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Hai Cai,1,* Shao-Ming Chen,2,* Zhi-Bin Ke,1,* Hang Chen,1,* Jun-Ming Zhu,1 Ting-Ting Lin,1 Fei Huang,3,4 Yong Wei,1 Qing-Shui Zheng,1 Xue-Yi Xue,1 Xiong-Lin Sun,1 Ning Xu1,3 1Department of Urology, Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2Department of Nuclear Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 3Fujian Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 4Central Lab, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning Xu; Xiong-Lin Sun Tel +86-059187981687Email drxun@fjmu.edu.cn; sunxionglin@fjmu.edu.cnObjective: To develop and validate hub genes involving in the development and progression of primary aldosteronism (PA) and adrenal aldosterone-producing adenoma (APA).Materials and Methods: A total of four datasets of gene expression profiles related to APA were downloaded from GEO datasets. GSE60042 and GSE8514 were used to identify DEGs. Weighted gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) network module analysis were conducted. GO and KEGG enrichment analysis was performed. GSE10927 and GSE33371 were used for further external validation.Results: We identified a total of 892 DEGs from GSE60042 and 1167 DEGs from GSE8514. WGCNA analysis demonstrated that the blue module (255 genes) and turquoise module (303 genes) were significantly correlated with APA. PPI networks were then constructed. GO term enrichment analysis suggested that cellular divalent inorganic cation homeostasis, calcium ion homeostasis, collagen-containing extracellular matrix, transport vesicle and metal ion transmembrane transporter activity were the vital annotations. KEGG pathway analysis found that these genes were significantly enriched in neuroactive ligand−receptor interaction, calcium signaling pathway. Finally, we identified a total of 11 candidate genes involving in the development and progression of APA and PA. Besides, two independent datasets (GSE10927 and GSE33371) were used for external validation, and there were seven hub genes successfully verified, including C3, GRM3, AVPR1A, WFS1, PTGFR, NTSR2, and JUN.Conclusion: These newly identified genes could contribute to the understanding of potential mechanism in APA and PA and might be promising targets for the treatment of APA and PA.Keywords: aldosterone-producing adenoma, bioinformatics, primary aldosteronism, gene expression omnibus datasets

Ye-Hui Chen,1,* Ru-Nan Dong,1,* Jian Hou,1,* Ting-Ting Lin,1,* Shao-Hao Chen,1 Hang Chen,1 Jun-Ming Zhu,1 Jia-Yin Chen,1 Zhi-Bin Ke,1 Fei Lin,1 Xue-Yi Xue,1 Yong Wei,1 Ning Xu1,2 1Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning Xu; Yong WeiDepartment of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, People’s Republic of ChinaTel +86-059187981687Email drxun@fjmu.edu.cn; weiyong2017@fjmu.edu.cnBackground: Urethral stricture is a clinical challenge for both patients and clinicians. Post-traumatic urethral stricture is associated with formation of scar tissue caused by excessive inflammation. The aim of this study is exploring potential therapeutic strategies for this condition.Methods: In vivo experiments on New Zealand rabbits and in vitro experiments on THP-1 monocytes and urethral fibroblasts were performed to investigate the effects on post-traumatic urethral stricture of exosomes isolated from IL-1β-treated mesenchymal stem cells (Exo-MSCsIL− 1β) and the role of macrophage M2 polarization in this process. Additionally, related signaling and mechanism behind were explored.Results: In a New Zealand rabbit model of post-traumatic urethral stricture, injection of Exo-MSCsIL− 1β significantly reduced urethral stricture and collagen fiber accumulation compared with Exo-MSCs. Addition of Exo-MSCsIL− 1β to THP-1 monocytes in vitro induced M2 macrophage polarization, which, in turn, inhibited activation of urethral fibroblasts and synthesis of collagen. Mechanistically, Exo-MSCsIL− 1β were found to contain high levels of the microRNA let-7c, and luciferase reporter assays showed that let-7c interacted with the 3′UTR of PAK1 mRNA. Transfection of THP-1 cells with a let-7c mimic downregulated PAK1 expression and inhibited activation of the NF-κB signaling pathway.Conclusion: These results support a role for let-7c-containing Exo-MSCsIL− 1β in reducing urethral stricture via inhibition of PAK1–NF-κB signaling, M2 macrophage polarization, and differentiation of urethral myofibroblasts.Keywords: urethral stricture, mesenchymal stem cells, polarization of macrophages, exosomes, let-7c

Li-Li Liu,1,2,* Ji-Min Zhu,1,2,* Xiang-Nan Yu,1,2 Hai-Rong Zhu,1,2 Xuan Shi,1,2 Enkhnaran Bilegsaikhan,1,2 Hong-Ying Guo,1,2 Jian Wu,1–3 Xi-Zhong Shen1–3 1Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China; 2Shanghai Institute of Liver Diseases, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of Medical Microbiology and Parasitology, Ministry of Education/National Health Commission/Chinese Academy of Medical Sciences, Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi-Zhong ShenDepartment of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel +86 216 404 1990Email shen.xizhong@zs-hospital.sh.cn Jian WuDepartment of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Yixue Yuan Road, P.O. Box 228, Shanghai 200032, People’s Republic of ChinaTel +86 21 5423 7705Email jian.wu@fudan.edu.cnBackground: Growing evidence suggests that the ubiquitin-proteasome system is involved in the pathogenesis and recurrence of hepatocellular carcinoma (HCC); yet, little is known about the role of ubiquitin-conjugating enzyme E2T (UBE2T) in HCC.Materials and methods: UBE2T levels were detected in HCC tissues and hepatoma cell lines using quantitative reserve transcriptase-polymerase chain reaction and Western blot analysis. Next, the changes of phenotypes after UBE2T knockdown or overexpression were evaluated using in vitro methods. Finally, the mechanism of UBE2T in HCC was tested using ex vivo and in vivo methods.Results: In the present study, we reported that UBE2T mRNA and protein levels were significantly upregulated in HCC tissues compared to adjacent non-tumor tissues. Additionally, suppression of UBE2T expression inhibited proliferation, colony formation, tumorigenesis, migration, and invasion of hepatoma cells, whereas UBE2T overexpression led to the opposite outcomes. Moreover, suppression of UBE2T expression resulted in an increase in G2/M phase and a decrease in the percentage of cells in G1 phase, which indicated a cell cycle arrest at the G2/M phase. In contrast, the percentage of cells in G2/M phase decreased following UBE2T overexpression. Further study indicated that UBE2T regulated the G2/M transition by modulating cyclin B1 and cyclin-dependent kinase 1.Conclusion: Taken together, the findings of the present study uncover biological functions of UBE2T in hepatoma cells, and delineate preliminary molecular mechanisms of UBE2T in modulating HCC development and progression.Keywords: hepatocellular carcinoma, UBE2T, ubiquitination, cell cycle

Hong Chen,1 Hai-Rong Zhu,2 Xiang-Nan Yu,2 Xuan Shi,2 Enkhnaran Bilegsaikhan,2 Hong-Ying Guo,2 Ren-Zheng Huang,2 Tao-Tao Liu,2 Xi-Zhong Shen,2–4 Ji-Min Zhu2,31Department of Endocrinology, Zhongshan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Gastroenterologyand Hepatology, Zhongshan Hospital of Fudan University, Shanghai, People’s Republic of China; 3Shanghai Institute of Liver Disease, Zhongshan Hospital of Fudan University, Shanghai, People’s Republic of China; 4Key Laboratory of Medical Molecular Virology, Shanghai Medical College of Fudan University, Shanghai, People’s Republic of ChinaBackground: Aberrant expression of pepsinogen C (PGC) has been observed in human cancers. However, its role in hepatocellular carcinoma (HCC) remains to be established. The goal of this study is to illustrate PGC expression and to evaluate its clinical relevance in HCC.Materials and methods: PGC expression was examined in 75 pairs of HCC and adjacent non-tumor tissues using tissue microarray. The correlations between its expression and clinical parameters were also analyzed.Results: PGC overexpression was significantly associated with larger tumor size (≥5 cm; P=0.017) and incomplete encapsulation (P

Abstract Background and Aim of the Study: Aortic regurgitation (AR) caused by Behçet's disease is a rare clinical condition and surgical experience is limited. Many patients undergoing simple aortic valve replacement (AVR) required a second or third operation as a result of prosthetic valve dehiscence. We analyze our experience with surgical management for AR in Behçet's disease during an 11-year period. Methods: From April 1997 through December 2008, 10 male patients (mean age, 38.4 ± 6.9 years) with AR caused by Behçet's disease underwent surgical treatment. The primary procedures were AVR in seven cases and aortic root replacement in three (two Bentall, one Cabrol). The duration of follow-up was 5.3 ± 3.6 years. Results: In the seven patients with simple AVR, valve dehiscence occurred in six after an interval of 2.9 ± 1.7 months, necessitating 11 reoperations (four redo AVRs, one redo redo-AVR, four aortic root replacements, and two heart transplants) with one early death. In aortic root replacement patients, two Bentall patients survived and required no reintervention, and the Cabrol patient died from electromechanical uncoupling one year postoperatively. Of the seven survivors, the definite procedure was aortic root replacement in four cases, heart transplantation in two, and AVR in one. Conclusions: The rate of valve dehiscence was high after isolated AVR in patients with AR caused by Behçet's disease. At the first operation, aortic root replacement should be the procedure of choice, preferably with a homograft. Heart transplantation might be a feasible alternative to aortic root replacement in selected patients. (J Card Surg 2012;27:39-44). [ABSTRACT FROM AUTHOR]

The standard addition method (SAM) is widely used to measure the isotopic compositions of natural samples, particularly those with a complex matrix. However, traditional SAM has limitations for isotope systems with significant variations in isotope composition due to its reliance on approximation in calculation and the requirement for a priori estimates of analyte isotopic compositions and accurate concentrations. To overcome the issues, our work proposes an improved SAM that explicitly calculates isotope ratio R (i.e., X E/ Y E, 34 S/ 32 S for example) instead of approximating R * (mass number of isotope X divided by total mass number of all isotopes of an element) with R in SAM. Additionally, the sample fraction within standard-sample mixture in improved SAM is determined using the isotope compositions of standards, sample-standard mixtures, and the mixtures of both standards, rather than relying on sample concentrations and volumes. Both improvements not only overcome the shortcomings of traditional SAM but also empowered the approach's ability to accurately determine sample concentrations. To validate its effectiveness, we applied the improved SAM to natural samples with substantial sulfur (S) isotope variation (1.94 to 27.19‰) and low S concentration (0.81 to 3.47 μg g -1 ). The calculated δ 34 S values and concentrations of these samples are consistent with direct measurements within the error ranges while reducing sample sizes to 20% of those required for direct measurement. Moreover, our method achieves higher accuracy in δ 34 S values compared with traditional SAM. Both comparisons affirm the reliability and superiority of improved SAM.

Background: Acute aortic dissection (AD) in pregnancy poses a lethal risk to both mother and fetus. However, well-established therapeutic guidelines are lacking. This study aimed to investigate clinical features, outcomes and optimal management strategies for pregnancy-related AD., Methods: We conducted a retrospective multicentre cohort study including 67 women with acute AD during pregnancy or within 12 weeks postpartum from three major cardiovascular centres in China between 2003 and 2021. Patient characteristics, management strategies and short-term outcomes were analysed., Results: Median age was 31 years, with AD onset at median 32 weeks gestation. Forty-six patients (68.7%) had type A AD, of which 41 underwent immediate surgery. Overall maternal mortality was 10.4% (7/67) and fetal mortality was 26.9% (18/67). Compared with immediate surgery, selective surgery was associated with higher risk of composite maternal and fetal death (adjusted RR: 12.47 (95% CI 3.26 to 47.73); p=0.0002) and fetal death (adjusted RR: 8.77 (95% CI 2.33 to 33.09); p=0.001)., Conclusions: Immediate aortic surgery should be considered for type A AD at any stage of pregnancy or postpartum. For pregnant women with AD before fetal viability, surgical treatment with the fetus in utero should be considered. Management strategies should account for dissection type, gestational age, and fetal viability., Trial Registration Number: NCT05501145., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Exploring the effect of radiofrequency ablation treatment to restore sinus rhythm on the improvement of functional mitral regurgitation (FMR) and cardiac structure in patients with atrial fibrillation combined with moderate or severe FMR, compared with drug therapy alone. Methods: This retrospective cohort study consecutively enrolled patients diagnosed with persistent atrial fibrillation and moderate or severe FMR who were admitted to the Third Affiliated Hospital of Sun Yat-sen University from January 2019 to December 2021. Forty-eight patients who were treated with radiofrequency ablation and maintained sinus rhythm were enrolled in the ablation group, and 63 patients who were treated with medication alone during the same period were in the medicine group. Patients in the ablation group and medicine group were matched in a 1∶1 ratio using a propensity score, and 41 patients were finally included in each of the 2 groups. All patients reexamined echocardiography after 3-month of treatment. The proportion of patients with FMR improvement and the differences in changes of cardiac structural and functional parameters were compared between groups. Results: After propensity score matching, the ablation group was aged (69.3±7.1) years with 21 males (51.2%) and the medicine group was aged (71.3±9.4) years with 21 males (51.2%). The echocardiography after 3-month of treatment showed the rate of FMR improvement was significantly higher in the ablation group than in the medicine group (19 (46.3%) vs. 33 (80.5%), P <0.001), and patients in the ablation group showed a significant decrease in FMR extent (Δmitral regurgitation area: (-1.30±2.64) cm 2 vs. (-3.55±2.50) cm 2 , P <0.001), left atrial size (Δleft atrial diameter: (-0.17±3.78) mm vs. (-2.46±4.01) mm, P =0.009) and E/e' (ΔE/e':-2.54±7.34 vs.-6.34±7.08, P =0.021) compared with the medicine group. There was also a significant decrease in left ventricular size (Δleft ventricular end diastolic diameter: (-3.12±6.62) mm vs. (-0.73±3.62) mm, P =0.046) and significant increase in left ventricular ejection fraction (Δleft ventricular ejection fraction: (2.73±9.69) % vs. (-0.93±5.41) %, P =0.038) in ablation group. Conclusion: Performing radiofrequency ablation to restore sinus rhythm can effectively reduce the severity of mitral regurgitation and improve left atrial and left ventricular remodeling and cardiac function in patients with atrial fibrillation and FMR.

Sorafenib (SOR), a multi-kinase inhibitor for advanced hepatocellular carcinoma (HCC), has limited clinical application due to severe side effects and drug resistance. To overcome these challenges, we developed a bismuth-based nanomaterial (BOS) for thermal injury-assisted continuous targeted therapy in HCC. Initially, the mesoporous nanomaterial was loaded with SOR, forming the BOS@SOR nano-carrier system for drug delivery and controlled release. Notably, compared to targeted or photothermal therapy alone, the combination therapy using this nano-carrier system significantly impaired cell proliferation and increased apoptosis. In vivo efficacy evaluations demonstrated that BOS@SOR exhibited excellent biocompatibility, confirmed through hemolysis and biochemical analyses. Additionally, BOS@SOR enhanced contrast in computed tomography, aiding in the precise identification of HCC size and location. The photothermal therapeutic properties of bismuth further contributed to the synergistic anti-tumor activity of BOS@SOR, significantly reducing tumor growth in an orthotopic xenograft HCC model. Taken together, encapsulating SOR within a bismuth-based mesoporous nanomaterial creates a multifunctional and environmentally stable nanocomposite (BOS@SOR), enhancing the therapeutic effect of SOR and presenting an effective strategy for HCC treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: This study aimed to explore the Liquid-liquid phase separation (LLPS)-related genes associated with the prognosis of bladder cancer (BCa) and assess the potential application of LLPS-related prognostic signature for predicting prognosis in BCa patients., Methods: Clinical information and transcriptome data of BCa patients were extracted from the Cancer Genome Atlas-BLCA (TCGA-BLCA) database and the GSE13507 database. Furthermore, 108 BCa patients who received treatment at our institution were subjected to a retrospective analysis. The least absolute shrinkage and selection operator (LASSO) analysis was performed to develop an LLPS-related prognostic signature for BCa. The CCK8, wound healing and Transwell assays were performed., Results: Based on 62 differentially expressed LLPS-related genes (DELRGs), three DELRGs were screened by LASSO analysis including kallikrein-related peptidase 5 (KLK5), monoacylglycerol O-acyltransferase 2 (MOGAT2) and S100 calcium-binding protein A7 (S100A7). Based on three DELRGs, a novel LLPS-related prognostic signature was constructed for individualized prognosis assessment. Kaplan-Meier curve analyses showed that LLPS-related prognostic signature was significantly correlated with overall survival (OS) of BCa. ROC analyses demonstrated the LLPS-related prognostic signature performed well in predicting the prognosis of BCa patients in the training group (the area under the curve (AUC) = 0.733), which was externally verified in the validation cohort 1 (AUC = 0.794) and validation cohort 2 (AUC = 0.766). Further experiments demonstrated that inhibiting KLK5 could affect the proliferation, migration, and invasion of BCa cells., Conclusions: In this study, a novel LLPS-related prognostic signature was successfully developed and validated, demonstrating strong performance in predicting the prognosis of BCa patients., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

The environmental risk of Cd in soils strongly depends on the mobilization of Cd in soils. However, limited knowledge exists on the redistribution of exogenic Cd inputs in soils, especially across diverse lithological regions. Herein, we aimed to investigate the fate of Cd in soils from two mining areas with contrasting lithologies (siliceous and calcareous) using stable Cd isotopes. The isotope tracing results confirm that mining activities are the main Cd source in both areas. The positive correlation between δ 114/110 Cd values and goethite/dolomite content indicates the release of heavy Cd isotopes during the dissolution of exogenetic minerals. Additionally, high contents of exchangeable Cd (11 % to 36 %) and Fe oxide-bound Cd (29 % to 42 %) drive plant pumps to transport heavy Cd isotopes from the deeper to upper horizons of the soils from the siliceous area. In the calcareous area, the total organic carbon content is positively correlated with the Cd concentration and δ 114/110 Cd value, suggesting potential complexation of Cd with organic matter due to the stabilizing effect of carbonate minerals on soil organic matter. This study highlights the different redistributions of exogenous Cd in soils from diverse lithological regions, emphasizing the need to consider regional lithology when developing soil quality standards for Cd., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Bladder cancer (BCa) is a highly lethal urological malignancy characterized by its notable histological heterogeneity. Autophagy has swiftly emerged as a diagnostic and prognostic biomarker in diverse cancer types. Nonetheless, the currently accessible autophagy-related signature specific to BCa remains limited., Methods: A refined autophagy-related signature was developed through a 10-fold cross-validation framework, incorporating 101 combinations of machine learning algorithms. The performance of this signature in predicting prognosis and response to immunotherapy was thoroughly evaluated, along with an exploration of potential drug targets and compounds. In vitro and in vivo experiments were conducted to verify the regulatory mechanism of hub gene., Results: The autophagy-related prognostic signature (ARPS) has exhibited superior performance in predicting the prognosis of BCa compared to the majority of clinical features and other developed markers. Higher ARPS is associated with poorer prognosis and reduced sensitivity to immunotherapy. Four potential targets and five therapeutic agents were screened for patients in the high-ARPS group. In vitro and vivo experiments have confirmed that FKBP9 promotes the proliferation, invasion, and metastasis of BCa., Conclusions: Overall, our study developed a valuable tool to optimize risk stratification and decision-making for BCa patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cost and insurance coverage remain important barriers to mental health care, including psychotherapy and mental health counseling services ("psychotherapy"). While data are scant, psychotherapy services are often delivered in private practice settings, where providers frequently do not take insurance and instead rely on direct pay. In this cross-sectional analysis, we use a large national online directory of 175 083 psychotherapy providers to describe characteristics of private practice psychotherapy providers who accept and do not accept insurance, and assess self-reported private pay rates. Overall, about one-third of private practice psychotherapists did not accept insurance, with insurance acceptance varying substantially across states. We also found significant session rate differentials, with Medicaid rates being on average 40% lower than reported cash pay rates, which averaged $143.26 a session. Taken together, low insurance acceptance across a broad swath of mental health provider types means that access to care is disproportionately reliant on patients' ability to afford out-of-pocket payments-even when covered by insurance. While our findings are descriptive and may not be representative of all US psychotherapists, they add to scant existing knowledge about the cash pay market for an important mental health service that has experienced increased use and demand over time., Competing Interests: Conflict of interest Dr. Zhu reports grants and/or contracts with the National Institute for Health Care Management Foundation, Agency for Healthcare Research and Quality, National Institute of Mental Health, and American Psychological Association as well as personal consulting fees from Cambia Health Solutions unrelated to this work. Dr. Haeder reports grants from the Robert Wood Johnson Foundation and Pennsylvania Department of Insurance as well as personal consulting fees from CERA LLP, GUERRA LLP and the Washington State Attorney General’s Office unrelated to this work. Dr. Wolk reports grants from NIMH and Agency for Healthcare Research and Quality as well as royalties from Oxford University Press and personal consulting fees from Massachusetts General Hospital unrelated to this work. Dr. McConnell reports grants from NIMH, Arnold Ventures, Commonwealth Fund, Robert Wood Johnson Foundation, and contracts with states of Washington and Oregon unrelated to this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

The COVID-19 public health emergency (PHE) caused significant disruptions in the delivery of care, with in-person visits decreasing and telehealth use increasing. We investigated the impact of these changes on mental health services for Medicaid-enrolled adults and youth in Washington State. Among enrollees with existing mental health conditions, the first year of the PHE was associated with a surge in specialty outpatient mental health visits (13% higher for adults and 7% higher for youth), returning to pre-PHE levels in the second year. Conversely, youth with new mental health needs experienced a decline in specialty outpatient visit rates by ∼15% and 37% in the first and second years of the PHE, respectively. These findings indicate that while mental health service use was maintained or improved for established patients, these patterns did not extend to Medicaid-enrolled youth with new mental health needs, potentially due to barriers such as difficulty in finding providers and establishing new patient-provider relationships remotely. To bridge this gap, there is a need for a multi-faceted approach that includes improving service accessibility, enhancing provider availability, and optimizing initial care encounters, whether in-person or virtual, to better support new patients., Competing Interests: Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials. Author McConnell reports support from multiple grants from NIH, Arnold Ventures, Commonwealth Fund, Robert Wood Johnson Foundation; contracts with states of Washington and Oregon and an honorarium from the Genesis Research Group. Author Edelstein's time was supported by a grant from the National Institute of Mental Health. Author Wolk is supported by NIH grants and reports royalties from a textbook on childhood mental health and consulting fees from Massachusetts General Hospital to support a grant application. She also reports honoraria from Rutgers University Honorarium, Elwyn, Inc, and Behavior Analysis and Therapy Partners, and Participation on an Advisory Board at Penn. Author Lindner's time was supported by grants from NIH and contracts with the states of Oregon and Washington. Author Zhu reports grants from the NIHCM Foundation, AHRQ, NIMH, APA and payment for participation on an Advisory Board (Cambia Medical Policy Physician External Advisory Panel)., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Objective: This study aimed to analyze research on anxiety disorders using VOSviewer and CiteSpace to identify research hotspots and future directions., Methods: We conduct ed a comprehensive search on the Web of Science Core Collection (WoSCC) for relevant studies about anxiety disorders published within the past two decades (from 2004 to 2024). VOSviewer and CiteSpace were mainly used to analyze the authors, institutions, countries, publishing journals, reference co-citation patterns, keyword co-occurrence, keyword clustering, and other aspects to construct a knowledge atlas., Results: A total of 22,267 publications related to anxiety disorders were retrieved. The number of publications about anxiety disorders has generally increased over time, with some fluctuations. The United States emerged as the most productive country, with Harvard University identified as the most prolific institution and Brenda W. J. H. Penninx as the most prolific author in the field., Conclusion: This research identified the most influential publications, authors, journals, institutions, and countries in the field of anxiety research. Future research directions are involved advanced treatments based on pharmacotherapy, psychotherapy and digital interventions, mechanism exploration to anxiety disorders based on neurobiological and genetic basis, influence of social and environmental factors on the onset of anxiety disorders., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Wei Xie reports financial support was provided by 10.13039/501100001809National Natural Science Foundation of China. Wei-Peng Li reports financial support was provided by 10.13039/501100002858China Postdoctoral Science Foundation. Wei-Peng Li reports financial support was provided by Medical Scientific Research Foundation of Guangdong Province. Wei Xie reports financial support was provided by College Students Innovation and Entrepreneurship Training Program Project of Southern Medical University. Wei Xie reports financial support was provided by Key Discipline Construction Project of Traditional Chinese Medicine of Guangdong Province.Wei Xie reports financial support was provided by The second national famous Traditional Chinese Medicine Inheritance Studio. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8 + CD44 + CD62L + central memory T cells into CD8 + CD44 - CD62L - T cells, designated as inter-organ migratory T cells (T IM cells). T IM cells move from the BM to the intestine by upregulating integrin β 7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived T IM cells return from the intestine to the BM through integrin α 4 -vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Despite Medicaid's outsized role in delivering and financing medications for opioid use disorder (MOUD), little is known about the extent to which buprenorphine prescriber networks vary across Medicaid health plans, and whether network characteristics affect quality of treatment received. In this observational cross-sectional study, we used 2018-2019 Medicaid claims in Oregon to assess network variation in the numbers and types of buprenorphine prescribers, as well as the association of prescriber and network characteristics with quality of care., Methods: We describe prescribers (MD/DOs and advanced practice providers) of OUD-approved buprenorphine formulations to patients with an OUD diagnosis, across networks. For each patient who initiated buprenorphine treatment during 2018, we assigned a "usual prescriber" and assessed four measures of quality in the 180d following initiation: 1) continuous receipt of buprenorphine; 2) receipt of any behavioral health counseling services; 3) receipt of any urine drug screen; and 4) receipt of any prescription for a benzodiazepine. We used multivariable linear regressions to examine the association of prescriber and network characteristics with quality of buprenorphine care following initiation., Results: We identified 645 providers who prescribed buprenorphine to 20,739 eligible Medicaid enrollees with an OUD diagnosis. The composition of buprenorphine prescriber networks varied in terms of licensing type, specialty, and panel size, with the majority of prescribers providing buprenorphine to small panels of patients. In the 180 days following initiation, a third of patients were maintained on buprenorphine; 69.9 % received behavioral health counseling; 88.4 % had a urine drug screen; and 11.3 % received a benzodiazepine prescription. In regression analyses, while no single network characteristic was associated with higher quality across all examined measures, each one unit increase in prescriber-to-enrollee ratio was associated with a 1.18 p.p. increase in the probability of continuous buprenorphine maintenance during the 180 days following initiation (95 % confidence interval = [0.21, 2.15], p = 0.017)., Conclusions: Medicaid plans may be able to leverage their networks to provide higher quality care. Our findings, which should be interpreted as descriptive only, suggest that higher prescriber-to-enrollee ratio is associated with increased buprenorphine maintenance. Future research should focus on isolating the causal relationships between MOUD prescribing network design and patient outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jane Zhu reports financial support was provided by National Institute of Mental Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Coleman Drake reports financial support from the National Institute on Drug Abuse. No other competing financial interests are declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cellular mechanical force plays a crucial role in numerous biological processes, including wound healing, cell development, and metastasis. To enable imaging of intercellular tension, molecular tension probes were designed, which offer a simple and efficient method for preparing Au-DNA intercellular tension probes with universal applicability. The proposed approach utilizes gold nanoparticles linked to DNA hairpins, enabling sensitive visualization of cellular force in vitro . Specifically, the designed Au-DNA intercellular tension probe includes a molecular spring flanked by a fluorophore-quencher pair, which is anchored between cells. As intercellular forces open the hairpin, the fluorophore is de-quenched, allowing for visualization of cellular force. The effectiveness of this approach was demonstrated by imaging the cellular force in living cells using the designed Au-DNA intercellular tension probe., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A growing literature has identified substantial inaccuracies in consumer-facing provider directories, but it is unclear how long these inaccuracies persist. We re-surveyed inaccurately listed Pennsylvania providers ( n = 5170) between 117 to 280 days after a previous secret-shopper survey. Overall, 19.0% ( n = 983) of provider directory listings that had been identified as inaccurate were subsequently removed, 44.8% ( n = 2316) of provider listings continued to show at least 1 inaccuracy, and 11.6% ( n = 600) were accurate at follow-up. We were unable to reach 24.6% ( n = 1271) of providers. Longer passage of time was associated with reductions in directory inaccuracies, particularly related to contact information, and to a lesser degree, with removal of inaccurate listings. We found substantial differences in corrective action by carrier. Together, these findings suggest persistent barriers to maintaining and updating provider directories, with implications for how well these tools can help consumers select health plans and access care., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting β-catenin/TGF-β1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

