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Background Relatively little is known about the cognitive processes of healthcare workers that mediate between performance-shaping factors (eg, workload, time pressure) and adherence to infection prevention and control (IPC) practices. We taxonomised the cognitive work involved in IPC practices and assessed its role in how pathogens spread. Methods Forty-two registered nurses performed patient care tasks in a standardised high-fidelity simulation. Afterwards, participants watched a video of their simulation and described what they were thinking, which we analysed to obtain frequencies of macrocognitive functions (MCFs) in the context of different IPC practices. Performance in the simulation was the frequency at which participants spread harmless surrogates for pathogens (bacteriophages). Using a tertiary split, participants were categorised into a performance group: high, medium or low. To identify associations between the three variables--performance groups, MCFs and IPC practices--we used multiblock discriminant correspondence analysis (MUDICA). Results MUDICA extracted two factors discriminating between performance groups. Factor 1 captured differences between high and medium performers. High performers monitored the situation for contamination events and mitigated risks by applying formal and informal rules or managing their uncertainty, particularly for sterile technique and cleaning. Medium performers engaged more in future-oriented cognition, anticipating contamination events and planning their workflow, across many IPC practices. Factor 2 distinguished the low performers from the medium and high performers who mitigated risks with informal rules and sacrificed IPC practices when managing trade-offs, all in the context of minimising cross-contamination from physical touch. Conclusions To reduce pathogen transmission, new approaches to training IPC (eg, cognitive skills training) and system design are needed. Interventions should help nurses apply their knowledge of IPC fluidly during patient care, prioritising and monitoring situations for risks and deciding how to mitigate risks. Planning IPC into one's workflow is beneficial but may not account for the unpredictability of patient care. [ABSTRACT FROM AUTHOR]