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Background: The precise association between lncRNA H19 and ferroptosis in the context of atherosclerosis remains uncertain., Objective: This study is to clarify the underlying process and propose novel approaches for the advancement of therapeutic interventions targeting atherosclerosis., Methods: Assessment of ferroptosis, which entails the evaluation of cell viability using CCK-8 and the quantification of intracellular MDA, GSH, and ferrous ions. Simultaneously, the protein expression levels of assessed by western blot analysis, while the expression level of lncRNA H19 was also determined. Furthermore, HAECs that were cultured with ox-LDL were subjected to Fer-1 interference. HAECs were exposed to ox-LDL and then transfected with H19 shRNA and H19 overexpression vector pcDNA3.1. The level of ferroptosis in the cells was then measured. Then, HAECs were subjected to incubation with ox-LDL, followed by transfection with H19 shRNA and treated with Erastin to assess the levels of ferroptosis, cell viability, and inflammatory factor production. and the ability for blood vessel development., Results: The survival rate of HAECs in the ox-LDL group was much lower. Ox-LDL resulted in an upregulation of ACSL4 expression in HAECs, while the expression of SLC7A11 and GPX4 decreased., Conclusions: lncRNA H19 enhances ferroptosis and exacerbates arterial endothelial cell damage induced by LDL.

Background: Alopecia areata (AA) is an autoimmune disorder characterized by hair loss on the scalp, face, and other body areas. Despite affecting approximately 2% of the global population, there has been no previous bibliometric analysis specifically focusing on AA treatment that can guide researchers in exploring promising treatment options and directing future research efforts., Summary: This study conducted a bibliometric analysis of AA treatment research, encompassing publications from 2003 to 2022. A total of 1,323 papers from 65 countries, predominantly led by the USA and China, were included in the analysis. The number of publications related to AA treatment showed a notable increase over the years. Prominent research institutions included the University of Manchester, Icahn School of Medicine at Mount Sinai, University of Miami, and Columbia University. Among the journals, Dermatologic Therapy stood out as the most popular, while the Journal of the American Academy of Dermatology appeared as the most frequently co-cited publication., (© 2023 S. Karger AG, Basel.)

Histone methyltransferase SETDB1 (SET domain bifurcated histone lysine methyltransferase 1, also known as ESET or KMT1E) is known to be involved in the deposition of the di- and tri-methyl marks on H3K9 (H3K9me2 and H3K9me3), which are associated with transcription repression. SETDB1 exerts an essential role in the silencing of endogenous retroviruses (ERVs) in embryonic stem cells (mESCs) by tri-methylating H3K9 (H3K9me3) and interacting with DNA methyltransferases (DNMTs). Additionally, SETDB1 is engaged in regulating multiple biological processes and diseases, such as ageing, tumors, and inflammatory bowel disease (IBD), by methylating both histones and non-histone proteins. In this review, we provide an overview of the complex biology of SETDB1, review the upstream regulatory mechanisms of SETDB1 and its partners, discuss the functions and molecular mechanisms of SETDB1 in cell fate determination and stem cell, as well as in tumors and other diseases. Finally, we discuss the current challenges and prospects of targeting SETDB1 for the treatment of different diseases, and we also suggest some future research directions in the field of SETDB1 research., (© 2023. The Author(s).)

Pyridalyl, as a novel insecticide with an unknown mode of action, has shown excellent control efficacy against lepidopterous larvae and thrips. Previous modifications of this compound have mostly focused on the pyridine moiety, with limited information available about modifications to other parts of pyridalyl. In this paper, we report the synthesis and insecticidal activity of a series of azidopyridryl-containing dichlorolpropene ether derivatives, based on modifications to the middle alkyl chain of pyridalyl. Screening results for insecticidal activity indicate that our synthesized compounds show moderate to high activities at the tested concentrations against P. xylostella . Particularly, compound III-10 exhibits a LC 50 value of 0.831 mg L -1 , compared to the LC 50 value of pyridalyl at 2.021 mg L -1 . Furthermore, compound III-10 also displays a relatively broad insecticidal spectrum against Lepidoptera pests M. separata , C. suppressalis , O. nubilalis , and C. medinalis . Finally, in field trials, III-10 demonstrates better control efficiency against Chilo suppressalis compared to pyridalyl. Overall, our findings suggest that the modification of the middle alkyl chain of pyridalyl may be a promising approach for developing insecticides with improved efficacy.

This article analyzed the clinical data and on-site occupational health survey results of a patient with occupational acute methyl acetate poisoning in Zhejiang. Based on the pathways of methyl acetate poisoning and the characteristics of target organ damage, diagnosis and treatment experience were summarized, providing reference for the diagnosis and treatment of occupational acute methyl acetate poisoning and occupational health monitoring of methyl acetate.

Objectives: To study the efficacy and safety of Xiyanping injection through intramuscular injection for the treatment of acute bronchitis in children., Methods: A prospective study was conducted from December 2021 to October 2022, including 78 children with acute bronchitis from three hospitals using a multicenter, randomized, parallel-controlled design. The participants were divided into a test group (conventional treatment plus Xiyanping injection; n =36) and a control group (conventional treatment alone; n =37) in a 1:1 ratio. Xiyanping injection was administered at a dose of 0.3 mL/(kg·d) (total daily dose ≤8 mL), twice daily via intramuscular injection, with a treatment duration of ≤4 days and a follow-up period of 7 days. The treatment efficacy and safety were compared between the two groups., Results: The total effective rate on the 3rd day after treatment in the test group was significantly higher than that in the control group ( P <0.05), while there was no significant difference in the total effective rate on the 5th day between the two groups ( P >0.05). The rates of fever relief, cough relief, and lung rale relief in the test group on the 3rd day after treatment were higher than those in the control group ( P <0.05). The cough relief rate on the 5th day after treatment in the test group was higher than that in the control group ( P <0.05), while there was no significant difference in the fever relief rate and lung rale relief rate between the two groups ( P >0.05). The cough relief time, daily cough relief time, and nocturnal cough relief time in the test group were significantly shorter than those in the control group ( P <0.05), while there were no significant differences in the fever duration and lung rale relief time between the two groups ( P >0.05). There was no significant difference in the incidence of adverse events between the two groups ( P >0.05)., Conclusions: The overall efficacy of combined routine treatment with intramuscular injection of Xiyanping injection in the treatment of acute bronchitis in children is superior to that of routine treatment alone, without an increase in the incidence of adverse reactions.

Excessive oxidative stress will cause significant injury to osteoblasts, serving as one major pathological mechanism of osteoporosis. Neuroligin-3 (NLGN3) is a postsynaptic cell adhesion protein and is expressed in the bone. We here explored its potential activity against hydrogen peroxide (H 2 O 2 )-induced oxidative injury in cultured osteoblasts. In primary murine and human osteoblasts, NLGN3 stimulation dose-dependently induced Akt, Erk1/2 and S6K activation. NLGN3 pretreatment ameliorated H 2 O 2 -induced cytotoxicity and death in osteoblasts. Moreover, H 2 O 2 -induced reactive oxygen species (ROS) production and oxidative injury were alleviated with NLGN3 pretreatment in cultured osteoblasts. Further studies showed that NLGN3 activated Nrf2 signaling cascade and induced Nrf2 protein Serine-40 phosphorylation, Keap1-Nrf2 dissociation, Nrf2 protein stabilization and nuclear translocation in osteoblasts. NLGN3 also increased antioxidant response element (ARE) activity and induced expression of Nrf2-ARE-dependent genes (HO1, GCLC and NQO1) in osteoblasts. Moreover NLGN3 mitigated osteoblast oxidative injury by dexamethasone or sodium fluoride (NaF). Nrf2 cascade activation is essential for NLGN3-induced cytoprotective activity in osteoblasts. Nrf2 shRNA or knockout (KO) abolished NLGN3-induced osteoblast cytoprotection against H 2 O 2 . Contrarily forced Nrf2 cascade activation by Keap1 KO mimicked NLGN3-induced anti-oxidative activity in murine osteoblasts. Importantly, NLGN3-induced Serine-40 phosphorylation and Nrf2 cascade activation were blocked by an Akt inhibitor MK-2206 or by Akt1 shRNA. Importantly, Akt inhibition, Akt1 silencing or Nrf2 S40T mutation largely inhibited NLGN3-induced osteoblast cytoprotection against H 2 O 2 . At last, we showed that NLGN3 mRNA and protein expression was significantly downregulated in necrotic bone tissues of dexamethasone-taken patients. Taken together, NLGN3 activated Akt-dependent Nrf2 cascade to protect osteoblasts from oxidative stress., Competing Interests: Declaration of competing interest All the authors listed assure that the data in the manuscript is original and the manuscript is not under consideration elsewhere. None of the manuscript contents have been previously published. All authors have made significant contributions of this work, and have read and approved all versions of the manuscript, its content, and its submission to the Free Radical Biology and Medicine. The authors have no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Ovarian cancer is a common gynecological malignant tumor in women. Most patients have reached the advanced stage when they visit the hospital. In order to diagnose ovarian cancer at an early stage, treat it at an early stage, and improve the survival rate of patients, this study has used the imaging computed tomography (CT) method to diagnose stage IA ovarian cancer., Purpose: The purpose of this work was to study CT features of stage IA ovarian cancer, and compare the borderline tumor and stage IC ovarian cancer at the same time so as to improve the CT diagnosis of early ovarian cancer., Methods: We retrospectively collected clinical and CT data of patients with stage I ovarian cancer and borderline ovarian tumor admitted to Nantong Tumor Hospital from 2013 to 2021. Altogether, 23 cases of patients (borderline ovarian tumor, 9 cases; stage IA ovarian cancer, 5 cases; stage IC ovarian cancer, 9 cases) were involved. CT characteristics of these patients were analyzed in terms of the tumor diameter, cystic solid structure, solid component, septation, enhancement, peritoneal thickening, ascites, and abdominal lymph nodes., Results: CT features of stage IA ovarian cancer included large tumor size (average diameter: 15 cm), cystic solid structure (4/5; 80%), septation (4/5; 80%), and enhanced cystic wall, septum, or solid components of the tumor on contrast-enhanced CT (5/5; 100%) no peritoneal thickening (0/5; 0%), no ascites (0/5; 0%), and no abdominal lymph node enlargement (0/5; 0%). The tumor structure did not differ significantly between stage IA and IC ovarian cancers (p > 0.05), while intraperitoneal ascites did (χ2 = 0.031; p < 0.05). Stage IA and borderline ovarian tumors did not differ significantly in ovarian tumor structure (p > 0.05)., Conclusion: CT features of stage IA ovarian cancer included large tumor size, cystic solid structure, septation, and enhanced cystic wall and solid parts in the tumors. No pelvic or abdominal metastasis was observed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Emerging evidence indicates that DNA methylation plays an important role in the initiation and progression of nasopharyngeal carcinoma (NPC). DNAJA4 is hypermethylated in NPC, while its role in regulating NPC progression remains unclear. Here, we revealed that the promoter of DNAJA4 was hypermethylated and its expression was downregulated in NPC tissues and cells. Overexpression of DNAJA4 significantly suppressed NPC cell migration, invasion, and EMT in vitro, and markedly inhibited the inguinal lymph node metastasis and lung metastatic colonization in vivo, while it did not affect NPC cell viability and proliferation capability. Mechanistically, DNAJA4 facilitated MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Furthermore, the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT were reversed by overexpression of MYH9 in NPC cells. Clinically, a low level of DNAJA4 indicated poor prognosis and an increased probability of distant metastasis in NPC patients. Collectively, DNAJA4 serves as a crucial driver for NPC invasion and metastasis, and the DNAJA4-PSMD2-MYH9 axis might contain potential targets for NPC treatments., (© 2023. The Author(s).)

Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-β (Aβ) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aβ metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aβ is essential for preventing Aβ deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepatic sEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology, and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The behavior of vascular smooth muscle cells (VSMCs) contributes to the formation of neointima. We previously found that EHMT2 suppressed autophagy activation in VSMCs. BRD4770, an inhibitor of EHMT2/G9a, plays a critical role in several kinds of cancers. However, whether and how BRD4770 regulates the behavior of VSMCs remain unknown. In this study, we evaluate the cellular effect of BRD4770 on VSMCs by series of experiments in vivo and ex vivo. We demonstrated that BRD4770 inhibited VSMCs' growth by blockage in G2/M phase in VSMCs. Moreover, our results demonstrated that the inhibition of proliferation was independent on autophagy or EHMT2 suppression which we previous reported. Mechanistically, BRD4770 exhibited an off-target effect from EHMT2 and our further study reveal that the proliferation inhibitory effect by BRD4770 was associated with suppressing on SUV39H2/KTM1B. In vivo, BRD4770 was also verified to rescue VIH. Thus, BRD4770 function as a crucial negative regulator of VSMC proliferation via SUV39H2 and G2/M cell cycle arrest and BRD4770 could be a molecule for the therapy of vascular restenosis., (© 2023. The Author(s).)

Introduction: The current study aims to investigate the etiology spectrum and the clinical characteristics of bronchiectasis in Chinese children., Methods: The study is designed as a multicenter retrospective study. 193 cases were enrolled in 13 centers in China between 2008 and 2017. The inclusive cases must meet the clinical as well as the HRCT criteria. Only if both two radiologists confirmed the diagnosis, the case could be enrolled. The cases that could not provide clinical and imageology data were excluded. The data were entered into the specialized system and then analyzed., Results: One hundred sixty-nine cases (87%) were found to have the underlying etiology. Post-infective (46%), primary immunodeficiency (14%), and PCD (13%) were the common causes. All cases came from 28 provinces in Mainland China. The median age of symptom onset was 5.8 (2.0, 8.9) years. The median age of diagnosis was 8.4 (4.5, 11.6) years. The main symptoms were cough, sputum expectoration, and fever during the exacerbation. Nineteen percent of patients suffered from limited exercise tolerance. Clubbing was found in 17% of cases. Nearly 30% of patients presented growth limitations. On the HRCT findings, 126 cases had diffused bronchiectasis, and bilateral involvement was found in 94 cases. The lower lobes and right middle lobes were most commonly involved. Approximately 30% of cultures of sputum and bronchoalveolar lavage were positive., Conclusion: A majority of cases could be found the underlying etiology. Post-infective, primary immunodeficiency, and PCD were the most common causes. Some clinical figures might indicate a specific etiology., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Objective: We compared the outcome of radical prostatectomy (RP) with seed brachytherapy (BT) in clinically localized prostate cancer (LPCa) using two different biochemical recurrence (BCR) definitions., Methods: Clinical data of 1117 patients with non-metastatic prostate cancer (PCa) treated with either RP or BT as the basis of the multimodal therapy from a single tertiary hospital between 2007 and 2021 were retrospectively analyzed. 843 LPCa patients (RP = 737, BT = 106) with at least one prostate-specific antigen (PSA) test after treatment were finally included. The BCR survival was evaluated by direct comparison and one-to-one propensity score matching (PSM) analysis using surgical definition (PSA ≥ 0.2ng/ml) for RP and surgical/Phoenix definition (PSA nadir + 2ng/ml ) for BT. The propensity score (PS) was calculated by multivariable logistic regression based on the clinicopathological parameters., Results: Median follow-up was 43 months for RP patients and 45 months for BT patients. Kaplan-Meier analysis did not show any statistically significant differences in terms of BCR-free survival (BFS) between the two groups when using Phoenix definition for BT (P > 0.05). Similar results were obtained in all D'Amico risk groups when stratified analyses were conducted. However, RP achieved improved BFS compared to BT in the whole cohort and all risk groups with the surgical definition for BT(P < 0.05). After adjusting PS, 192 patients were divided into RP and BT groups (96 each). RP presented a better BFS than BT when using the surgical definition (P < 0.001), but no significant difference was found when using the Phoenix definition (P = 0.609)., Conclusion: Inconsistent BCR-free survival outcomes were acquired using two different BCR definitions for BT patients. RP provided comparable BFS with BT using the Phoenix definition but better BFS using the surgical definition, regardless of whether the PSM was performed. Our findings indicated that an exact BCR definition was critical for prognostic assessment. The corresponding results will assist physicians in pretreatment consultation and treatment selection., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disorder that causes syndromes characterized by physiological dysfunction in many organs and tissues. Despite the recognizable morphological and behavioral deficits associated with MPS I, neither the underlying alterations in functional neural connectivity nor its restoration following gene therapy have been shown. By employing high-resolution resting-state fMRI (rs-fMRI), we found significant reductions in functional neural connectivity in the limbic areas of the brain that play key roles in learning and memory in MPS I mice, and that adeno-associated virus (AAV)-mediated gene therapy can reestablish most brain connectivity. Using logistic regression in MPS I and treated animals, we identified functional networks with the most alterations. The rs-fMRI and statistical methods should be translatable into clinical evaluation of humans with neurological disorders., (© 2023. Springer Nature Limited.)