In order to analyze the similarities and differences of chemical compositions between the roots and stems and leaves of Isodon japonicus(IJ), this study utilized UPLC-Q-TOF-MS technology to systematically characterize its chemical compositions, analyzed and identified the structure of its main compounds, and established a method for simultaneous determination of its content by refe-rence substance. A total of 34 major compounds in IJ, including 14 reference compounds, were identified or predicted online. Moreover, an UPLC-UV content determination method was developed for 11 compounds [danshensu, caffeic acid, vicenin-2,(1S,2S)-globoidnan B, rutin,(+)-rabdosiin,(-)-rabdosiin,(1S,2S)-rabdosiin, shimobashiric acid C, rosmarinic acid, and pedalitin]. The method exhibited excellent separation, stability, and repeatability, with a wide linear range(0.10-520.00 μg·mL~(-1)) and high linearity(R~2&gt;0.999). The average recovery rates ranged from 94.72% to 104.2%. The principal component analysis(PCA) demonstrated a clear difference between the roots and stems and leaves of IJ, indicating good separation by cluster. Furthermore, the orthogonal partial least squares discriminant analysis(OPLS-DA) model was employed, and six main differentially identified compounds were identified: rosmarinic acid, shimobashiric acid C, epinodosin, pedalitin, rutin, and(1S,2S)-rabdosiin. In summary, this study established a strategy and method for distinguishing different parts of IJ, providing a valuable tool for quality control of IJ and a basis for the ratio-nal utilization and sustainable development of IJ.

Objectives: Overdose mortality has risen most rapidly among racial and ethnic minority groups while buprenorphine prescribing has increased disproportionately in predominantly non-Hispanic White urban areas. To identify whether buprenorphine availability equitably meets the needs of diverse populations, we examined the differential geographic availability of buprenorphine in areas with greater concentrations of racial and ethnic minority groups., Methods: Using IQVIA longitudinal prescription data, IQVIA OneKey data, and Microsoft Bing Maps, we calculated 2 outcome measures across the continental United States: the number of buprenorphine prescribers per 1000 residents within a 30-minute drive of a ZIP code, and the number of buprenorphine prescriptions dispensed per capita at retail pharmacies among nearby buprenorphine prescribers. We then estimated differences in these outcomes by ZIP codes' racial and ethnic minority composition and rurality with t tests., Results: Buprenorphine prescribers per 1000 residents within a 30-minute drive decreased by 3.8 prescribers per 1000 residents in urban ZIP codes (95% confidence interval = -4.9 to -2.7) and 2.6 in rural ZIP codes (95% confidence interval = -3.0 to -2.2) whose populations consisted of ≥5% racial and ethnic minority groups. There were 45% to 55% fewer prescribers in urban areas and 62% to 79% fewer prescribers in rural areas as minority composition increased. Differences in dispensed buprenorphine per capita were similar but larger in magnitude., Conclusions: Achieving more equitable buprenorphine access requires not only increasing the number of buprenorphine-prescribing clinicians; in urban areas with higher racial and ethnic minority group populations, it also requires efforts to promote greater buprenorphine prescribing among already prescribing clinicians., (Copyright © 2024 American Society of Addiction Medicine.)

