The well person's health check

[Extract] Primary health care is based on the central premise that prevention is better than cure. The preventive approach to health has shown returns on investment in mainstream Australia, especially federal expenditure on immunisation, public health campaigns, and the incorporation of preventive measures into primary care. I There is also good evidence that comprehensive and organised primary health care to Aboriginal peoples and Torres Strait Islanders is cost-saving. Internationally, developed countries with very weak primary health care infrastructures have poorer performance on major aspects of health (such as low birth weight (LBW) ratios and child survival) and higher total health care costs. Lower mortality and low birth weight rates are evident where there are more primary health care workers. Primary health care may also alleviate adverse effects of income inequalities on health. The medical profession and governments internationally encourage preventive health care

Clonal fitness inferred from time-series modelling of single-cell cancer genomes

Progress in defining genomic fitness landscapes in cancer, especially those defined by copy number alterations (CNAs), has been impeded by lack of time-series single-cell sampling of polyclonal populations and temporal statistical models1-7. Here we generated 42,000 genomes from multi-year time-series single-cell whole-genome sequencing of breast epithelium and primary triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), revealing the nature of CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy. Using a new Wright-Fisher population genetics model8,9 to infer clonal fitness, we found that TP53 mutation alters the fitness landscape, reproducibly distributing fitness over a larger number of clones associated with distinct CNAs. Furthermore, in TNBC PDX models with mutated TP53, inferred fitness coefficients from CNA-based genotypes accurately forecast experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDXs resulted in cisplatin-resistant clones emerging from low-fitness phylogenetic lineages in the untreated setting. Conversely, high-fitness clones from treatment-naive controls were eradicated, signalling an inversion of the fitness landscape. Finally, upon release of drug, selection pressure dynamics were reversed, indicating a fitness cost of treatment resistance. Together, our findings define clonal fitness linked to both CNA and therapeutic resistance in polyclonal tumours