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Abstract Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). This BBOX1-DCLK2-TBK1 axis unveils an important mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.

Abstract During infection and cancer, mTORC1-mediated metabolic regulation impacts CD8+ T cell effector expansion and memory development. However, the mechanisms by which CD8+ T cells regulate mTORC1 to support their unique metabolic requirements remain unknown. Here we show that NKG7, a lysosomal protein whose expression is restricted to cytotoxic lymphocytes, negatively regulates mTORC1 recruitment and activation by inhibiting assembly and function of the lysosomal proton pump, vacuolar ATPase (v-ATPase). Human and mouse CD8+ T cells lacking NKG7 show more acidic lysosomes and increased activation of mTORC1 signaling, which could be reversed by inhibition of v-ATPase activity. In mice responding to LCMV infection, NKG7-deleted effector CD8+ T cells are less durable and generate fewer memory precursors, whereas induced expression of NKG7 in CD8+ T cells results in increased presence of intra-tumoral T cells. Overall, our work identifies NKG7 as a CD8+ T cell-specific regulator of mTORC1 activity, required for optimal immune responses.

Abstract Background Insulin resistance is a crucial factor in the development of cardiovascular diseases (CVD), yet the relationship between the estimated glucose disposal rate (eGDR), an index reflecting insulin resistance, and the risk of new-onset CVD among individuals with cardiovascular-kidney-metabolic (CKM) syndrome stage 0–3 remains underexplored, and large-scale prospective cohort studies are needed to clarify this relationship. Methods All data for this study were extracted from the China Health and Retirement Longitudinal Study (CHARLS). The primary outcome was the incidence of new-onset CVD (including heart diseases (HD) and stroke) during the follow-up period (from 2013 to 2020). Multivariable logistic regression models were applied to elucidate the relationship between the eGDR and the risk of developing CVD. The restricted cubic splines (RCS), mediation analysis, and stratified analyses were also employed. Results This study included 6752 participants, of whom 1495 (22%) developed CVD. Odds ratios and 95% confidence intervals from lowest eGDR level (

Abstract Background Methylglyoxal (MGO)-induced cell death in vascular endothelial cells (VECs) plays a critical role in the progression of diabetic vascular complications (DVCs). Previous studies have shown that MGO can induce inflammatory pyroptosis, leading to VEC damage. However, the underlying mechanism remains unclear, and effective interventions are yet to be developed. Methods Human umbilical vein endothelial cells (HUVECs) were used for in vitro experiments. Cell death modes were assessed through morphological observations. Mechanistic investigations were performed using immunofluorescence, flow cytometry, Western blotting, and ELISA. Inhibitors and adenoviruses were employed to validate the mechanisms. Vascular organoids in conjunction with AngioTool plug-in assays were used to evaluate VEC damage and angiogenic capacity. Mouse blood pressure was measured using the tail-cuff method, and vascular morphology was examined through hematoxylin and eosin (H&E) staining as well as immunofluorescence staining. Data were analyzed using the GraphPad Prism software. Results Our study revealed that MGO induces pyroptosis in VECs via the Caspase3/gasdermin E (GSDME) pathway. Furthermore, the saponin monomer 13 of dwarf lilyturf tuber (DT-13), inhibited MGO-induced pyroptosis and promoted the generation of apoptotic bodies, facilitating the transition from pyroptosis to apoptosis. Mechanistically, DT-13 suppressed the Caspase3-mediated cleavage of GSDME and non-muscle myosin heavy chain IIA (NMMHC IIA), while increasing the phosphorylation of myosin light chain 2 (MLC2), which facilitated apoptotic body formation. Additionally, DT-13 was shown to mitigate VEC damage, inhibit angiogenesis, reduce vascular remodeling, and alleviate MGO-induced hypertension. Conclusions This study uncovers a novel mechanism through which MGO induces VEC damage, highlighting the therapeutic significance of the transition from pyroptosis to apoptosis in this process. These findings suggest potential therapeutic strategies for managing diabetic angiopathy. Furthermore, DT-13 emerges as a promising compound for therapeutic intervention, offering new possibilities for clinical applications.