Background: Empathy is a critical component of nursing care, impacting both nurses' and patients' outcomes. However, perceived empathy from spouses during pregnancy and its impact on health-related quality of life (HRQoL) are unclear. This study aimed to examine pregnant women's perceived empathy from their spouses and assess the relation of perceived empathy on HRQoL., Methods: This cross-sectional study, performed in the obstetric clinics or wards of four well-known hospitals in Anhui Province, China, included 349 pregnant women in the second or third trimester; participants were recruited by convenience sampling and enrolled from October to December 2021. A general information questionnaire, the Interpersonal Reactivity Index (IRI), a purpose-designed empathy questionnaire and the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12) were used to evaluate the pregnant women's general information, perceptions of empathy and HRQoL. Data were analysed using SPSS 22 at a threshold of P < 0.05. Descriptive analysis, Pearson correlation analysis, Student's t test, ANOVA, and multiple regression analysis were used for analysis., Results: The pregnant women's total empathy, physical component summary (PCS) and mental component summary (MCS) scores were 41.6 ± 9.0, 41.6 ± 7.6, and 47.7 ± 9.1, respectively. Correlation analysis revealed that the purpose-designed empathy questionnaire items were significantly positively correlated with perspective taking and empathic concern but were not correlated with the personal distress dimension and were only partially correlated with the fantasy dimension. Maternal physical condition during pregnancy, planned pregnancy, and occupational stress were predictors of the PCS score (β = 0.281, P < 0.01; β = 0.132, P = 0.02; β = -0.128, P = 0.02). The behavioural empathy item of our purpose-designed empathy questionnaire and empathic concern were important predictors of the MCS score (β = 0.127, P = 0.02; β = 0.158, P < 0.01), as well as other demographic and obstetric information, explaining 22.0% of the variance in MCS scores totally (F = 12.228, P < 0.01)., Conclusions: Pregnant women perceived lower empathy from their spouses and reported lower HRQoL. Perceived empathy, particularly behavioural empathy, may significantly impact pregnant women's MCS scores but has no effect on their PCS scores. Strategies that foster perceived empathy from spouses among pregnant women are essential for facilitating healthy pregnancies and potentially improving maternal and child health., (© 2024. The Author(s).)

Private equity (PE) firms acquire and grow physician practices through add-on consolidation, generating outsized returns on the sale of the acquisition in 3-8 years ("exit"). Private equity's abbreviated investment timeline and exit incentives may deter long-term investments in care delivery and workforce needed for high-quality care. To our knowledge, there has been no published analyses of the nature or duration of PE exits from physician practices. We address this knowledge gap by using novel data to characterize PE exits from dermatology, ophthalmology, and gastroenterology, physician specialties with the largest number of acquisitions between 2016 and 2020. Of 807 acquisitions, over half (51.6%) of PE-acquired practices underwent an exit within 3 years of initial investment. In nearly all instances (97.8%), PE firms exited investments through secondary buyouts, where physician practices were resold to other PE firms with larger investment funds. Between investment and exit, PE firms increased the number of physician practices affiliated with the PE firm by an average of 595% in 3 years. Findings highlight the rapid scale of ownership change and consolidation under PE ownership and motivate evaluations by policymakers on the effects of PE ownership over the life cycle of PE investments., Competing Interests: Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Background: Aberrant iron metabolism is commonly observed in multiple tumor types, including hepatocellular carcinoma (HCC). However, as the key regulator of iron metabolism involved in iron absorption, the role of transferrin receptor (TFRC) in HCC remains elusive., Methods: The mRNA and protein expression of TFRC were evaluated in paired HCC and adjacent non-tumor specimens. The correlation between TFRC level and clinicopathological features or prognostic significance was also analyzed. The role of TFRC on biological functions was finally studied in vitro and in vivo., Results: The TFRC level was remarkably upregulated in HCC tissues compared to paired peritumor tissues. Overexpressed TFRC positively correlated with serum alpha-fetoprotein, carcinoembryonic antigen, and poor tumor differentiation. Multivariate analysis demonstrated that upregulated TFRC was an independent predictive marker for poorer overall survival and disease-free survival in HCC patients. Loss of TFRC markedly impaired cell proliferation and migration in vitro and notably suppressed HCC growth and metastasis in vivo, while overexpression of TFRC performed an opposite effect. Mechanistically, the mTOR signaling pathway was downregulated with TFRC knockdown, and the mTOR agonist MHY1485 completely reversed the biological inhibition in HCC cells caused by TFRC knockdown. Furthermore, exogenous ferric citrate (FAC) or iron chelator reversed the changed biological functions and signaling pathway expression of HCC cells caused by TFRC knockdown or overexpression, respectively., Conclusions: Our study indicates that TFRC exerts an oncogenic role in HCC and may become a promising therapeutic target to restrain HCC progression., (© 2023. Asian Pacific Association for the Study of the Liver.)

Objective: To investigate the incidence of postoperative complications in Chinese patients with gastric or colorectal cancer, and to evaluate the risk factors for postoperative complications. Methods: This was a national, multicenter, prospective, registry-based, cohort study of data obtained from the database of the Prevalence of Abdominal Complications After Gastro- enterological Surgery (PACAGE) study sponsored by the China Gastrointestinal Cancer Surgical Union. The PACAGE database prospectively collected general demographic characteristics, protocols for perioperative treatment, and variables associated with postoperative complications in patients treated for gastric or colorectal cancer in 20 medical centers from December 2018 to December 2020. The patients were grouped according to the presence or absence of postoperative complications. Postoperative complications were categorized and graded in accordance with the expert consensus on postoperative complications in gastrointestinal oncology surgery and Clavien-Dindo grading criteria. The incidence of postoperative complications of different grades are presented as bar charts. Independent risk factors for occurrence of postoperative complications were identified by multifactorial unconditional logistic regression. Results: The study cohort comprised 3926 patients with gastric or colorectal cancer, 657 (16.7%) of whom had a total of 876 postoperative complications. Serious complications (Grade III and above) occurred in 4.0% of patients (156/3926). The rate of Grade V complications was 0.2% (7/3926). The cohort included 2271 patients with gastric cancer with a postoperative complication rate of 18.1% (412/2271) and serious complication rate of 4.7% (106/2271); and 1655 with colorectal cancer, with a postoperative complication rate of 14.8% (245/1655) and serious complication rate of 3.0% (50/1655). The incidences of anastomotic leakage in patients with gastric and colorectal cancer were 3.3% (74/2271) and 3.4% (56/1655), respectively. Abdominal infection was the most frequently occurring complication, accounting for 28.7% (164/572) and 39.5% (120/304) of postoperative complications in patients with gastric and colorectal cancer, respectively. The most frequently occurring grade of postoperative complication was Grade II, accounting for 65.4% (374/572) and 56.6% (172/304) of complications in patients with gastric and colorectal cancers, respectively. Multifactorial analysis identified (1) the following independent risk factors for postoperative complications in patients in the gastric cancer group: preoperative comorbidities (OR=2.54, 95%CI: 1.51-4.28, P <0.001), neoadjuvant therapy (OR=1.42, 95%CI:1.06-1.89, P =0.020), high American Society of Anesthesiologists (ASA) scores (ASA score 2 points:OR=1.60, 95% CI: 1.23-2.07, P <0.001, ASA score ≥3 points:OR=0.43, 95% CI: 0.25-0.73, P =0.002), operative time >180 minutes (OR=1.81, 95% CI: 1.42-2.31, P <0.001), intraoperative bleeding >50 mL (OR=1.29,95%CI: 1.01-1.63, P =0.038), and distal gastrectomy compared with total gastrectomy (OR=0.65,95%CI: 0.51-0.83, P <0.001); and (2) the following independent risk factors for postoperative complications in patients in the colorectal cancer group: female (OR=0.60, 95%CI: 0.44-0.80, P <0.001), preoperative comorbidities (OR=2.73, 95%CI: 1.25-5.99, P =0.030), neoadjuvant therapy (OR=1.83, 95%CI:1.23-2.72, P =0.008), laparoscopic surgery (OR=0.47, 95%CI: 0.30-0.72, P =0.022), and abdominoperineal resection compared with low anterior resection (OR=2.74, 95%CI: 1.71-4.41, P <0.001). Conclusion: Postoperative complications associated with various types of infection were the most frequent complications in patients with gastric or colorectal cancer. Although the risk factors for postoperative complications differed between patients with gastric cancer and those with colorectal cancer, the presence of preoperative comorbidities, administration of neoadjuvant therapy, and extent of surgical resection, were the commonest factors associated with postoperative complications in patients of both categories.

