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Wound healing is the physiologic response to a disruption in normal skin architecture and requires both spatial and temporal coordination of multiple cell types and cytokines. This complex process is prone to dysregulation secondary to local and systemic factors such as ischemia and diabetes that frequently lead to chronic wounds. Chronic wounds such as diabetic foot ulcers are epidemic with great cost to the healthcare system as they heal poorly and recur frequently, creating an urgent need for new and advanced therapies. Stem cell therapy is emerging as a potential treatment for chronic wounds, and adult-derived stem cells are currently employed in several commercially available products; however, stem cell therapy is limited by the need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo. Induced pluripotent stem cells (iPSC) are an exciting cell type with enhanced therapeutic and translational potential. iPSC are derived from adult cells by in vitro induction of pluripotency, obviating the ethical dilemmas surrounding the use of embryonic stem cells; they are harvested non-invasively and can be transplanted autologously, reducing immune rejection; and iPSC are the only cell type capable of being differentiated into all of the cell types in healthy skin. This review focuses on the use of iPSC in animal models of wound healing including limb ischemia, as well as their limitations and methods aimed at improving iPSC safety profile in an effort to hasten translation to human studies.

Arteriovenous fistulae (AVF) are the most common access created for hemodialysis, but up to 60% do not sustain dialysis within a year, suggesting a need to improve AVF maturation and patency. In a mouse AVF model, Akt1 regulates fistula wall thickness and diameter. We hypothesized that inhibition of the Akt1-mTORC1 axis alters venous remodeling to improve AVF patency. Daily intraperitoneal injections of rapamycin reduced AVF wall thickness with no change in diameter. Rapamycin decreased smooth muscle cell (SMC) and macrophage proliferation; rapamycin also reduced both M1 and M2 type macrophages. AVF in mice treated with rapamycin had reduced Akt1 and mTORC1 but not mTORC2 phosphorylation. Depletion of macrophages with clodronate-containing liposomes was also associated with reduced AVF wall thickness and both M1- and M2-type macrophages; however, AVF patency was reduced. Rapamycin was associated with improved long-term patency, enhanced early AVF remodeling and sustained reduction of SMC proliferation. These results suggest that rapamycin improves AVF patency by reducing early inflammation and wall thickening while attenuating the Akt1-mTORC1 signaling pathway in SMC and macrophages. Macrophages are associated with AVF wall thickening and M2-type macrophages may play a mechanistic role in AVF maturation. Rapamycin is a potential translational strategy to improve AVF patency.

Objectives To determine if three-dimensional whole liver and baseline tumor enhancement features on MRI can serve as staging biomarkers and help predict survival of patients with colorectal cancer liver metastases (CRCLM) more accurately than one-dimensional and non-enhancement-based features. Methods This retrospective study included 88 patients with CRCLM, treated with transarterial chemoembolization or Y90 transarterial radioembolization between 2001 and 2014. Semi-automated segmentations of up to three dominant lesions were performed on pre-treatment MRI to calculate total tumor volume (TTV) and total liver volumes (TLV). Quantitative 3D analysis was performed to calculate enhancing tumor volume (ETV), enhancing tumor burden (ETB, calculated as ETV/TLV), enhancing liver volume (ELV), and enhancing liver burden (ELB, calculated as ELV/TLV). Overall and enhancing tumor diameters were also measured. A modified Kaplan-Meier method was used to determine appropriate cutoff values for each metric. The predictive value of each parameter was assessed by Kaplan-Meier survival curves and univariable and multivariable cox proportional hazard models. Results All methods except whole liver (ELB, ELV) and one-dimensional/non-enhancement-based methods were independent predictors of survival. Multivariable analysis showed a HR of 2.1 (95% CI 1.3–3.4, p = 0.004) for enhancing tumor diameter, HR 1.7 (95% CI 1.1–2.8, p = 0.04) for TTV, HR 2.3 (95% CI 1.4–3.9, p < 0.001) for ETV, and HR 2.4 (95% CI 1.4–4.0, p = 0.001) for ETB. Conclusions Tumor enhancement of CRCLM on baseline MRI is strongly associated with patient survival after intra-arterial therapy, suggesting that enhancing tumor volume and enhancing tumor burden are better prognostic indicators than non-enhancement-based and one-dimensional-based markers. Key Points • Tumor enhancement of colorectal cancer liver metastases on MRI prior to treatment with intra-arterial therapies is strongly associated with patient survival. • Three-dimensional, enhancement-based imaging biomarkers such as enhancing tumor volume and enhancing tumor burden may serve as the basis of a novel prognostic staging system for patients with liver-dominant colorectal cancer metastases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

To assess the potential of human induced pluripotent stem cell-derived smooth muscle cells (hiPSC-SMC) to accelerate diabetic wound healing. hiPSC-SMC were embedded in 3D collagen scaffolds and cultured for 72 h; scaffolds were then applied to diabetic, nude mouse, splinted back wounds to assess healing. Cultured medium after scaffold incubation was collected and analyzed for expression of pro-angiogenic cytokines. hiPSC-SMC secrete increased concentration of pro-angiogenic cytokines, compared with murine adipose derived stem cells. Delivery of hiPSC-SMC-containing collagen scaffolds accelerates diabetic wound healing and is associated with an increased number of total and M2 type macrophages. hiPSC-SMC promote angiogenesis and accelerate diabetic wound healing, making them a promising new candidate for treatment of diabetic wounds.

