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Hong-Da Zhang,&ast; Lei Ding,&ast; Li-Jie Mi, Ai-Kai Zhang, Yuan-Dong Liu, Xiang-Nan Li, Xin-Xin Yan, Yu-Jing Shen, Min Tang State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100037, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Tang; Yu-Jing Shen, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, 167 Beilishi Road, Xicheng District, Beijing, 100037, People’s Republic of China, Email doctortangmin@yeah.net; shenyj0328@126.comBackground: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in critically ill patients and significantly impacts mortality. This study sought to evaluate the impact of new-onset AF on mortality in a critically ill population.Methods: This study identified 48018 adult patients admitted to the ICU from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Patients were categorized as no AF, pre-existing AF, or new-onset AF. We analyzed mortality at 3 months, 6 months, and 1 year.Results: Overall, 31,562 (65.73%) patients had no AF, 4877 (10.16%) had pre-existing AF, and 11,579 (24.11%) had new-onset AF. Median ages were 61.47 years (no AF), 76.12 years (pre-existing AF), and 75.26 years (new-onset AF). New-onset AF was associated with the highest mortality rates: 25.16% at 3 months, 29.23% at 6 months, and 34.04% at 1 year, compared to 17.94%, 22.55%, and 28.52% for pre-existing AF, and 14.54%, 17.25%, and 20.69% for no AF respectively (p < 0.001 for all). Multivariate Cox regression indicated that new-onset AF significantly increased the risk of 1-year mortality by 15.5% compared to no AF (HR: 1.155, 95% CI: 1.101– 1.212; p < 0.001) and by 23.9% compared to pre-existing AF (HR: 1.239, 95% CI: 1.164– 1.318; p < 0.001). Kaplan-Meier analysis confirmed lower survival probabilities for new-onset AF over one year compared to the other groups (p < 0.001).Conclusion: In patients with critical illness, new-onset AF is associated with an increased risk of mortality compared with pre-existing AF or no AF.Keywords: atrial fibrillation, mortality, intensive care unit

Shao-Long Chen,1 Yao-Jie Shen,2 Guo-Zhi Chen1 1Department of Infectious Disease Control and Prevention, Yueqing Center for Disease Control and Prevention, Wenzhou, 325600, People’s Republic of China; 2Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Shao-Long Chen, Yueqing Center for Disease Control and Prevention, Wenzhou, 325600, People’s Republic of China, Email chenshaolong@zjsru.edu.cnPurpose: Worldwide, chronic hepatitis B virus (CHB) infection is a public health concern, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Currently, patients with CHB can be treated using polyethylene glycol (PEG)ylated interferon (PEG-IFN) antiviral therapy, which has both immune modulatory and antiviral properties. This study aimed to reveal the mechanism underlying the effect of PEG-IFN therapy, to rationally optimize this therapeutic option.Patients and Methods: Ten patients with CHB who were positive for the hepatitis B virus e antigen (HBeAg) and were receiving PEG-IFN treatment were enrolled. Clinical and virological parameters were monitored during 48 weeks of treatment. In addition, peripheral blood mononuclear cells (PBMCs) were collected from the 10 patients at 0, 24, and 36 weeks. RNA sequencing technology was used to analyze the RNA expression profile in the PBMC samples.Results: Following PEG-IFN treatment, we identified 217 differentially expressed genes (DEGs), most of which were upregulated. Gene ontology enrichment analysis of the DEGs revealed that they were enriched in 29 clusters, mainly associated with “antiviral defense”, “innate immunity”, “immunity”, “defense response to virus”, “response to virus”, “type I interferon signaling pathway”, “negative regulation of viral genome replication”, “innate immune response”, and “RNA-binding”.Conclusion: After PEG-IFN treatment, a certain mRNA expression profile was observed in patients with CHB, providing further mechanistic insights into the antiviral effect of this therapy.Keywords: Chronic infection, Hepatitis B, PEGylated interferon, RNA sequencing

Shao-Long Chen,1 Hong Xiao,2 Guo-Jun Li,3 Yao-Jie Shen4 1Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China; 2Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, People’s Republic of China; 3Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, 315100, People’s Republic of China; 4Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Shao-Long Chen, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China, Email chenshaolong@zjsru.edu.cnPurpose: Chronic hepatitis B virus (CHB) infection is a worldwide health problem. Polyethylene glycol (PEG)ylated interferon (PEG-IFN) is an available therapy for CHB that has antiviral and immunomodulatory effects. However, PEG-IFN therapy is limited by the fact that only a subset of patients show a sustained response, its severe side effects, and high cost. The aim of this study was to explore novel biomarkers for the early prediction of PEG-IFN treatment response and to uncover its underlying mechanism.Patients and Methods: We enrolled 10 paired patients with Hepatitis B e antigen (HBeAg)-positive CHB who received PEG-IFN-α 2a monotherapy. Patient serum samples were collected at 0, 4, 12, 24, and 48 weeks and serum samples were collected from eight healthy people as healthy controls. For confirmation, we enrolled 27 patients with HBeAg-positive CHB receiving PEG-IFN therapy and serum samples at 0 and 12 weeks were obtained. Serum samples were analyzed using Luminex technology.Results: Among 27 assessed cytokines, 10 cytokines were identified to have high expression levels. Among them, six cytokines had significant differences in their levels between the patients with HBeAg-positive CHB and the healthy controls (P < 0.05). Potentially, treatment response could be predicted using the early time points of 4, 12, and 24 weeks. Moreover, after 12 weeks of PEG-IFN treatment, increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines were observed. The fold change of IP-10 between 12 weeks and 0 weeks correlated with the decrease in ALT levels from 0 to 12 weeks (r = 0.2675, P = 0.0024).Conclusion: In patients with CHB, we observed a certain pattern in the levels of cytokines during treatment with PEG-IFN, and the cytokine IP-10 might be a potential biomarker for treatment response.Keywords: chronic hepatitis B, PEGylated interferon, cytokine, chemokine, Luminex

Ming-Ming Li,* Jia Cao,* Jia-Chun Yang, Yu-Jie Shen, Xiao-Lei Cai, Yuan-Wen Chen, Chun-Ying Qu, Yi Zhang, Feng Shen, Lei-Ming Xu Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Quantum dots (QDs) conjugated with integrin antagonist arginine–glycine–aspartic acid (RGD) peptides (QDs-RGD) are novel nanomaterials with a unique optical property: a high molar extinction coefficient. Previously, we have shown that QDs-RGD demonstrate a photodynamic therapy (PDT) effect as new photosensitizers for the pancreatic cancer cell line SW1990 in vitro. Here, we investigate the application of QDs-RGD in mice bearing pancreatic tumors using PDT. To ensure that more photosensitizers accumulated in tumors, QDs-RGD were injected intratumorally. After selection of an adequate dosage for injection from analyses of biodistribution images captured by an IVIS system, PDT was initiated. Three groups were created according to different PDT procedures. In group 1, mice were injected with QDs-RGD intratumorally, and an optical fiber connected to a laser light was inserted directly into the tumor. Irradiation was sustained for 20 min with a laser light (630 nm) at 100 mW/cm2. In group 2, the laser optical fiber was placed around, and not inserted into, tumors. In group 3, PDT was conducted as in group 1 but without injection of QDs-RGD. After 28 days of observation, tumors on the back of mice in group 1 grew slowly (V/V0 =3.24±0.70) compared with the control groups, whose tumors grew quickly, and the mean V/V0 reached 6.08±0.50 (group 2) and 7.25±0.82 (group 3). Histology of tumor tissues showed more necrotic tissues, more inflammatory cells, and less vascular tissue in the PDT group than those in the control groups. These results suggest that QDs-RGD-mediated PDT, with illumination using an optical fiber inserted directly into the tumor, can inhibit the growth of SW1990 tumors with high efficiency in nude mice. Keywords: quantum dots, RGD peptides, pancreatic neoplasm, intratumoral injection, photodynamic therapy

