Organ Offer Review Cards: Improving Transparency on the Kidney Transplant Waitlist.

INTRODUCTION: The 2022 National Academy of Sciences, Engineering, and Medicine report on equity in organ transplantation highlighted limited transparency and accountability for organ offer declines and recommended prioritizing patient engagement in decisions regarding organ offers. Yet, there is no guidance on how to incorporate patients in organ offers. We elected to study the experiences of patients on the waitlist and their perception of a novel Organ Offer Review Card (OORC). METHODS: A prototype OORC was created using Donornet refusal codes. Sixty randomly selected kidney waitlist patients at a single center were asked to participate in a web-based survey focusing on current medical decision-making preferences and perceptions of the prototype OORC. RESULTS: Among the 43 patients reached, 17 (39.5%) completed the survey. Most participants (88.2%) expressed it was important to be involved in the decision-making about organ offers, with 100.0% of respondents wanting to know why an organ was declined. Regarding the prototype OORC, 94.1% thought it helped them understand the factors and priorities considered when selecting an organ, and 88.2% said it increased their belief that their team was acting in their best interest. CONCLUSION: An OORC could increase transparency and communication during the waitlist process while enhancing trust in the transplant team.

Macrophage TGF-ß signaling is critical for wound healing with heterotopic ossification after trauma.

Transforming growth factor-ß1 (TGF-ß1) plays a central role in normal and aberrant wound healing, but the precise mechanism in the local environment remains elusive. Here, using a mouse model of aberrant wound healing resulting in heterotopic ossification (HO) after traumatic injury, we find autocrine TGF-ß1 signaling in macrophages, and not mesenchymal stem/progenitor cells, is critical in HO formation. In-depth single-cell transcriptomic and epigenomic analyses in combination with immunostaining of cells from the injury site demonstrated increased TGF-ß1 signaling in early infiltrating macrophages, with open chromatin regions in TGF-ß1-stimulated genes at binding sites specific for transcription factors of activated TGF-ß1 (SMAD2/3). Genetic deletion of TGF-ß1 receptor type 1 (Tgfbr1; Alk5), in macrophages, resulted in increased HO, with a trend toward decreased tendinous HO. To bypass the effect seen by altering the receptor, we administered a systemic treatment with TGF-ß1/3 ligand trap TGF-ßRII-Fc, which resulted in decreased HO formation and a delay in macrophage infiltration to the injury site. Overall, our data support the role of the TGF-ß1/ALK5 signaling pathway in HO.

NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma.

Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. Here, the role of sensory nerve fibers in this abnormal cell fate decision is investigated using a severe extremity injury model in mice. Soft tissue trauma results in NGF (Nerve growth factor) expression, particularly within perivascular cell types. Consequently, NGF-responsive axonal invasion occurs which precedes osteocartilaginous differentiation. Surgical denervation impedes axonal ingrowth, with significant delays in cartilage and bone formation. Likewise, either deletion of Ngf or two complementary methods to inhibit its receptor TrkA (Tropomyosin receptor kinase A) lead to similar delays in axonal invasion and osteochondral differentiation. Mechanistically, single-cell sequencing suggests a shift from TGFß to FGF signaling activation among pre-chondrogenic cells after denervation. Finally, analysis of human pathologic specimens and databases confirms the relevance of NGF-TrkA signaling in human disease. In sum, NGF-mediated TrkA-expressing axonal ingrowth drives abnormal osteochondral differentiation after soft tissue trauma. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation.