Explore the vast range of titles available.

Background The global emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has seen the dominance of specific clones in different regions around the world with the PVL-positive ST93-IV as the predominant CA-MRSA clone in Australia. In this study we applied a genome-wide association study (GWAS) approach on a collection of Australian ST93-IV MRSA genomes to screen for genetic traits that might have assisted the ongoing transmission of ST93-IV in Australia. We also compared the genomes of ST93-IV bacteraemia and non-bacteraemia isolates to search for potential virulence genes associated with bacteraemia. Results Based on single nucleotide polymorphism phylogenetics we revealed two distinct ST93-IV clades circulating concurrently in Australia. One of the clades contained isolates primarily isolated in the northern regions of Australia whilst isolates in the second clade were distributed across the country. Analyses of the ST93-IV genome plasticity over a 15-year period (2002–2017) revealed an observed gain in accessory genes amongst the clone’s population. GWAS analysis on the bacteraemia isolates identified two gene candidates that have previously been associated to this kind of infection. Conclusions Although this hypothesis was not tested here, it is possible that the emergence of a ST93-IV clade containing additional virulence genes might be related to the high prevalence of ST93-IV infections amongst the indigenous population living in the northern regions of Australia. More importantly, our data also demonstrated that GWAS can reveal candidate genes for further investigations on the pathogenesis and evolution of MRSA strains within a same lineage.

Over the last three decades, hospital adapted clonal complex (CC) 17 strains of Enterococcus faecium have acquired and exchanged antimicrobial resistance genes leading to the widespread resistance to clinically important antimicrobials globally. In Australia, a high prevalence of vancomycin resistance has been reported in E. faecium in the last decade. In this study, we determined the phylogenetic relationship and genetic characteristics of E. faecium collected from hospitalized patients with blood stream infections throughout Australia from 2015 to 2017 using high throughput molecular techniques. Using single nucleotide polymorphism based phylogenetic inference, three distinct clusters of isolates were observed with additional sub-clustering. One cluster harboured mostly non-CC17 isolates while two clusters were dominant for the vanA and vanB operons. The gradual increase in dominance of the respective van operon was observed in both the vanA and vanB dominant clusters suggesting a strain-van operon affinity. The high prevalence of the van operon within isolates of a particular sub-cluster was linked to an increased number of isolates and 30-day all-cause mortality. Different dominant sub-clusters were observed in each region of Australia. Findings from this study can be used to put future surveillance data into a broader perspective including the detection of novel E. faecium strains in Australia as well as the dissemination and evolution of each strain.

Antimicrobials are an integral component of healthcare delivery. When resistance to an antimicrobial emerges, it has a significant impact on an individual’s treatment and the community more broadly. In Australia, to monitor antimicrobial resistance in human health, the Australian Group on Antimicrobial Resistance (AGAR) performs three ongoing blood-based antimicrobial surveillance programs: the Australian Staphylococcus aureus Surveillance Outcome Program (ASSOP); the Australian Enterococcal Surveillance Outcome Program (AESOP); and the Gram-negative Surveillance Outcome Program (GnSOP). All data are available on the AGAR website and are included in the Australian Government Department of Health and Aged Care’s Antimicrobial Use and Resistance in Australia Surveillance System.

Background Genetic variants at the vitamin D receptor (VDR) locus are associated with asthma and atopy. We hypothesized that polymorphisms in other genes of the vitamin D pathway are associated with asthma or atopy. Methods Eleven candidate genes were chosen for this study, five of which code for proteins in the vitamin D metabolism pathway ( CYP27A1 , CYP27B1 , CYP2R1 , CYP24A1 , GC ) and six that are known to be transcriptionally regulated by vitamin D ( IL10 , IL1RL1 , CD28 , CD86 , IL8 , SKIIP ). For each gene, we selected a maximally informative set of common SNPs (tagSNPs) using the European-derived (CEU) HapMap dataset. A total of 87 SNPs were genotyped in a French-Canadian family sample ascertained through asthmatic probands (388 nuclear families, 1064 individuals) and evaluated using the Family Based Association Test (FBAT) program. We then sought to replicate the positive findings in four independent samples: two from Western Canada, one from Australia and one from the USA (CAMP). Results A number of SNPs in the IL10 , CYP24A1 , CYP2R1 , IL1RL1 and CD86 genes were modestly associated with asthma and atopy (p < 0.05). Two-gene models testing for both main effects and the interaction were then performed using conditional logistic regression. Two-gene models implicating functional variants in the IL10 and VDR genes as well as in the IL10 and IL1RL1 genes were associated with asthma (p < 0.0002). In the replicate samples, SNPs in the IL10 and CYP24A1 genes were again modestly associated with asthma and atopy (p < 0.05). However, the SNPs or the orientation of the risk alleles were different between populations. A two-gene model involving IL10 and VDR was replicated in CAMP, but not in the other populations. Conclusion A number of genes involved in the vitamin D pathway demonstrate modest levels of association with asthma and atopy. Multilocus models testing genes in the same pathway are potentially more effective to evaluate the risk of asthma, but the effects are not uniform across populations.

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV(1) and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy \"mid-life\" volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy \"mid-life\" volunteers (p<.001). Compared to individuals in the 4(th) quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.

The past decade has seen an increase in the prevalence of sequence type (ST) 45 methicillin-resistant Staphylococcus aureus (MRSA), yet the underlying drivers for its emergence and spread remain unclear. To better understand the worldwide dissemination of ST45 S. aureus , we performed phylogenetic analyses of Australian isolates, supplemented with a global population of ST45 S. aureus genomes. Our analyses revealed a distinct lineage of multidrug-resistant ST45 MRSA harbouring qacA , predominantly found in Australia and Singapore. Bayesian inference predicted that the acquisition of qacA occurred in the late 1990s. qacA was integrated into a structurally variable region of the chromosome containing Tn 552 (carrying blaZ ) and Tn 4001 (carrying aac(6 ’ )-aph(2 ” ) ) transposable elements. Using mutagenesis and in vitro assays, we provide phenotypic evidence that qacA confers tolerance to chlorhexidine. These findings collectively suggest both antimicrobial resistance and the carriage of qacA may play a role in the successful establishment of ST45 MRSA. A study underscores the emergence of a qacA -harbouring multidrug-resistant sequence type 45 methicillin-resistant  Staphylococcus aureus lineage, highlighting the potential impact of biocide tolerance on its recent clonal spread in Australia and Asia.

Abstract Background and objectives There are few Australian data regarding the burden of hospital-onset bloodstream infections (HO-BSIs). To quantify the impact of antimicrobial-susceptible and -resistant HO-BSIs on patient outcomes by augmenting laboratory-based surveillance data. Methods We performed a retrospective cohort study at a tertiary referral hospital in Melbourne, Australia, from 2015 to 2020. We linked administrative data with bloodstream infection surveillance data from the Australian Group on Antimicrobial Resistance. We performed cause-specific Cox proportional hazards regression to quantify the impact of HO-BSI on inpatient mortality and discharge alive, with separate models for Enterobacterales, Staphylococcus aureus, Enterococcus species and the non-fermenting Gram-negative bacilli (NFGNB), Pseudomonas aeruginosa and Acinetobacter species, compared to admissions without HO-BSI. Excess length of stay (LOS) was estimated using multistate models. Results The cohort of 278 984 admissions included 814 (0.3%) HO-BSIs. Enterobacterales were the most frequent pathogens, followed by enterococci, S. aureus and NFGNB (incidence 3.62, 2.34, 1.11 and 0.80 events per 10 000 patient-days, respectively). Both antimicrobial-resistant and -susceptible HO-BSI increased risk of death and LOS compared with admissions without HO-BSI. Antimicrobial-resistant and -susceptible HO-BSIs, respectively, increased LOS by 5.7 days (95% CI: 4.9–6.5) and 4.1 days (95% CI: 3.8–4.5) for Enterobacterales, 4.9 days (95% CI: 4.5–5.4) and 3.1 days (95% CI: 2.6–3.6) for enterococci, and 6.3 days (95% CI: 5.3–7.3) and 9.8 days (95% CI: 9.1–10.5) for S. aureus. Conclusions Antimicrobial-susceptible and -resistant HO-BSIs have a substantial impact on patient outcomes. We demonstrated the feasibility of leveraging a national laboratory-based surveillance system to quantify the impact of HO-BSI.

