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Jing-Bo Liu,1 Qiao-Jun Zhang,2 Jian-Zhi Liu,1 Wen-Ting Zhang,3 Yi Li,3 Hao-Hong Li,3 Zhi-Rong Chen,3 Da-Li Zheng2 1Department of Otorhinolaryngology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People’s Republic of China; 2Fujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian 350004, People’s Republic of China; 3College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, People’s Republic of ChinaCorrespondence: Da-Li ZhengFujian Key Laboratory of Oral Diseases, Fujian Biological Materials Engineering and Technology Center of Stomatology, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Road, Fuzhou 350004, People’s Republic of ChinaTel +86-591-83720599Email dalizheng@fjmu.edu.cnJian-Zhi LiuDepartment of Otorhinolaryngology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, People’s Republic of ChinaTel +86-591- 83357896Email liujianzhi@aliyun.comBackground: The realization of multifunction in one bulk material is fascinating for developing a new generation of devices. Quaternary phosphorus salts were seldom utilized as templates in haloargentate systems, and the hybridization of alkyl(triphenyl)phosphonium with halometallate will be a good strategy for the development of multifunctional material, especially for biological material.Methods: Under the template of (triphenyl)phosphonium-based quaternary phosphorus salts with different spacer lengths (n=2, 3, 4), three bromoargentate hybrids were constructed via the solution method, ie, (1,2-DBTPP)(Ag2Br4) ( 1), {(1,3-DBTPP)2(Ag7Br11)]∙CH3CN∙H2O}n ( 2), and {[(1,4-DBTPP)(Ag5Br7)](CH3CN)2∙H2O}n ( 3) (1,2-DBTPP2+=ethane-1,2-diylbis (triphenyl)phosphonium, 1,3-DBTPP2+=propane-1,3-diylbis (triphenyl)phosphonium, 1,4-DBTPP2+=butane-1,4-diylbis (triphenyl)phosphonium)).Results: The (Ag7Br11)n4n- chain in 2 is a new type of 1-D bromoargentate chain constructed from cubane-like Ag4Br4 nodes, AgBr4 tetrahedrons and AgBr3 triangles. Interestingly, by elongating spacer n from 2 to 4, argentophilicity interactions are weakened, and the hydrogen bonds are strengthened. Consequently, their water stabilities and photocurrents are improved, in which the Ag-4d/Br-4p to π* anti-bonding orbital of the quaternary phosphorus transfer is facilitated. Furthermore, the greenish blue emissions can be detected. Finally, high inhabitation rates against Streptococcus mutans and Candida albicans can be observed in 2 and 3.Conclusion: In all experiments, by elongating the spacer lengths of quaternary phosphorus salts, multifunctions were integrated in the quaternary phosphorus/bromoargentate hybrids, including greenish blue luminescence, repeatable photocurrent responses and durable antimicrobial activities with enhanced water stability. This work could provide a theoretical guide for the design of new biologically multifunctional materials.Keywords: quaternary phosphorus, bromoargentates, nanoparticles, luminescence, antimicrobial

1. The pharmacokinetics of pholcodine after two single doses and after chronic administration were studied in healthy human volunteers. 2. Six subjects received single oral doses of 20 and 60 mg of pholcodine according to a balanced cross-over design with an interval of 3 weeks between the two treatments. Blood and saliva samples and all urine were collected over 168 h after each dosage administration. Subsequently, the same subjects received 20 mg pholcodine 8 hourly orally for 10 days. Blood and saliva samples and all urine were collected during an 8 h dosing interval after the last dose on day 11. 3. Plasma, saliva and urine concentrations of pholcodine were determined by a high performance liquid chromatographic assay. 4. After the single doses, pholcodine was absorbed rapidly (tmax = 1.6 +/- 1.2 h) and eliminated slowly with a mean half-life of 50.1 +/- 4.1 h. The renal clearance of pholcodine was 137 +/- 34 ml min-1 and was inversely correlated with urine pH (r = 0.60) but not with urine flow rate. 26.2 +/- 3.3% of the dose was excreted as unchanged pholcodine after both doses. The concentration of pholcodine in saliva was 3.6 times higher than in plasma. 5. After chronic administration, the pharmacokinetics of pholcodine were not statistically different from the single dose parameters. 6. Pholcodine did not appear to undergo conjugation. The plasma protein binding was 23.5%. Morphine, in unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine administration. [ABSTRACT FROM AUTHOR]

Worldwide use of robotic-assisted hepatectomy has increased dramatically over the past two decades. The role of robotic liver surgery is still controversial, especially with respect to its long-term oncological outcomes in treating early-stage hepatocellular carcinoma (HCC). The Glissonean approach is a fundamental technique for anatomical resection using open and laparoscopic liver surgery. To our knowledge, there have been few reports on purely robotic anatomical segmentectomy 7 for HCC using the Glissonean approach have been described. The present study describes the technical details and surgical outcomes of totally robotic segmentectomy 7 using the Glissonean approach. Fourteen patients with HCC limited to segment 7 underwent segmentectomy 7 from January 2019 through April 2023 in our hospital. The surgical techniques, peri-operative, and oncological outcomes were analyzed. Purely robotic anatomical segmentectomy 7 using the Glissonean approach was safe and feasible with the technology described herein in all of the 14 patients. The peri-operative and oncological outcomes were better and/or comparable with those of other similar hepatic resections using open approach and/or laparoscopic approach. The median follow-up time was 18 months. Intrahepatic recurrence occurred in 2 (14.3%) patient within one year following surgery. The 3-year overall survival rate was 81%. Although technically challenging, the purely robotic segmentectomy 7 could be performed safely and simultaneously with oncological radicality using the Glissonean approach., (© 2024. Italian Society of Surgery (SIC).)

Excessive or inappropriate fear responses can lead to anxiety-related disorders, such as post-traumatic stress disorder (PTSD). Studies have shown that microglial activation occurs after fear conditioning and that microglial inhibition impacts fear memory. However, the role of microglia in fear memory recall remains unclear. In this study, we investigated the activated profiles of microglia after the recall of remote-cued fear memory and the role of activated microglia in the extinction of remote-cued fear in adult male C57BL/6 mice. The results revealed that the expression of the microglia marker Iba1 increased in the medial prefrontal cortex (mPFC) at 10 min and 1 h following remote-cued fear recall, which was accompanied by amoeboid morphology. Inhibiting microglial activation through PLX3397 treatment before remote fear recall did not affect recall, reconsolidation, or regular extinction but facilitated recall-extinction and mitigated spontaneous recovery. Moreover, our results demonstrated reduced co-expression of Iba1 and postsynaptic density protein 95 (PSD95) in the mPFC, along with decreases in the p-PI3K/PI3K ratio, p-Akt/Akt ratio, and KLF4 expression after PLX3397 treatment. Our results suggest that microglial activation after remote fear recall impedes fear extinction through the pruning of synapses in the mPFC, accompanied by alterations in the expression of the PI3K/AKT/KLF4 pathway. This finding can help elucidate the mechanism involved in remote fear extinction, contributing to the theoretical foundation for the intervention and treatment of PTSD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immunotherapy for esophageal squamous cell carcinoma (ESCC) exhibits notable variability in efficacy. Concurrently, recent research emphasizes circRNAs' impact on the ESCC tumor microenvironment. To further explore the relationship, we leveraged circRNA, microRNA, and mRNA sequence datasets to construct a comprehensive immune-related circRNA-microRNA-mRNA network, revealing competing endogenous RNA (ceRNA) roles in ESCC. The network comprises 16 circular RNAs, 13 microRNAs, and 1,560 mRNAs. Weighted gene co-expression analysis identified immune-related modules, notably cancer-associated fibroblast (CAF) and myeloid-derived suppressor cell modules, correlating significantly with immune and stemness scores. Among them, the CAF module plays a crucial role in extracellular matrix function and effectively discriminates ESCC patients. Four hub collagen family genes within CAF correlated robustly with CAF, macrophage infiltration, and T-cell exclusion. In-house sequencing and RT-qPCR validated their elevated expression. We also identified CAF module-targeting drugs as potential ESCC treatments. In summary, we established an immune-related circRNA-miRNA-mRNA network that not only illuminates ceRNA functionality but also highlights circRNAs' involvement in the CAF through collagen gene targeting. These findings hold promise to predict ESCC immune landscapes and therapy responses, ultimately aiding in more personalized and effective clinical decision-making.

