Citations

Background: Dysfunction of systemic vascular endothelial cells (ECs) is common in heart failure with preserved ejection fraction (HFpEF). We sought to determine if organ-specific EC translational heterogeneity is present in HFpEF. Using a transgenic mouse model (RiboTag EC ), we analyzed the translatome (the mRNAs bound with ribosomes) of organ-specific ECs in a mouse HFpEF model induced by hypertensive/metabolic stresses. Methods: Six-month-old male RiboTag EC ( Cdh5 CreERT2+ / Rpl22 HA/+ ) mice, expressing a hemagglutinin tag in EC ribosomal protein Rpl22, were fed a high-fat diet and L-NAME water (N=4) or a normal diet and water (N=5) for 7 weeks. Organs were collected for Translating Ribosome Affinity Purification, RNA isolation, and RNA-seq. RNA-seq data were visualized using uniform manifold approximation and projection (UMAP). Differentially expressed genes (DEGs; absolute fold change ≥ 2 and false discovery rate (FDR) adjusted p-value ≤ 0.05). Pathway enrichment analyses were conducted (Ingenuity Pathways Analysis (IPA)). Results: In UMAP, the EC translatome clustered by organ (heart, lung, skeletal muscle, and liver) highlighting organ-specific EC heterogeneity and by disease (HFpEF) status with cardiac ECs showing the most dramatic changes with HFpEF (Fig A). Cardiac ECs in HFpEF (vs Control) had 283 downregulated and 23 upregulated DEG (Fig B) out of 14,923 genes identified. There were significant differences in 142 canonical pathways (16 upregulated, 126 downregulated), including LXR/RXR activation, DHCR 24 signaling, regulation of insulin-like growth factors, eNOS signaling, acute phrase response (all down regulated) and IL-1b-mediated inhibition of RXR and unfolded protein response (both up regulated) (Fig C). Conclusion: HFpEF induction caused extensive translational changes in EC but particularly cardiac ECs. In cardiac ECs, metabolism, anti-inflammatory, vasodilation, tissue repair, and angiogenesis pathways were inhibited, while pro-inflammatory response, insulin resistance, and proteostasis pathways were activated.

SUMMARY Goal While studies have examined quality and health outcomes related to the Centers for Medicare & Medicaid Services’ (CMS’s) Hospital Value-Based Purchasing (HVBP) Program, a significant gap exists in the literature regarding the relationship between pay-for-performance initiatives and hospital financial performance in the program’s Efficiency and Cost Reduction domain. This study examined the association between hospitals’ cost inefficiency and participation in the HVBP Program by estimating the probability and magnitude of improvement or achievement in the program’s Efficiency and Cost Reduction domain. Methods The 2014–2019 Efficiency and Cost Reduction domain data were obtained from CMS and merged with the American Hospital Association’s Annual Survey Database. We conducted a zero-inflated negative binomial regression to account for the excessive number of zeros in the data. Principal Findings The negative binomial component of the model assessed the magnitude of the impact on the Efficiency and Cost Reduction improvement from each covariate, while the zero-inflated component assessed the odds of being in the “certain-zero” group, meaning no chance to improve or achieve. Hospital ownership, location, size, safety-net status, percentage of Medicare patients, and the number of registered nurses per bed were statistically significant. Additionally, the Herfindahl-Hirschman Index and teaching status significantly influenced efficiency performance. Practical Applications Changes in hospital performance in this domain exist and have evolved. Hospitals might be at a disadvantage with this performance measure because of their inherent organizational structure. The HVBP Program may not provide clear enough direction or actionable incentive to address the needs of stakeholders influenced primarily by measures of Medicare spending per beneficiary. This study’s findings hold practical value for policymakers, healthcare administrators, and researchers. Policymakers can use this information to tailor future pay-for-performance programs and effectively allocate resources. Healthcare administrators can identify areas for improvement and benchmark their performance against similar institutions. Researchers can explore the program’s long-term sustainability and investigate cost drivers within different hospital groups. By understanding the link between hospital characteristics and cost reduction, all stakeholders can contribute to a more efficient healthcare system.

Background and Objective: Decline of cardiovascular (CV) function is commonly observed in patients with severe acute pancreatitis (AP), which is associated with high mortality and morbidity. While the pathological changes in the pancreas during severe AP have been extensively studied, the impact on the CV system has not been well characterized. Furthermore, obesity is a major risk factor for severe AP. Hereby we utilized an obesity-associated mouse AP model to assess potential alterations in vascular integrity and cardiac function, two major components of circulatory failure. Methods: Wild-type male C57BL6J mice were fed a normal or a high fat (to induce obesity) diet. Both groups received intraperitoneal injection of cerulein (100 mg/kg/h x12) to induce AP. H&E and TUNEL staining of pancreas were performed to assess histology and cell death. To measure vascular integrity, we measured the leakiness of a fluorescein-conjugated dextran (70 kDa) in tissue parenchyma and serum levels of soluble vascular endothelial (VE)-cadherin, which has recently shown to be shed from endothelial cells with disrupted adherens junctions. Cardiac systolic and diastolic function were assessed by echocardiography at baseline and post-AP induction. Results: Compared to lean mice, obese mice developed more severe pancreatic edema, cell death and inflammatory cell infiltration, along with significantly increased accumulation of fluorescent dextran in multiple organs including pancreas, heart, lung, and kidney, suggesting systemic disruption of vascular integrity. Increased serum levels of soluble VE-cadherin in obese mice (vs. lean) after AP induction further supported compromised endothelial cell barrier function. At baseline, obese mice exhibited similar cardiac function to lean mice. However, obese mice, but not lean mice, developed impaired systolic and diastolic function post-AP induction, as supported by decreased ejection fraction and e’ velocity respectively. Conclusion: In this obesity-associated severe AP mouse model, systemic vascular permeability is increased, and cardiac function is substantially compromised. Systemic vascular hyperpermeability and cardiac dysfunction may represent therapeutic targets to enhance the outcomes in severe AP.

