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Prostate cancer is characterised by significant global disparity; mortality rates in Sub-Saharan Africa are double to quadruple those in Eurasia1. Hypothesising unknown interplay between genetic and non-genetic factors, tumour genome profiling envisages contributing mutational processes2,3. Through whole-genome sequencing of treatment-naïve prostate cancer from 183 ethnically/globally distinct patients (African versus European), we generate the largest cancer genomics resource for Sub-Saharan Africa. Identifying ~2 million somatic variants, Africans carried the greatest burden. We describe a new molecular taxonomy using all mutational types and ethno-geographic identifiers, including Asian. Defined as Global Mutational Subtypes (GMS) A–D, although Africans presented within all subtypes, we found GMS-B to be ‘African-specific’ and GMS-D ‘African-predominant’, including Admixed and European Africans. Conversely, Europeans from Australia, Africa and Brazil predominated within ‘mutationally-quiet’ and ethnically/globally ‘universal’ GMS-A, while European Australians shared a higher mutational burden with Africans in GMS-C. GMS predicts clinical outcomes; reconstructing cancer timelines suggests four evolutionary trajectories with different mutation rates (GMS-A, low 0.968/year versus D, highest 1.315/year). Our data suggest both common genetic factors across extant populations and regional environmental factors contributing to carcinogenesis, analogous to gene-environment interaction defined here as a different effect of an environmental surrounding in persons with different ancestries or vice versa. We anticipate GMS acting as a proxy to intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

There is an increasing worldwide incidence of patients under 50 years of age presenting with oral squamous cell carcinoma (OSCC). The molecular mechanisms driving disease in this emerging cohort remain unclear, limiting impactful treatment options for these patients. To identify common clinically actionable targets in this cohort, we used whole genome and transcriptomic sequencing of OSCC patient samples from 26 individuals under 50 years of age. These molecular profiles were compared with those of OSCC patients over 50 years of age (n=11) available from TCGA. We show for the first time that a molecular signature comprising of EGFR amplification and increased EGFR RNA abundance is specific to the young subset of OSCC patients. Furthermore, through functional assays using patient tumor-derived cell lines, we reveal that this EGFR amplification results in increased activity of the EGFR pathway. Using a panel of clinically relevant EGFR inhibitors we determine that an EGFR-amplified patient-derived cell line is responsive to EGFR inhibition, suggesting EGFR amplification represents a valid therapeutic target in this subset of OSCC patients. In particular, we demonstrate sensitivity to the second-generation EGFR tyrosine kinase inhibitor afatinib, which offers a new and promising therapeutic avenue versus current EGFR-targeting approaches. We propose that testing for EGFR amplification could easily be integrated into current diagnostic workflows and such measures could lead to more personalized treatment approaches and improved outcomes for this younger cohort of OSCC patients.

Community transmission of the new coronavirus SARS-CoV-2 is a major public health concern that remains difficult to assess. We present a genomic survey of SARS-CoV-2 from a during the first 10 weeks of COVID-19 activity in New South Wales, Australia. Transmission events were monitored prospectively during the critical period of implementation of national control measures. SARS-CoV-2 genomes were sequenced from 209 patients diagnosed with COVID-19 infection between January and March 2020. Only a quarter of cases appeared to be locally acquired and genomic-based estimates of local transmission rates were concordant with predictions from a computational agent-based model. This convergent assessment indicates that genome sequencing provides key information to inform public health action and has improved our understanding of the COVID-19 evolution from outbreak to epidemic.

Maintaining optimal infection prevention and control (IPC) in a busy, clinical environment is challenging. Video-reflexive ethnography (VRE) is a collaborative, interventionist approach to practice improvement. We hypothesised that giving clinicians opportunities to view and reflect on video footage of everyday ward activities would raise awareness of, and suggest strategies to reduce, pathogen transmission risks. We undertook a VRE project, between March and September 2013, in two tertiary hospital surgical wards, with persistently high methicillin resistant Staphylococcus aureus (MRSA) endemicity, despite previous IPC interventions.This study was a retrospective/prospective observational study, using interrupted time-series analyses, to assess the effects of the VRE project on hand hygiene compliance, inpatient MRSA infections (newly infected patients, per 1000 occupied bed days) and inpatient MRSA colonisation prevalence, measured by serial point prevalence surveys. Follow-up continued until June 2016.The VRE project was associated with changes in IPC behaviour and outcomes. Hand hygiene compliance increased (from 62% to 75%; p 0.0001) and MRSA colonisation prevalence decreased significantly, in both wards (baseline 42%; average post-VRE 12%; p=0.0001), MRSA infection rate decreased in one ward. Interpretation of results was complicated by a potential confounding effect of unplanned environmental hydrogen peroxide decontamination (HPD). Improved hand hygiene compliance was a predicted outcome of VRE, but also a potential contributor to reduced MRSA transmission.Separate contributions of VRE (the intervention), HPD and hand hygiene compliance were uncertain, but their combined effect was significantly reduced MRSA endemicity, which previously had been resistant to attempted IPC interventions.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of preventable nosocomial infections and is endemic in hospitals worldwide. The effectiveness of infection control policies varies significantly across hospital settings. The impact of the hospital context towards the rate of nosocomial MRSA infections and the success of infection control is understudied. We conducted a modelling study to evaluate several infection control policies in surgical, intensive care, and medical ward specialties, each with distinct ward conditions and policies, of a tertiary public hospital in Sydney, Australia. We reconfirm hand hygiene as the most successful policy and find it to be necessary for the success of other policies. Active screening for MRSA, patient isolation in single-bed rooms, and additional staffing were found to be less effective. Across these ward specialties, MRSA transmission risk varied by 13% and reductions in the prevalence and nosocomial incidence rate of MRSA due to infection control policies varied by up to 45%. Different levels of infection control were required to reduce and control nosocomial MRSA infections for each ward specialty. Infection control policies and policy targets should be specific for the ward and context of the hospital. The model we developed is generic and can be calibrated to represent different ward settings and pathogens transmitted between patients indirectly through health care workers. This can aid the timely and cost effective design of synergistic and context specific infection control policies.