Obstructive sleep apnea, characterized by airway exposure to intermittent hypoxia (IH), is associated with laryngeal airway hyperreactivity (LAH) and laryngeal inflammation. The sensitization of capsaicin-sensitive superior laryngeal afferents (CSSLAs) by inflammatory mediators has been implicated in the pathogenesis of LAH. Nerve growth factor (NGF) is an inflammatory mediator that acts on tropomyosin receptor kinase A (TrkA) and the p75 neurotrophin receptor (p75 NTR ) to induce lower airway hyperresponsiveness. In this study, we investigated the role of NGF in the development of LAH and laryngeal inflammation induced by IH in anesthetized rats. Compared with rats subjected to room air exposure for 14 days, rats with 14-day IH exposure exhibited augmented reflex apneic responses to the laryngeal provocation of three different chemical stimulants of CSSLAs, resulting in LAH. The apneic responses to laryngeal stimulants were abolished by either perineural capsaicin treatment (a procedure that selectively blocks the conduction of CSSLAs) or denervation of the superior laryngeal nerves, suggesting that the reflex was mediated through CSSLAs. The IH-induced LAH was significantly attenuated by daily treatment with anti-NGF antibody, but was unaffected by daily treatment with immunoglobulin G. IH exposure also induced laryngeal inflammation as evidenced by increases in laryngeal levels of NGF, lipid peroxidation, tumor necrosis factor-α, interleukin-1β, TrkA, and p75 NTR . Similarly, IH-induced laryngeal inflammation was significantly reduced by daily treatment with anti-NGF antibody. We concluded that NGF contributes to the development of LAH and laryngeal inflammation induced by IH in rats. The LAH may result from the sensitizing effect of NGF on CSSLAs., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The impact of landscape patterns on river water quality has been widely studied; however, it remains unclear which spatial scale has the greatest impact on water quality. Here, we analyzed the spatial scale and threshold impacts of the link between landscape metrics and water quality in a large-scale basin using the random forest (RF) model and nonparametric change point analysis (nCPA) method. The concentrations of nitrate nitrogen (NO 3 - -N) and total nitrogen (TN) were comparatively high in winter and relatively low during spring and summer, whereas the total phosphorus (TP) concentrations were comparatively low during winter and summer and relatively high during spring. The R 2 values of the RF models at the sub-basin scale were generally higher than those at the riparian zone scale. Moreover, the R 2 of water quality modelling at the riparian zone scale demonstrated a declining tendency from a riparian zone 30 m-210 m wide in the majority of seasons. This shows that landscape metrics at the subbasin scale provide a better explanation for the variability in water quality than those at the riparian zone scale in the Hutuo River Basin. The results of the RF model indicated that landscape metrics of landscape configuration were more important in determining water quality during winter, whereas landscape metrics of landscape composition or physiography were more important in determining water quality during summer. Furthermore, several abrupt thresholds were estimated by nCPA; for example, the summertime slope abrupt threshold was 10.79° in the relationship between the slope and NO 3 - -N. This study contributes to the understanding of the debate regarding the scale effects of landscape patterns on water quality, emphasizing the significance of the basin area and offering managers valuable insights into the control of non-point source pollution., Competing Interests: Declaration of competing interest All authors of this paper have not any financial and personal relationships with other people or organizations that could inappropriately influence their work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The synthesis and stabilization of heteroatom-doped nanocarbon molecules, such as carbazole-containing (super)helicenes, present significant challenges due to the complexities involved in maintaining structural integrity and electronic functionality. In this study, we successfully synthesized a carbazole-centered expanded tris-hexabenzo[7]helicene (1) via a facile FeCl3-mediated Scholl coupling reaction. 1 exhibits both chemical and chiral stability and demonstrates fluorescence at 628 nm with a quantum yield of 0.40. Additionally, the enantiomers of 1 display pronounced chiroptical properties, including a distinct circular dichroism (CD) signal spanning from 300 to 600 nm. The absorption dissymmetry factor (|gabs|) is determined to be 2.98 × 10-3, while the circularly polarized luminescence brightness (BCPL) is measured as 32.50 M-1 cm-1., (© 2024 Wiley‐VCH GmbH.)

The introduction of precise pore defects into nanocarbon structures results in the emergence of distinct physicochemical characteristics. However, there is a lack of research on non-planar chiral nanographene involving precise pore defects. Herein, we have developed two analogues to the π-extended pentadecabenzo[9]helicene (EP9H) containing embedded pore defects. Each molecules, namely extended dodecabenzo[7]helicene (ED7H; 1) or extended nonabenzo[5]helicene (EN5H; 2), exhibits dual-state emission. Significantly, the value of |g lum | of 1 is exceptionally high at 1.41×10 -2 in solution and B CPL as 254 M -1  cm -1 . In PMMA film, |g lum | of 1 is 8.56×10 -3 , and in powder film, it is 5.00×10 -3 . This study demonstrates that nanocarbon molecules with pore defects exhibit dual-state emission properties while maintaining quite good chiral luminescence properties. It was distinguished from the aggregation-caused quenching (ACQ) effect corresponding to the nanocarbon without embedded defect. Incorporating pore defects into chiral nanocarbon molecules also simplifies the synthesis process and enhances the solubility of the resulting product. These findings suggest that the introduction of pore defects can be a viable approach to improve nanocarbon molecules., (© 2024 Wiley-VCH GmbH.)

Objective: To explore the clinical correlation and prognostic value of the Albumin-Bilirubin (ALBI) score in children with secondary hemophagocytic syndrome(sHLH)., Methods: A retrospective analysis was conducted on the data of children's sHLH cases clearly diagnosed in the Affiliated Hospital of Zunyi Medical University from January 2012 to March 2023. Survival analysis was conducted according to the ALBI classification. Spearman correlation analysis was conducted between the ALBI score and clinical indicators. The Receiver Operating Characteristic(ROC) curve was used to evaluate the ALBI score, select the best cutoff value, and evaluate the accuracy of prognostic prediction value. Kaplan-Meier method was used to draw the survival curve. Log-rank method was used to compare the differences of survival curve between groups. Cox regression was used for prognostic analysis and restricted cubic spline curves used to calculate the relationship between ALBI scores and the risk of death in children with sHLH., Results: A total of 128 children with sHLH were included in this study, with a median age of 38(13.25, 84) months. There were 70 males (54.69%) and 58 females (45.31%). The survival analysis results of ALBI grading showed that the survival rate of HLH patients with ALBI grade 3 was significantly lower than those with ALBI grades 1 and 2. Spearman correlation analysis results showed that ALBI score was positively correlated with splenomegaly, respiratory failure, disseminated intravascular coagulation(DIC), pulmonary hemorrhage, gastrointestinal hemorrhage, central nervous system involvement, ALT, AST, TG, LDH, PT, APTT, and SF (the correlation coefficients are: r =0.181, 0.362, 0.332, 0.221, 0.351, 0.347, 0.391, 0.563, 0.180, 0.448, 0.483, 0.37, 0.356), and was negatively correlated with HB, PLT, and FIB (the correlation coefficients are: r =-0.321, -0.316, -0.423), but was not significantly correlated with EBV infection, fungal infection, hepatomegaly, and ANC ( P ＞0.05). Using the ROC curve, the cutoff value of ALBI was -1.76. Single factor Cox regression analysis results showed that HB< 90 g/L, ALT≥80 U/L, AST≥200 U/L, LDH≥1 000 U/L, PT≥20 s, APTT≥40 s, FIB< 1.5 g/L, ALBI≥-1.76, combined pulmonary hemorrhage, DIC, central nervous system involvement, gastrointestinal bleeding, and not using blood purification may be the prognostic risk factors for children with sHLH ( P < 0.05). Multivariate Cox regression results showed that FIB< 1.5 g/L ( HR =2.119, 95% CI :1.028-4.368), ALBI≥-1.76 ( HR =2.452, 95% CI :1.233-4.875), and central nervous system involvement ( HR =4.674, 95% CI :2.486-8.789) were independent risk factors affecting prognosis, while blood purification ( HR =0.306, 95% CI :0.153-0.612) was an independent protective factor for prognosis. The application of restricted cubic splines shows that the risk of death increases with the increase of ALBI score. The area under the ROC curve (AUC) of the ALBI score for predicting the risk of 1-week, 2-week, 4-week, and overall mortality were 0.825, 0.807, 0.700, and 0.693, respectively, indicating good predictive performance for early mortality risk. According to subgroup analysis results of clinical manifestations, compared with the ALBI < -1.76 group, ALBI≥-1.76 was associated with age ≤2 years, EBV infection, HLH-1994/2004 treatment, concomitant respiratory failure, and ANC≤1.0×10 9 /L, HB< 90 g/L, PLT < 100×10 9 /L, TG≥3.0 mmol/L, LDH≥1 000 U/L, APTT≥40 s, and FIB< 1.5 g/L ( P < 0.05)., Conclusion: The ALBI score is related to the clinical characteristics and laboratory indicators of sHLH, and can be used as a beneficial indicator for assessing the prognostic risk of sHLH in children. It has good accuracy and clinical application value in predicting the prognosis of sHLH in children.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) respond poorly to immune checkpoint inhibitors (ICIs). It has been reported that the number of CD8 + T cells is reduced in EGFR-mutated NSCLC. However, the extent of heterogeneity and effector function of distinct populations of CD8 + T cells has not been investigated intensively. In addition, studies investigating whether a combination of radiotherapy and ICIs can improve the efficacy of ICIs in EGFR-mutated lung cancer are lacking. Single-cell RNA sequencing (scRNA-seq) was used to investigate the heterogeneity of CD8 + T cell populations in EGFR-mutated NSCLC. The STING pathway was explored after hypofractionated radiation of EGFR-mutated and wild-type cells. Mice bearing LLC-19del and LLC-EGFR tumors were treated with radiotherapy plus anti-PD-L1. The scRNA-seq data showed the percentage of progenitor exhausted CD8 + T cells was lower in EGFR-mutated NSCLC. In addition, CD8 + T cells in EGFR-mutated NSCLC were enriched in oxidative phosphorylation. In EGFR-mutated and wild-type cells, 8 Gy × 3 increased the expression of chemokines that recruit T cells and activate the cGAS-STING pathway. In the LLC-19del and LLC-EGFR mouse model, the combination of radiation and anti-PD-L1 significantly inhibited the growth of abscopal tumors. The enhanced abscopal effect was associated with systemic CD8 + T cell infiltration. This study provided an intensive understanding of the heterogeneity and effector functions of CD8 + T cells in EGFR-mutated NSCLC. We showed that the combination of hypofractionated radiation and anti-PD-L1 significantly enhanced the abscopal responses in both EGFR-mutated and wild-type lung cancer by activating CD8 + T cells in mice., 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 Inc.)

Traumatic injury to the spinal cord can lead to significant, permanent disability. Mammalian spinal cords are not capable of regeneration; in contrast, adult zebrafish are capable of such regeneration, fully recovering motor function. Understanding the mechanisms underlying zebrafish neuroregeneration may provide useful information regarding endogenous regenerative potential and aid in the development of therapeutic strategies in humans. DELTEX proteins (DTXs) regulate a variety of cellular processes. However, their role in neural regeneration has not been described. We found that zebrafish dtx2 , encoding Deltex E3 ubiquitin ligase 2, is expressed in ependymo-radial glial cells in the adult spinal cord. After spinal cord injury, the heterozygous dtx2 mutant fish motor function recovered quicker than that of the wild-type controls. The mutant fish displayed increased ependymo-radial glial cell proliferation and augmented motor neuron formation. Moreover, her gene expression, downstream of Notch signaling, increased in Dtx2 mutants. Notch signaling inactivation by dominant-negative Rbpj abolished the increased ependymo-radial glia proliferation caused by Dtx2 deficiency. These results indicate that ependymo-radial glial proliferation is induced by Dtx2 deficiency by activating Notch-Rbpj signaling to improve spinal cord regeneration and motor function recovery.

Central nervous system lesions often cause permanent motility defects in mammals since the injured neurons cannot regenerate. In contrast, lower vertebrates like zebrafish can regenerate lost neurons and restore motor function. This study investigates the efficacy of SC79, a pan-Akt activator, and A674563, a selective Akt1 inhibitor, as potential therapeutic agents for promoting spinal cord recovery post-injury. Spinal cord injury was induced in zebrafish larvae, and the effects of SC79 and A674563 on neuronal and glial regeneration were examined. SC79 promoted neuronal regeneration without affecting glial bridging, while A674563 induced glial bridging but reduced neuronal regeneration. The combination of SC79 and A674563 induced both glial bridging and neuronal regeneration. Optomotor response tests revealed improved motor function recovery with the combined treatment compared to individual treatments. Additionally, these chemical treatments altered the expression of 12 Akt downstream transcriptional target genes, affirming that the combination treatment preferentially regulates spinal cord regeneration through its action on Akt signaling. These findings highlight the complex interplay of Akt signaling pathways in spinal cord regeneration and suggest potential therapeutic strategies for enhancing functional recovery in spinal cord injury patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A chiral W-shaped fully π-extended double [7]helicene ( ED7H ) has been synthesized and fully characterized. It displays fluorescence emission (λ em = 636 nm) with a quantum yield (Φ f ) of 0.10. In comparison to its X-shaped and monomict π-extended [7]helicene analogues, enantiopure W-shaped ED7H exhibited superior chiral optical characteristics, including distinct circular dichroism signals from 400 to 650 nm, a good dissymmetric emission factor | g lum | of 4 × 10 -3 , and a circularly polarized luminescence brightness value B CPL of 42 M -1 cm -1 .

Objective: To estimate a causal relationship between mental health staffing and time to initiation of mental health care for new patients., Data Sources and Study Setting: As the largest integrated health care delivery system in the United States, the Veterans Health Administration (VHA) provides a unique setting for isolating the effects of staffing on initiation of mental health care where demand is high and out-of-pocket costs are not a relevant confounder. We use data from the Department of Defense and VHA to obtain patient and facility characteristics and health care use., Study Design: To isolate exogenous variation in mental health staffing, we used an instrumental variables approach-two-stage residual inclusion with a discrete time hazard model. Our outcome is time to initiation of mental health care after separation from active duty (first appointment) and our exposure is mental health staffing (standardized clinic time per 1000 VHA enrollees per pay period)., Data Collection/extraction Methods: Our cohort consists of all Veterans separating from active duty between July 2014 and September 2017, who were enrolled in the VHA, and had at least one diagnosis of post-traumatic stress disorder, major depressive disorder, and/or substance use disorder in the year prior to separation from active duty (N = 54,209)., Principal Findings: An increase of 1 standard deviation in mental health staffing results in a higher likelihood of initiating mental health care (adjusted hazard ratio: 3.17, 95% confidence interval: 2.62, 3.84, p < 0.001). Models stratified by tertile of mental health staffing exhibit decreasing returns to scale., Conclusions: Increases in mental health staffing led to faster initiation of care and are especially beneficial in facilities where staffing is lower, although initiation of care appears capacity-limited everywhere., (© 2024 The Author(s). Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Philadelphia chromosome-positive acute lymphoblastic leukemia (PH + ALL) is the most common cytogenetic abnormality of B-ALL in adults and is associated with poor prognosis. Previously, the only curative treatment option in PH + ALL was allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL. Currently, the remission rate and survival rate of Imatinib are superior to those of simple chemotherapy, and it can also improve the efficacy of transplantation. More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin. For patients with ABL1 mutations and those who have relapsed or are refractory to other treatments, targeted oral small molecule drugs, monoclonal antibodies, Bispecific T cell Engagers (BiTE), and chimeric antigen receptor (CAR) T cells immunotherapy are emerging as potential treatment options. These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.

Glioblastoma multiforme (GBM) is the most severe form of brain cancer and presents unique challenges to developing novel treatments due to its immunosuppressive milieu where receptors like programmed death ligand 1 (PD-L1) are frequently elevated to prevent an effective anti-tumor immune response. To potentially shift the GBM environment from being immunosuppressive to immune-enhancing, we engineered a novel nanovehicle from reduced graphene oxide quantum dot (rGOQD), which are loaded with the immunomodulatory drug resiquimod (R848) and conjugated with an anti-PD-L1 antibody (aPD-L1). The immunomodulatory rGOQD/R8/aPDL1 nanoparticles can actively target the PD-L1 on the surface of ALTS1C1 murine glioblastoma cells and release R848 to enhance the T-cell-driven anti-tumor response. From in vitro experiments, the PD-L1-mediated intracellular uptake and the rGOQD-induced photothermal response after irradiation with near-infrared laser light led to the death of cancer cells and the release of damage-associated molecular patterns (DAMPs). The combinational effect of R848 and released DAMPs synergistically produces antigens to activate dendritic cells, which can prime T lymphocytes to infiltrate the tumor in vivo. As a result, T cells effectively target and attack the PD-L1-suppressed glioma cells and foster a robust photothermal therapy elicited anti-tumor immune response from a syngeneic mouse model of GBM with subcutaneously implanted ALTS1C1 cells.

Environmental estrogens (EEs) are found extensively in natural waters and negatively affect fish reproduction. Research on the reproductive toxicity of EEs mixtures in fish at environmentally relevant concentrations is scarce. In this study, adult male zebrafish were exposed for 60 days to EES (a mixture of EEs), EE2-low (5.55 ng/L, with an estrogenic potency equal to EES), and EE2-high (11.1 ng/L). After exposure, the expression levels of vtg1, vtg3, and esr1 in the livers in EES-treated fish remained unaltered, whereas they were significantly increased in EE2-treated fish. Both EE2-high and EES exposures notably reduced the gonad somatic index and sperm count. A disrupted spermatogenesis was also observed in the testes of EE2-high- and EES-exposed fish, along with an alteration in the expression of genes associated with spermatogonial proliferation (pcna, nanog), cell cycle transition (cyclinb1, cyclind1), and meiosis (aldh1a2, cyp26a1, sycp3). Both EE2 and EES significantly lowered plasma 11-ketotestosterone levels in males, likely by inhibiting the expression level of genes for its synthesis (scc, cyp17a1 and cyp11b2), and increased 17β-estradiol (E2) levels, possibly through upregulating the expression of cyp19a1a. A significant increase in tnfrsf1a expression and the tnfrsf1a/tnfrsf1b ratio in EE2-high and EES-treated males also suggests increased apoptosis via the extrinsic pathway. Further investigation showed that both EE2-high and EES diminished the sexual behavior of male fish, accompanied with reduced E2 levels in the brain and the expression of genes in the kisspeptin/gonadotropin-releasing hormone system. Interestingly, the sexual behavior of unexposed females paired with treated males was also reduced, indicating a synergistic effect. This study suggests that EES have a more severe impact on reproduction than EE2-low, and EEs could interfere not only with spermatogenesis in fish, but also with the sexual behaviors of both exposed males and their female partners, thereby leading to a more significant disruption in fish reproduction., 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.)

Background: The interplay between atrial fibrillation (AF) and obesity on mortality in critically ill patients warrants detailed exploration, given their individual impacts on patient prognosis. This study aimed to assess the associations between AF, obesity, and 1-year mortality in a critically ill population., Methods: Utilizing data from the Medical Information Mart for Intensive Care (MIMIC)-IV database, we conducted a retrospective analysis of adult patients admitted to the intensive care unit. The primary endpoint was 1-year mortality, analyzed through Cox regression with hazard ratio (HR) and Kaplan-Meier survival methods., Results: The study included 25,654 patients (median age 67.0 years, 40.6% female), with 39.0% having AF and 36.1% being obese. Multivariate COX regression analysis revealed that AF was associated with a 14.7% increase in the risk of 1-year mortality (p < 0.001), while obesity was linked to a 13.9% reduction in mortality risk (p < 0.001). The protective effect of obesity on mortality was similar in patients with (HR = 0.85) and without AF (HR = 0.86). AF led to a slightly higher risk of mortality in patients without obesity (HR = 1.16) compared to those with obesity (HR = 1.13). Kaplan-Meier survival curves highlighted that non-obese patients with AF had the lowest survival rate, whereas the highest survival was observed in obese patients without AF., Conclusions: AF significantly increased 1-year mortality risk in critically ill patients, whereas obesity was associated with a decreased mortality risk. The most adverse survival outcomes were identified in non-obese patients with AF., (© 2024. The Author(s).)

Inappropriate antibiotic use contributes to antimicrobial resistance, a global public health threat. The non-specific manifestations of dengue, itself a growing public health threat, lead to avoidable empiric antibiotic prescription, particularly in children. In this national pooled population-based cross-sectional study, we evaluated child and physician characteristics associated with antibiotics prescription in confirmed dengue cases in Taiwan. Linking national health care insurance claims and reports of confirmed dengue cases from 2008 to 2015, there were 7086 children with confirmed dengue with 21 744 outpatient visits and 2520 inpatient admissions. We assessed the presence of antibiotic prescription in outpatient and inpatient settings separately a week before or after the confirmation date. Logistic regression models with generalized estimating equations were applied to identify patient, practitioner, and other factors associated with antibiotic prescription. A total of 29.4% of children <18 years old with dengue who did not have a concomitant bacterial infection were prescribed antibiotics during the 14-day assessment period. Antibiotics prescription was reduced from 13.5% to 6.3% and from 43.2% to 19.3% in outpatient and inpatient settings, respectively, after dengue was confirmed. Young children were more likely to receive antibiotics. Significant variations in antibiotic prescribing across physicians were observed only in outpatient settings: physicians ≥60 years old and physicians practicing at clinics and in non-urban facilities were more likely to prescribe antibiotics. Antibiotics were less likely to be prescribed during an exceptional 2-year epidemic than in other years. Antibiotic prescribing for dengue, an arboviral infection affecting half of the global population, was shown to occur in 29% of paediatric cases in Taiwan. That potentially avoidable antibiotic consumption could be reduced by improving antibiotic stewardship, informed by understanding the conditions under which antibiotics are prescribed and the availability of prevention strategies for viral diseases, including dengue. We identified a number of such factors in this national population-based study., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Quality in Health Care.)