Abstract Imaging flow cytometry (IFC) combines the imaging capabilities of microscopy with the high throughput of flow cytometry, offering a promising solution for high-precision and high-throughput cell analysis in fields such as biomedicine, green energy, and environmental monitoring. However, due to limitations in imaging framerate and real-time data processing, the real-time throughput of existing IFC systems has been restricted to approximately 1000-10,000 events per second (eps), which is insufficient for large-scale cell analysis. In this work, we demonstrate IFC with real-time throughput exceeding 1,000,000 eps by integrating optical time-stretch (OTS) imaging, microfluidic-based cell manipulation, and online image processing. Cells flowing at speeds up to 15 m/s are clearly imaged with a spatial resolution of 780 nm, and images of each individual cell are captured, stored, and analyzed. The capabilities and performance of our system are validated through the identification of malignancies in clinical colorectal samples. This work sets a new record for throughput in imaging flow cytometry, and we believe it has the potential to revolutionize cell analysis by enabling highly efficient, accurate, and intelligent measurement.

Abstract Background It is well established that increased lipoprotein(a) [Lp(a)] is a significant risk factor for coronary artery disease (CAD). Plasma Lp(a) levels are genetically determined and vary widely between different races, regions and individuals. However, most studies on Lp(a) associated genetic variants have focused on the Caucasian population currently. Our study aimed to test the associations among LPA genetic variants, Lp(a) concentrations, and CAD in a Han Chinese cohort. Methods A total of 3779 patients undergoing coronary angiography were recruited from Tongji Hospital. LPA Kringle IV type 2 (KIV-2) copies were detected using TaqMan probe real-time quantitative polymerase chain reaction (qPCR) analysis and fifteen single nucleotide polymorphisms (SNPs) within the LPA gene were detected using TaqMan probe genotyping analysis. LPA genetic risk score (GRS) was computed based on seven SNPs associated with Lp(a). Associations of LPA genetic variants with Lp(a) and CAD were evaluated using linear regression analyses and Logistic regression analyses, respectively. Results Compared with the first quartile of Lp(a), the fourth quartile exhibited a significant association with CAD [odds ratio (OR): 2.08, 95% confidence interval (CI): 1.67–2.59, p

Abstract Aim Explore the relationship between the triglyceride-glucose (TyG) index, along with its derivative indices, and the prevalence of cataracts. Methods Data from 20,497 participants in the 2005–2008 National Health and Nutrition Examination Survey (NHANES) were compiled. A final total of 4,499 individuals met the eligibility criteria. Cataract presence was assessed through a self-reported history of cataract surgery. The TyG index and its derivatives—TyG-waist-to-height ratio (WHtR), TyG-neutrophil-to-lymphocyte ratio (NLR), TyG-monocyte-to-lymphocyte ratio (MLR), TyG-log platelet-to-lymphocyte ratio (lgPLR), TyG-log systemic inflammation index (lgSII), and TyG-systemic inflammation response index (SIRI)—were calculated. Statistical analyses included multivariable logistic regression, restricted cubic spline (RCS) curves for nonlinear relationships, and receiver operating characteristic (ROC) analysis. Results Higher TyG indices were significantly associated with cataract presence (P

