Physician well-being is vital to delivering high-quality emergency care. A supported and healthy emergency medicine workforce leads to better patient outcomes, fewer medical errors, and greater job satisfaction and staff retention.[1,2] Emergency physicians (EPs) face unique pressures, including shift work, high patient volumes and acuities, overcrowding, and systemic inefficiencies that escalate their risk of burnout. As a result, EPs have reported the highest rates of burnout among physician specialties.[1,3] Over the past decade, multiple attempts have been made to promote EP well-being. However, early initiatives were oriented around individual “wellness”, such as exercise, diet, sleep, yoga, and finding “work-life balance”. Recently, there has been evolving recognition of the effects of a number of aspects of burnout that are outside the control of individual EPs, including administrative duties superseding clinical duties, diminishing resources and support, overcrowding and boarding, adverse working conditions, and medico-legal challenges. These factors progressively constrain the ability and capacity of EPs to do the work that they are trained and entrusted to do - rapidly and effectively evaluate, treat, and dispose of acutely ill patients. This sense of “moral injury” has contributed to growing dissatisfaction and premature departure from emergency medicine through reduced hours, transitions to other fields, early retirement, and, tragically, suicide.[4,5]

This study aims to delve into the influences and underlying mechanisms of Banxia Xiexin Decoction(BXD) on the proliferation, apoptosis, invasion, and migration of colon cancer cells. Firstly, the components of BXD in blood were identified by UPLC-MS/MS, and subsequently the content of these components were determined by HPLC. Then, different concentrations of BXD were used to treat both the normal intestinal epithelial cells(NCM460) and the colon cancer cells(HT29 and HCT116). The cell viability and apoptosis were examined by the cell counting kit-8(CCK-8) and flow cytometry, respectively. Western blot was employed to determine the expression of the apoptosis regulators B-cell lymphoma-2(Bcl-2) and Bcl-2-associated X(Bax). The cell wound healing assay and Transwell assay were employed to measure the cell migration and invasion, respectively. Additionally, Western blot was employed to determine the expression levels of epithelial-mesenchymal transition(EMT)-associated proteins, including epithelial cadherin(E-cadherin), neural cadherin(N-cadherin), and vimentin. The protein and mRNA levels of the factors in the poly(ADP-ribose) glycohydrolase(PARG)/poly(ADP-ribose) polymerase 1(PARP1)/nuclear factor kappa-B p65(NF-κB p65) signaling pathway were determined by Western blot and RT-qPCR, respectively. The results demonstrated that following BXD intervention, the proliferation of HT29 and HCT116 cells was significantly reduced. Furthermore, BXD promoted the apoptosis, enhanced the expression of Bcl-2, and suppressed the expression of Bax in colon cancer cells. At the same time, BXD suppressed the cell migration and invasion and augmented the expression of E-cadherin while diminishing the expression of N-cadherin and vimentin. In addition, BXD down-regulated the protein and mRNA levels of PARG, PARP1, and NF-κB p65. In conclusion, BXD may inhibit the malignant phenotypes of colon cancer cells by mediating the PARG/PARP1/NF-κB signaling pathway.
Colonic Neoplasms/pathology* ; Drugs, Chinese Herbal/pharmacology* ; Phenotype ; Signal Transduction/drug effects* ; Cell Proliferation/drug effects* ; Apoptosis ; Cell Movement/drug effects* ; Neoplasm Invasiveness ; HCT116 Cells ; Proto-Oncogene Proteins c-bcl-2/biosynthesis* ; Humans ; Poly (ADP-Ribose) Polymerase-1 ; Glycoside Hydrolases ; bcl-2-Associated X Protein ; NF-kappa B p50 Subunit

This study explores the effect and mechanism of Banxia Xiexin Decoction(BXD) in inhibiting colon cancer progression by reshaping tryptophan metabolism. Balb/c mice were assigned into control, model, low-dose BXD(BXD-L), and high-dose BXD(BXD-H) groups. Except the control group, the other groups were subcutaneously injected with CT26-Luc cells for the modeling of colon cancer, which was followed by the intervention with BXD. Small animal live imaging was employed to monitor tumor growth, and the tumor volume and weight were measured. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in mouse tumors. Immunohistochemistry was used to detect Ki67 expression in tumors. Immunofluorescence and flow cytometry were used to detect the infiltration and number changes of CD3~+/CD8~+ T cells in the tumor tissue. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of interferon-gamma(IFN-γ) and interleukin-2(IL-2) in tumors. Targeted metabolomics was employed to measure the level of tryptophan(Trp) in the serum, and the Trp content in the tumor tissue was measured. Western blot and RT-qPCR were employed to determine the protein and mRNA levels, respectively, of indoleamine 2,3-dioxygenase 1(IDO1), MYC proto-oncogene, and solute carrier family 7 member 5(SLC7A5) in the tumor tissue. Additionally, a co-culture model with CT26 cells and CD8~+ T cells was established in vitro and treated with the BXD-containing serum. The cell counting kit-8(CCK-8) assay was used to examine the viability of CT26 cells. The content of Trp in CT26 cells and CD8~+ T cells, as well as the secretion of IFN-γ and IL-2 by CD8~+ T cells, was measured. RT-qPCR was used to determine the mRNA levels of MYC and SLC7A5 in CT26 cells. The results showed that BXD significantly inhibited the tumor growth, reduced the tumor weight, and decreased the tumor volume in the model mice. In addition, the model mice showed sparse arrangement of tumor cells, varying degrees of patchy necrosis, and downregulated expression of Ki67 in the tumor tissue. BXD elevated the levels of IFN-γ and IL-2 in the tumor tissue, while upregulating the ratio of CD3~+/CD8~+ T cells and lowering the levels of Trp, IDO1, MYC, and SLC7A5. The co-culture experiment showed that BXD-containing serum reduced Trp uptake by CT26 cells, increased Trp content in CD8~+T cells, enhanced IL-2 and IFN-γ secretion of CD8~+T cells, and down-regulated the mRNA levels of MYC and SLC7A5 in CT26 cells. In summary, BXD can inhibit the MYC/SLC7A5 pathway to reshape Trp metabolism and adjust Trp uptake by CD8~+ T cells to enhance the cytotoxicity, thereby inhibiting the development of colon cancer.
Animals ; Tryptophan/metabolism* ; Colonic Neoplasms/pathology* ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Mice, Inbred BALB C ; Humans ; Cell Line, Tumor ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism* ; Female ; Disease Progression ; Cell Proliferation/drug effects* ; Proto-Oncogene Mas ; Male

Objective:To analyze the clinical data of patients with end-stage ankle and hindfoot ar-thropathy who underwent tibiotalocalcaneal(TTC)arthrodesis by the same surgeon,explore the short-and mid-term clinical results,complications and functional improvement,and discuss the clinical progno-sis and precautions of TTC arthrodesis.Methods:Retrospective analysis was made on the clinical data of 40 patients who underwent TTC arthrodesis by the same surgeon from March 2011 to December 2020.In this study,23 males and 17 females were included,with an average age of(49.1±16.0)years.All the patients underwent unilateral surgery.The clinical characteristics,imaging manifestations,main diagno-sis and specific surgical techniques of the patients were recorded.The clinical outcomes were evaluated by comparison of the American Orthopaedic Foot and Ankle Society(AOFAS)ankle-hindfoot score and visual analogue scale(VAS)between pre-operation and at the last follow-up.The fusion healing time,symptom improvement(significant improvement,certain improvement,no improvement or deterioration)and postoperative complications were also recorded.Results:The median follow-up time was 38.0(26.3,58.8)months.The preoperative VAS score was 6.0(4.0,7.0),and the AOFAS score was 33.0(25.3,47.3).At the last follow-up,the median VAS score was 0(0,3.0),and the AOFAS score was 80.0(59.0,84.0).All the significantly improved compared with their preoperative corre-sponding values(P＜0.05).There was no wound necrosis or infection in the patients.One patient suf-fered from subtalar joint nonunion,which was syphilitic Charcot arthropathy.The median bony healing time of other patients was 15.0(12.0,20.0)weeks.Among the included patients,there were 25 cases with significant improvement in symptom compared with that preoperative,8 cases with certain improve-ment,4 cases with no improvement,and 3 cases with worse symptoms than that before operation.Con-clusion:TTC arthrodesis is a reliable method for the treatment of the end-stage ankle and hindfoot ar-thropathy.The function of most patients was improved postoperatively,with little impact on daily life.The causes of poor prognosis included toe stiffness,stress concentration in adjacent knee joints,nonunion and pain of unknown causes.

Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19.However,the efficacy is compromised by the SARS-CoV-2 evolvement and mutation.Here we report the SARS-CoV-2 S protein receptor-binding domain(RBD)inhibitor licorice-saponin A3(A3)could widely inhibit RBD of SARS-CoV-2 variants,including Beta,Delta,and Omicron BA.1,XBB and BQ1.1.Furthermore,A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells,with EC50 of 1.016 pM.The mechanism was related to binding with Y453 of RBD deter-mined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quan-tum mechanics/molecular mechanics(QM/MM)simulations.Interestingly,phosphoproteomics analysis and multi fluorescent immunohistochemistry(mIHC)respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase(MAPK)path-ways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.