Orthopedic surgery in Palau-Current capacity, needs, and future directions.

BACKGROUND: Palau, an island nation in Micronesia, is a medically underserved area with a shortage of specialty care services. Orthopedic diagnoses in Palau remain among the three most common reasons for costly off-island medical referral. The purpose of this study was to assess Palau's current orthopedic surgery capacity and needs to inform interventions to build capacity to improve care access and quality. METHODS: Orthopedic needs and capacity assessment tools developed by global surgical outreach experts were utilized to gather information and prompt discussions with a broad range of Palau's most knowledgeable stakeholders (n = 6). Results were reported descriptively. RESULTS: Finance, community impact, governance, and professional development were the lowest-scored domains from the Capacity Assessment Tool for orthopedic surgery (CAT-os), indicating substantial opportunity to build within these domains. According to administrators (n = 3), governance and finance were the greatest capacity-building priorities, followed by professional development and partnership. Belau National Hospital (BNH) had adequate surgical infrastructure. Skin grafting, soft tissue excision/resection, infection management, and amputation were the most commonly selected procedures by stakeholders reporting orthopedic needs. CONCLUSIONS: This study utilizes a framework for orthopedic capacity-building in Palau which may inform partnership between Palau's healthcare system and orthopedic global outreach organizations with the goal of improving the quality, safety, and value of the care delivered. This demonstration of benchmarking, implementation planning, and subsequent re-evaluation lays the foundation for the understanding of capacity-building and may be applied to other medically underserved areas globally to improve access to high-quality orthopedic care.

Multivalent, asymmetric IL-2-Fc fusions show enhanced selectivity for regulatory T cells.

The cytokine interleukin-2 (IL-2) has the potential to treat autoimmune disease but is limited by its modest specificity toward immunosuppressive regulatory T (Treg) cells. IL-2 receptors consist of combinations of α, ß, and γ chains of variable affinity and cell specificity. Engineering IL-2 to treat autoimmunity has primarily focused on retaining binding to the relatively Treg-selective, high-affinity receptor while reducing binding to the less selective, low-affinity receptor. However, we found that refining the designs to focus on targeting the high-affinity receptor through avidity effects is key to optimizing Treg selectivity. We profiled the dynamics and dose dependency of signaling responses in primary human immune cells induced by engineered fusions composed of either wild-type IL-2 or mutant forms with altered affinity, valency, and fusion to the antibody Fc region for stability. Treg selectivity and signaling response variations were explained by a model of multivalent binding and dimer-enhanced avidity-a combined measure of the strength, number, and conformation of interaction sites-from which we designed tetravalent IL-2-Fc fusions that had greater Treg selectivity in culture than do current designs. Biasing avidity toward IL2Rα with an asymmetrical multivalent design consisting of one α/ß chain-binding and one α chain-binding mutant further enhanced Treg selectivity. Comparative analysis revealed that IL2Rα was the optimal cell surface target for Treg selectivity, indicating that avidity for IL2Rα may be the optimal route to producing IL-2 variants that selectively target Tregs.