Background: Lipid metabolism plays an important role in viral infections. We aimed to assess the causal effect of lipid-lowering drugs (HMGCR inhibitiors, PCSK9 inhibitiors, and NPC1L1 inhibitior) on COVID-19 outcomes using two-sample Mendelian randomization (MR) study.Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including expression quantitative trait loci of drugs target genes, and genetic variants within or nearby drugs target genes associated with low-density lipoprotein (LDL cholesterol from genome-wide association study). Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) were used to calculate the effect estimates.Results: SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.06–1.81). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR = 1.32, 95% CI = 1.00–1.74). No consistent evidence from both analyses was found for other associations.Conclusions: This two-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization.Funding: Start-up Fund for high-level talents of Fujian Medical University.

Introduction: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and their small extracellular vesicles (hUC-MSC-sEVs) have shown attractive prospects applying in regenerative medicine. This study aimed to compare the therapeutic effects of two agents on osteoarthritis (OA) and investigate underlying mechanism using proteomics. Methods: In vitro, the proliferation and migration abilities of chondrocytes treated with hUC-MSCs or hUC-MSC-sEVs were detected by Cell Counting Kit-8 assay and scratch wound assay. In vivo, hUC-MSCs (a single dose of 5 × 10⁵) or hUC-MSC-sEVs (30 μg/time) were injected into the knee joints of anterior cruciate ligament transection-induced OA model. Hematoxylin and eosin, Safranin O/Fast Green staining were used to observe cartilage degeneration. The levels of cartilage matrix metabolic molecules (Collagen II, MMP13 and ADAMTS5) and macrophage polarization markers (CD14, IL-1β, IL-10 and CD206) were assessed by immunohistochemistry. Finally, proteomics analysis was performed to characterize the proteinaceous contents of two agents. Results: In vitro data showed that hUC-MSC-sEVs were taken up by chondrocytes. A total of 15 μg/mL of sEVs show the greatest proliferative and migratory capacities among all groups. In the animal study, hUC-MSCs and hUC-MSC-sEVs alleviated cartilage damage. This effect was mediated via maintaining cartilage homeostasis, as was confirmed by upregulation of the COL II and downregulation of the MMP13 and ADAMTS5. Moreover, the M1 macrophage markers (CD14) were significantly reduced, while the M2 macrophage markers (CD206 and IL-10) were increased in the hUC-MSCs and hUC-MSC-sEVs relative to the untreated group. Mechanistically, we found that many proteins connected to cartilage repair were more abundant in sEVs. Notably, compared to hUC-MSCs, the upregulated proteins in sEVs were mostly involved in the regulation of immune effector process, extracellular matrix organization, PI3K-AKT signaling pathways, and Rap1 signaling pathway. Conclusion: Our study indicated that hUC-MSC-sEVs protect cartilage from damage and many cartilage repair-related proteins are probably involved in the restoration process. These data suggest the promising potential of hUC-MSC-sEVs as a therapeutic agent for OA.

Autologous fat grafting is an effective reconstructive surgery technique; however, its success is limited by inconsistent graft retention and an environment characterized by high oxidative stress and inflammation. Adipose-derived stem cells (ADSCs) increase the survival of fat grafts, although the underlying mechanisms remain unclear. Here, TLR4^−/− and Nrf2^−/− mice were used to explore the effects of oxidative stress and inflammation on the viability and function of ADSCs in vitro and in vivo. Enrichment of fat grafts with ADSCs inhibited inflammatory cytokine production, enhanced growth factor levels, increased fat graft survival, downregulated NADPH oxidase (NOX)1 and 4 expression, increased vascularization and reduced ROS production in a manner dependent on toll-like receptor (TLR)-4 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Immunohistochemical analysis showed that exposure to hypoxia enhanced ADSC growth and promoted the differentiation of ADSCs into vascular endothelial cells. Hypoxia-induced inflammatory cytokine, growth factor and NOX1/4 upregulation, as well as increased ROS production and apoptosis in ADSCs were dependent on TLR4 and Nrf2, which also modulated the effect of ADSCs on promoting endothelial progenitor cell migration and angiogenesis. Western blot analyses showed that the effects of hypoxia on ADSCs were regulated by crosstalk between Nrf2 antioxidant responses and NF-κB- and TLR4-mediated inflammatory responses. Taken together, our results indicate that ADSCs can increase the survival of fat transplants through the modulation of inflammatory and oxidative responses via Nrf2 and TLR4, suggesting potential strategies to improve the use of ADSCs for cell therapy.