Overcoming temozolomide (TMZ)-resistance is a major challenge in glioblastoma therapy. Therefore, identifying the key molecular player in chemo-resistance becomes urgent. We previously reported the downregulation of PDCD10 in primary glioblastoma patients and its tumor suppressor-like function in glioblastoma cells. Here, we demonstrate that the loss of PDCD10 causes a significant TMZ-resistance during treatment and promotes a rapid regrowth of tumor cells after treatment. PDCD10 knockdown upregulated MGMT, a key enzyme mediating chemo-resistance in glioblastoma, accompanied by increased expression of DNA mismatch repair genes, and enabled tumor cells to evade TMZ-induced cell-cycle arrest. These findings were confirmed in independent models of PDCD10 overexpressing cells. Furthermore, PDCD10 downregulation led to the dedifferentiation of glioblastoma cells, as evidenced by increased clonogenic growth, the upregulation of glioblastoma stem cell (GSC) markers, and enhanced neurosphere formation capacity. GSCs derived from PDCD10 knockdown cells displayed stronger TMZ-resistance and regrowth potency, compared to their parental counterparts, indicating that PDCD10-induced stemness may independently contribute to tumor malignancy. These data provide evidence for a dual role of PDCD10 in tumor suppression by controlling both chemo-resistance and dedifferentiation, and highlight PDCD10 as a potential prognostic marker and target for combination therapy with TMZ in glioblastoma.

The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To study and analyze the epidemiological regularity of acute poisoning in Tianjin-Hebei region from 2020 to 2022, and to provide reference for the treatment and prevention of related patients. Methods: In December 2023, the analysis results and clinical data of 4695 patients with drug poisoning from January 2020 to December 2022 in multiple centers of Tianjin-Hebei region were collected as research objects. Gender, age, type of drug poisoning, season and poisoning route of the research objects were analyzed, and statistical analysis was conducted as well. Results: The sex ratio of men and women was 1∶1.16 (2173/2522). The poisoning of antidepressants and benzodiazepines were the most common drug poisonings, accounting for 1550 and 1274 cases respectively (33%, 27.1%). Paraquat poisoning has decreased year by year, while the poisonings of herbicides with low toxicity such as diquat, glyphosate and cremart have increased. The number of cases reached a peak during May to August which was the poisoning season, while was relatively fewer during October to December. Conclusion: Effective intervention measures should be taken according to the age of high incidence of poisoning, different seasons and populations. Essential drug poisoning prevention measures should be established and improved. The systems of sedative drug management and use should be established, and pesticide management and storage need to be strengthened.

Background: With the rapid progress of systematic therapy for hepatocellular carcinoma (HCC), therapeutic strategies combining hepatic arterial infusion chemotherapy (HAIC) with systematic therapy arised increasing concentrations. However, there have been no systematic review comparing HAIC and its combination strategies in the first-line treatment for advanced HCC., Aim: To investigate the efficacy and safety of HAIC and its combination therapies for advanced HCC., Methods: A network meta-analysis was performed by including 9 randomized controlled trails and 35 cohort studies to carry out our study. The outcomes of interest comprised overall survival (OS), progression-free survival (PFS), tumor response and adverse events. Hazard ratios (HR) and odds ratios (OR) with a 95% confidence interval (CI) were calculated and agents were ranked based on their ranking probability., Results: HAIC outperformed Sorafenib (HR = 0.55, 95%CI: 0.42-0.72; HR = 0.51, 95%CI: 0.33-0.78; OR = 2.86, 95%CI: 1.37-5.98; OR = 5.45, 95%CI: 3.57-8.30; OR = 7.15, 95%CI: 4.06-12.58; OR = 2.89, 95%CI: 1.99-4.19; OR = 0.48, 95%CI: 0.25-0.92, respectively) and transarterial chemoembolization (TACE) (HR = 0.50, 95%CI: 0.33-0.75; HR = 0.62, 95%CI: 0.39-0.98; OR = 3.08, 95%CI: 1.36-6.98; OR = 2.07, 95%CI: 1.54-2.80; OR = 3.16, 95%CI: 1.71-5.85; OR = 2.67, 95%CI: 1.59-4.50; OR = 0.16, 95%CI: 0.05-0.54, respectively) in terms of efficacy and safety. HAIC + lenvatinib + ablation, HAIC + ablation, HAIC + anti- programmed cell death 1 (PD-1), and HAIC + radiotherapy had the higher likelihood of providing better OS and PFS outcomes compared to HAIC alone. HAIC + TACE + S-1, HAIC + lenvatinib, HAIC + PD-1, HAIC + TACE, and HAIC + sorafenib had the higher likelihood of providing better partial response and objective response rate outcomes compared to HAIC. HAIC + PD-1, HAIC + TACE + S-1 and HAIC + TACE had the higher likelihood of providing better complete response and disease control rate outcomes compared to HAIC alone., Conclusion: HAIC proved more effective and safer than sorafenib and TACE. Furthermore, combined with other interventions, HAIC showed improved efficacy over HAIC monotherapy according to the treatment ranking analysis., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Limited research exists regarding the effects of resistance exercise (RE) combined with whole body vibration (WBV), blood flow restriction (BFR), or both on the neuropsychological performance of working memory (WM) in late-middle-aged and older adults and regarding the physiological mechanisms underlying this effect. This study thus explored the acute molecular and neurophysiological mechanisms underlying WM performance following RE combined with WBV, BFR, or both. Sixty-six participants were randomly assigned into a WBV, BFR, or WBV + BFR group. Before and after the participants engaged in a single bout of isometric RE combined with WBV, BFR, or both, this study gathered data on several neurocognitive measures of WM performance, namely, accuracy rate (AR), reaction time (RT), and brain event-related potential (specifically P3 latency and amplitude), and data on biochemical indices, such as the levels of insulin-like growth factor-1 (IGF-1), norepinephrine (NE), and brain-derived neurotrophic factor (BDNF). Although none of the RE modalities significantly affected RTs and P3 latencies, ARs and P3 amplitudes significantly improved in the WBV and WBV + BFR groups. The WBV + BFR group exhibited greater improvements than the WBV group did. Following acute RE combined with WBV, BFR, or both, IGF-1 and NE levels significantly increased in all groups, whereas BDNF levels did not change. Crucially, only the changes in NE levels were significantly correlated with improvements in ARs in the WBV + BFR and WBV groups. The findings suggest that combining acute RE with WBV, BFR, or both could distinctively mitigate neurocognitive decline in late-middle-aged and older adults., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies., Competing Interests: Declaration of competing interest Xin-Fu Zhou and Yong-Tao Li are employees of Suzhou Auzone Biotechnology. Funders did not play any roles in the data generation, interpretation and conclusion of the paper. All other authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

High levels of acetyl-CoA are considered a key metabolic feature of metastatic cancers. However, the impacts of acetyl-CoA metabolic accumulation on cancer microenvironment remodeling are poorly understood. In this study, using human hepatocellular carcinoma (HCC) tissues and orthotopic xenograft models, we found a close association between high acetyl-CoA levels in HCCs, increased infiltration of tumor-associated neutrophils (TANs) in the cancer microenvironment and HCC metastasis. Cytokine microarray and enzyme-linked immunosorbent assays (ELISA) revealed the crucial role of the chemokine (C-X-C motif) ligand 1(CXCL1). Mechanistically, acetyl-CoA accumulation induces H3 acetylation-dependent upregulation of CXCL1 gene expression. CXCL1 recruits TANs, leads to neutrophil extracellular traps (NETs) formation and promotes HCC metastasis. Collectively, our work linked the accumulation of acetyl-CoA in HCC cells and TANs infiltration, and revealed that the CXCL1-CXC receptor 2 (CXCR2)-TANs-NETs axis is a potential target for HCCs with high acetyl-CoA levels., 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.)