Short- and medium-chain chlorinated paraffins (SCCPs and MCCPs) have attracted significant attention because of their persistence, biotoxicity, bioaccumulation, and long-range migration. Given their worldwide detection in a variety of environmental matrices, concerns related to the high exposure risks of SCCPs and MCCPs to humans have grown. Thus, knowledge of the contamination patterns of SCCPs and MCCPs and their distribution characteristics in the vivo exposure of humans is of great importance. However, little information is available on the contamination of SCCPs and MCCPs in human blood/plasma/serum, mainly because of the difficulty of sample preparation and quantitative analysis. In this study, a new blood sample pretreatment method based on Percoll discontinuous density gradient centrifugation was developed to separate plasma, red blood cells, white blood cells, and platelets from human whole blood. A series of Percoll sodium chloride buffer solutions with mass concentrations of 1.095, 1.077, and 1.060 g/mL were placed in a centrifuge tube from top to bottom to establish discontinuous density gradients. The dosage for each density gradient was 1.5 mL. Human whole blood samples mixed with 0.85% sodium chloride aqueous solution were then added to the top layer of the Percoll sodium chloride solution. After centrifugation, the whole blood was separated into four components. The plasma was located at the top layer of the centrifuge tube, whereas the platelets, white blood cells, and red blood cells were retained at the junction of the various Percoll sodium chloride solutions. The sampling volume of human whole blood and incubation time were optimized, and results indicated that an excessively long incubation time could lead to hemolysis, resulting in a decrease in the recoveries of SCCPs and MCCPs. Therefore, a sampling volume of 1.5 mL and incubation time of 10 min at 4 ℃ were adopted. The cells of the blood components were further broken and extracted by ultrasonic pretreatment, followed by multilayer silica gel column chromatography for lipid removal. The use of 80 mL of n -hexane-dichloromethane (1∶1, v/v) and 50 mL of dichloromethane as the elution solvents (collected together) for the gel column separated the SCCPs and MCCPs from the lipid molecules in the blood samples. Gas chromatography-electron capture negative ion-low resolution mass spectrometry (GC-ECNI-LRMS) was used to determine the SCCPs and MCCPs. Quantification using the corrected total response factor with degrees of chlorination was achieved with linear corrections ( R 2 =0.912 and 0.929 for the SCCPs and MCCPs, respectively). The method detection limits (MDLs) for the SCCPs and MCCPs were 1.57 and 8.29 ng/g wet weight (ww, n =7), respectively. The extraction internal standard recoveries were 67.0%-126.6% for the SCCPs and 69.5%-120.5% for the MCCPs. The developed method was applied to determine SCCPs and MCCPs in actual human whole blood samples. The contents of SCCPs and MCCPs were 10.81-65.23 and 31.82-105.65 ng/g (ww), respectively. Red blood cells exhibited the highest contents of CPs, followed by plasma, white blood cells, and platelets. The proportions of SCCPs and MCCPs in red blood cells and plasma were 70% and 66%, respectively. In all four components, the MCCP contents were higher than the SCCP contents, and the ratios of MCCPs to SCCPs ranged from 1.04 to 3.78. Similar congener patterns of SCCPs and MCCPs were found in the four components of human whole blood. C 10 -CPs and C 14 -CPs were predominantly observed in the SCCPs and MCCPs, respectively. In summary, a simple and efficient method was proposed to determine low concentrations of SCCPs and MCCPs in human blood with high sensitivity and selectivity. This method can meet requirements for the quantitative analysis of SCCPs and MCCPs in human blood components, thereby providing technical support for human health risk assessment.

Low-γ X-nuclear MRS and imaging have played a key role in studying metabolism and physiopathology, especially at ultrahigh fields. We design and demonstrate a novel and simple dual-frequency RF resonant coil that can operate at both low-γ X-nuclear and proton frequencies. The dual-frequency resonant coil comprises an LC coil loop and a tuning-matching circuit bridged by two short wires of the desired length to generate two resonant modes: one for proton MRI and the other for low-γ X-nuclear MRS imaging with a large difference in their Larmor frequencies at ultrahigh fields. The coil parameters for the desired coil size and resonant frequencies can be determined via numerical simulations based on LC circuit theory. We designed, constructed, and evaluated several prototype surface coils and quadrature array coils for 1 H and 2 H or 17 O imaging, with small-sized (diameter ≤ 5 cm) coils evaluated using a 16.4 T animal scanner, and a large-sized (15 cm diameter) coil on a 7 T human scanner. All coils could be tuned/matched and driven in the single coil or array coil mode to the resonant frequencies of 1 H (698 and 298 MHz), 2 H (107 and 45.8 MHz), or 17 O (94.7 and 40.4 MHz) for imaging measurements and evaluation at 16.4 and 7 T, respectively. The dual-frequency resonant coil or array provides adequate detection sensitivity for 1 H MRI and excellent performance for low-γ X-nuclear MRS imaging applications, and excellent coil decoupling efficiency between the array coils at both resonant frequencies with an optimal geometric overlap. It provides a simple, cost-effective dual-frequency RF coil solution to perform low-γ X-nuclear MRS imaging for preclinical and human applications, especially at ultrahigh fields., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

The significant health implications of e-waste toxicants have triggered the global tightening of regulation on informal e-waste recycling sites (ER) but with disparate governance that requires effective monitoring. Taking advantage of the opportunity to implement e-waste control in the Guiyu ER since 2015, we investigated the temporal variations in levels of oxidative DNA damage, 25 volatile organic compound metabolites (VOCs), and 16 metals/metalloids (MeTs) in urine in 918 children between 2016 and 2021 to demonstrate the effectiveness of e-waste control in reducing population exposure risks. The hazard quotients of most MeTs and levels of 8-hydroxy-2'-deoxyguanosine in children decreased significantly during this time, indicating that e-waste control effectively reduces the noncarcinogenic risks of MeT exposure and levels of oxidative DNA damage. Using mVOC-derived indexes as a feature, a bagging-support vector machine algorithm-based machine learning model was constructed to predict the extent of e-waste pollution (EWP). The model exhibited excellent performance with accuracies >97.0% in differentiating between slight and severe EWP. Five simple functions established using mVOC-derived indexes also had high accuracy in predicting the presence of EWP. These models and functions provide a novel human exposure monitoring-based approach for assessing e-waste governance or the presence of EWP in other ERs.

Objective: This study aims to quantify the uncertainties of CyberKnife Synchrony fiducial tracking for liver stereotactic body radiation therapy (SBRT) cases, and evaluate the required planning target volume (PTV) margins., Methods: A total of 11 liver tumor patients with a total of 57 fractions, who underwent SBRT with synchronous fiducial tracking, were enrolled for the present study. The correlation/prediction model error, geometric error, and beam targeting error were quantified to determine the patient-level and fraction-level individual composite treatment uncertainties. The composite uncertainties and multiple margin recipes were compared for scenarios with and without rotation correction during treatment., Results: The correlation model error-related uncertainty was 4.3±1.8, 1.4±0.5 and 1.8±0.7 mm in the superior-inferior (SI), left-right, and anterior-posterior directions, respectively. These were the primary contributors among all uncertainty sources. The geometric error significantly increased for treatments without rotation correction. The fraction-level composite uncertainties had a long tail distribution. Furthermore, the generally used 5-mm isotropic margin covered all uncertainties in the left-right and anterior-posterior directions, and only 75% of uncertainties in the SI direction. In order to cover 90% of uncertainties in the SI direction, an 8-mm margin would be needed. For scenarios without rotation correction, additional safety margins should be added, especially in the superior-inferior and anterior-posterior directions., Conclusion: The present study revealed that the correlation model error contributes to most of the uncertainties in the results. Most patients/fractions can be covered by a 5-mm margin. Patients with large treatment uncertainties might need a patient-specific margin., (© 2023. Huazhong University of Science and Technology.)

Polycyclic N-heterocycles are important structural motifs commonly found in bioactive compounds, however, their selective construction via the cyclization of allenynes remains challenging yet highly desirable. Here we show a homogeneous copper-catalyzed hetero Diels-Alder (HDA) reaction of allenynes with cis-diazenes (PTAD, 4-phenyl-1,2,4-triazoline-3,5-dione), allowing the practical and efficient synthesis of a diverse array of valuable polycyclic N-heterocycles. A temperature-controlled and stereocontrolled chemoselectivity of the reaction was observed, leading to the chemodivergent synthesis of tetracyclic pyrrolidines, pentacyclic triazepanes and tricyclic pyrrolidines. Compared with related Au-catalyzed cyclization of allenynes, this copper catalysis achieves cyclization of allenynes terminating in C-N bond formation via the HDA reaction., (© 2023. The Author(s).)

Objective: Local combined systemic therapy has been an important method for the treatment of unresectable hepatocellular carcinoma (HCC).The purpose of this study was to compare the effectiveness and safety of transarterial chemoembolization (TACE) plus Sorafenib versus TACE plus Apatinib for treating patients with unresectable HCC., Methods: The clinical data of patients with unresectable HCC who were treated with TACE plus Sorafenib or TACE plus Apatinib at 5 Chinese medical centers between January 2016 and December 2020 were retrospectively analyzed. Propensity score matching (PSM) was applied to reduce the bias from confounding factors., Results: A total of 380 patients were enrolled, of whom 129 cases were treated with TACE plus Sorafenib and 251 cases with TACE plus Apatinib. After the 1:1 PSM, 116 pairs of patients were involved in this study. The results showed that the PFS and OS in the TACE-Sorafenib group were significantly longer than those in the TACE-Apatinib group (PFS: 16.79 ± 6.45 vs. 14.76 ± 6.98 months, P = 0.049; OS: 20.66 ± 6.98 vs. 17.69 ± 6.72 months, P = 0.013). However, the ORR in the TACE-Apatinib group was markedly higher than that in the TACE-Sorafenib group (70.69% vs. 56.03%, P = 0.021). There were more patients with adverse events (AEs) in the TACE-Apatinib group than those in the TACE-Sorafenib group before dose adjustment (87 vs. 63, P = 0.001); however, the number of patients who suffered from AEs was not significantly different between the two groups after the dose adjustment (62 vs. 55, P = 0.148). No treatment-related death was found in the two groups. Subgroup analysis revealed that patients with unresectable HCC could better benefit from regular doses than reduced doses (Sorafenib, 22.59 vs. 18.02, P < 0.001; Apatinib, 19.75 vs. 16.86, P = 0.005)., Conclusion: TACE plus either Sorafenib or Apatinib could effectively treat patients with unresectable HCC, the safety of TACE plus Sorafenib was better. and the ORR of TACE plus Apatinib was higher., (© 2023. The Author(s).)

Background: To explore the effect and mechanism of action of miR-210 on postmenopausal osteoporosis (PMPO) in ovariectomized rats in vivo., Methods: An ovariectomized (OVX) rat model was established by ovariectomy. Tail vein injection was performed to overexpress and knock down miR-210 in OVX rats, followed by the collection of blood and femoral tissues from each group of rats. And quantitative real-time polymerase chain reaction (qRT-PCR) was applied to assess the expression level of miR-210 in femoral tissues of each group. Micro computed tomography (Micro CT) was adopted to scan the microstructure of the femoral trabecula in each group to obtain relevant data like bone mineral density (BMD), bone mineral content (BMC), trabecular bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone surface-to-volume ratio (BS/BV), and trabecular separation (Tb.Sp). ELISA was used for determining the level of bone alkaline phosphatase (BALP), amino-terminal propeptide of type I procollagen (PINP), osteocalcin (OCN), and C-terminal telopeptide of type I collagen (CTX-1) in serum; and Western blot for the protein level of Runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen type I alpha 1 (COL1A1) in femoral tissues., Results: MiR-210 expression was significantly decreased in femoral tissues of OVX rats. Overexpression of miR-210 could obviously increase BMD, BMC, BV/TV and Tb.Th, whereas significantly decrease BS/BV and Tb.Sp in femurs of OVX rats. Moreover, miR-210 also downregulated BALP and CTX-1 level, upregulated PINP and OCN level in the serum of OVX rats promoted the expression of osteogenesis-related markers (Runx2, OPN and COL1A1) in the femur of OVX rats. Additionally, further pathway analysis revealed that high expression of miR-210 activated the vascular endothelial growth factor (VEGF)/Notch1 signaling pathway in the femur of OVX rats., Conclusion: High expression of miR-210 may improve the micromorphology of bone tissue and modulate bone formation and resorption in OVX rats by activating the VEGF/Notch1 signaling pathway, thereby alleviating osteoporosis. Consequently, miR-210 can serve as a biomarker for the diagnosis and treatment of osteoporosis in postmenopausal rats., (© 2023. The Author(s).)

Background: Previous studies have found that patients with schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD) all have facial emotion recognition deficits, but the differences and similarities of these deficits in the three groups of patients under different social interaction situations are not clear. The present study aims to compare the ability of facial emotion recognition in three different conversation situations from a cross-diagnostic perspective., Methods: Thirty-three participants with SCZ, 35 participants with MDD, and 30 participants with BD were recruited, along with 31 healthy controls. A computer-based task was given to assess the ability of Facial Emotion Categorization (FEC) under three different conversational situations (praise, blame, and inquiry)., Results: In the "praise" situation, patients with SCZ, MDD and BD were all slower to recognize anger emotion than the healthy controls. In all three clinical groups, patients with SCZ recognized angry faces faster than those with MDD and BD on a continuum from happy faces to angry faces in the "inquiry" situation, while no significant difference was found in the latter two groups. In addition, no significant defect was found in the percentage and threshold of angry face recognition in all three patient groups., Conclusions: Our findings indicate that patients with SCZ, MDD, and BD share both common and distinct deficits in facial emotion recognition during social interactions, which may be beneficial for early screening and precise intervention for these mental disorders., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Padsevonil (PSL) is a novel antiepileptic drug candidate that inhibits seizure activity in both presynaptic and postsynaptic ways. The pharmacokinetic (PK) profiles and volumetric absorptive microsampling (VAMS) application of PSL in the Chinese population are limited. The objectives of this study were to evaluate the PK profile of PSL and its 2 metabolites, the safety of PSL, and compare the PK profile of PSL from samples collected using the VAMS technique with that of conventional venous samples in healthy Chinese subjects., Subjects and Methods: In this randomized, double-blind, placebo-controlled single-dose study, the participants received either 200 mg PSL or placebo. Blood samples for the PK variables were collected using both the traditional venous method and the VAMS Mitra® technique at the scheduled time points. The PK parameters of PSL and 2 metabolites were calculated, and the concentration agreement of VAMS and venous samples were also evaluated., Results: A total of 14 subjects were enrolled. The concentration-time profile of PSL showed rapid absorption with a median tmax of 1.25 h (range: 0.5 to 3.0), followed by an apparent biphasic disposition. For PSL, the geometric means of AUC(0-t), AUC, Cmax, and t1/2 were 6,573 h*ng/mL, 6,588 h*ng/mL, 1,387 ng/mL, and 5.275 h, respectively. The geometric mean body weight-normalized AUC(0-t), AUC, and Cmax were 5,712 h*ng/mL, 5,725 h*ng/mL, and 1,205 ng/mL, respectively. The AUC(0-t), AUC, Cmax of PSL and metabolites in VAMS-dried blood were all lower than those in plasma. The Passing-Bablok regression showed that the PSL and metabolite concentrations obtained by VAMS analysis were comparable to those obtained by plasma at some time points. The most frequently reported treatment-emergent adverse events (TEAEs) were somnolence and dizziness. There were no serious TEAEs, severe TEAEs, discontinuations due to TEAEs, or deaths reported during this study. No clinically significant laboratory, vital signs, electrocardiograph (ECG), or physical examination results were reported., Conclusions: PSL has a favorable PK profile after single-dose oral administration and good safety properties in healthy Chinese volunteers. The regression analysis results of VAMS and plasma indicated that the application of VAMS for therapeutic drug monitoring in novel antiepileptic drug development is promising and needs further validation.

Pyrometallurgy technique is usually applied as a pretreatment to enhance the leaching efficiencies in the hydrometallurgy process for recovering valuable metals from spent lithium-ion batteries. However, traditional pyrometallurgy processes are energy and time consuming. Here, we report a carbothermal shock (CTS) method for reducing LiNi 0.3 Co 0.2 Mn 0.5 O 2 (NCM325) cathode materials with uniform temperature distribution, high heating and cooling rates, high temperatures, and ultrafast reaction times. Li can be selectively leached through water leaching after CTS process with an efficiency of >90 %. Ni, Co, and Mn are recovered by dilute acid leaching with efficiencies >98 %. The CTS reduction strategy is feasible for various spent cathode materials, including NCM111, NCM523, NCM622, NCM811, LiCoO 2 , and LiMn 2 O 4 . The CTS process, with its low energy consumption and potential scale application, provides an efficient and environmentally friendly way for recovering spent lithium-ion batteries., (© 2023 Wiley-VCH GmbH.)

Sample extraction is a crucial step in forensic analysis, especially when dealing with trace and ultra-trace levels of target analytes present in various complex matrices (e. g., soil, biological samples, and fire debris). Conventional sample preparation techniques include Soxhlet extraction and liquid-liquid extraction. However, these techniques are tedious, time-consuming, labor-intensive and require large amounts of solvents, which poses a threat to the environment and health of researchers. Moreover, sample loss and secondary pollution can easily occur during the preparation procedure. Conversely, the solid phase microextraction (SPME) technique either requires a small amount of solvent or no solvent at all. Its small and portable size, simple and fast operation, easy-to-realize automation, and other characteristics thus make it a widely used sample pretreatment technique. More attention was given to the preparation of SPME coatings by using various functional materials, as commercialized SPME devices used in early studies were expensive, fragile, and lacked selectivity. Examples of those functional materials include metal-organic frameworks, covalent organic frameworks, carbon-based materials, molecularly imprinted polymers, ionic liquids, and conducting polymers, all widely used in environmental monitoring, food analysis, and drug detection. However, these SPME coating materials have relatively few applications in forensics. Given the high potential of SPME technology for the in situ and efficient extraction of samples from crime scenes, this study briefly introduces functional coating materials and summarizes the applications of SPME coating materials for the analysis of explosives, ignitable liquids, illicit drugs, poisons, paints, and human odors. Compared to commercial coatings, functional material-based SPME coatings exhibit higher selectivity, sensitivity, and stability. These advantages are mainly achieved through the following approaches: First, the selectivity can be improved by increasing the π-π , hydrogen bonds, and hydrophilic/hydrophobic interactions between the materials and analytes. Second, the sensitivity can be improved by using porous materials or by increasing their porosity. Third, thermal, chemical, and mechanical stability can be improved by using robust materials or fixing the chemical bonding between the coating and substrate. In addition, composite materials with multiple advantages are gradually replacing the single materials. In terms of the substrate, the silica support was gradually replaced by the metal support. This study also outlines the existing shortcomings in forensic science analysis of functional material-based SPME techniques. First, the application of functional material-based SPME techniques in forensic science remains limited. On one hand, the analytes are narrow in scope. As far as explosive analysis is concerned, functional material-based SPME coatings are mainly applied to nitrobenzene explosives, while other categories, such as nitroamine and peroxides, are rarely or never involved. Research and development of coatings is insufficient and the application of COFs in forensic science has not yet been reported. Second, functional material-based SPME coatings have not been commercialized as they don't yet have inter-laboratory validation tests or established official standard analytical methods. Therefore, some suggestions are proposed for the future development of forensic science analyses of functional material-based SPME coatings. First, research and development of functional material-based SPME coatings, especially fiber coatings with broad-spectrum applicability and high sensitivity, or outstanding selectivity for some compounds, is still an important direction for SPME future research. Second, a theoretical calculation of the binding energy between the analyte and coating was introduced to guide the design of functional coatings and improve the screening efficiency of new coatings. Third, we expand its application in forensic science by expanding the number of analytes. Fourth, we focused on the promotion of functional material-based SPME coatings in conventional laboratories and established performance evaluation protocols for the commercialization of functional material-based SPME coatings. This study is expected to serve as a reference for peers engaged in related research.

The implementation of short-term traffic restriction policies (TRPs) during major events positively influences the traffic emission reduction. However, few studies explore the impact of diesel vehicle emissions on air quality during short-term TRP. In particular, the intertwined influences of short-term TRP and Spring Festival remains unclear. Based on Beijing 2022 Olympic Games, this study analyzed the spatiotemporal changes in urban air quality and diesel vehicle emission during short-term TRP. The results showed that the TRPs and Spring Festival contributed equally to the improvement of air quality and reduction of diesel vehicle emissions. The "interruption-recovery" pattern of short-term TRPs is characterized by a longer duration and a slower decline/recovery rate. Additionally, the individual contribution rate of diesel vehicle emissions to urban air pollutants was 15-20 % higher than that of meteorological factors during short-term TRPs., 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 B.V. All rights reserved.)

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MG A1 neurons) in resilient mice. In addition, this temporal neural plasticity of MG A1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MG A1 neurons, rather than merely activating MG A1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis., (© 2022. The Author(s).)

Background: This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR)., Methods: For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety., Results: Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA., Conclusions: PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT., Trial Registration Number: NCT02616185., Competing Interests: Competing interests: This work was sponsored by Pfizer. KAA: PI/research funding to institution: Amgen, AstraZeneca, CytomX, Eli Lilly and Company, GlaxoSmithKline, Parker Institute for Cancer Immunotherapy, Pfizer, Trishula. CSH: consulting fees: Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Carrick Therapeutics, Clovis Oncology, Ferring Pharmaceuticals, Genentech, Hinova, Janssen, Menarini, Merck Sharp & Dohme, Myovant Sciences, Novartis, Pfizer; contracted research support: Aragon Pharmaceuticals, Astellas, AstraZeneca, Bayer, Clovis Oncology, eFFECTOR Therapeutics, Emergent BioSolutions, Ferring Pharmaceuticals, Medivation, Roche; ownership interest: CTI BioPharma; honoraria: Astellas. LN and X-HZ: nothing to disclose. LJA: consulting or advisory role: AADi; research funding (institution as recipient): Amgen, Astellas, Aveo, Bayer, BioNTech, Bristol Myers Squibb, Calithera Biosciences, Eisai, Eli Lilly and Company, Epizyme, Exelixis, Genentech/Roche, Inovio, Merck, Novartis, Peloton Therapeutics, Pfizer, Seattle Genetics, Surface Oncology; other relationship: Pfizer; uncompensated relationships: Exelixis. TZ: PI/research funding: AbbVie/StemCentrx, Acerta, Astellas, AstraZeneca, Eli Lilly and Company, Janssen, Merck, Merrimack, Mirati Therapeutics, Novartis, OmniSeq, Personal Genome Diagnostics, Pfizer, Regeneron; speaker: Genomic Health (end 2020), Sanofi-Aventis (end 2020); advisory board/consultant: Amgen, Aptitude Health, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera Biosciences, Clinical Care Options, Dendreon, Eisai, Eli Lilly and Company, Exelixis, Janssen, Merck, MJH Associates, Peerview, Pfizer, Pharmacyclics, QED Therapeutics, Sanofi-Aventis, Seattle Genetics, Vaniam; employee/stockholder: Archimmune Therapeutics (spouse), Capio Biosciences (spouse), Nanorobotics (spouse). HB: consultancy: Caris, Idera, Myovant, Novocure, Tracon; speaker’s bureau: Guardant360. NJV: PI/research funding: none; advisory boards: Caris, Clovis, Eisai, Fujifilm, Gilead Sciences, Merck, OnQuality Pharmaceuticals, Pfizer-Myovant, Sanofi-Aventis, Seagen; speaker’s bureau: Aveo, Bayer, Caris, Janssen, PER, Pfizer-Myovant, Sanofi, Seagen. SMP: PI funding: Janssen, Merck, Pfizer, UroGen Pharma. MTS: paid consultant and/or received honoraria: AstraZeneca, PharmaIn, Resverlogix, Sanofi; research funding to institution: Ambrx, AstraZeneca, Bristol Myers Squibb, F. Hoffman-La Roche, Immunomedics, Janssen, Madison Vaccines, Merck, Pfizer, SignalOne Bio, Tmunity, Zenith Epigenetics. RAM: research funding: Bayer. SB, NC, OB, RL, MK, I-MW, JZ, S-YT, and KAK: employees of Pfizer with stock and/or stock options. KC, HC, and RH: employees of Pfizer at the time of the study. DPP: stock and other ownership interests: Bellicum Pharmaceuticals, TYME Technologies; consulting or advisory role: Advanced Accelerator Applications, Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly and Company, Exelixis, Gilead Sciences, Incyte, Ipsen, Janssen, Mirati Therapeutics, Monopteros Therapeutics, Pfizer, Pharmacyclics, Regeneron, Roche, Seattle Genetics, UroGen Pharma; research funding: Advanced Accelerator Applications (Inst), Agensys (Inst), Astellas Medivation (Inst), AstraZeneca (Inst), Bayer (Inst), BioXcel Therapeutics (Inst), Bristol Myers Squibb (Inst), Clovis Oncology (Inst), Eisai (Inst), Endocyte (Inst), Eli Lilly and Company (Inst), Genentech (Inst), Gilead Sciences (Inst), Innocrin Pharma (Inst), MedImmune (Inst), Medivation (Inst), Merck (Inst), Mirati Therapeutics (Inst), Novartis (Inst), Pfizer (Inst), Progenics (Inst), Replimune (Inst), Roche (Inst), Sanofi (Inst), Seattle Genetics (Inst); expert testimony: Celgene, Sanofi., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Short-term prediction of urban air quality is critical to pollution management and public health. However, existing studies have failed to make full use of the spatiotemporal correlations or topological relationships among air quality monitoring networks (AQMN), and hence exhibit low precision in regional prediction tasks. With this consideration, we proposed a novel deep learning-based hybrid model of Res-GCN-BiLSTM combining the residual neural network (ResNet), graph convolutional network (GCN), and bidirectional long short-term memory (BiLSTM), for predicting short-term regional NO 2 and O 3 concentrations. Auto-correlation analysis and cluster analysis were first utilized to reveal the inherent temporal and spatial properties respectively. They demonstrated that there existed temporal daily periodicity and spatial similarity in AQMN. Then the identified spatiotemporal properties were sufficiently leveraged, and monitoring network topological information, as well as auxiliary pollutants and meteorology were also adaptively integrated into the model. The hourly observed data from 51 air quality monitoring stations and meteorological data in Shanghai were employed to evaluate it. Results show that the Res-GCN-BiLSTM model was better adapted to the pollutant characteristics and improved the prediction accuracy, with nearly 11% and 17% improvements in mean absolute error for NO 2 and O 3 , respectively compared to the best performing baseline model. Among the three types of monitoring stations, traffic monitoring stations performed the best for O 3 , but the worst for NO 2 , mainly due to the impacts of intensive traffic emissions and the titration reaction. These findings illustrate that the hybrid architecture is more suitable for regional pollutant concentration., 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 Ltd. All rights reserved.)

General access to highly valuable seven-membered rings via Büchner-type reaction remains a formidable challenge. Here we report a Cu-catalyzed intermolecular oxidation of alkynes using N-oxides as oxidants, which enables expedient preparation of valuable benzo[6,7]azepino[2,3-b]quinolines and pyridine-based diones. Importantly, in contrast to the well-established gold-catalyzed intermolecular alkyne oxidation, the dissociated pyridine or quinoline partner could be further utilized to construct N-heterocycles in this system and the reaction most likely proceeds by a Büchner-type ring expansion pathway. A mechanistic rationale for this cascade cyclization is supported by DFT calculations., (© 2023. The Author(s).)

Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that the expression of the E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with the response to radiation and CD8 + T cell-mediated antitumour immunity in nasopharyngeal carcinoma (NPC). Knockout of TRIM21 modulates the cGAS/STING cytosolic DNA sensing pathway, potentiates the antigen-presenting capacity of NPC cells, and activates cytotoxic T cell-mediated antitumour immunity in response to radiation. Mechanistically, TRIM21 promotes the degradation of the mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for mitochondrial DNA (mtDNA) release, thereby inhibiting type-I interferon responses following radiation exposure. In patients with NPC, high TRIM21 expression was associated with poor prognosis and early tumour relapse after radiotherapy. Our findings reveal a critical role of TRIM21 in radiation-induced antitumour immunity, providing potential targets for improving the efficacy of radiotherapy in patients with NPC., (© 2023. The Author(s).)

Introduction: Previous studies demonstrated that metformin could lead to an inhibition of proliferation of cancer cells through a shift from anabolic to catabolic metabolism. In this study, we seek to investigate the effect of metformin in metastatic prostate cancer., Methods: Patients followed at Northwell Health Zuckerberg Cancer Center during 2014-2018 were included if they were diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC), with ⩾6 months follow-up with and without metformin treatment. The primary outcomes, 6-month prostate-specific antigen (PSA) response, overall survival (OS), and radiographic progression free survival (rPFS), were evaluated., Results: There were 267 patients included in the final analysis; 196 patients had mHSPC (73.2%) and 71 had mCRPC (26.8%). Within the mHSPC subjects, there was a significant difference in OS between metformin vs nonmetformin groups (148.5 vs 85.6 months; P < .046) in a univariate analysis; patients who took metformin had a significantly longer OS than subjects who did not (median OS: 148.5 vs 86 months; P < .046). There was no significant difference between the 2 groups with respect to either PSA response rate at 6 months or rPFS or OS in patients with mHSPC in both univariate and multivariate analysis. Within the mCRPC subjects, there was no significant difference between metformin and nonmetformin groups with respect to OS (43.3 vs 51.5 months; P < 0.160) or PSA response at 6 months (38.5% vs 57.1%; p < 0.24); however, patients on metformin had a significantly shorter rPFS in both the univariate analysis (7.3 vs 17.4; P < .0002) and in the multivariate analysis (HR = 2.52; 95% CI: 1.24m 5.11; P < .0109)., Conclusions: Among patients with mHSPC, use of metformin was not significantly associated with improved OS in the multivariate analysis., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Objective: To clarify the long-term characteristics of tinnitus following treatment of sudden deafness and its long-term physical and mental effects on patients. Methods: A retrospective analysis was performed on 88 patients (46 males and 42 females; Age from 11 to 89 years) with sudden deafness treated in Department of Otoscope Surgery of Peoples's Libration Army General Hospital in Beijing from April 2020 to January 2021, and the occurrence of tinnitus and treatment effect of all patients were analyzed. Follow-up was conducted for patients with residual tinnitus after treatment for more than 1 year by the investigation and filling in the survey information collection form, Tinnitus Evaluation Questionnaire (TEQ) and Tinnitus Handicap Inventory (THI). Descriptive statistics and SPSS 22.0 software were used for statistical data analysis. Results: In this study, 93.2% (82/88) of patients with sudden deafness were accompanied by tinnitus at the onset, and the proportion of long-term tinnitus after treatment was 90.2% (74/82). After 1 year of treatment for sudden deafness, the improvement of tinnitus was significant in low-frequency sudden deafness compared with those of high-frequency, flat and total deafness sudden deafness (χ2 value was 6.801, 4.568 and 4.038, all P <0.05). In patients with residual tinnitus, 9 (12.2%) patients felt minimal loudness or even no loudness, 34 (46.0%) patients felt slight loudness, 28 (37.8%) patients felt tinnitus was relatively loud, and 3 (4.1%) patients felt tinnitus was loud or noisy. Nine (12.2%) patients's sleep was often affected, 41 (55.4%) patients's sleep was sometimes affected, 9 (12.2%) patients's sleep was rarely affected, 15 (20.3%) patients's sleep was almost not affected. Twenty-eight (37.8%) patients basically completely adapted to tinnitus and 46 (62.2%) patients did not completely adapted to residual tinnitus. Eight (10.8%) patients had no impact on life, 39 (52.7%) patients had slight impact, 22 (29.7%) patients had moderate impact, and the other 5 (6.8%) patients had greater impact. According to tinnitus evaluation questionnaire(TEQ), there were 12 cases (16.2%) of grade Ⅰ, 26 cases (35.1%) of grade Ⅱ, 28 cases (37.8%) of grade Ⅲ, 7 cases (9.5%) of grade Ⅳ and 1 case (1.4%) of grade Ⅴ. According to tinnitus handicap inventory(THI), tinnitus disability was classified into grade Ⅰ, 22 cases (29.7%), grade Ⅱ, 14 cases (18.9%), Grade Ⅲ, 27 cases (36.5%) and grade Ⅳ, 11 cases (14.9%). Conclusion: The rate of residual tinnitus following treatment of sudden deafness is high. Some of the patients can completely adapt residual tinnitus after one year, but some of them will be affected when sleep, work and study. Residual tinnitus can lead to tinnitus disability in different degrees.

In hazy days, several local authorities always implemented the strict traffic-restriction measures to improve the air quality. However, owing to lack of data, the quantitative relationships between them are still not clear. Coincidentally, traffic restriction measures during the COVID-19 pandemic provided an experimental setup for revealing such relationships. Hence, the changes in air quality in response to traffic restrictions during COVID-19 in Spain and United States was explored in this study. In contrast to pre-lockdown, the private traffic volume as well as public traffic during the lockdown period decreased within a range of 60-90%. The NO 2 concentration decreased by approximately 50%, while O 3 concentration increased by approximately 40%. Additionally, changes in air quality in response to traffic reduction were explored to reveal the contribution of transportation to air pollution. As the traffic volume decreased linearly, NO 2 concentration decreased exponentially, whereas O 3 concentration increased exponentially. Air pollutants did not change evidently until the traffic volume was reduced by less than 40%. The recovery process of the traffic volume and air pollutants during the post-lockdown period was also explored. The traffic volume was confirmed to return to background levels within four months, but air pollutants were found to recover randomly. This study highlights the exponential impact of traffic volume on air quality changes, which is of great significance to air pollution control in terms of traffic restriction policy., Supplementary Information: The online version contains supplementary material available at 10.1007/s00477-022-02351-7., Competing Interests: Conflict of interestThe authors declare that there is no conflict of interests regarding the publication of this article., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Plant stomata phenotypic traits can provide a basis for enhancing crop tolerance in adversity. Manually counting the number of stomata and measuring the height and width of stomata obviously cannot satisfy the high-throughput data. How to detect and recognize plant stomata quickly and accurately is the prerequisite and key for studying the physiological characteristics of stomata. In this research, we consider stomata recognition as a multi-object detection problem, and propose an end-to-end framework for intelligent detection and recognition of plant stomata based on feature weights transfer learning and YOLOv4 network. It is easy to operate and greatly facilitates the analysis of stomata phenotypic traits in high-throughput plant epidermal cell images. For different cultivars, multi-scales, rich background features, high density, and small stomata object images, the proposed method can precisely locate multiple stomata in microscope images and automatically give phenotypic traits of stomata. Users can also adjust the corresponding parameters to maximize the accuracy and scalability of automatic stomata detection and recognition. Experimental results on actual data provided by the National Maize Improvement Center show that the proposed method is superior to the existing methods in high stomata automatic detection and recognition accuracy, low training cost, strong generalization ability.