Objective: Numerous investigations have indicated a correlation between air pollution (AP) and an elevated ischemic stroke (IS) likelihood. The existing literature does not provide a consensus about the possible link between AP and IS. A two-sample Mendelian randomization (MR) analysis was utilized to systematically measure the causal link between AP and ischemic stroke. Furthermore, the mediating impact of inflammatory factors was also performed by a two-step MR., Materials and Methods: A two-sample MR analysis was utilized to examine the AP impact on the incidence of IS. Additionally, a two-step MR approach was carried out to account for possible mediating variables. The indirect impact was determined by employing the product approach, which included multiplying the AP impact on inflammatory factors by the inflammatory factors' impacts on IS. The MR effect was identified through inverse variance-weighted (IVW) meta-analysis of each Wald Ratio. Additionally, complementary studies were conducted using the weighted median and MR-egger approaches., Results: The IVW method with random effects showed that the per unit increase in genetically predicted PM2.5 was linked to the 0.362-fold elevated ischemic stroke risk (OR: 1.362, 95% CI: 1.032-1.796, p=0.029). Furthermore, the IVM technique, incorporating random effects, demonstrated that the per unit increase in genetically predicted PM2.5 was related to an elevated Interleukin (IL)-1β risk (OR: 1.529, 95% CI: 1.191-1.963, p=0.001), IL-6 (OR: 1.498, 95% CI: 1.094-2.052, p=0.012) and IL-17 (OR: 1.478, 95% CI: 1.021-2.139, p=0.038). IL-1β, IL-6, and IL-17 modulated the PM2.5 impact on ischemic stroke, while the proportion mediated by them was 59.5%., Conclusions: A positive correlation between genetically predicted PM2.5 levels and elevated ischemic stroke risk is mediated by IL-1β, IL-6, and IL-17.

Aberrant activation of the epithelial-mesenchymal transition (EMT) pathway drives the development of solid tumors, which is precisely regulated by core EMT-related transcription factors, including Twist1. However, the expression pattern and regulatory mechanism of Twist1 in the progression of bladder cancer is still unclear. In this study, we explore the role of Twist1 in the progression of bladder cancer. We discovered that the EMT regulon Twist1 protein, but not Twist1 mRNA, is overexpressed in bladder cancer samples using RT-qPCR, western blot and immunohistochemistry (IHC). Mechanistically, co-immunoprecipitation (Co-IP) coupled with liquid chromatography and tandem mass spectrometry identified USP5 as a binding partner of Twist1, and the binding of Twist1 to ubiquitin-specific protease 5 (USP5) stabilizes Twist through its deubiquitinase activity to activate the EMT. Further studies found that USP5 depletion reduces cell proliferation, invasion and the EMT in bladder cancer cells, and ectopic expression of Twist1 rescues the adverse effects of USP5 loss on cell invasion and the EMT. A xenograft tumor model was used to reconfirmed the inhibitor effect of silencing USP5 expression on tumorigenesis in vivo. In addition, USP5 protein levels are significantly elevated and positively associated with Twist1 levels in clinical bladder cancer samples. Collectively, our study revealed that USP5-Twist1 axis is a novel regulatory mechanism driving bladder cancer progression and that approaches targeting USP5 may become a promising cancer treatment strategy., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Chimeric antigen receptor (CAR)-positive cell therapy, specifically with anti-CD19 CAR-T (CAR19-T) cells, achieves a high complete response during tumor treatment for hematological malignancies. Large-scale production and application of CAR-T therapy can be achieved by developing efficient and low-cost enrichment methods for CAR-T cells, expansion monitoring in vivo, and overcoming tumor escape. Here, novel CAR-specific binding aptamers (CAR-ap) to traceless sort CAR-positive cells and obtain a high positive rate of CAR19-T cells is identified. Additionally, CAR-ap-enriched CAR19-T cells exhibit similar antitumor capacity as CAR-ab (anti-CAR antibody)-enriched CAR-T cells. Moreover, CAR-ap accurately monitors the expansion of CAR19-T cells in vivo and predicts the prognosis of CAR-T treatment. Essentially, a novel class of stable CAR-ap-based bispecific circular aptamers (CAR-bc-ap) is constructed by linking CAR-ap with a tumor surface antigen (TSA): protein tyrosine kinase 7 (PTK7) binding aptamer Sgc8. These CAR-bc-aps significantly enhance antitumor cytotoxicity with a loss of target antigens by retargeting CAR-T cells to the tumor in vitro and in vivo. Overall, novel CAR-aptamers are screened for traceless enrichment, monitoring of CAR-positive cells, and overcoming tumor cell immune escape. This provides a low-cost and high-throughput approach for CAR-positive cell-based immunotherapy., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Purpose: Private equity (PE) firms increasingly are acquiring physician practices in the United States, particularly within procedural-based specialties such as ophthalmology including retina. To date, the potential impact of ophthalmology practice acquisitions remains unknown. We evaluated the association between PE acquisition and Medicare spending and use for common retina services., Design: Retrospective difference-in-differences analysis using the 20% Medicare fee-for-service claims dataset from January 1, 2015, through December 31, 2019., Participants: Eighty-two practices acquired by PE during the study period and matched control practices., Methods: We used novel data on PE acquisitions of retina practices linked to the 20% sample Medicare claims data. Retina practices acquired by PE between 2016 and 2019 were matched to up to 3 non-PE (control) practices based on characteristics before acquisition. Private equity-acquired practices were compared with matched control practices through 6 quarters after acquisition using a difference-in-differences event study design. Data analyses were performed between August 2022 and April 2023., Main Outcome Measures: Medicare spending and use of common retina services., Results: Relative to control practices, PE-acquired retina practices increased the use of higher-priced anti-vascular endothelial growth factor (VEGF) agents including aflibercept, which differentially increased by 6.5 injections (95% confidence interval, 0.4-12.5; P = 0.03) per practice-quarter, or 22% from baseline. As a result, Medicare spending on aflibercept differentially increased by $13 028 per practice-quarter, or 21%. No statistically significant differences were found in use or spending for evaluation and management visits or diagnostic imaging., Conclusions: Private equity acquisition of retina practices are associated with modest increases in the use of higher-priced anti-VEGF drugs like aflibercept, leading to higher Medicare spending. This finding highlights the need to monitor the influence of PE firms' financial incentives over clinician decision-making and the appropriateness of care, which could be swayed by strong economic incentives., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Gastric cancer remains a leading cause of cancer-related death worldwide, largely due to inadequate screening methods, late diagnosis, and limited treatment options. Liquid biopsy has emerged as a promising non-invasive approach for cancer screening and prognosis by detecting circulating tumor components like circulating tumor DNA (ctDNA) in the blood. Numerous gastric cancer-specific ctDNA biomarkers have now been identified. CtDNA analysis provides insight into genetic and epigenetic alterations in tumors, holding promise for predicting treatment response and prognosis in gastric cancer patients. This review summarizes current research on ctDNA biology and detection technologies, while highlighting clinical applications of ctDNA for gastric cancer diagnosis, prognosis, and guiding treatment decisions. Current challenges and future perspectives for ctDNA analysis are also discussed., (© 2024. The Author(s).)