Finding novel therapeutic modalities, improving drug delivery efficiency and targeting, and reducing the immune escape of tumor cells are currently hot topics in the field of tumor therapy. Bacterial therapeutics have proven highly effective in preventing tumor spread and recurrence, used alone or in combination with traditional therapies. In recent years, a growing number of researchers have significantly improved the targeting and penetration of bacteria by using genetic engineering technology, which has received widespread attention in the field of tumor therapy. In this paper, we provide an overview and assessment of the advancements made in the field of tumor therapy using genetically engineered bacteria. We cover three major aspects: the development of engineered bacteria, their integration with other therapeutic techniques, and the current state of clinical trials. Lastly, we discuss the limitations and challenges that are currently being faced in the utilization of engineered bacteria for tumor therapy., 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.)

Although adsorbents are good candidates for removing phosphorus and heavy metals from wastewater, the use of biosorbents for the sequential treatment of phosphorus and copper has not yet been studied. Porous chitosan (CS)-based biosorbents (CGBs) were developed to adsorb phytic acid (PA), a major form of organic phosphate. This first adsorbate (PA) further served as an additional ligand (P-type ligand) for the CGBs (N-type ligand) to form a complex with the second adsorbate (copper). After the adsorption of PA (the first adsorbate), the spent CGBs were recycled and used as a new adsorbent to adsorb Cu(II) ions (the second adsorbate), which was expected to have a dual coordination effect through P, N-ligand complexation with copper. The interactions and complexation between CS, PA and Cu(II) ions on the PA-adsorbed CGBs (PACGBs) were investigated by performing FTIR, XPS, XRD, and SEM-EDS analyses. The PACGBs exhibited fast and enhanced adsorption of Cu(II) ions, owing to the synergistic effect of the amino groups of CS (the original ligand, N-type) and the phosphate groups of PA (an additional ligand, P-type) on the adsorption of Cu(II) ions. This is the first time that sequential removal of phosphorus and heavy metals by biosorbents has been performed using biosorbents., 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.)

Background: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood., Methods: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse., Results: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae., Conclusion: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD., (© 2024. The Author(s).)

Background: Gastric cancer (GC) is prevalent and aggressive, especially when patients have distant lung metastases, which often places patients into advanced stages. By identifying prognostic variables for lung metastasis in GC patients, it may be possible to construct a good prediction model for both overall survival (OS) and the cumulative incidence prediction (CIP) plot of the tumour., Aim: To investigate the predictors of GC with lung metastasis (GCLM) to produce nomograms for OS and generate CIP by using cancer-specific survival (CSS) data., Methods: Data from January 2000 to December 2020 involving 1652 patients with GCLM were obtained from the Surveillance, epidemiology, and end results program database. The major observational endpoint was OS; hence, patients were separated into training and validation groups. Correlation analysis determined various connections. Univariate and multivariate Cox analyses validated the independent predictive factors. Nomogram distinction and calibration were performed with the time-dependent area under the curve (AUC) and calibration curves. To evaluate the accuracy and clinical usefulness of the nomograms, decision curve analysis (DCA) was performed. The clinical utility of the novel prognostic model was compared to that of the 7 th edition of the American Joint Committee on Cancer (AJCC) staging system by utilizing Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI). Finally, the OS prognostic model and Cox-AJCC risk stratification model modified for the AJCC system were compared., Results: For the purpose of creating the OS nomogram, a CIP plot based on CSS was generated. Cox multivariate regression analysis identified eleven significant prognostic factors ( P < 0.05) related to liver metastasis, bone metastasis, primary site, surgery, regional surgery, treatment sequence, chemotherapy, radiotherapy, positive lymph node count, N staging, and time from diagnosis to treatment. It was clear from the DCA (net benefit > 0), time-dependent ROC curve (training/validation set AUC > 0.7), and calibration curve (reliability slope closer to 45 degrees) results that the OS nomogram demonstrated a high level of predictive efficiency. The OS prediction model (New Model AUC = 0.83) also performed much better than the old Cox-AJCC model (AUC difference between the new model and the old model greater than 0) in terms of risk stratification ( P < 0.0001) and verification using the IDI and NRI., Conclusion: The OS nomogram for GCLM successfully predicts 1- and 3-year OS. Moreover, this approach can help to appropriately classify patients into high-risk and low-risk groups, thereby guiding treatment., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Evidence suggests that damage to the ribbon synapses (RS) may be the main cause of auditory dysfunction in noise-induced hearing loss (NIHL). Oxidative stress is implicated in the pathophysiology of synaptic damage. However, the relationship between oxidative stress and RS damage in NIHL remains unclear. To investigate the hypothesis that noise-induced oxidative stress is a key factor in synaptic damage within the inner ear, we conducted a study using mice subjected to single or repeated noise exposure (NE). We assessed auditory function using auditory brainstem response (ABR) test and examined cochlear morphology by immunofluorescence staining. The results showed that mice that experienced a single NE exhibited a threshold shift and recovered within two weeks. The ABR wave I latencies were prolonged, and the amplitudes decreased, suggesting RS dysfunction. These changes were also demonstrated by the loss of RS as evidenced by immunofluorescence staining. However, we observed threshold shifts that did not return to baseline levels following secondary NE. Additionally, ABR wave I latencies and amplitudes exhibited notable changes. Immunofluorescence staining indicated not only severe damage to RS but also loss of outer hair cells. We also noted decreased T-AOC, ATP, and mitochondrial membrane potential levels, alongside increased hydrogen peroxide concentrations post-NE. Furthermore, the expression levels of 4-HNE and 8-OHdG in the cochlea were notably elevated. Collectively, our findings suggest that the production of reactive oxygen species leads to oxidative damage in the cochlea. This mitochondrial dysfunction consequently contributes to the loss of RS, precipitating an early onset of NIHL., Competing Interests: None., (AJTR Copyright © 2024.)