Changcheng Tao,1,&ast; Liguo Liu,2,&ast; Nan Hu,1,&ast; Hongwei Wang,1,&ast; Kai Zhang,1 Yue Liu,1 Fan Wu,1 Liming Wang,1 Weiqi Rong,1 Jianxiong Wu1 1Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Second Department of Hepatopancreatobiliary Surgery, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiqi Rong, Email dr_rongweiqi@163.com; Jianxiong Wu, Email dr_wujx@163.comBackground: Radiotherapy offers potential benefits for patients with hepatocellular carcinoma (HCC); however, the distinct role of intraoperative radiotherapy (IORT) during narrow-margin hepatectomy remains inadequately defined. This study aims at assessing the safety and effectiveness of IORT for centrally located HCCs during narrow-margin hepatectomy.Methods: This single-center, retrospective research incorporated 659 patients with centrally located HCCs. After applying exclusion criteria, 607 patients remained and were divided into two groups: IORT integrated with liver resection (IORT+LR, 54 patients) and mere liver resection (LR, 553 patients). Propensity score matching (PSM) was performed to balance baseline characteristics. Post PSM, surgical outcomes, long-term recurrence, survival rates and adverse events were analyzed.Results: A total of 54 patients were successfully matched, without significant differences upon baseline characteristics (standardized mean difference, SMD < 0.15). Post-matching analysis revealed that overall survival (OS) and disease-free survival (DFS) were notably improved in the IORT+LR group (P =0.027 and 0.015, respectively). Multivariate Cox regression identified IORT as an independent prognostic factor for better DFS and OS. Among the 108 patients included after matching, 57 experienced HCC recurrence, 23 in the IORT group and 34 in the LR group, showing a clear difference in recurrence rates (P =0.034). Also, there were no apparent differences in mild/severe complications between IORT and RT groups (96.3% vs 98.2%, P =0.558, respectively).Conclusion: IORT is an effective and well-tolerated therapy for HCC patients. The combination of narrow-margin hepatectomy and IORT enhances patient prognosis, with IORT identified as an independent prognostic factor.Keywords: centrally located hepatocellular carcinoma, intraoperative radiotherapy, hepatectomy, recurrence, prognosis

Pengcheng Hu,1 Jilu Zheng,1 Hongjuan Wang,1 Yongxin Li,2 Tao Ye,1,3 Quanjun Li,1 Xiaopeng Lan,1 Chunzhao Liu,2 Chunlei Liu1 1Department of Urology, Department of Primary Healthcare, Department of Cardiology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, People’s Republic of China; 2College of Materials Science and Engineering, Qingdao University, Qingdao, 266071, People’s Republic of China; 3School of Clinical Medicine, Shandong second Medical University, Weifang, Shandong, 261053, People’s Republic of ChinaCorrespondence: Chunlei Liu; Chunzhao Liu, Email liuchunlei1969@126.com; czliu@qdu.edu.cnAbstract: Natural enzyme systems possess extraordinary functions and characteristics, making them highly appealing for use in eco-friendly technologies and innovative cancer treatments. However, their inherent instability and structural complexity often limit their practical applications, leading to the exploration of biomolecular nanozyme alternatives. Supramolecular nanozymes, constructed using self-assembly techniques and various non-covalent interactions, have emerged as a promising solution. Amino acids, peptides, and protein motifs offer flexible building blocks for constructing these nanozymes. Importantly, the well-defined structural regulation mechanisms of biomolecular nanozymes, along with their unique properties as fundamental biological modules in living systems—such as selectivity, permeability, retention, and biocompatibility—present new opportunities for cancer therapy. This review highlights recent advances in supramolecular self-assembled nanozymes, including peroxidases, oxidases, catalases, superoxide dismutases, and other nanozyme systems, as building blocks for tumor therapy. Additionally, it discusses precise functional modulation through supramolecular non-covalent interactions and their therapeutic applications in targeting the tumor microenvironment. These studies provide valuable insights that may inspire the design of novel supramolecular nanozymes with enhanced catalytic selectivity, biocompatibility, and tumor-killing efficacy.Keywords: supramolecular nanozymes, self-assembly, biomolecular, tumor therapy