Purpose: Hearing loss is a frequently observed comorbidity in patients with nasopharyngeal carcinoma (NPC). Accumulating evidence demonstrated that acupuncture can safely manage cancer and its treatment-related symptoms, but its effect in minimizing the likelihood of experiencing sudden sensorineural hearing loss (SSHL) has not been established. So this work aimed to determine the risk of SSHL among NPC persons with or without acupuncture use., Methods: One population-level, nested case-control design within a cohort study is employed. Relevant information on persons aged 20-80 years who were afflicted with NPC between 2000 and 2010 was extracted from a nationwide health claims database. From them, we identified the cases who had the first SSHL diagnosis occurring after NPC, and all of them were randomly matched to two controls without SSHL. Conditional logistic regression was employed to calculate odds ratios (OR) and its respective 95% confidence intervals (CI) for incident SSHL in relation to acupuncture treatment., Results: Eight hundred eleven SSHL cases were randomly matched to 1452 controls. Those receiving conventional care plus acupuncture use had a reduced adjusted OR of 0.39 (95% CI, 0.25-0.60) for SSHL. We further discovered that the longer usage of acupuncture remarkably correlated with reduction of SSHL risk in a dose-dependent manner., Conclusions: Delineation of the benefit from integration of acupuncture into conventional care may be a reference in instituting more appropriate care for NPC subjects., Implications for Cancer Survivors: Patients living with NPC may benefit from a timely integration of acupuncture into routine care to lessen SSHL risk., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Semaglutide, a glucagon-like peptide-1 receptor agonist, is reported to have cardiac benefits, but its effects on preventing atrial fibrillation (AF) remain inconclusive. This study aimed to investigate whether semaglutide can prevent AF occurrence in patients with type 2 diabetes mellitus (T2DM), obesity, or overweight., Methods: We searched MEDLINE, EMBASE, the Cochrane CENTRAL database, and clinicaltrials.gov from inception to December 29, 2023. Randomized controlled trials of semaglutide in patients with T2DM, obesity, or overweight were included. The primary outcome was AF occurrence. Relative risks (RRs) with 95 % confidence intervals (CIs) were calculated for the overall population and subgroups., Results: Twenty-one trials comprising 25957 patients were included. In the overall pooled analysis, semaglutide decreased AF occurrence compared to control drugs (RR 0.70, 95 % CI 0.52-0.95). This result was consistent in trials using other antihyperglycemic medications as controls (RR 0.43, 95 % CI 0.21-0.89), but not in placebo-controlled trials (RR 0.77, 95 % CI 0.56-1.07). The outcome was favorable for patients with T2DM (RR 0.71, 95 % CI 0.52-0.97), but not for patients with overweight or obesity (RR 0.56, 95 % CI 0.18-1.73). Results varied by type of semaglutide, with oral semaglutide showing an RR of 0.49 (95 % CI 0.25-0.97) and subcutaneous semaglutide showing an RR of 0.77 (95 % CI 0.55-1.07)., Conclusion: Semaglutide was associated with a reduced risk of AF occurrence in the overall analysis. Favorable outcomes were observed in subsets using other antihyperglycemic medications as controls, in patients with T2DM, and with oral semaglutide., 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 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.)

Aims: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are reported to have cardiac benefits. The effects of SGLT2 inhibitors on the prevention of atrial fibrillation (AF) remain inconclusive. We aimed to investigate whether SGLT2 inhibitors can prevent AF occurrence in patients with cardiometabolic diseases., Methods and Results: We searched MEDLINE, EMBASE, and the Cochrane CENTRAL database up to 1 July 2023. Randomized, placebo-controlled trials of SGLT2 inhibitors in patients with diabetes, heart failure, chronic kidney diseases (CKDs), or cardiometabolic risk factors were included. The primary outcome was AF occurrence. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated in the overall population and selected subgroups. Forty-six trials comprising 101 100 patients were included. Overall, no significant risk reduction of AF occurrence was observed with SGLT2 inhibitors, although there was a favourable trend (RR 0.90, 95% CI 0.80-1.01). In trials with follow-up durations of over 1 year, a similar result was achieved (RR 0.90, 95% CI 0.80-1.01). The results were consistent across different SGLT2 inhibitors, with RRs (95% CIs) of 0.82 (0.60-1.12) for canagliflozin, 0.87 (0.73-1.03) for dapagliflozin, 0.97 (0.78-1.22) for empagliflozin, 0.99 (0.66-1.50) for sotagliflozin, and 0.87 (0.58-1.29) for ertugliflozin. Analyses in different doses of SGLT2 inhibitors yielded similar results. The associations between SGLT2 inhibitors and AF occurrence were also absent in patients with diabetes, heart failure, and CKDs., Conclusion: For patients with cardiometabolic diseases or risk factors, SGLT2 inhibitors did not decrease the risk of AF occurrence, regardless of follow-up duration, type or dose of the drug, or the patient population., Competing Interests: Conflict of interest: H.-D.Z., L.D., Y.-J.S., and M.T. take responsibility for the content of the manuscript, including the data and analysis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite promising overall survival of stage I lung adenocarcinoma (LUAD) patients, 10-25 % of them still went through recurrence after surgery. [1] While it is still disputable whether adjuvant chemotherapy is necessary for stage I patients. [2] IASLC grading system for non-mucinous LUAD shows that minor high-grade patterns are significant indicator of poor prognosis. [3] Other risk factors, such as, pleura invasion, lympho-vascular invasion, STAS, etc. are also related to poor prognosis. [4-6] There still lack evidence whether IASLC grade itself or together with other risk factors can guide the use of adjuvant therapy in stage I patients. In this article, we tried to establish a multi-variable recurrence prediction model for stage I LUAD patients that is able to identify candidates of adjuvant chemotherapy., Methods: We retrospectively collected patients who underwent lung surgery from 2018.8.1 to 2018.12.31 at our institution and diagnosed with lung adenocarcinoma pT1-2aN0M0 (stage I). Clinical data, manifestation on CT scan, pathologic features, driver gene mutations and follow-up information were collected. Cox proportional hazards regression analyses were performed utilizing the non-adjuvant cohort to predict disease free survival (DFS) and a nomogram was constructed and applied to the total cohort. Kaplan-Meier method was used to compare DFS between groups. Statistical analysis was conducted by R version 3.6.3., Findings: A total of 913 stage I LUAD patients were included in this study. Median follow-up time is 48.1 months.4-year and 5-year DFS are 92.9 % and 89.6 % for the total cohort. 65 patient experienced recurrence or death. 4-year DFS are 97.0 %,94.6 % and 76.2 %, and 5-year DFS are 95.5 %, 90.0 % and 74.1 % in IASLC Grade1, 2 and 3, respectively(p < 0.0001). High-risk patients defined by single risk factors, such as, IASLC grade 3, pleura invasion, STAS, less LN resected could not benefit from adjuvant therapy. A LASSO-COX regression model was built and patients are divided into high-risk and low-risk groups. In the high-risk group, patients underwent adjuvant chemotherapy have longer DFS than those who did not (p = 0.024), while in the low-risk group, patients underwent adjuvant chemotherapy have inferior DFS than those who did not (p < 0.001)., Interpretation: IASLC grading is a significant indicator of DFS, however it could not guide adjuvant therapy in our stage I LUAD cohort. Growth patterns and T indicators together with other risk factors could identify high-risk patients that are potential candidate of adjuvant therapy, including some stage IA LUAD patients., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Nicotine exposure from smoking constitutes a significant global public health concern. Furthermore, smoking represents a pivotal risk factor for head and neck squamous cell carcinoma (HNSCC). However, the influence of nicotine on HNSCC remains relatively underexplored. Our aim was to unravel the molecular mechanisms that underlie the effect of nicotine on the metastatic cascade of HNSCC. In this study, we discovered a significant association between smoking and HNSCC metastasis and prognosis. Nicotine significantly enhanced HNSCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro. Analysis of TCGA-HNSCC and FDEENT-HNSCC cohorts revealed reduced miR-375-3p levels in HNSCC tumor tissues, particularly among current smokers. Additionally, miR-375-3p level was strongly correlated with both lymph node metastasis and tumor stage. By downregulating miR-375-3p, nicotine promotes HNSCC cell metastasis in vitro and hematogenous metastatic capacity in vivo. Utilizing transcriptomic sequencing, molecular docking, dual-luciferase reporter assay, and fluorescence in situ hybridization (FISH), we demonstrated that miR-375-3p specifically binds to 3' untranslated region (3'UTR) of NTRK2 mRNA. Thus, this study uncovers a novel nicotine-induced mechanism involving miR-375-3p-mediated NTRK2 targeting, which promotes HNSCC metastasis. These findings have implications for improving the prognosis of patients with HNSCC, especially in smokers., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Vaccination is the most effective means of preventing and controlling porcine epidemic diarrhea (PED). Conventional vaccines developed from porcine epidemic diarrhea virus (PEDV) GI-a subtypes (CV777 and SM98) have played a vital role in preventing classical PED. However, with the emergence of PEDV mutants in 2010, conventional PEDV GI-a subtype-targeting vaccines no longer provide adequate protection against PEDV GII mutants, thereby making novel-type PED vaccine development an urgent concern to be addressed. Novel vaccines, including nucleic acid vaccines, genetically engineered subunit vaccines, and live vector vaccines, are associated with several advantages, such as high safety and stability, clear targeting, high yield, low cost, and convenient usage. These vaccines can be combined with corresponding ELISA kits to differentiate infected from vaccinated animals, which is beneficial for disease confirmation. This review provides a detailed overview of the recent advancements in PED vaccines, emphasizing on the research and application evaluation of novel PED vaccines. It also considers the future directions and challenges in advancing these vaccines to widespread use in clinics., Competing Interests: Conflict of interest statement Neither of the authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dinitrosyl iron unit (DNIU), [Fe(NO) 2 ], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO) 2 Fe(μ-SCH 2 CH 2 COOH) 2 Fe(NO) 2 ] ( DNIC-COOH ) and [(NO) 2 Fe(μ-SCH 2 CH 2 COOCH 3 ) 2 Fe(NO) 2 ] ( DNIC-COOMe ) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway ( t max = 0.5 h), intracellular assembly of mononuclear DNIC [(NO) 2 Fe(SR)(S Cys )] n - /[(NO) 2 Fe(SR)(S Cys-protein )] n - occurred, followed by O 2 -induced release of free NO ( t max = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis ( t max = 2-8 h) and for intracellular release of NO ( t max = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH -primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH / DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