Hypericumliboense M.T.An & T.R.Wu, sp. nov. (Hypericaceae) is a newly described species found in the Maolan National Nature Reserve of Guizhou Province, where it grows in rocky habitats without soil on karst mountain tops. In this study, key morphological characters were compared between the new species and the other known Hypericum species of Hypericaceae. DNA sequences were extracted from the leaves of the new species, with nuclear gene sequences (ITS) generated to reconstruct phylogenetic trees and describe its phylogenetic position in relation to other species of Hypericum . Our results show that the proposed new species has the typical characteristics of the genus Hypericum in morphology being similar to Hypericummonogynum , but differing in its sessile and semi-clasped leaves, long elliptical to long circular leaf blades, thickly papery to thinly leathery, with entire and wavy leaf margins. The abaxial side of the leaves is covered with white powder, giving them a grey-white appearance. The main lateral veins of the leaves are 8-15-paired, and the midvein on both sides is convex. The main lateral veins and midvein branch are conspicuous, with tertiary venation forming a network on the leaf surface and appearing prominently sunken. The inflorescences are 1-3-flowered, with a large calyx and conspicuous veins. The molecular phylogenetic analysis (PP = 1.00) provided substantial evidence for the proposition of H.liboense as a new species within Hypericum . Morphological and molecular evidence is presented, corroborating the proposition of the new species, including a comprehensive account of the distinctive morphological attributes of H.liboense , along with its key distinguishing features from similar species., Competing Interests: The authors have declared that no competing interests exist., (Tian-Rou Wu, Jian Xu, Ming-Tai An, Jiang-Hong Yu, Feng Liu, Zheng-Ren Chen.)

Background: Considering that right paraduodenal hernia is a rare internal hernia with abnormal anatomy and is often encountered during an emergency, surgeons may lack knowledge about it and choose incorrect treatment. Thus, this case report is a helpful complement to the few previously reported cases of right paraduodenal hernia. Additionally, we reviewed all the reported right paraduodenal hernia cases and proposed appropriate surgical strategies according to different anatomical features., Case Presentation: The case involved a 33-year-old Chinese male patient who was admitted to the hospital due to abdominal pain. The patient was initially diagnosed with small bowel obstruction, and conservative treatment failed. An emergency operation was arranged, during which a diagnosis of right paraduodenal hernia was made instead. After surgery, the patient recovered well without abdominal pain for 2 years., Conclusion: Although right paraduodenal hernia accounts only for a small proportion of paraduodenal hernia, its anatomical characteristics can vary considerably. We divided right paraduodenal hernia into three types, with each type requiring a different surgical strategy., (© 2023. The Author(s).)

Background: In December 2022, the Taiwan National Health Insurance Administration (NHIA) announced the reimbursement of three dosages of pemigatinib 4.5 mg, 9 mg, and 13.5 mg for treating advanced intrahepatic cholangiocarcinoma (ICC) with fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements and set the reimbursement price for pemigatinib 4.5 mg at NT$6600. This study aims to analyze the cost-effectiveness of pemigatinib 13.5 mg as a second-line treatment compared to mFOLFOX and 5-FU chemotherapy for advanced ICC patients with FGFR2 fusions/rearrangements from the perspective of Taiwan's NHIA., Methods: This study used a 3-state partitioned survival model to analyze the 5 year cost-effectiveness of pemigatinib as a second-line treatment for advanced ICC patients in whom first-line gemcitabine-based chemotherapy failed and to compare the results with those for the mFOLFOX and 5-FU chemotherapy regimens. Overall survival and progression-free survival were estimated from the FIGHT-202 trial (pemigatinib), ABC-06 trial (mFOLFOX), and NIFTY trial (5-FU). The price of pemigatinib 13.5 mg was set at the potentially highest listing price (NT$17,820). Other parameters of utility, disutility, and costs related to advanced ICC were obtained from the published literature. The willingness-to-pay threshold was three times the forecasted gross domestic product per capita in 2022 (NT$2,928,570). A 3% discount rate was applied to quality-adjusted life-years (QALYs) and costs. Several scenario analyses were performed, including a gradual price reduction for pemigatinib. Deterministic sensitivity analysis, probabilistic sensitivity analysis (PSA), and value of information were performed to assess uncertainty., Results: Pemigatinib was not cost-effective compared to mFOLFOX or 5-FU in the base-case analysis. When the price of pemigatinib was reduced by 50% or more, pemigatinib gained a positive net monetary benefit (mFOLFOX: NT$55,374; 5-FU: NT$92,437) and a 72% (mFOLFOX) and 77.1% (5-FU) probability of being cost-effective. Most of the uncertainty came from the medication cost of pemigatinib, health state utility, and the overall survival associated with pemigatinib., Conclusions: According to the NCCN guidelines, the daily use of pemigatinib 13.5 mg at the hypothesized NHIA price of NT$17,820/13.5 mg was not cost-effective compared to mFOLFOX or 5-FU. The price reduction scenario suggested a 50% price reduction, NT$8910 per 13.5 mg, for advanced ICC patients with FGFR2 fusions/rearrangements., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To explore the mechanism of Shenrong pills in improving oligoasthenospermia by inhibiting oxidative stress-induced Leydig cell apoptosis in mouse testis., Methods: The oxidative stress model of mouse Leydig cells (TM3) was induced by 3% hydrogen peroxide (H2O2) of 600 μmol/L, and then TM3 cells were treated with 7.5%, 10% and 12.5% serum containing Shenrong pills, respectively. TM3 cells were divided into normal control group, model group, and low, medium and high dose groups of Shenrong pills containing serum. The cell viability of TM3 after treatment was detected by CCK-8 method, reactive oxygen species (ROS) were detected by DCFH probe method, and SOD-1, CAT, GSH-px, MDA and LPO in cell lysates were detected by ELISA method. The changes of apoptosis-related proteins Bcl-2, Bax in cell lysates were detected by Western Blot., Results: After H2O2 treatment, compared with normal control group, cell viability was significantly decreased (P< 0.01), MDA and LPO contents were significantly increased (P<0.01), SOD-1, CAT and GSH-px contents were significantly decreased (P<0.01). Reactive oxygen species (ROS) were significantly increased, the relative expression ratio of Bcl-2 protein was significantly decreased (P<0.01, P<0.05), and the relative expression of Bax protein was increased. After the administration of Shenrong pills containing serum, the above indexes were reversed to varying degrees., Conclusion: Shenrong pills can resist oxidative stress, inhibit the apoptosis of TM3 cells in mice, maintain high levels of testosterone required for spermatogenic cells, and improve the sperm quality of mice with oligonasthenospermia.

(1) Purpose: To investigate the efficacy of myopia treatment in children using atropine 0.125% once every two nights (QON) compared with atropine 0.125% once every night (HS). (2) Methods: This retrospective cohort study reviewed the medical records of two groups of children with myopia. Group 1 comprised children treated with atropine 0.125% QON, while group 2 included children treated with atropine 0.125% HS. The first 6 months of data of outcome measurements were subtracted as washout periods in those children undergoing both atropine QON and HS treatment. The independent t-test and Pearson's chi-square test were used to compare the baseline clinical characteristics between the two groups. A generalized estimating equations (GEE) model was used to determine the factors that influence treatment effects. (3) Results: The average baseline ages of group 1 (38 eyes from 19 patients) and group 2 (130 eyes from 65 patients) were 10.6 and 10.2 years, respectively. There were no significant differences in axial length (AL) or cycloplegic spherical equivalent (SEq) at baseline or changes of them after 16.9 months of follow-up. GEE showed that the frequency of atropine 0.125% use has no association with annual AL (QON vs. HS: 0.16 ± 0.10 vs. 0.18 ± 0.12) and SEq (QON vs. HS: -0.29 ± 0.44 vs. -0.34 ± 0.36) changes in all children with myopia. It also showed that older baseline age (B = -0.020, p < 0.001) was associated with lesser AL elongation. (4) Conclusion: The treatment effects of atropine 0.125% HS and QON were similar in this pilot study. The use of atropine 0.125% QON may be an alternative strategy for children who cannot tolerate the side effects of atropine 0.125% HS. This observation should be confirmed with further large-scale studies.

Background: Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism is still insufficiently understood., Methods: In vivo, myocardial ischemia/reperfusion (30 minutes/120 minutes) was induced via ligation and then reperfusion of the left anterior descending coronary artery (LAD) in mice. Intravenous infusion of 10 μg/kg DEX was performed 20 minutes before ligation. Moreover, the α2-adrenoreceptor antagonist Yohimbine and STAT3 inhibitor Stattic were applied 30 minutes ahead of DEX infusion. In vitro, hypoxia/reoxygenation (H/R) with DEX pretreatment for 1 hour was performed in isolated neonatal rat cardiomyocytes. In addition, Stattic was applied before DEX pretreatment., Results: In the mouse cardiac ischemia/reperfusion model, DEX pretreatment lowered the serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 ± 0.165 vs 1.55 ± 0.183; P < .0001), downregulated the inflammatory response ( P ≤ .0303), decreased 4-hydroxynonenal (4-HNE) production and cell apoptosis ( P = .0074), and promoted the phosphorylation of STAT3 (4.94 ± 0.690 vs 6.68 ± 0.710, P = .0001), which could be blunted by Yohimbine and Stattic. The bioinformatic analysis of differentially expressed mRNAs further confirmed that STAT3 signaling might be involved in the cardioprotection of DEX. Upon H/R treatment in isolated neonatal rat cardiomyocytes, 5 μM DEX pretreatment improved cell viability ( P = .0005), inhibited reactive oxygen species (ROS) production and calcium overload (both P ≤ .0040), decreased cell apoptosis ( P = .0470), and promoted STAT3 phosphorylation at Tyr705 (0.102 ± 0.0224 vs 0.297 ± 0.0937; P < .0001) and Ser727 (0.586 ± 0.177 vs 0.886 ± 0.0546; P = .0157), which could be abolished by Stattic., Conclusions: DEX pretreatment protects against myocardial IRI, presumably by promoting STAT3 phosphorylation via the α2-adrenoreceptor in vivo and in vitro., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.)

The use of crystalline metal-organic complexes with definite structures as multilevel memories can enable explicit structure-property correlations, which is significant for designing the next generation of memories. Here, four Zn-polysulfide complexes with different degrees of conjugation have been fabricated as memory devices. ZnS 6 (L) 2 -based memories (L = pyridine and 3-methylpyridine) can exhibit only bipolar binary memory performances, but ZnS 6 (L)-based memories (L = 2,2'-bipyridine and 1,10-phenanthroline) illustrate non-volatile ternary memory performances with high ON2/ON1/OFF ratios (10 4.22 /10 2.27 /1 and 10 4.85 /10 2.58 /1) and ternary yields (74% and 78%). Their ON1 states stem from the packing adjustments of organic ligands upon the injection of carriers, and the ON2 states are a result of the ring-to-chain relaxation of S 6 2- anions. The lower conjugated degrees in ZnS 6 (L) 2 result in less compact packing; consequently, the adjacent S 6 2- rings are too long to trigger the S 6 2- relaxation. The deep structure-property correlation in this work provides a new strategy for implementing multilevel memory by triggering polysulfide relaxation based on the conjugated degree regulation of organic ligands.

Background: To identify the risk factors for postoperative hydrocephalus and the need for ventriculoperitoneal (VP) shunt after posterior fossa tumor (PFT) resection in pediatric patients and establish a predictive model., Methods: A total of 217 pediatric patients (≤14 years old) with PFTs who underwent tumor resection from November 2010 to December 2020 were divided into a VP shunt group (n = 29) and non-VP shunt group (n = 188). Univariate and multivariate logistic regression were performed. A predictive model was established based on the independent predictors. Receiver operating characteristic curves were generated to determine the cutoff values and areas under the curve (AUCs). The Delong test was performed to compare the AUCs., Results: Age less than three years (P = 0.015, odds ratio [OR] = 3.760), blood loss (BL) (P = 0.002, OR = 1.601), and locations at fourth ventricle (P < 0.001, OR = 7.697) were the independent predictors. The predictive model was as follows: total score = age (<3; yes = 2, no = 0) + BL + tumor locations (fourth ventricle; yes = 5, no = 0). The AUC of our model was higher than those of age less than three years, BL, locations at the fourth ventricle, and compound factors (age <3 + locations) (0.842 vs 0.609, 0.734, 0.732, and 0.788, respectively). The cutoff values of the model and BL were 7.5 points and 2.75 U, respectively., Conclusions: BL, age less than three years, and tumors at the fourth ventricle were independent predictors. Model scores over 7.5 points predict a high risk., Competing Interests: Declaration of Competing Interest The authors declare that they research was conducted without any commercial or financial relationships construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Mineral resource bases have dual properties, e.g., mineral resources and environmental pollution. The latter could be classified into natural and anthropogenic pollution based on identifying the spatial distribution characteristics and sources of heavy metals in the soil. The Hongqi vanadium titano-magnetite mineral resources base in Luanping County, Luanhe watershed, was taken as the research object. The geo-accumulation index ( I geo ), Nemerow comprehensive pollution index ( P N ), and potential ecological risk ( E i ) were utilized to assess the soil heavy metal pollution characteristics, and redundancy analysis (RDA) and positive determinate matrix factorization (PMF) were employed to identify sources of the soil heavy metals. The results revealed that the mean contents of Cr, Cu, and Ni in the parent material of medium-basic hornblende metamorphic rock and medium-basic gneisses metamorphic rock were 1-2 times that in other parent materials in the concentrated area of mineral resources. However, the mean contents of Pb and As were lower. Fluvial alluvial-proluvial parent materials had the highest mean content of Hg, and the mean content of Cd was higher in the parent materials of medium-basic gneisses metamorphic rocks, acid rhyolite volcanic rocks, and fluvial alluvial-proluvial facies. The I geo decreased in the following order:Cd>Cu>Pb>Ni>Zn>Cr>Hg>As. P N ranged from 0.61 to 18.99, and the sample proportion of moderate and severe pollution reached 10.00% and 8.08% respectively. P i showed that the contents of Cu, Cd, Cr, and Ni were relatively higher in the parent material of intermediate-basic hornblende metamorphic rocks and intermediate-basic gneiss metamorphic rocks. E i decreased in the order of Hg(58.06)>Cd(39.72)>As(10.98)>Cu(6.56) >Pb(5.60)>Ni(5.43)>Cr(2.01)>Zn(1.10). Samples whose RI was lower than 150 accounted for 84.27%, showing that the research area was predominantly at a slight potential ecological risk level. The sources of soil heavy metals were dominated by parent material weathering, followed by the mixed sources of agricultural activities and transportation, the exploitation of mining, and fossil burning, which accounted for 41.44%, 31.83%, 22.01%, and 4.73%, respectively. The risks of heavy metal pollution in the mineral resource base were characterized as multi-source instead of the single source from the mining industry. These research results provide the scientific basis for regional green mining development and eco-environmental protection.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint damage and disability. However, the specific mechanism of RA has not been thoroughly clarified over the past decade. Nitric oxide (NO), a kind of gas messenger molecule with many molecular targets, is demonstrated to have significant roles in histopathology and homeostasis. Three nitric oxide synthases (NOS) are related to producing NO and regulating the generation of NO. Based on the latest studies, NOS/NO signaling pathways play a key role in the pathogenesis of RA. Overproduction of NO can induce the generation and release of inflammatory cytokines and act as free radical gas to accumulate and trigger oxidative stress, which can involve in the pathogenesis of RA. Therefore, targeting NOS and its upstream and downstream signaling pathways may be an effective approach to managing RA. This review clearly summarizes the NOS/NO signaling pathway, the pathological changes of RA, the involvement of NOS/NO in RA pathogenesis and the conventional and novel drugs based on NOS/NO signaling pathways that are still in clinical trials and have good therapeutic potential in recent years, with an aim to provide a theoretical basis for further exploration of the role of NOS/NO in the pathogenesis, prevention and treatment of RA.

Immune and inflammatory responses have an important function in the pathophysiology of pulmonary hypertension (PH). However, little is known about the immune landscape in peripheral circulation in patients with high-altitude pulmonary hypertension (HAPH). We apply single-cell transcriptomics to characterize the monocytes that are significantly enriched in the peripheral blood mononuclear cells (PBMC) of HAPH patients. We discover an increase in C1 (non-classical) and C2 (intermediate) monocytes in PBMCs and a decrease in hypoxia-inducible transcription factor-1α (HIF-1α) in all monocyte subsets associated with HAPH. In addition, we demonstrate that similar immune adaptations may exist in HAPH and PH. Overall, we characterize an immune cell atlas of the peripheral blood in HAPH patients. Our data provide evidence that specific monocyte subsets and HIF-1α downregulation might be implicated in the pathogenesis of HAPH., (© 2023. The Author(s).)

Background: Refractory mycoplasma pneumoniae pneumonia (RMPP) is a serious mycoplasma pneumoniae infection and is difficult to diagnose early. The levels of serum soluble B7-dendritic cell (sB7-DC) in children with mycoplasma pneumoniae pneumonia (MPP) were assessed to explore the clinical significance of sB7-DC levels in RMPP., Methods: A total of 65 patients with mycoplasma pneumoniae pneumonia (MPP) were enrolled in this study between January 2017 and December 2018. The patients were divided into the general mycoplasma pneumoniae pneumonia (GMPP) (n=30) and RMPP groups (n=35); the data of 20 normal children served as a control group (n=20). An enzyme-linked immunoassay kit was used to detect the expression of soluble B7-dendritic cell (sB7-DC) and other inflammatory factors. Binary logistic regression was performed to identify the independent predictors of RMPP. Receiver operating characteristic (ROC) curves were drawn to evaluate the value of each independent risk factor in the early diagnosis of RMPP., Results: The results showed that compared to the GMPP group, children in the RMPP group had a significantly longer hospital stay and had a significantly longer fever duration (P<0.05). The values of interferon-gamma (IFN-γ), interleukin 17 (IL-17), and sB7-DC in the RMPP group were significantly higher than those in the normal control and GMPP groups (all P<0.05). The results of the correlation analysis showed that sB7-DC was positively correlated with IFN-γ and IL-17 and these indicators could be used in combination to evaluate the severity of the disease. The binary logistic regression analysis identified IL-17 and sB7-DC as independent risk factors for RMPP (P<0.05). The ROC curve analysis showed that the cut-off values of IL-17 and sB7-DC were 309.6 pg/L and 1,109.7 pg/mL, respectively. The areas under the curve (AUCs) of IL-17 and sB7-DC were 0.741 and 0.794, respectively. The sensitivity of IL-17 to RMPP prediction was 83.3%, and the specificity was 62.9%. The sensitivity and specificity of sB7-DC to RMPP were 86.7% and 62.9%, indicating that sB7-DC had the highest predictive power for RMPP., Conclusions: The level of serum sB7-DC may play an important role in the early diagnosis of RMPP. Our research results provide a theoretical basis for the early diagnosis of RMPP., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-86/coif). The authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

This study aimed to investigate the effect of varying the hardness of prefabricated orthopedic insoles on plantar pressure and muscle fatigue during uphill walking with a heavy backpack. Fifteen healthy male recreational athletes (age: 20.4 ± 1.0 years, height: 176.9 ± 5.7 cm, weight: 76.5 ± 9.0 kg) wore prefabricated orthopedic insoles with foot arch support; a heel cup with medium (MI), hard (HI), and soft (SI) relative hardnesses; and flat insoles (FI). They performed treadmill walking on uphill gradients with 25 kg backpacks. The plantar pressure and surface electromyographic activity were recorded separately, in 30 s and 6 min uphill treadmill walking trials, respectively. The HI, MI, and SI significantly decreased peak plantar pressure in the lateral heel compared to FI. The MI and SI significantly decreased the peak plantar pressure in the fifth metatarsal compared to FI. The MI significantly reduced the pressure-time integral in the lateral heel compared to FI. The HI significantly increased the peak plantar pressure and pressure-time integral in the toes compared to other insoles, and decreased the contact area in the metatarsal compared to SI. In conclusion, a prefabricated orthopedic insole made of soft material at the fore- and rearfoot, with midfoot arch support and a heel cup, may augment the advantages of plantar pressure distribution during uphill weighted walking.

Background and Objectives: The National Comprehensive Cancer Network recommends a second-line treatment of pemigatinib for patients with intrahepatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements and modified FOLFOX (mFOLFOX) for those without FGFR2 alterations. However, these regimens are not yet covered by Taiwa's National Health Insurance. This cost-effectiveness analysis evaluated the cost-effectiveness of the pemigatinib/mFOLFOX regimen as the second-line treatment for advanced intrahepatic cholangiocarcinoma based on FGFR2 status in comparison with the regimen of fluorouracil chemotherapy and provided a cost-effectiveness analysis-based reference price for pemigatinib., Methods: A three-state partitioned survival model with a 5-year time horizon was constructed for patients with advanced intrahepatic cholangiocarcinoma who did not respond to first-line therapy. Overall and progression-free survival functions of pemigatinib, mFOLFOX, and fluorouracil were estimated from the FIGHT-202, ABC-06, and NIFTY trials, respectively. The utility of health states and disutility of adverse events were obtained from the literature. The genetic testing fee and price of pemigatinib were set as the market price. Other costs related to advanced intrahepatic cholangiocarcinoma were calculated using National Health Insurance claims data. The willingness-to-pay threshold was three times the gross domestic product per capita in 2021 (NT$2,889,684). A 3% discount rate was applied to quality-adjusted life-years and costs. Scenario analyses included a gradual price reduction of pemigatinib, alternative survival models, application of a National Health Insurance payment conversion factor to non-medication costs, and consideration of life-years as effectiveness. A deterministic sensitivity analysis, probabilistic sensitivity analysis, and a value of information analysis were performed., Results: The new regimen provided an incremental 0.13 quality-adjusted life-years, with incremental costs of NT$459,697, yielding an incremental cost-effectiveness ratio of NT$3,411,098 per quality-adjusted life-year and an incremental net monetary benefit of - NT$70,268. The new regimen was found to be 53.2% cost effective in the probabilistic sensitivity analysis. The expected value of uncertainty measured by the expected value of perfect information was NT$80,695/person. In scenario analyses, the incremental net monetary benefit was positive when the price of pemigatinib was reduced by 40% or more. When applying a conversion factor to non-medical costs, the probability of the new regimen being cost effective was slightly increased from 53.2 to 56.5% compared with the base-case analysis. The utility and the cost of the new regimen were the main drivers of uncertainty., Conclusions: Although the new second-line genetic-based and biomarker-driven regimen of pemigatinib/mFOLFOX appears not cost effective for patients with advanced intrahepatic cholangiocarcinoma in the base-case analysis, our analysis suggests it is highly likely to be cost effective in the case of a 40% price reduction on pemigatinib., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Schizophrenia is a chronic and severe mental disorder. People with schizophrenia have transferred from hospital-based care to community-based care with the support of mental health legal policies. Challenges faced in the community should be emphasized. Limited qualitative studies have explored the challenges of living with schizophrenia., Aims: To explore the challenges of people living with schizophrenia in the community., Methods: A narrative method was used, including semi-structured, face-to-face interviews. Thematic analysis approach was used to analyze data., Results: Ten clients and their family members participated in the study. Analysis revealed three main themes related to their challenges in the community: deficits in self-management of illness; insufficient community mental health care; and the influence of policy. These challenges prevent those with schizophrenia from effectively managing their illness, returning to a productive role in society, and improving their quality of life., Conclusions: There are challenges in mental health rehabilitation and social reintegration of individuals with schizophrenia. There is a need for continuous community mental rehabilitation services, appropriate policy support, and the need to educate the public to reduce social bias and discrimination which allows individuals with schizophrenia to assume a productive role in the community.

