One of the major concerns of research in integrated healthcare information systems is to enable decision support among clinicians across boundaries of organizations and regional workgroups. A necessary precursor, however, is to facilitate the construction of appropriate awareness of local clinical practices, including a clinician's actual cognitive capabilities, peculiar workplace circumstances, and specific patient-centered needs based on real-world clinical contexts across work settings. In this paper, a user-centered study aimed to investigate clinical practices across three different geographical areas-the U.K., the UAE and Nigeria-is presented. The findings indicate that differences in clinical practices among clinicians are associated with differences in local work contexts across work settings, but are moderated by adherence to best practice guidelines and the need for patient-centered care. The study further reveals that an awareness especially of the ontological, stereotypical, and situated practices plays a crucial role in adapting knowledge for cross-boundary decision support. The paper then outlines a set of design guidelines for the development of enterprise information systems for e-health. Based on the guidelines, the paper proposes the conceptual design of CaDHealth, a practice-centered framework for making sense of clinical practices across work settings for effective cross-boundary e-health decision support.