Collaborative approaches in health, such as One Health (OH), are promising; nevertheless, several authors point at persistent challenges for designing and implementing OH initiatives. Among other challenges, OH practitioners struggle in their efforts to collaborate across disciplines and domains. This paper aims to provide insights into the existing challenges for designing and implementing OH initiatives, their causes and solutions, and points out strategic solutions with the potential to solve practical challenges. A systematic literature search was performed for emerging challenges and proposed solutions in the process of conducting OH initiatives. Next, a thematic and a causal analysis were performed to unravel challenges and their causes. Finally, solutions were discriminated on whether they were only recommended, or implemented as a proof-of-principle. The 56 included papers describe 21 challenges endured by OH initiatives that relate to different themes (policy and funding; education and training; surveillance; multi-actor, multi-domain, and multi-level collaborations; and evidence). These challenges occur in three different phases: the acquisition of sufficient conditions to start an initiative, its execution, and its monitoring and evaluation. The findings indicate that individual challenges share overlapping causes and crosscutting causal relations. Accordingly, solutions for the successful performance of OH initiatives should be implemented to tackle simultaneously different types of challenges occurring in different phases. Still, promoting collaboration between the wide diversity of stakeholders, as a fundamental aspect in the OH approach, is still by far the most challenging factor in performing OH initiatives. Causes for that are the difficulties in promoting meaningful and equal participation from diverse actors. Solutions proposed for this challenge focused on guiding stakeholders to think and collaborate beyond their professional and cultural silos to generate knowledge co-creation and innovative methodologies and frameworks. Finally, the biggest knowledge gap identified, in terms of proposed solutions, was for monitoring and evaluating OH initiatives. This highlights the need for future research on evaluation methods and tools specific for the OH approach, to provide credible evidence on its added value. When considering challenges endured by former OH initiatives and the proposed solutions for these challenges, practitioners should be able to plan and structure such initiatives in a more successful way, through the strategic pre-consideration of solutions or simply by avoiding known barriers.
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