Background: Defined by the emergence of antibiotic resistant strains, Staphylococcus aureus is a priority bacterial species with high antibiotic resistance. However, a rise in the prevalence of penicillin-susceptible S. aureus (PSSA) bloodstream infections has recently been observed worldwide, including in Australia, where the proportion of methicillin-susceptible S. aureus causing bacteremia identified phenotypically as penicillin-susceptible has increased by over 35%, from 17.5% in 2013 to 23.7% in 2020. Objectives: To determine the population structure of PSSA causing community- and hospital-onset bacteremia in Australia and to evaluate routine phenotypic antimicrobial susceptibility methods to reliably confirm penicillin resistance on blaZ-positive S. aureus initially classified as penicillin-susceptible by the Vitek® 2 automated microbiology system. Results: Whole genome sequencing on 470 PSSA collected in the 2020 Australian Group on Antimicrobial Resistance Australian Staphylococcus aureus Sepsis Outcome Programme identified 84 multilocus sequence types (STs), of which 79 (463 isolates) were grouped into 22 clonal complexes (CCs). The dominant CCs included CC5 (31.9%), CC97 (10.2%), CC45 (10.0%), CC15 (8.7%), and CC188 (4.9%). Many of the CCs had multiple STs and spa types and, based on the immune evasion cluster type, isolates within a CC could be classified into different strains harboring a range of virulence and resistance genes. Phylogenetic analyses of the isolates showed most CCs were represented by one clade. The blaZ gene was identified in 45 (9.6%) PSSA. Although multiclonal, approximately 50% of blaZ-positive PSSA were from CC15 and were found to be genetically distant from the blaZ-negative CC15 PSSA. The broth microdilution, Etest® and cefinase, performed poorly; however, when the appearance of the zone edge was considered; as per the EUCAST and CLSI criteria, disc diffusion detected 100% of blaZ-positive PSSA. Conclusions: In Australia, PSSA bacteremia is not caused by the expansion of a single clone. Approximately 10% of S. aureus classified as penicillin-susceptible by the Vitek® 2 harbored blaZ. Consequently, we recommend that confirmation of Vitek® 2 PSSA be performed using an alternative method, such as disc diffusion with careful interpretation of the zone edge.

Non-Hodgkin lymphomas are a heterogeneous group of solid tumours that constitute the 5(th) highest cause of cancer mortality in the United States and Canada. Poor control of cell death in lymphocytes can lead to autoimmune disease or cancer, making genes involved in programmed cell death of lymphocytes logical candidate genes for lymphoma susceptibility. We tested for genetic association with NHL and NHL subtypes, of SNPs in lymphocyte cell death genes using an established population-based study. 17 candidate genes were chosen based on biological function, with 123 SNPs tested. These included tagSNPs from HapMap and novel SNPs discovered by re-sequencing 47 cases in genes for which SNP representation was judged to be low. The main analysis, which estimated odds ratios by fitting data to an additive logistic regression model, used European ancestry samples that passed quality control measures (569 cases and 547 controls). A two-tiered approach for multiple testing correction was used: correction for number of tests within each gene by permutation-based methodology, followed by correction for the number of genes tested using the false discovery rate. Variant rs928883, near miR-155, showed an association (OR per A-allele: 2.80 [95% CI: 1.63-4.82]; p(F) = 0.027) with marginal zone lymphoma that is significant after correction for multiple testing. This is the first reported association between a germline polymorphism at a miRNA locus and lymphoma.

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of solid tumours of lymphoid cell origin. Three important aspects of lymphocyte development include immunity and inflammation, DNA repair, and programmed cell death. We have used a previously established case-control study of NHL to ask whether genetic variation in genes involved in these three important processes influences risk of this cancer. 118 genes in these three categories were tagged with single nucleotide polymorphisms (SNPs), which were tested for association with NHL and its subtypes. The main analysis used logistic regression (additive model) to estimate odds ratios in European-ancestry cases and controls. 599 SNPs and 1116 samples (569 cases and 547 controls) passed quality control measures and were included in analyses. Following multiple-testing correction, one SNP in MSH3, a mismatch repair gene, showed an association with diffuse large B-cell lymphoma (OR: 1.91; 95% CI: 1.41-2.59; uncorrected p = 0.00003; corrected p = 0.010). This association was not replicated in an independent European-ancestry sample set of 251 diffuse large B-cell lymphoma cases and 737 controls, indicating this result was likely a false positive. It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings.