly associated with increased gastric atrophy across all stomach conditions. In vitro, depletion of Hp0305 and Hp1564 significantly reduced levels of gastric cell-associated bacteria and markedly impaired the ability of H. pylori to stimulate pro-inflammatory cytokine production. Remarkably, our studies revealed that Hp1564 is required for translocation of the oncoprotein CagA into gastric epithelial cells. Our data provide experimental insight into the molecular mechanisms governing novel H. pylori pathogenicity factors that are strongly associated with gastric disease and highlight the potential of Hp0305 and Hp1564 as robust molecular tools that can improve identification of individuals that are highly susceptible to gastric cancer. We demonstrate that Hp0305 and Hp1564 augment H. pylori-mediated inflammation and gastric cancer risk by promoting key bacteria-gastric cell interactions that facilitate delivery of oncogenic microbial cargo to target cells. Thus, therapeutically targeting microbial interactions driven by Hp0305/Hp1564 may enable focused H. pylori eradication strategies to prevent development of gastric malignancies in high-risk populations

Common infections and neuroimaging markers of dementia in three UK cohort studies

INTRODUCTION: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. METHODS: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain  = 2632; NAPOE-interaction  = 1810). RESULTS: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (β = -3.89 mL [-5.81, -1.97], Padjusted  < 0.05); these were largely attenuated in fully adjusted models (β = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed. DISCUSSION: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication

Comparison of multiplex-serology and ELISA based methods in detecting HPV16 L1 antibody responses in paired saliva and serum samples of healthy men

Human papilloma viruses (HPV) are a common cause of transient infections on mucosal surfaces, also in the oral cavity. Some infections remain persistent and can, especially with high risk HPV genotypes, lead to malignancies in the oral-oropharyngeal area. Our understanding of the natural course of oral HPV infections is limited, and the local host responses are poorly known. In this study we show that anti-HPV16L1 antibodies, the IgA response being most abundant, can be measured in saliva of asymptomatic males. HPV16L1 specific multiplex serology and commercial ELISA methods were compared and also the total salivary IgA levels measured. The total salivary IgA concentrations varied from 36 to 163 μg/ml. All the assays could detect anti-HPV16 IgA from saliva, but the correlation between assays varied from non-significant 0.22 to highly significant 0.81, p </p

Theoretical analysis of cross-validation for estimating the risk of the k-Nearest Neighbor classifier

The present work aims at deriving theoretical guaranties on the behavior of some cross-validation procedures applied to the $k$-nearest neighbors ($k$NN) rule in the context of binary classification. Here we focus on the leave-$p$-out cross-validation (L$p$O) used to assess the performance of the $k$NN classifier. Remarkably this L$p$O estimator can be efficiently computed in this context using closed-form formulas derived by \cite{CelisseMaryHuard11}. We describe a general strategy to derive moment and exponential concentration inequalities for the L$p$O estimator applied to the $k$NN classifier. Such results are obtained first by exploiting the connection between the L$p$O estimator and U-statistics, and second by making an intensive use of the generalized Efron-Stein inequality applied to the L$1$O estimator. One other important contribution is made by deriving new quantifications of the discrepancy between the L$p$O estimator and the classification error/risk of the $k$NN classifier. The optimality of these bounds is discussed by means of several lower bounds as well as simulation experiments