As an adaptor protein functions essentially in the activation of NF-κΒ and MAPK signaling pathways mediated by NOD1 and NOD2, RIP2 plays important roles in the host innate immune responses. In the present study, the RIP2 ortholog termed Lc-RIP2 was identified and characterized in large yellow croaker (Larimichthys crocea). It was revealed that Lc-RIP2 is consisted of an open reading frame (ORF) of 1695 bp, encoding a protein of 564 aa, with an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD). Subcellular localization assays demonstrated that Lc-RIP2 was a cytosolic protein, which was broadly distributed in the examined tissues/organs, and could be induced in response to poly I:C, LPS, PGN, and Pseudomonas plecoglossicida stimulations in vivo according to qRT-PCR analysis. Notably, Lc-RIP2 overexpression in vitro was sufficient to abolish SVCV proliferation in EPC cells, and could significantly induce the activation of NF-κB, IRF3, IRF7, and IFN1 promoters. In addition, luciferase assays found that Lc-RIP2 could cooperate with Lc-MAVS, Lc-TRAF3, Lc-TRAF6, Lc-IRF3, and Lc-IRF7 in NF-κB activation, associate with Lc-TRIF, Lc-MAVS, Lc-TRAF3, Lc-IRF3, and Lc-IRF7 in IRF3 activation, enhance Lc-TRIF, Lc-MAVS, Lc-TRAF3, and Lc-TRAF6 mediated IRF7 activation, and Lc-IRF3 mediated IFN1 activation, whereas suppress NF-κB activation when co-expressed with Lc-TRIF. Co-immunoprecipitation (Co-IP) assays also demonstrated that Lc-RIP2 interacts separately with Lc-TRIF, Lc-MAVS, Lc-TRAF3, Lc-TRAF6, Lc-IRF3, and Lc-IRF7. It is thus collectively indicated that Lc-RIP2 function dominantly in the regulation of the host innate immune signaling., (Copyright © 2024. Published by Elsevier Ltd.)

M1 microglial activation is crucial for the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and there is growing evidence that glucose metabolism is frequently involved in microglial activation. However, the molecular mechanism of glycolysis and its role in M1 microglial activation in the context of EBI are not yet fully understood. In this study, firstly, the relationship between aerobic glycolysis and M1 microglial activation as well as SAH-induced EBI was researched in vivo. Then, intervention on mammalian target of rapamycin (mTOR) was performed to investigate the effects on glycolysis-dependent M1 microglial activation and EBI and its relationship with hypoxia-inducible factor-1α (HIF-1α) in vivo. Next, Hif-1α was inhibited to analyze its role in aerobic glycolysis, M1 microglial activation, and EBI in vivo. Lastly, both in vivo and in vitro, mTOR inhibition and Hif-1α enhancement were administered simultaneously, and the combined effects were further confirmed again. The results showed that aerobic glycolysis and M1 microglial polarization were increased after SAH, and glycolytic inhibition could attenuate M1 microglial activation and EBI. Inhibition of mTOR reduced glycolysis-dependent M1 microglial polarization and EBI severity by down-regulating HIF-1α expression, while enhancement had the opposite effects. Blockading HIF-1α had the similar effects as suppressing mTOR, while HIF-1α agonist worked against mTOR antagonist when administered simultaneously. In conclusion, the present study showed new evidence that aerobic glycolysis induced by mTOR/HIF-1α might promote EBI after SAH by activating M1 microglia. This finding provided new insights for the treatment of EBI., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Endobronchial ultrasound (EBUS) is commonly used to guide transbronchial needle biopsies for the staging of lymph nodes in non-small cell lung cancer patients. Although contrast-enhanced ultrasound (CEUS) and microbubbles (MBs) can improve the diagnostic accuracy in tumors, the ability of contrast-enhanced EBUS (CE-EBUS) to image MBs has not yet been comprehensively evaluated. In this study, we assessed the ability of a CE-EBUS system (Olympus EU-ME2 PREMIER and BF-UC180F bronchoscope) to detect laboratory-synthesized MBs in comparison to clinical (Toshiba Aplio SSA-790A) and pre-clinical (VisualSonics Vevo 2100) CEUS systems in vitro and in vivo, respectively., Methods: Agar flow phantoms and reference tissue were used to assess CE-EBUS MB imaging in vitro, and A549 tumor-bearing athymic nude and AE17-OVA tumor-bearing C57BL/6 mice were used to assess MB detectability and perfusion in vivo, respectively., Results: Results revealed that despite the lower sensitivity of CE-EBUS to MB concentration in comparison to clinical CEUS, CE-EBUS yielded a similar contrast-to-tissue ratio (CTR) in vitro of 28.9 ± 4.5 dB for CE-EBUS, compared with 29.7 ± 2.6 dB for clinical CEUS (p < 0.05). In vivo, CE-EBUS generated a perfusion curve highly correlated with that obtained with the pre-clinical CEUS system (Pearson correlation coefficient = 0.927, p < 0.05). Moreover, CE-EBUS yielded a CTR 2.7 times higher than that obtained with the pre-clinical ultrasound system., Conclusion: These findings together suggest that CE-EBUS can perform contrast imaging comparable to that produced by commercial pre-clinical and clinical ultrasound systems, with potential for clinical characterization of mediastinal lymph nodes in lung cancer patients., Competing Interests: Conflict of interest K.Y. is a consultant for Olympus, and the work was partially supported by a research grant from Olympus Corporation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The trade-off between high-quality images and cellular health in optical bioimaging is a crucial problem. We demonstrated a deep-learning-based power-enhancement (PE) model in a harmonic generation microscope (HGM), including second harmonic generation (SHG) and third harmonic generation (THG). Our model can predict high-power HGM images from low-power images, greatly reducing the risk of phototoxicity and photodamage. Furthermore, the PE model trained only on normal skin data can also be used to predict abnormal skin data, enabling the dermatopathologist to successfully identify and label cancer cells. The PE model shows potential for in-vivo and ex-vivo HGM imaging., (© 2023 Wiley-VCH GmbH.)