Arteriovenous fistulae (AVF) are the most common access created for hemodialysis, but up to 60% do not sustain dialysis within a year, suggesting a need to improve AVF maturation and patency. In a mouse AVF model, Akt1 regulates fistula wall thickness and diameter. We hypothesized that inhibition of the Akt1-mTORC1 axis alters venous remodeling to improve AVF patency. Daily intraperitoneal injections of rapamycin reduced AVF wall thickness with no change in diameter. Rapamycin decreased smooth muscle cell (SMC) and macrophage proliferation; rapamycin also reduced both M1 and M2 type macrophages. AVF in mice treated with rapamycin had reduced Akt1 and mTORC1 but not mTORC2 phosphorylation. Depletion of macrophages with clodronate-containing liposomes was also associated with reduced AVF wall thickness and both M1- and M2-type macrophages; however, AVF patency was reduced. Rapamycin was associated with improved long-term patency, enhanced early AVF remodeling and sustained reduction of SMC proliferation. These results suggest that rapamycin improves AVF patency by reducing early inflammation and wall thickening while attenuating the Akt1-mTORC1 signaling pathway in SMC and macrophages. Macrophages are associated with AVF wall thickening and M2-type macrophages may play a mechanistic role in AVF maturation. Rapamycin is a potential translational strategy to improve AVF patency.

BackgroundThis study aimed at developing and evaluating a tool for computer-assisted 3D bowel length measurement (BMS) to improve objective measurement in minimally invasive surgery. Standardization and quality of surgery as well as its documentation are currently limited by lack of objective intraoperative measurements. To solve this problem, we developed BMS as a clinical application of Quantitative Laparoscopy (QL).MethodsBMS processes images from a conventional 3D laparoscope. Computer vision algorithms are used to measure the distance between laparoscopic instruments along a 3D reconstruction of the bowel surface. Preclinical evaluation was performed in phantom, ex vivo porcine, and in vivo porcine models. A bowel length of 70 cm was measured with BMS and compared to a manually obtained ground truth. Afterwards 70 cm of bowel (ground truth) was measured and compared to BMS.ResultsGround truth was 66.1 ± 2.7 cm (relative error + 5.8%) in phantom, 65.8 ± 2.5 cm (relative error + 6.4%) in ex vivo, and 67.5 ± 6.6 cm (relative error + 3.7%) in in vivo porcine evaluation when 70 cm was measured with BMS. Using 70 cm of bowel, BMS measured 75.0 ± 2.9 cm (relative error + 7.2%) in phantom and 74.4 ± 2.8 cm (relative error + 6.3%) in ex vivo porcine evaluation. After thorough preclinical evaluation, BMS was successfully used in a patient undergoing laparoscopic Roux-en-Y gastric bypass for morbid obesity.ConclusionsQL using BMS was shown to be feasible and was successfully translated from studies on phantom, ex vivo, and in vivo porcine bowel to a clinical feasibility study.

Objective: To enhance health literacy and accessibility of health information for a diverse patient population by developing a patient-centered artificial intelligence (AI) solution using large language models (LLMs) and Fast Healthcare Interoperability Resources (FHIR) application programming interfaces (APIs). Materials and Methods: The research involved developing LLM on FHIR, an open-source mobile application allowing users to interact with their health records using LLMs. The app is built on Stanford's Spezi ecosystem and uses OpenAI's GPT-4. A pilot study was conducted with the SyntheticMass patient dataset and evaluated by medical experts to assess the app's effectiveness in increasing health literacy. The evaluation focused on the accuracy, relevance, and understandability of the LLM's responses to common patient questions. Results: LLM on FHIR demonstrated varying but generally high degrees of accuracy and relevance in providing understandable health information to patients. The app effectively translated medical data into patient-friendly language and was able to adapt its responses to different patient profiles. However, challenges included variability in LLM responses and the need for precise filtering of health data. Discussion and Conclusion: LLMs offer significant potential in improving health literacy and making health records more accessible. LLM on FHIR, as a pioneering application in this field, demonstrates the feasibility and challenges of integrating LLMs into patient care. While promising, the implementation and pilot also highlight risks such as inconsistent responses and the importance of replicable output. Future directions include better resource identification mechanisms and executing LLMs on-device to enhance privacy and reduce costs.

Tooth extraction results in resorptive remodeling of the alveolar bone,but alveolar ridge preservationprocedure maintains the original shape of the extraction socket. This may be beneficial for space closure by orthodontic tooth movement (OTM). In the current pilot study forrandomized controlled clinical trial the effect of alveolar ridge preservationwith partial demineralized freeze-dried bone allograft (PDFDBA) on OTM rate, formation of gingival invagination and root resorptionwas evaluated. Both mandibular first premolars of6 patients were extracted due to orthodontic treatment. In a split-mouth study design,alveolar ridge preservation was performed on one side, while the other side served as a control and the extraction socket healed naturally. After 6 weeks of healing period, the canines were moved to the extraction siteto close the extraction space. Eight weeks later, the amount of OTM was measured. After space closure, the extraction sites were examined for the presence of gingival invagination. Root resorption was evaluated on digital panoramic radiographs. Photographs were taken for documentation. There was no significant difference in OTM rate betweenthe ridge preserved areas and naturally healed sockets. Gingival invagination formed in 5 of 6 naturally healed sockets; none of the ridge preserved areas showed formation of gingival invagination. No root resorption was observed in any of the teeth adjacent to the extraction sites. Alveolar ridge preservation with PDFDBA has no effect on the rate of OTM and root resorptionbut preventsformation of gingival invagination during orthodontic space closure.