Objective: Medicaid enrollees in rural and frontier areas face inadequate access to mental health services, but the extent to which access varies for different provider types is unknown. We assessed access to Medicaid-participating prescribing and nonprescribing mental health clinicians, focusing on Oregon, which has a substantial rural population., Methods: Using 2018 Medicaid claims data, we identified enrollees aged 18-64 with psychiatric diagnoses and specialty mental health providers who billed Medicaid at least once during the study period. We measured both 30- and 60-minute drive time to a mental health provider, and a spatial access score derived from the enhanced 2-step floating catchment area (E2SFCA) approach at the level of Zip Code Tabulation Areas (ZCTAs). Results were stratified for prescribers and nonprescribers, across urban, rural, and frontier areas., Results: Overall, a majority of ZCTAs (68.6%) had at least 1 mental health prescriber and nonprescriber within a 30-minute drive. E2SFCA measures demonstrated that while frontier ZCTAs had the lowest access to prescribers (84.3% in the lowest quintile of access) compared to other regions, some frontier ZCTAs had relatively high access to nonprescribers (34.3% in the third and fourth quartiles of access)., Conclusions: Some frontier areas with relatively poor access to Medicaid-participating mental health prescribers demonstrated relatively high access to nonprescribers, suggesting reliance on nonprescribing clinicians for mental health care delivery amid rural workforce constraints. Efforts to monitor network adequacy should consider differential access to different provider types, and incorporate methods, such as E2SFCA, to better account for service demand and supply., (© 2023 National Rural Health Association.)

Many states are experiencing a behavioral health workforce crisis, particularly in the public behavioral health system. An understanding of the factors influencing the workforce shortage is critical for informing public policies to improve workforce retention and access to care. The aim of this study was to assess factors contributing to behavioral health workforce turnover and attrition in Oregon. Semistructured qualitative interviews were conducted with 24 behavioral health providers, administrators, and policy experts with knowledge of Oregon's public behavioral health system. Interviews were transcribed and iteratively coded to reach consensus on emerging themes. Five key themes emerged that negatively affected the interviewees' workplace experience and longevity: low wages, documentation burden, poor physical and administrative infrastructure, lack of career development opportunities, and a chronically traumatic work environment. Large caseloads and patients' high symptom acuity contributed to worker stress. At the organizational and system levels, chronic underfunding and poor administrative infrastructure made frontline providers feel undervalued and unfulfilled, pushing them to leave the public behavioral health setting or behavioral health altogether. Behavioral health providers are negatively affected by systemic underinvestment. Policies to improve workforce shortages should target the effects of inadequate financial and workplace support on the daily work environment., Competing Interests: Dr. Howington received contracting fees from the Center for Health Systems Effectiveness for work on this project. Dr. Zhu has received funding from the National Institute for Health Care Management Foundation. The other authors report no financial relationships with commercial interests.

Moderately siderophile (e.g., Ni) and highly siderophile elements (HSEs) in the bulk silicate Earth (BSE) are believed to be partly or near-completely delivered by late accretion after the depletion caused by metallic core formation. However, the extent and rate of remixing of late-accreted materials that equilibrated with Earth's pre-late-veneer mantle have long been debated. Observing evidence of this siderophile element-depleted pre-late-veneer mantle would provide powerful confirmation of this model of early mantle evolution. We find that the mantle source of the ~3.8-billion-year-old (Ga) Narssaq ultramafic cumulates from Southwest Greenland exhibits a subtle 60 Ni/ 58 Ni excess of ~0.05 per mil and contains a clear HSE deficiency of ~60% relative to the BSE. The intermediate Ni isotopic composition and HSE abundances of the ~3.8-Ga Narssaq mantle mark a transitional Eoarchean snapshot as the poorly mixed 3.8-Ga mantle containing elements of pre-late-veneer mantle material transitions to modern Earth's mantle.

Glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that negatively regulates ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC 50  = 0.49 ± 0.02 μM). Further studies suggested that 31 could induce ferroptosis in colon cancer cells and its cytotoxic activity could be reversed by ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel ferroptosis inducer agent for colon cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)