The flavonoids and phenolic acids in grape berries greatly influence the quality of wine. Various methods are used to shape and prune grapevines, but their effects on the flavonoids and phenolic acids remain unclear. The flavonoids and phenolic acids in the berry pericarps from grapevines pruned using three types of leaf canopy, namely, V-shaped, T-shaped, and vertical shoot-positioned (VSP) canopies, were compared in this study. Results showed that the V-shaped canopy was more favorable for the accumulation of flavonoids and phenolic acids. Transcriptome and metabolome analyses revealed that the differentially expressed genes (DEGs) and differentially regulated metabolites (DRMs) were significantly enriched in the flavonoid and phenylpropanoid biosynthesis pathways. A total of 96 flavonoids and 32 phenolic acids were detected among the DRMs. Their contents were higher in the V-shaped canopy than in the T-shaped and VSP canopies. Conjoint analysis of transcriptome and metabolome showed that nine DEGs (e.g., cytochrome P450 98A9 and 98A2) were significantly correlated to nine phenolic acids (e.g., gentisic acid and neochlorogenic acid) and three genes (i.e., chalcone isomerase, UDP-glycosyltransferase 88A1, and caffeoyl-CoA O-methyltransferase) significantly correlated to 15 flavonoids (e.g., baimaside and tricin-7-O-rutinoside). These genes may be involved in the regulation of various flavonoids and phenolic acids in grape berries, but their functions need validation. This study provides novel insights into the effects of leaf canopy on flavonoids and phenolic acids in the skin of grape berries and reveals the potential regulatory networks involved in this phenomenon., 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 © 2022 Elsevier Ltd. All rights reserved.)

Background: Acute Liver Failure (ALF) is a difficult problem to solve in clinical practice. The presence of non-SMC condensin I complex subunit G (NCAPG) has previously been linked to vascular invasion of digestive system tumors, foreshadowing poor prognosis. Its role in ALF biology, however, remains unknown. This article explores the role of NCAPG as a potential biomarker candidate for the accurate diagnosis and targeted treatment of ALF., Methods: The study included transcription data (GSE14668, GSE38941, GSE62029, GSE96851, and GSE120652) of ALF, normal tissues, and clinical samples, where NCAPG was selected as the differential gene by the "DESeq2" R package to analyze the immune cell functions and signal pathways. Furthermore, RT-qPCR and Western blot analyses were used to confirm the RNA and protein levels of NCAPG in ALF cell models, respectively., Results: Bioinformatics analysis revealed that NACPG was up-regulated in ALF tissues, and the functional signaling pathway was primarily associated with immune infiltration. Based on the results of clinical samples, we suggest that NCAPG was overexpressed in ALF tissues. We also found that the expression of NCAPG increased with the degree of liver injury in vitro . Enrichment analysis suggested that NCAPG influenced ALF as a PI3K/AKT pathway activator., Conclusion: Our study suggests that NCAPG is a preliminary tool for the diagnosis of ALF. It can affect ALF via the PI3K/AKT pathway and is a potential therapeutic target to improve prognosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Human dental pulp stem cells (hDPSCs) are considered promising multipotent cell sources for tissue regeneration. Regulation of apoptosis and maintaining the cell homeostasis is a critical point for the application of hDPSCs. Osteomodulin (OMD), a member of the small leucine-rich proteoglycan family, was proved an important regulatory protein of hDPSCs in our previous research. Thus, the role of OMD in the apoptosis of hDPSCs was explored in this study. The expression of OMD following apoptotic induction was investigated and then the hDPSCs stably overexpressing or knocking down OMD were established by lentiviral transfection. The proportion of apoptotic cells and apoptosis-relative genes and proteins were examined with flow cytometry, Hoechst staining, Caspase 3 activity assay, qRT-PCR and western blotting. RNA-Seq analysis was used to explore possible biological function and mechanism. Results showed that the expression of OMD decreased following the apoptotic induction. Overexpression of OMD enhanced the viability of hDPSCs, decreased the activity of Caspase-3 and protected hDPSCs from apoptosis. Knockdown of OMD showed the opposite results. Mechanistically, OMD may act as a negative modulator of apoptosis via activation of the Akt/Glycogen synthase kinase 3β (GSK-3β)/β-Catenin signaling pathway and more functional and mechanistic possibilities were revealed with RNA-Seq analysis. The present study provided evidence of OMD as a negative regulator of apoptosis in hDPSCs. Akt/GSK-3β/β-Catenin signaling pathway was involved in this process and more possible mechanism detected needed further exploration. This anti-apoptotic function of OMD provided a promising application prospect for hDPSCs in tissue regeneration., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To study the demographic features of children with allergic diseases receiving standardized sublingual immunotherapy (SLIT) and the influencing factors for the compliance with SLIT., Methods: A retrospective analysis was performed on the demographic features and follow-up data of 1 789 children with allergic diseases who received SLIT in Children's Hospital of Jiangxi Province from January 1, 2018 to December 31, 2020. The compliance with SLIT and its influencing factors were analyzed., Results: A total of 1 789 children received SLIT, among whom there were 1 271 boys (71.05%) and 518 girls (28.95%), with an age range of 4-14 years. Among these children, 777 (43.43%) had complete compliance with SLIT and 1 012 (56.57%) withdrew from the treatment within one year. Among the 1 012 children, 354 (34.98%) withdrew from the treatment due to self-conscious inconvenient use, 346 (34.19%) withdrew due to unsatisfactory treatment outcome, 253 (25.00%) stopped the treatment due to the improvement in symptoms, and 59 (5.83%) terminated the treatment due to adverse reactions. Withdrawal was mainly observed within 1-4 months after treatment (74.31%, 752/1 012). Girls tended to have a lower compliance rate than boys, and the children with a single disease had a lower compliance rate than those with multiple diseases ( P <0.05). The multivariate analysis showed that compared with boys, girls had an increased risk of withdrawal ( OR =0.811, 95% CI : 0.658-0.998, P <0.05), and compared with the children with multiple diseases, the children with a single disease were more likely to withdraw from the treatment ( OR =1.313, 95% CI : 1.005-1.715, P <0.05)., Conclusions: Children with allergic diseases tend to have poor compliance with SLIT, which is associated with sex and the number of diseases, and the main reasons for withdrawal are self-conscious inconvenient use and unsatisfactory treatment outcome.

Objective: To investigate the therapeutic effect of lateral rectus abdominis incision combined with winged calcaneal plate on pelvic and acetabular fractures involving quadrilateral body., Methods: From January 2017 to April 2021, 21 cases of pelvic and acetabular fractures involving quadrilateral bodies were retrospectively analyzed, including 12 males and 9 females. The age ranged from 21 to 73 years with an average of (43.23±6.45) years. All patients were treated by lateral incision of rectus abdominis combined with open reduction and internal fixation with aerofoil plate, including 12 cases of pelvis with anterior and posterior column fractures, 7 cases of acetabular fractures with quadrilateral involvement, and 2 cases of acetabular fractures with central dislocation., Results: All 21 patients were followed up for 12 to 36 months with an average of (18.60±6.45) months. All fractures healed. According to Matta's image reduction evaluation after operation, 11 cases of pelvic anterior and posterior column fractures were all anatomic reduction, 1 case was satisfactory reduction, 7 cases of acetabular fractures involving quadrilateral were anatomic reduction, 1 case with central dislocation was anatomic reduction, and 1 case was satisfactory reduction. The modified Merle D'Aubigne Postel hip joint score was 13 to 17 points., Conclusion: Lateral incision approach of rectus abdominis combined with wing-shaped steel plate can obtain good radiological and clinical results in the treatment of complex pelvic and acetabular fractures involving quadrilateral bodies, and has advantages in the treatment of complex pelvic fractures and acetabular quadrilateral fractures.