Ping Wu,1,2 Jiahui Zhang,1 Yijing Hu1 1Department of Pulmonology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China; 2School of Medicine, Tongji University, Shanghai, People’s Republic of ChinaCorrespondence: Yijing Hu, Department of Pulmonology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, 505 TongPu Road, PuTuo District, Shanghai, 200062, People’s Republic of China, Tel +8618917180737, Email huyijing@shchildren.com.cnObjective: This study aimed to clarify the emotional and practical burden on primary caregivers of children with severe asthma and identify the support needs of those caring for individuals with severe asthma.Methods: A phenomenological research approach in qualitative research was used. Semi-structured interviews with caregivers of children with asthma waiting in the outpatient clinic of Shanghai Children’s Hospital were conducted from January to August 2024 through purposive sampling. The researcher transcribed audio-recorded interview data verbatim into text and thematically analyzed the data using the Colaizzi 7-step analysis method and then obtained the final results.Results: There were a total of 12 participants. Through these 12 in-depth one-on-one interviews, all necessary study data were obtained. The study identified the following four main burdens for caregivers of children with severe asthma: 1) Multiple barriers to the care-giving process. (Incomplete knowledge of disease management; lack of competence in care as well as poor child compliance making care more difficult; lack of support for asthma in schools). 2) Excessive consumption of time and energy. (Disturbed sleep rhythms and lack of physical energy). 3) Family dysfunction. (Conflicts among family members; disruption of normal life; increased financial burden). 4) Negative emotions. (fear; nervousness, worry).Conclusion: This study focuses on caregivers of children with severe asthma who face multiple stressors. Caregivers are critical to disease management: healthcare professionals and the community should provide support; family members should share tasks; and children’s poor self-management skills place a burden on caregivers, and professionals should teach children to better care for themselves. These findings have important implications for healthcare providers to develop targeted support programs and improve overall care for children with severe asthma.Keywords: severe asthma, caregiver burden, qualitative research

Qi Shi,1,&ast; Tingting Hu,2,&ast; Lixia Xu,2,&ast; Jiayuanyuan Fu,1 Yehong Fang,1 Yu Lan,1 Weijia Fan,2 Qiaoli Wu,2 Xiaoguang Tong,1– 3 Hua Yan1– 3 1Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, 300070, People’s Republic of China; 2Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, 300350, People’s Republic of China; 3Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, 300350, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hua Yan, Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, 300070, People’s Republic of China, Email yanh2023@tmu.edu.cnBackground: Acute lung injury (ALI) is a serious yet common complication in patients with traumatic brain injury (TBI), often associated with poor prognosis. The development of TBI-induced ALI is closely associated with excessive oxidative stress and NLRP3 inflammasome activation. Fingolimod, an immunomodulatory agent, has been reported to attenuate inflammatory responses, restore blood-brain barrier integrity, reduce cerebral edema, and mitigate associated neurological deficits.Objective: This study aimed to investigate the mechanistic role of NLRP3 inflammasome activation in TBI-induced ALI and to evaluate the therapeutic potential of fingolimod in targeting this inflammatory pathway.Results: A rat TBI model was established using the classical free-fall method, and animals were treated with fingolimod (0.5 or 1 mg/kg) daily for three days. The TBI model rats presented with clear signs of histopathological pulmonary damage, an increase in the permeability of capillaries in the lung, and pulmonary edema that coincided with significantly increased NLRP3, caspase-1, and ASC expression in lung tissue samples. This overexpression of NLRP3 inflammasome machinery resulted in the release of IL-1β. Fingolimod treatment, however, reversed all of these effects such that it suppressed NLRP3 activity and normalized levels of IL-1β, leading to the alleviation of inflammation. In line with these results, LPS and nigericin (NLRP3 agonist)-treated NR8383 cells treated using fingolimod exhibited reductions in reactive oxygen species production and NLRP3 inflammasome activation.Conclusion: These findings suggest that NLRP3 inflammasome activation and oxidative stress are key mediators of TBI-induced ALI. Fingolimod exerts protective effects against this condition by inhibiting NLRP3 inflammasome activation, highlighting its potential as a therapeutic agent for TBI-associated pulmonary complications. Keywords: traumatic brain injury, acute lung injury, fingolimod, NLRP3 inflammasomes, reactive oxygen species

Zhisheng Duan, Heping Xie, Huaping Zhong, Shuo Hu, Xu Chen, Ziyou Liu Department of Critical Care II, First Affiliated Hospital of Gannan Medical College of Jiangxi Province, Ganzhou, People’s Republic of ChinaCorrespondence: Ziyou Liu, Department of Critical Care II, The First Affiliated Hospital of Gannan Medical University, No. 23 of Qing Nian Avenue, Zhanggong District, Ganzhou, Jiangxi, 341000, People’s Republic of China, Tel +86 15297716789, Fax +0797-8269500, Email ziyoul74m@163.comPurpose: This study aimed to investigate the predictors of successful weaning from veno-venous extracorporeal membrane oxygenation (VV-ECMO) among patients with severe acute respiratory distress syndrome (ARDS) in our centre.Methods: The clinical data of patients with severe ARDS who were treated with VV-ECMO between January 2019 and January 2022 were retrospectively analysed. Due to the outcomes of weaning from extracorporeal membrane oxygenation (ECMO), the considered patients with ARDS were divided into a successful weaning group and an unsuccessful weaning group. Logistic regression analysis was employed to evaluate predictors for successful VV-ECMO weaning among patients with severe ARDS.Results: A total of 65 patients with severe ARDS were included for analysis. Among them, 31 (47.69%) patients were grouped into the successful weaning group, while 34 (52.30%) patients were grouped into the unsuccessful weaning group. Univariate analysis showed that Age (odds ratio [OR] =0.939; 95% confidence interval [CI] =0.896– 0.983; p = 0.008), APACHEII scores before ECMO (OR =0.651; 95% CI =0.537– 0.789; p < 0.001), Renal insufficiency (OR =0.061; 95% CI =0.012 − 0.298; p = 0.001), MAP before ECMO (OR =1.246; 95% CI =1.114– 1.392; p< 0.001), PaO2 during ECMO (OR =1.083; 95% CI =1.033– 1.135; p = 0.001), and CRRT (OR =0.080; 95% CI =0.022– 0.285; p = 0.008) were identified as an independent predictor of successful VV-ECMO weaning. After multivariate analysis was performed, APACHE II scores before ECMO (OR = 0.651; 95% CI = 0.462– 0.919; p = 0.015) were identified as independent predictors for successful VV-ECMO weaning.Conclusion: In conclusion, in severe ARDS patients, lower APACHE II scores predicted successful wean from VV-ECMO.Keywords: acute respiratory distress syndrome, extracorporeal membrane oxygenation, predictor, weaning, acute physiology and chronic health evaluation II