Abstract Safe delivery of mRNA to the brain will revolutionize the treatment of brain tumors. While lipid nanoparticles (LNPs) are clinically most advanced non-viral delivery vehicles for therapeutic mRNA, LNP-mediated mRNA delivery to the brain remains challenging. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain cells without undue toxicity. We engineered LNPs consisting of four components similar to the formulation used in the mRNA COVID-19 vaccines (Moderna and Pfizer-BioNTech): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. We screened ten classes of helper lipids based on lipids enriched in extracellular vesicles to engineer biomimetic LNPs and tested their GFP mRNA delivery efficacy in SIM-A9 mouse microglia cell line. Several unique LNP formulations with potent delivery efficacy (>90% cells transfected) and stable GFP expression kinetics (5 days) were identified. LNP formulations with high transfection efficacy were then tested in vivo for luciferase mRNA delivery via intrathecal injection in C57BL/6 mice. Luciferase expression in vivo confirmed widespread mRNA delivery in the brain. We then tested Cre recombinase mRNA delivery in Ai9 mouse to identify LNP-targeted cells via flow cytometry and histology. Flow cytometry and expansion microscopy confirmed Cre recombinase mRNA delivery to a variety of brain cells, including microglia (75-90%), neurons (31-40%), neural stem cells (39-62%), oligodendrocytes (70-90%), and astrocytes (44-76%). LNPs were further evaluated for Cas9 mRNA and CD81 sgRNA delivery in C57BL/6 mouse brains to assess brain-targeted gene editing. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~40% of cells in the mouse brain. In summary, we engineered extracellular vesicle-based LNP library that can deliver RNA therapeutics to a variety of brain cells in vivo. With further development, this technology could potentially enable genetic and epigenetic therapies targeting drivers of brain tumors.

Abstract This study reports the first pig-to-human lung xenotransplantation using a six gene-edited pig lung. A left lung from a gene-edited Chinese Bama Xiang pig was transplanted into a 39-year-old brain-dead human recipient. The xenograft maintained viability and functionality for 216 hours without signs of hyperacute rejection. Postoperatively, severe edema resembling primary graft dysfunction (PGD) was observed, potentially due to ischemia-reperfusion injury. Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9 under the current immunosuppressive regimen. This pioneering study suggests that genetically modified pig lungs could potentially be used for future clinical applications in xenotransplantation.

Abstract 3D printing, also known as additive manufacturing, holds immense potential for rapid prototyping and customized production of functional health‐related devices. With advancements in polymer chemistry and biomedical engineering, polymeric biomaterials have become integral to 3D‐printed biomedical applications. However, there still exists a bottleneck in the compatibility of polymeric biomaterials with different 3D printing methods, as well as intrinsic challenges such as limited printing resolution and rates. Therefore, this review aims to introduce the current state‐of‐the‐art in 3D‐printed functional polymeric health‐related devices. It begins with an overview of the landscape of 3D printing techniques, followed by an examination of commonly used polymeric biomaterials. Subsequently, examples of 3D‐printed biomedical devices are provided and classified into categories such as biosensors, bioactuators, soft robotics, energy storage systems, self‐powered devices, and data science in bioplotting. The emphasis is on exploring the current capabilities of 3D printing in manufacturing polymeric biomaterials into desired geometries that facilitate device functionality and studying the reasons for material choice. Finally, an outlook with challenges and possible improvements in the near future is presented, projecting the contribution of general 3D printing and polymeric biomaterials in the field of healthcare.

As a treatment for the widely spread cardiovascular diseases (CVD), bypass vascular grafts have room for improvement in terms of mechanical property match with native arteries. A 3D‐printed nozzle is presented, featuring unique internal structures, to extrude artificial vascular grafts with a flower‐mimicking geometry. The multilayer‐structured graft wall allows the inner and outer layers to interfere sequentially during lateral expansion, replicating the nonlinear elasticity of native vessels. Both experiment and simulation results verify the necessity and benefit of the flower‐mimicking structure in obtaining the self‐toughening behavior. The gelation study of natural polymers and the utilization of sacrificial phase enables the smooth extrusion of the multiphase conduit, where computer‐assisted image analysis is employed to quantify manufacturing fidelity. The cell viability tests demonstrate the cytocompatibility of the gelatin methacryloyl (GelMA)/sodium alginate grafts, suggesting potential for further clinical research with further developments. This study presents a feasible approach for fabricating bypass vascular grafts and inspires future treatments for CVD.

AbstractLiver fibrosis is a pathological process resulting from prolonged exposure to various injury factors. It is characterized by the abnormal proliferation and activation of hepatic stellate cells and excessive deposition of extracellular matrix. If left untreated, it can progress to cirrhosis, liver failure, and even liver cancer. There is currently no efficient and accurate clinical diagnostic method for early liver fibrosis. Therefore, there is an urgent need to address the challenge of accurate staging and early diagnosis of liver fibrosis in clinical practice. Recently, nanomaterials have demonstrated significant potential for enhancing the diagnosis of liver fibrosis. Nanomaterials possess the ability to precisely identify and target the microenvironment associated with liver fibrosis. By enhancing their enrichment in the target area, nanomaterials can improve imaging contrast of fibrosis lesions in the liver, thereby enabling accurate diagnosis of liver fibrosis. Accordingly, this review delves into the latest research and advancements concerning nanomaterials in liver fibrosis diagnosis.