Objective: To construct and verificate an RNA-binding protein (RBP)-associated prognostic model for gliomas using integrated bioinformatics analysis., Methods: RNA-sequencing and clinic pathological data of glioma patients from The Cancer Genome Atlas (TCGA) database and the Chinese Glioma Genome Atlas database (CGGA) were downloaded. The aberrantly expressed RBPs were investigated between gliomas and normal samples in TCGA database. We then identified prognosis related hub genes and constructed a prognostic model. This model was further validated in the CGGA-693 and CGGA-325 cohorts., Results: Totally 174 differently expressed genes-encoded RBPs were identified, containing 85 down-regulated and 89 up-regulated genes. We identified five genes-encoded RBPs (ERI1, RPS2, BRCA1, NXT1, and TRIM21) as prognosis related key genes and constructed a prognostic model. Overall survival (OS) analysis revealed that the patients in the high-risk subgroup based on the model were worse than those in the low-risk subgroup. The area under the receiver operator characteristic curve (AUC) of the prognostic model was 0.836 in the TCGA dataset and 0.708 in the CGGA-693 dataset, demonstrating a favorable prognostic model. Survival analyses of the five RBPs in the CGGA-325 cohort validated the findings. A nomogram was constructed based on the five genes and validated in the TCGA cohort, confirming a promising discriminating ability for gliomas., Conclusion: The prognostic model of the five RBPs might serve as an independent prognostic algorithm for gliomas., (© 2023. Huazhong University of Science and Technology.)

Objectives: To investigate the epidemiological characteristics of respiratory Haemophilus influenzae (HI) infection in children in Suzhou, China and its association with climatic factors and air pollutants., Methods: The data on air pollutants and climatic factors in Suzhou from January 2016 to December 2019 were collected. Respiratory secretions were collected from 7 940 children with acute respiratory infection who were hospitalized during this period, and bacterial culture results were analyzed for the detection of HI. A stepwise regression analysis was used to investigate the association of HI detection rate with air pollutants (PM 2.5 , PM 10 , NO 2 , SO 2 , CO, and O 3 ) and climatic factors (monthly mean temperature, monthly mean humidity, monthly total rainfall, monthly total sunshine duration, and monthly mean wind speed)., Results: In 2016-2019, the 4-year overall detection rate of HI was 9.26% (735/7 940) among the children in Suzhou. The children aged <1 year and 1-<3 years had a significantly higher HI detection rate than those aged ≥3 years ( P <0.01). The detection rate of HI in spring was significantly higher than that in the other three seasons, and the detection rate of HI in autumn was significantly lower than that in the other three seasons ( P <0.001). The multiple linear regression analysis showed that PM 10 and monthly mean wind speed were independent risk factors for the detection rate of HI: the detection rate of HI was increased by 0.86% for every 10 µg/m 3 increase in the concentration of PM 10 and was increased by 5.64% for every 1 m/s increase in monthly mean wind speed. Air pollutants and climatic factors had a lag effect on the detection rate of HI., Conclusions: HI is an important pathogen for acute respiratory infection in children in Suzhou and is prevalent in spring. PM 10 and monthly mean wind speed are independent risk factors for the detection rate of HI.

Background: The effect of chronic psychological stress on hepatitis and liver fibrosis is concerned. However, its mechanism remains unclear. We investigated the effect and mechanism of chronic psychological stress in promoting liver injury and fibrosis through gut., Methods: Sixty male SD rats were randomly assigned to 6 groups. Rat models of chronic psychological stress (4 weeks) and liver fibrosis (8 weeks) were established. The diversity of gut microbiota in intestinal feces, permeability of intestinal mucosa, pathologies of intestinal and liver tissues, collagen fibers, protein expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa β (NF-κβ), tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) in liver tissue, liver function and coagulation function in blood and lipopolysaccharide (LPS) in portal vein blood were detected and analyzed., Results: The diversities and abundances of gut microbiota were significant differences in rats among each group. The pathological lesions of intestinal and liver tissues, decreased expression of occludin protein in intestinal mucosa, deposition of collagen fibers and increased protein expression of TLR4, MyD88, NF-κβ, TNF-α and IL-1 in liver tissue, increased LPS level in portal vein blood, and abnormalities of liver function and coagulation function, were observed in rats exposed to chronic psychological stress or liver fibrosis. There were significant differences with normal rats. When the dual intervention factors of chronic psychological stress and liver fibrosis were superimposed, the above indicators were further aggravated., Conclusion: Chronic psychological stress promotes liver injury and fibrosis, depending on changes in the diversity of gut microbiota and increased intestinal permeability caused by psychological stress, LPS that enters liver and acts on TLR4, and active LPS-TLR4 pathway depend on MyD88. It demonstrates the possibility of existence of brain-gut-liver axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Guo, Li, Lou, Chen, Liu and Lan.)

Polo-like kinase 1 (PLK1) is a serine/threonine kinase involving lipid metabolism and cardiovascular disease. However, its role in atherogenesis has yet to be determined. The aim of this study was to observe the impact of PLK1 on macrophage lipid accumulation and atherosclerosis development and to explore the underlying mechanisms. We found a significant reduction of PLK1 expression in lipid-loaded macrophages and atherosclerosis model mice. Lentivirus-mediated overexpression of PLK1 promoted cholesterol efflux and inhibited lipid accumulation in THP-1 macrophage-derived foam cells. Mechanistic analysis revealed that PLK1 stimulated the phosphorylation of AMP-activated protein kinase (AMPK), leading to activation of the peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα) pathway and up-regulation of ATP binding cassette transporter A1 (ABCA1) and ABCG1 expression. Injection of lentiviral vector expressing PLK1 increased reverse cholesterol transport, improved plasma lipid profiles and decreased atherosclerotic lesion area in apoE-deficient mice fed a Western diet. PLK1 overexpression also facilitated AMPK and HSL phosphorylation and enhanced the expression of PPARγ, LXRα, ABCA1, ABCG1 and LPL in the aorta. In summary, these data suggest that PLK1 inhibits macrophage lipid accumulation and mitigates atherosclerosis by promoting ABCA1- and ABCG1-dependent cholesterol efflux via the AMPK/PPARγ/LXRα pathway., Competing Interests: Declaration of competing interest The authors declare they do not have anything to disclose regarding conflicts of interest with respect to this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cochlear ribbon synapses formed between spiral ganglion neurons and inner hair cells in postnatal mice must undergo significant morphological and functional development to reach auditory maturation. However, the mechanisms underlying cochlear ribbon synapse remodeling remain unclear. This study found that cochlear resident macrophages are essential for cochlear ribbon synapse development and maturation in mice via the CX3CR1/CX3CL1 axis. CX3CR1 expression (a macrophage surface-specific receptor) and macrophage count in the cochlea were significantly increased from postnatal day 7 then decreased from days 14 to 28. Seven-day treatment with CX3CR1 inhibitors and artificial upregulation of CX3CL1 levels in the inner ear environment using the semicircular canal injection technique were initiated on day 7, and this resulted in a significant increase in hearing threshold on day 28. Additionally, abnormalities in the morphology and number of cochlear ribbon synapses were detected on day P14, which may be associated with hearing impairment. In conclusion, macrophage regulation of cochlear ribbon synapse remodeling via the CX3CR1/CX3CL1 axis is required during hearing development and offers a new perspective on immune-related hearing loss throughout auditory development. Importantly, it could be a new treatment target for sensorineural hearing loss., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Song, Li, Guo, Yu, Liu, Teng, Chen, Xie, Gong and Liu.)