Many groundwater construction projects such as South-to-North Water Diversion Project (SNWDP) were conducted for controlling groundwater overexploitation in the North China Plain (NCP). However, more insight is required into the magnitude and distribution of water table depth (WTD) in time and space over the NCP. This study evaluated the variability and the hotspots of WTD based on 83 unconfined monitoring wells and took trend, breakpoint, and time stability into consideration. We found the average WTD of unconfined aquifer for the Southern Hebei Plain generally increased continuously from 1998 to 2020 in spite of the operation of the SNWDP since 2014. However, the rise rate of WTD slows down in recent years and the WTD has decreased in certain subregions. We further divided these groundwater wells into five groups: climb accelerating (Group 1), increase decelerating (Group 2), first rise then descend (Group 3), first descend then rise (Group 4), decrease decelerating (Group 5), and reduce accelerating (Group 6). Moreover, we found that the number of wells that divided into Group1 to Group 5 account for 15 %, 41 %, 25 %, 18 %, and 1 % of the total number of observation wells. The breakpoints of all the wells are from 2001 to 2017 and most of the breakpoints were found before 2014, which demonstrates that other groundwater management strategies implemented in the Southern Hebei Plain prior to the operation of the SNWDP plays a crucial part. The hotspots area for group 1 is mainly distributed in the north region of Shijiazhuang City, group 2 is in southern region of piedmont plain, group 3 is in northern region of Baoding and south-west region of Xingtai City, and group 4 is in Cangzhou City and eastern region of Xingtai City. The method and framework of this study can be applied in other regions suffering from groundwater depletion., Competing Interests: Declaration of competing interest All authors of this paper have not any financial and personal relationships with other people or organizations that could inappropriately influence their work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Molecular folding regulation with environmental stimuli is critical in living and artificial molecular machine systems. Herein, we described a macrocycle, cyclo[4] (1,3-(4,6-dimethyl)benzene)[4](1,3-(4,6-dimethyl)benzene)(4-pyridine). Under 298 K, it has three stable stiff atropisomers with names as 1 (C s symmetry), 2 (C s symmetry), and 3 (C 4v symmetry). At 393 K, 1 can reversibly transform into 2, but at 473 K, it can irrevocably transform into 3. At 338 K, 3 and (PhCN) 2 PdCl 2 complex to produce the metal-organic cage 4. Only at 338 K does the combination of 1 or 2 and (PhCN) 2 PdCl 2 create a gel-like structure. Heating both gels to 473 K transforms them into 4. In addition to offering a thermally accelerated method for modifying self-assembled systems using macrocyclic building blocks, this study also has the potential to develop the nanoscale transformation material with a thermal response., (© 2023. The Author(s).)

Laryngeal squamous cell carcinoma (LSCC) is a common tumor type. High recurrence rates remain an important factor affecting the survival and quality of life of advanced LSCC patients. We aimed to build a new nomogram and a random survival forest model using machine learning to predict the risk of LSCC progress. The study included 671 patients with AJCC stages III-IV LSCC. To develop a prognostic model, Cox regression analyses were used to assess the relationship between clinic-pathologic factors and disease-free survival (DFS). RSF analysis was also used to predict the DFS of LSCC patients. The ROC curve revealed that the Cox model exhibited good sensitivity and specificity in predicting DFS in the training and validation cohorts (1 year, validation AUC = 0.679, training AUC = 0.693; 3 years, validation AUC = 0.716, training AUC = 0.655; 5 years, validation AUC = 0.717, training AUC = 0.659). Random survival forest analysis showed that N stage, clinical stage, and postoperative chemoradiotherapy were prognostically significant variables associated with survival. The random forest model exhibited better prediction ability than the Cox regression model in the training cohort; however, the two models showed similar prediction ability in the validation cohort., (© 2023. The Author(s).)

The three provinces of Northeast China are crucial to national commodity grain production. Soils in those areas have begun to severely degrade after long-term high-intensity use, with wind erosion as one of the main reasons. Based on meteorological and soil data from 1981 to 2019, we evaluated the spatial-temporal characteristics of wind erosion on bare land in the three provinces of Northeast China by using the revised wind erosion equation (RWEQ), and analyzed the contributions of meteorological factors to wind erosion on bare land. The results showed that, the meteorological factors of wind erosion were overall high in southwestern part and low in northeastern part of the region. In general, wind erosion in the region was substantial, especially in Liaoning. During the 39 years, wind erosion significantly increased throughout the whole year and during the growing season, at a rate of 129 and 105 t·km -2 per decade, respectively. The obvious increase in wind erosion was observed in the northwest Liaoning, Liaohe Plain, and Changbai Mountain area. Wind speed and air temperature were the main factors affecting wind erosion during the year and non-growing season, which contributed less during the growing season when precipitation contributed the most. We concluded that climate change has aggravated soil wind erosion in the three provinces of Northeast China.

Background: The convergence of infectious diseases and non-communicable diseases in South Africa is challenging to health systems. In this analysis, we assessed the multimorbidity health needs of individuals and communities in rural KwaZulu-Natal and established a framework to quantify met and unmet health needs for individuals living with infectious and non-communicable diseases., Methods: We analysed data collected between May 25, 2018, and March 13, 2020, from participants of a large, community-based, cross-sectional multimorbidity survey (Vukuzazi) that offered community-based HIV, hypertension, and diabetes screening to all residents aged 15 years or older in a surveillance area in the uMkhanyakude district in KwaZulu-Natal, South Africa. Data from the Vukuzazi survey were linked with data from demographic and health surveillance surveys with a unique identifier common to both studies. Questionnaires were used to assess the diagnosed health conditions, treatment history, general health, and sociodemographic characteristics of an individual. For each condition (ie, HIV, hypertension, and diabetes), individuals were defined as having no health needs (absence of condition), met health needs (condition that is well controlled), or one or more unmet health needs (including diagnosis, engagement in care, or treatment optimisation). We analysed met and unmet health needs for individual and combined conditions and investigated their geospatial distribution., Findings: Of 18 041 participants who completed the survey (12 229 [67·8%] were female and 5812 [32·2%] were male), 9898 (54·9%) had at least one of the three chronic diseases measured. 4942 (49·9%) of these 9898 individuals had at least one unmet health need (1802 [18·2%] of 9898 needed treatment optimisation, 1282 [13·0%] needed engagement in care, and 1858 [18·8%] needed a diagnosis). Unmet health needs varied by disease; 1617 (93·1%) of 1737 people who screened positive for diabetes, 2681 (58·2%) of 4603 people who screened positive for hypertension, and 1321 (21·7%) of 6096 people who screened positive for HIV had unmet health needs. Geospatially, met health needs for HIV were widely distributed and unmet health needs for all three conditions had specific sites of concentration; all three conditions had an overlapping geographical pattern for the need for diagnosis., Interpretation: Although people living with HIV predominantly have a well controlled condition, there is a high burden of unmet health needs for people living with hypertension and diabetes. In South Africa, adapting current, widely available HIV care services to integrate non-communicable disease care is of high priority., Funding: Fogarty International Center and the National Institutes of Health, the Bill & Melinda Gates Foundation, the South African Department of Science and Innovation, the South African Medical Research Council, the South African Population Research Infrastructure Network, and the Wellcome Trust., Translation: For the isiZulu translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Surface runoff has dropped sharply in the mountainous area of the Hutuo River, posing a huge challenge to the sustainable use of groundwater in the North China Plain (NCP). The Taihang Mountain area is the main recharge source area of groundwater in the NCP. An in-depth study of spatial variation characteristics, influencing factors, and sources of hydrogeochemical characteristics of surface water and groundwater in the mountainous area of the Hutuo River can facilitate a comprehensive understanding of regional water resource status and sustainable utilization of water resources. Based on isotopic, hydrogeochemical, and mathematical statistics methods, this study analyzed spatial variation of hydrochemical characteristics in surface water and groundwater and its sources and main controlling factors. The results showed that the river water, well water, and spring water were all recharged by atmospheric precipitation in the mountainous areas of the Hutuo River. Under the combined influence of natural factors and human factors, the hydrogeochemical characteristics of river, well, and spring water showed large spatial differences. On the whole, the hydrochemical types of mainstreams were relatively concentrated. In the upper and lower mining reach areas, the mainstream water chemical type was dominated by Ca·Mg-SO 4 ·HCO 3 , whereas that in the natural vegetation area (middle reach:between Qingshui River and Longhua River) was dominated by Ca·Mg-HCO 3 ·SO 4 . In the upper stream, the main hydrochemical type of the Yukou River and Ehe River tributaries was Ca·Mg-SO 4 ·HCO 3 , which was consistent with that of the main stream. The main hydrochemical types of the Muma River and Qingshui River tributaries were Ca-HCO 3 , Ca·Mg-HCO 3 , and Ca·Mg-HCO 3 ·SO 4 in the midstream. The main hydrochemical types of the Mianhe River and Yehe River tributaries were Ca-SO 4 , Ca·Mg-SO 4 , and Ca·Mg-SO 4 ·HCO 3 . Mineral dissolution was still the main controlling factor for the hydrochemical characteristics of surface water and groundwater in the mountainous area of the Hutuo River. The contribution rates were 69.86% and 18.84% for mineral dissolution and human activities, respectively. Therefore, in the future, water resource utilization in the upper reaches of the Hutuo River should not only consider the issue of water quantity but also a series of water environment problems such as nitrate pollution and mining pollution caused by human activities.