Mengxia Wang,1,&ast; Jieke Tang,1,&ast; Zhaojie Pan,2 Hongxue Jiang,1 Donghua Hu,1 Beibei Zhu,2 Zhaojia Liang,1 Xiangfeng Zhao,1 Yalan Li1 1Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Digestive Endoscopy Center, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yalan Li, Department of Anesthesiology, The First Affiliated Hospital of Jinan University, No. 613, Huangpu West Avenue, Tianhe District, Guangzhou, Guangdong Province, 510630, People’s Republic of China, Email tyalan@jnu.edu.cnPurpose: The provision of comfortable and safe environment for painless gastroscopy in obese patients is an urgent clinical problem. This study aimed to determine the efficacy and safety of the novel Li anesthetic protocol for obesity (LAPO) which included remifentanil-propofol regimen, manual right hypochondrial compression (MRHC), easy-to-create mask, and jaw thrust at preoperative painless gastroscopy in obese patients.Patients and Methods: This prospective, single-center, single-arm trial recruited 106 participants underwent LAPO for gastroscopy. The primary outcome was the incidence of hypoxemia (peripheral oxygen saturation [SpO2]: 75% ≤ SpO2 < 90%, for > 10 s and ≤ 60 s). Second outcomes included severe hypoxemia, the lowest SpO2 (L-SpO2), duration of hypoxemia, and other events.Results: The 98 obese patients under LAPO, the median body mass index (BMI) was 39.2 kg/m2 and the incidence of hypoxemia was 27.5%, while the conventional anesthetic protocol for obesity (CAPO) in the reference was 40.4% with BMI 31.4 kg/m2. With the increase of class of obesity, a significant rise in the incidence of hypoxemia was observed, from class I by 11.8%, to 15.1% in class II, and 41.7% in class III. Paired t test showed that the L-SpO2 was significantly higher than L-SpO2 in overnight polysomnography (Nadir SpO2) (92% vs 76%, P< 0.001). Moreover, severe obstructive sleep apnea (OSA) was associated with a 4.019-fold higher risk of hypoxemia (Odds ratios [OR], 4.019; 95% confidence interval [CI], 1.184 to 14.610; P=0.028); diabetes was associated with a 4.790-fold higher risk of hypoxemia (OR, 4.790; 95% CI, 1.288 to 23.600; P=0.030).Conclusion: Compared with CAPO, LAPO reduced the incidence of hypoxemia from 40.4% to 27.5%, so, LAPO was safe and effective for painless gastroscopy. The finding might provide some new schedules for anesthetic management in the absence of advanced airway support instruments.Clinical Trial Registration: ChiCTR2300077889.Plain Language Summary: With the advancement of comfortable-oriented medication, gastroscopy is mostly performed under sedation and anesthesia. However, for obesity, there are changes in airway anatomy structure such as short neck, round chin, and large tongue, which makes them prone to airway obstruction after sleep or anesthesia, blocking the passage of oxygen in and out, which will cause hypoxemia over time and further cause damage to the body. Therefore, it is necessary to explore a safe and effective anesthesia management for painless gastroscopy in obesity. Our team’s work demonstrates that the novel Li anesthetic protocol (strategic anesthesia management of remifentanil combined with propofol and effective respiratory support through MRHC and jaw thrust, increased oxygen reserve via a novel mask) for obesity for painless gastroscopy with lacking advanced airway management devices is safe and efficient. Furthermore, our findings contribute to the understanding of the lowest SpO2 values that obese patients can tolerate during such procedures, establishing Nadir SpO2 as the cut-off point. We also identified severe OSA and diabetes as independent predictive risk factors for hypoxemia. If these findings are supported by further research, LAPO could aid anesthesiologists in developing specific anesthesia protocols and managing the risk of hypoxemia during painless gastroscopy for obese patients. Ultimately, this could expand access to comfortable and safe medical treatment for a broader spectrum of patients with obesity.Keywords: compression, hypoxemia, obese patient, obstructive sleep apnea, painless gastroscopy, propofol, remifentanil

Jinqing Zhang,1,&ast; Gaolian Li,2,&ast; Jing Hu,3,&ast; Jingwen Tan,4 Heng Zhang,5 Yizheng Zhou5 1Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Gynaecology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei Province, People’s Republic of China; 3Department of Clinical Medicine, Xiangyang Polytechnic, Xiangyang, Hubei Province, People’s Republic of China; 4Department of Medical Mycology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 5Department of Clinical Laboratory, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yizheng Zhou, Email zhou_yizheng@163.comIntroduction: Treating infections caused by azole-resistant Candida spp. poses a significant challenge. Previous research has indicated that pyrvinium pamoate (PP) has the potential to augment the antifungal efficacy of azole antifungals against filamentous fungi. The objective of this study was to investigate the antifungal properties of PP, both independently and in conjunction with azoles, against Candida auris and other Candida spp.Materials and Methods: A total of 21 clinical Candida spp. strains and five azoles were assessed. The antifungal efficacy of PP, either alone or in combination with azoles, was tested according to the reference method. Galleria mellonella larvae were employed to evaluate the antifungal efficacy of PP and/or azoles in the treatment of C. auris infections in vivo.Results: When used to treat these different fungal isolates in vitro, the single-agent efficacy of PP was relatively poor, with minimum inhibitory concentration values ranging from 2 μg/mL - > 32 μg/mL. However, PP and azoles exhibited synergistic activity against the majority of analyzed C. albicans and C. auris isolates. To extend these results in vivo, G. mellonella was infected with C. auris strain AR385 and both survival and fungal burden were assessed for treated larvae. The inclusion of PP in combination with itraconazole, voriconazole, or posaconazole resulted in varying degrees of improvement in the survival rates of these larvae.Conclusion: Combining PP with azoles represents a promising approach to effectively disrupting the growth of azole-resistant C. auris and other Candida spp. such that it may be a promising anti-Candida therapeutic option.Keywords: Candida auris, pyrvinium pamoate, synergy azoles, Galleria mellonella

