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In this paper, we present a synthesis of our fundamental and theoretical research on human system integration and human in-the-loop system for enhancing human performance - especially for technical gestures, in safety critical systems operations such as surgery, astronauts' extra-vehicular activities and aeronautics. Grounding humans-systems integration engineering and design (modelling and simulation) on a formally and experimentally verified theoretical framework, is a necessity to make sure of human in-the-loop system security, safety and reliability. The rise issues concerned with scientific principles of human systems integration and rationale for human in-the-loop systems technical engineering and managerial specific rules.