Objective：The purpose of this study was to explore the causal relationship between nonalcoholic fatty liver disease (NAFLD) and the risk of erectile dysfunction (ED) by using two-sample Mendelian randomization (MR) analysis., Methods: Single nucleotide polymorphisms (SNPs) were screened as instrumental variables (IVs) using the public genome-wide association study summary data set (GWAS). Univariate MR, bidirectional MR and multivariate MR methods were used to analyze the causal relationship between NAFLD and ED., Results: IVW results showed that NAFLD was not associated with ED (OR=0.991 2, 95%CI: 0.955 2－1.0286, P=0.640 6). The results of reverse MR showed that there was no correlation between ED and NAFLD (OR=1.181 5, 95%CI: 0.820 8－1.7007, P=0.369 5). Multivariate MR results showed that there was still no causal relationship between the two diseases after adjusting for confounding factors., Conclusion: The results showed that there was no causal relationship between NAFLD and the risk of ED.

Dengue, a mosquitoborne flavivirus infection, is increasingly a disease of older adults who are more likely to have chronic diseases that confer risk for severe outcomes of dengue infection. In a population-based study in Taiwan, adjusted risks for dengue-related hospitalization, intensive care unit admission, and death increased progressively with age.

Despite the fact that metastasis is the leading cause of death in patients with head and neck squamous cell carcinoma, fundamental questions about the mechanisms that enable or inhibit metastasis remain unanswered. Tetraspanin CD63 has been linked to tumor progression and metastasis. However, few studies have examined the role of CD63 in HNSCC. In this study, we discovered that CD63 levels were abnormally altered in HNSCC tissue compared to adjacent tissue (n = 69 pairs), and that this was linked to prognosis. Through functional in vitro and in vivo experiments, the roles of CD63 in HNSCC were confirmed. Overexpression of CD63 inhibited the progression and metastasis of HNSCC cells. Using mass spectrometry and co-immunoprecipitation assays, we discovered that KRT1 could be a direct interacting partner of CD63. Furthermore, both CD63 and KRT1 expression was significantly decreased in metastatic tissue compared with primary tumor tissue (n = 13 pairs), suggesting that CD63 and KRT1 play a role in reducing the metastasis of HNSCC. In summary, we reveal a previously unrecognized role of CD63 in regulating KRT1-mediated cell cycle arrest in HNSCC cells, and our findings contribute to defining an important mechanism of HNSCC progression and metastasis., Competing Interests: 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., (© 2023 The Authors.)

Acute myeloid leukaemia (AML) with t (8;21) or inv (16), called core binding factor (CBF) AML, has a favourable prognosis. However, some CBF-AML patients have persistent measurable residual disease (MRD) and are more likely to relapse after standard chemotherapy treatment. The CAG regimen, composed of cytarabine, aclarubicin and granulocyte colony-stimulating factor, has been proven to be effective and safe in treating refractory AML patients. We performed a retrospective study to evaluate the efficacy of the CAG regimen to eliminate MRD detected by RUNX1::RUNX1T1 and CBFβ::MYH11 transcript levels by quantitative polymerase chain reaction (Q-PCR) among 23 patients. Molecular response was defined as the ratio of fusion transcript after treatment to that before treatment less than or equal to 0.5. The molecular response rate and median decrease ratio of fusion transcripts at the molecular level of the CAG regimen were 52% and 0.53, respectively. The median fusion transcripts before CAG treatment was 0.25% whereas after CAG was 0.11%. Among the 15 patients who had a poor molecular response to the high/intermediate-dose cytarabine regimen, the median decrease ratios of transcripts at the molecular level of high/intermediate-dose cytarabine and CAG were 1.55 and 0.53 (P = 0.028), respectively, and 6 of 15 patients achieved a molecular response to CAG (40%). The median disease-free survival was 18 months, and the overall survival rate at 3 years among all patients was 72.7% ± 10.7%. The common grades 3-4 adverse events were nausea (100%), thrombocytopenia (39%) and neutropenia (37.5%). The CAG regimen may have activity in CBF-AML patients and could provide a new option for patients who have a poor molecular response to high/intermediate-dose cytarabine., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Photoperiod has been well-documented to be involved in regulating many activities of animals. However, whether photoperiod takes part in mood control, such as fear response in fish and the underlying mode(s) of action remain unclear. In this study, adult zebrafish males and females (Danio rerio) were exposed to different photoperiods, Blank (12 h light: 12 h dark), Control (12 h light: 12 h dark), Short daylight (SD, 6 h light: 18 h dark) and Long daylight (LD, 18 h light: 6 h dark) for 28 days. After exposure, fear response of the fish was investigated using a novel tank diving test. After alarm substance administration, the onset to higher half, total duration in lower half and duration of freezing in SD-fish were significantly decreased, suggesting that short daylight photoperiod is capable of alleviating fear response in zebrafish. In contrast, comparing with the Control, LD didn't show significant effect on fear response of the fish. Further investigation revealed that SD increased the levels of melatonin (MT), serotonin (5-HT) and dopamine (DA) in the brain while decreased the plasma level of cortisol comparing to the Control. Moreover, the expressions of genes in MT, 5-HT and DA pathways and HPI axis were also altered consistently. Our data indicated that short daylight photoperiod might alleviate fear response of zebrafish probably through interfering with MT/5-HT/DA pathways and HPI axis., 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 Inc. All rights reserved.)

Background: Hong Kong catfish (Clarias fuscus) is an ecologically and economically important species that is widely distributed in freshwater regions of southern China. Hong Kong catfish has significant sexual growth dimorphism. The genome assembly of the Hong Kong catfish would facilitate study of the sex determination and evolution mechanism of the species., Results: The first high-quality chromosome-level genome of the Hong Kong catfish was constructed. The total genome was 933.4 Mb, with 416 contigs and a contig N50 length of 8.52 Mb. Using high-throughput chromosome conformation capture (Hi-C) data, the genome assembly was divided into 28 chromosomes with a scaffold N50 length of 36.68 Mb. A total of 23,345 protein-coding genes were predicted in the genome, and 94.28% of the genes were functionally annotated in public databases. Phylogenetic analysis indicated that C. fuscus and Clarias magur diverged approximately 63.7 million years ago. The comparative genome results showed that a total of 60 unique, 353 expanded and 851 contracted gene families were identified in Hong Kong catfish. A sex-linked quantitative trait locus identified in a previous study was located in a sex-determining region of 30.26 Mb (0.02 to 30.28 Mb) on chromosome 13 (Chr13), the predicted Y chromosome. This QTL region contained 785 genes, of which 18 were identified as sex-related genes., Conclusions: This study is the first to report the chromosome-level genome assembly of Hong Kong catfish. The study provides an excellent genetic resource that will facilitate future studies of sex determination mechanisms and evolution in fish., (© 2023. The Author(s).)