Adeno-associated virus (AAV)-mediated gene transfer is an efficient method of gene over-expression in the vestibular end organs. However, AAV has limited usefulness for delivering a large gene, or multiple genes, due to its small packaging capacity (< 5 kb). Co-transduction of dual-AAV vectors can be used to increase the packaging capacity for gene delivery to various organs and tissues. However, its usefulness has not been well validated in the vestibular sensory epithelium. In the present study, we characterized the co-transduction of dual-AAV vectors in mouse utricles following inoculation of two AAV-serotype inner ear (AAV-ie) vectors via canalostomy. Firstly, co-transduction efficiencies were compared between dual-AAV-ie vectors using two different promoters: cytomegalovirus (CMV) and CMV early enhancer/chicken β-actin (CAG). In the group of dual AAV-ie-CAG vectors, the co-transduction rates for striolar hair cells (HCs), extrastriolar HCs, striolar supporting cells (SCs), and extrastriolar SCs were 23.14 ± 2.25%, 27.05 ± 2.10%, 57.65 ± 7.21%, and 60.33 ± 5.69%, respectively. The co-transduction rates in the group of dual AAV-ie-CMV vectors were comparable to those in the dual AAV-ie-CAG group. Next, we examined the co-transduction of dual-AAV-ie-CAG vectors in the utricles of neonatal mice and damaged adult mice. In the neonatal mice, co-transduction rates were 52.88 ± 3.11% and 44.93 ± 2.06% in the striolar and extrastriolar HCs, respectively, which were significantly higher than those in adult mice. In the Pou4f3 +/DTR mice, following diphtheria toxin administration, which eliminated most HCs and spared the SCs, the co-transduction rate of SCs was not significantly different to that of normal utricles. Transgene expression persisted for up to 3 months in the adult mice. Furthermore, sequential administration of two AAV-ie-CAG vectors at an interval of 1 week resulted in a higher co-transduction rate in HCs than concurrent delivery. The auditory brainstem responses and swim tests did not reveal any disruption of auditory or vestibular function after co-transduction with dual-AAV-ie vectors. In conclusion, dual-AAV-ie vectors allow efficient co-transduction in the vestibular sensory epithelium and facilitate the delivery of large or multiple genes for vestibular gene therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Guo, He, Liu, Xu, Yang, Su, Liu, Gong and Wang.)

Stroke is a fatal neurological disease, which seriously threatens human health and life. Ischemic stroke (IS) is the most common type of stroke in clinic. Its pathogenesis is very complex, mainly caused by nerve damage caused by brain blood supply disorder. Previous studies have confirmed that natural products play important roles in improving neurological disorders. Furthermore, our previous results also suggested that Shenxiong Tongmai granule, a clinically used herbal medicines' prescription, has a good ameliorating effect on IS. In the present study, we found that Monomethyl lithospermate (MOL), a constituent of Shenxiong Tongmai granule, significantly improved the neurological damage in middle cerebral artery occlusion (MCAO) rats. MOL can significantly improve the neurological deficit score of MCAO rats, and improve the damage of hippocampal neurons caused by ischemia-reperfusion (IR). At the same time, we also found that MOL could reduce the level of oxidative stress in the brain tissues of MCAO rats. Furthermore, the oxygen and glucose deprivation/Reoxygenation (OGD/R)-induced SHSY-5Y cell model was established in vitro to investigate the pharmacological activity and molecular mechanisms of MOL in improving the nerve injury of IS rats. The results showed that MOL could increase the cell viability of SHSY-5Y cells, inhibit the mitochondrial membrane potential (MMOP) collapse and suppress apoptosis. In addition, MOL also ameliorated the elevated oxidative stress level caused by OGR/R treatment in SHSY-5Y cells. Further mechanistic studies showed that MOL could activate the PI3K/AKT pathway via promoting the phosphorylation of PI3K and AKT in MCAO rats and OGR/R-induced SHSY-5Y cells, which could be partially blocked by addition of PI3K/AKT pathway inhibitor of LY294002. Taken together, our current study suggested that MOL exerts a protective effect against neural damage caused by IS in vivo and in vitro by activating the PI3K/AKT pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Chen, Yang, Xu, Ran, Liu, Jin, Jia and Zhang.)

Shared decision-making (SDM) is a scientific and reasonable decision-making model. However, whether physicians choose SDM is usually influenced by many factors. It is not clear whether the strained doctor-patient relationship will affect physicians' willingness to choose SDM. Through a survey by questionnaire, 304 physicians' evaluations of doctor-patient relationship (DPR) were quantified by the difficult DPR questionnaire-8. Their preferences for SDM and the reasons were also evaluated. The correlation between physicians' evaluations of DPR and their preferences for SDM were analyzed. 84.5% physicians perceived DPR as poor or strained, 53.3% physicians preferred SDM, mainly because of the influences of medical ethics and social desirability bias. Their preferences for SDM were not significantly correlated with their evaluations of DPR ( P > 0.05). Physicians with different evaluations of DPR (good, poor, and strained) all had similar preferences for SDM (42.6, 56.4, and 42.9%), with no significant difference ( P > 0.05). There was no correlation between physicians' evaluations of DPR and their preferences for SDM. Physicians' evaluations of poor DPR did not affect their preferences for SDM. This may be influenced by the medical ethics and social desirability bias., Competing Interests: Author Y-WC was employed by the company Genecast Biotechnology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Zhang, Chen, Xu, Jia, Li, Lou and Lan.)

There was inconsistent evidence regarding the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for microorganism identification with/without antibiotic stewardship team (AST) and the clinical outcome of patients with bloodstream infections (BSI). In a systematic review and meta-analysis, we evaluated the effectiveness of rapid microbial identification by MALDI-TOF MS with and without AST on clinical outcomes. We searched PubMed and EMBASE databases from inception to 1 February 2022 to identify pre-post and parallel comparative studies that evaluated the use of MALDI-TOF MS for microorganism identification. Pooled effect estimates were derived using the random-effects model. Twenty-one studies with 14,515 patients were meta-analysed. Compared with conventional phenotypic methods, MALDI-TOF MS was associated with a 23% reduction in mortality (RR = 0.77; 95% CI: 0.66; 0.90; I 2  = 35.9%; 13 studies); 5.07-h reduction in time to effective antibiotic therapy (95% CI: -5.83; -4.31; I 2  = 95.7%); 22.86-h reduction in time to identify microorganisms (95% CI: -23.99; -21.74; I 2  = 91.6%); 0.73-day reduction in hospital stay (95% CI: -1.30; -0.16; I 2  = 53.1%); and US$4140 saving in direct hospitalization cost (95% CI: $-8166.75; $-113.60; I 2  = 66.1%). No significant heterogeneity sources were found, and no statistical evidence for publication bias was found. Rapid pathogen identification by MALDI-TOF MS with or without AST was associated with reduced mortality and improved outcomes of BSI, and may be cost-effective among patients with BSI., (© 2022 The Authors. Microbial Biotechnology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)