Introduction: Identifying neoadjuvant chemotherapy (NAC) response in patients with muscle invasive bladder cancer (MIBC) has had limited success based on clinicopathological features and molecular subtyping. Identification of chemotherapy responsive cohorts would facilitate delivery to those most likely to benefit., Objective: Develop a molecular signature that can identify MIBC NAC responders (R) and non-responders (NR) using a cohort of known NAC response phenotypes, and better understand differences in molecular pathways and subtype classifications between NAC R and NR., Materials and Methods: Presented are the messenger RNA (mRNA) and microRNA (miRNA) differential expression profiles from initial transurethral resection of bladder tumor (TURBT) specimens of a discovery cohort of MIBC patients consisting of 7 known NAC R and 11 NR, and a validation cohort consisting of 3 R and 5 NR. Pathological response at time of cystectomy after NAC was used to classify initial TURBT specimens as R (pT0) versus NR (≥pT2). RNA and miRNA from FFPE blocks were sequenced using RNAseq and qPCR, respectively., Results: The discovery cohort had 2309 genes, while the validation cohort had 602 genes and 13 miRNA differentially expressed between R and NR. Gene set enrichment analysis identified mitochondrial gene expression, DNA replication initiation, DNA unwinding in the R discovery cohort and positive regulation of vascular associated smooth muscle cell proliferation in the NR discovery cohort. Canonical correlation (CC) analysis was applied to differentiate R versus NR. 3 CCs (CC13, CC16, and CC17) had an AUC &gt;0.65 in the discovery and validation dataset. Gene ontology enrichment showed CC13 as nucleoside triphosphate metabolic process, CC16 as cell cycle and cellular response to DNA damage, CC17 as DNA packaging complex. All patients were classified using established molecular subtypes: Baylor, UNC, CIT, Lund, MD Anderson, TCGA, and Consensus Class. The MD Anderson p53-like subtype, CIT MC4 subtype and Consensus Class stroma rich subtype had the strongest correlation with a NR phenotype, while no subtype had a strong correlation with the R phenotype., Conclusions: Our results identify molecular signatures that can be used to differentiate MIBC NAC R versus NR, salient molecular pathway differences, and highlight the utility of molecular subtyping in relation to NAC response.

High-resolution functional MRI (fMRI) is largely hindered by random thermal noise. Random matrix theory (RMT)-based principal component analysis (PCA) is promising to reduce such noise in fMRI data. However, there is no consensus about the optimal strategy and practice in implementation. In this work, we propose a comprehensive RMT-based denoising method that consists of 1) rank and noise estimation based on a set of newly derived multiple criteria, and 2) optimal singular value shrinkage, with each module explained and implemented based on the RMT. By incorporating the variance stabilizing approach, the denoising method can deal with low signal-to-noise ratio (SNR) (such as <5) magnitude fMRI data with favorable performance compared to other state-of-the-art methods. Results from both simulation and in-vivo high-resolution fMRI data show that the proposed denoising method dramatically improves image restoration quality, promoting functional sensitivity at the same level of functional mapping blurring compared to existing denoising methods. Moreover, the denoising method can serve as a drop-in step in data preprocessing pipelines along with other procedures aimed at removal of structured physiological noises. We expect that the proposed denoising method will play an important role in leveraging high-quality, high-resolution task fMRI, which is desirable in many neuroscience and clinical applications.

An efficient and facile visible-light-mediated tandem difluoromethylation/cyclization of alkenyl aldehydes, with easily accessible and air-stable [Ph 3 PCF 2 H] + Br - as the difluoromethylation reagent, has been established. A range of CF 2 H-substituted chroman-4-one skeletons and their derivatives, such as 2,3-dihydroquinolin-4(1 H )-ones, chroman, 3,4-dihydronaphthalen-1(2 H )-one, 2,3-dihydrobenzofuran, and 2,3-dihydro-1 H -inden-1-one, are efficiently produced in moderate to good yields with excellent chemoselectivity under mild reaction conditions.

Schizophrenia is a polygenetic disease, the heterogeneity of which is likely complicated by epigenetic modifications yet to be elucidated. Here, we performed transcriptomic analysis of peripheral blood RNA from monozygotic twins discordant for schizophrenia and identified a schizophrenia-associated down-regulated microRNA, miR-501-3p. We showed that the loss of miR-501-3p in germline knockout (KO) male mice resulted in dendritic structure defects, glutamatergic transmission enhancement, and sociability, memory, and sensorimotor gating disruptions, which were attenuated when miR-501 expression was conditionally restored in the nervous system. Combining the results of proteomic analyses with the known genes linked to schizophrenia revealed that metabotropic glutamate receptor 5 (mGluR5) was one of the miR-501-3p targets and was elevated in vivo upon loss of miR-501. Treatment with the mGluR5 negative allosteric modulator 3-2((-methyl-4-thiazolyl) ethynyl) pyridine or the N -methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid ameliorated the deficits observed in Mir501 -KO mice. The epigenetic and pathophysiological mechanism that links miR-501-3p to the modulation of glutamatergic transmission provides etiological implications for schizophrenia.

Background: Vascular smooth muscle cell (VSMC) phenotype switching is critical for neointima formation, which is the major cause of restenosis after stenting or coronary artery bypass grafting. However, the epigenetic mechanisms regulating phenotype switching of VSMCs, especially histone methylation, are not well understood. As a main component of histone lysine demethylases, Jumonji demethylases might be involved in VSMC phenotype switching and neointima formation., Methods and Results: A mouse carotid injury model and VSMC proliferation model were constructed to investigate the relationship between histone methylation of H3K36 (downstream target molecule of Jumonji demethylase) and neointima formation. We found that the methylation levels of H3K36 negatively correlated with VSMC proliferation and neointima formation. Next, we revealed that JIB-04 (a pan-inhibitor of the Jumonji demethylase superfamily) could increase the methylation levels of H3K36. Furthermore, we found that JIB-04 obviously inhibited HASMC proliferation, and a cell cycle assay showed that JIB-04 caused G2/M phase arrest in HASMCs by inhibiting the phosphorylation of RB and CDC2 and promoting the phosphorylation of CHK1. Moreover, JIB-04 inhibited the expression of MMP2 to suppress the migration of HASMCs and repressed the expression of contraction-related genes. RNA sequencing analysis showed that the biological processes associated with the cell cycle and autophagy were enriched by using Gene Ontology analysis after HASMCs were treated with JIB-04. Furthermore, we demonstrated that JIB-04 impairs autophagic flux by downregulating STX17 and RAB7 expression to inhibit the fusion of autophagosomes and lysosomes., Conclusion: JIB-04 suppresses the proliferation, migration, and contractile phenotype of HASMCs by inhibiting autophagic flux, which indicates that JIB-04 is a promising reagent for the treatment of neointima formation., (© 2022. The Author(s).)

Background: Tuberculosis (TB) is one of the main infectious diseases that seriously threatens global health, while diagnostic delay (DD) and treatment dramatically threaten TB control., Methods: Between 2005 and 2017 in Shandong, China, we enrolled pulmonary tuberculosis (PTB) patients with DD. DD trends were evaluated by Joinpoint regression, and associations between PTB patient characteristics and DD were estimated by univariate and multivariate logistic regression. The influence of DD duration on prognosis and sputum smear results were assessed by Spearman correlation coefficients., Results: We identified 208,822 PTB cases with a median DD of 33 days (interquartile range (IQR) 18-63). The trend of PTB with DD declined significantly between 2009 and 2017 (annual percent change (APC): - 4.0%, P = 0.047, 2009-2013; APC: - 6.6%, P = 0.001, 2013-2017). Patients aged > 45 years old (adjusted odds ratio (aOR): 1.223, 95% confidence interval (CI) 1.189-1.257, 46-65 years; aOR: 1.306, 95% CI 1.267-1.346, > 65 years), farmers (aOR: 1.520, 95% CI 1.447-1.596), and those with a previous treatment history (aOR: 1.759, 95% CI 1.699-1.821) were prone to developing long DD (> 30 days, P < 0.05). An unfavorable outcome was negatively associated with a short DD (OR: 0.876, 95% CI 0.843-0.910, P < 0.001). Sputum smear positive rate and unfavorable outcomes were positively correlated with DD duration (Spearman correlation coefficients (rs) = 1, P < 0.001)., Conclusions: The DD situation remains serious; more efficient and comprehensive strategies are urgently required to minimize DD, especially for high-risk patients., (© 2022. The Author(s).)