Background—: To simplify extensive primary repair of the thoracic aorta in acute type A aortic dissection, we developed the open triple-branched stent graft placement technique. The early results of this new technique are reported. Methods and Results—: Between June 2008 and November 2009, 30 patients with acute Stanford type A aortic dissection underwent extensive primary repair of the thoracic aorta by means of ascending aorta replacement combined with open placement of triple-branched stent graft. Placement of the triple-branched stent graft into the true lumen of the descending aorta, arch, and 3 arch vessels was technically successful in all patients. The mean cardiopulmonary bypass time, aortic cross-clamp time, and lower body arrest time were 151.8±16.69, 84.1±6.97, and 31.17±5.34 minutes, respectively. The postoperative mechanical ventilation support period and duration of intensive care unit stay were 17.93±2.35 and 62.10±9.24 hours, respectively. All implanted stent grafts were fully opened and not kinked; there was no space or blood flow surrounding the triple-branched stent graft and no sidearm graft stenosis or occlusion. The false lumen of the descending aorta distal to the stent graft closed with thrombus in 25 of 30 patients at their first postoperative scans and in 26 of 30 at the 3-month postoperative scan. Conclusions: Open triple-branched stent graft placement is an effective technique with satisfactory early results. With this technique, extensive primary repair of the thoracic aorta may become easier and safer for acute type A aortic dissection.

Background: Postoperative delirium (POD) is an acute brain dysfunction that is frequently observed in patients undergoing cardiac surgery. Increasing evidence indicates POD is related to higher mortality among cardiac surgical patients, but the results remain controversial. Moreover, a quantitative evaluation of the influence of POD on hospital days, intensive care unit (ICU) time, and mechanical ventilation (MV) time has not been performed.Objective: This study aimed to evaluate the correlation between POD and outcomes in patients undergoing cardiac surgery by a systematic review and meta-analysis.Materials and methods: A total of 7 electronic databases (Cochrane Library, PubMed, EMBASE, CINAHL Complete, MEDLINE, Wan-fang database, and China National Knowledge Infrastructure) were searched from January 1980 to July 20, 2021, with language restrictions to English and Chinese, to estimate the impact of the POD on outcome in patients who underwent cardiac surgery. The meta-analysis was registered with PROSPERO (Registration: CRD42021228767).Results: Forty-two eligible studies with 19785 patients were identified. 3368 (17.0%) patients were in the delirium group and 16417 (83%) were in the non-delirium group. The meta-analysis showed that compared to patients without POD, patients with POD had 2.77-fold higher mortality (OR = 2.77, 95% CI 1.86–4.11, P < 0.001), 5.70-fold higher MV (>24h) rate (OR = 5.70, 95% CI 2.93–11.09, P < 0.001); and longer MV time (SMD = 0.83, 95% CI 0.57–1.09, P < 0.001), ICU time (SMD = 0.91, 95% CI 0.60–1.22, P < 0.001), hospital days (SMD = 0.62, 95% CI 0.48–0.76, P < 0.001).Conclusion: The synthesized evidence suggests that POD is causally related to the increased risk of mortality, prolonged length of ICU and hospital stay, and a longer duration of MV time. Future research should focus on the interventions for POD, to reduce the incidence.Systematic review registration: [www.crd.york.ac.uk/PROSPERO], identifier [CRD42021228767].

The highly heterogeneous characteristics of Wharton's jelly mesenchymal stem cells (WJ‐MSCs) may be responsible for the poor clinical outcomes and poor reproducibility of treatments based on WJ‐MSCs. Exploration of WJ‐MSC heterogeneity with multimodal single‐cell technologies will aid in establishing accurate MSC subtyping and developing screening protocols for dominant functional subpopulations. Here, the characteristics of WJ‐MSCs are systematically analyzed by single cell and spatial transcriptome sequencing. Single‐cell transcriptomics analysis identifies four WJ‐MSC subpopulations, namely proliferative_MSCs, niche‐supporting_MSCs, metabolism‐related_MSCs and biofunctional‐type_MSCs. Furthermore, the transcriptome, cellular heterogeneity, and cell‐state trajectories of these subpopulations are characterized. Intriguingly, the biofunctional‐type MSCs (marked by S100A9, CD29, and CD142) selected in this study exhibit promising wound repair properties in vitro and in vivo. Finally, by integrating omics data, it has been found that the S100A9⁺CD29⁺CD142⁺ subpopulation is more enriched in the fetal segment of the umbilical cord, suggesting that this subpopulation deriving from the fetal segment may have potential for developing into an ideal therapeutic agent for wound healing. Overall, the presented study comprehensively maps the heterogeneity of WJ‐MSCs and provides an essential resource for future development of WJ‐MSC‐based drugs.