Huiyue Hu, Xiaodie Mu, Shuya Zhao, Min Yang, Hua Zhou Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, People’s Republic of ChinaCorrespondence: Hua Zhou; Min Yang, Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, People’s Republic of China, Email zhouhua2323@suda.edu.cn; yangmin1516@suda.edu.cnAim: The aim of this study was to develop a predictive model for the progression of diabetic kidney disease (DKD) to end-stage renal disease (ESRD) and to evaluate the effectiveness of renal pathology and the kidney failure risk equation (KFRE) in this context.Methods: The study comprised two parts. The first part involved 555 patients with clinically diagnosed DKD, while the second part focused on 85 patients with biopsy-proven DKD. Cox regression analysis and competing risk regression were employed to identify independent predictors. Time-dependent receiver operating characteristic (ROC) was used to evaluate prediction performance, and the area under the curve (AUC) was calculated to assess the model’s accuracy.Results: The Cox regression model developed for the 555 patients clinically diagnosed with DKD identified 5 predictors (body mass index (BMI), estimated glomerular filtration rate (eGFR), 24-hour urinary total protein (UTP), systemic immune-inflammatory index (SII), and controlling nutritional status (CONUT), whereas the Competing risks model included 4 predictors (BMI, eGFR, UTP, CONUT). Among 85 patients with biopsy-proven diabetic DKD, the combined prognostic model integrating KFRE, interstitial fibrosis and tubular atrophy (IFTA), SII and BMI demonstrated enhanced predictive ability at 5 years. The developed models offer improved accuracy over existing methods by incorporating renal pathology and novel inflammatory indices, making them more applicable in clinical settings.Conclusion: The predictive model proved to be effective in assessing the progression of DKD to ESRD. Additionally, the combined model of KFRE, IFTA, SII, and BMI demonstrates high predictive performance. Future studies should validate these models in larger cohorts and explore their integration into routine clinical practice to enhance personalized risk assessment and management.Keywords: diabetic kidney disease, end-stage renal disease, pathologies, risk assessment

Tianxing Fang,1– 4 Liyu Hu,5 Tianshun Chen,4 Fei Li,6 Liu Yang,4 Bin Liang,7 Wenjun Wang,8 Fancai Zeng4 1Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People’s Republic of China; 3Institute of Nuclear Medicine, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 6Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 7Department of General Surgery (Breast Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 8Institute for Cancer Medicine and School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Fancai Zeng; Wenjun Wang, Email zfcai@swmu.edu.cn; wenjunwang1213@126.comBackground: Breast cancer (BC) has become the main malignant tumor threatening the health of women worldwide. Previous studies have reported that Lactate dehydrogenase-A (LDHA) has critical roles in cancer development and progression. We aimed to explore the roles of LDHA and LDH5 isoenzyme activity in BC, which provides a new insight into LDHA for the treatment of BC.Methods: The expression of LDHA in BC and its relationship with clinicopathological features were obtained from various databases including The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Breast Cancer-Gene Expression Miner (bc-GenExMiner), TNMplot, UALCAN. The Kaplan‒Meier Plotter was used to evaluate the prognostic value of LDHA. Western blot was performed to detect LDHA expression. Agarose gel electrophoresis was performed to detect the activities of LDH isoenzymes. The in vitro proliferation, migration and invasion potentials of BC cells were evaluated using MTT assays, colony formation, wound-healing assay, matrix metalloproteinase assays and transwell assays, respectively. The activities of LDH isoenzymes in serum and tissues were measured in patients with BC and healthy controls.Results: Compared to normal tissues, LDHA expression was significantly higher in BC tissues. Patients’ nodal status, histological types, TP53 mutation status and PAM50 subtypes were significant factors influencing the LDHA expression. By overexpressing or silencing LDHA gene in BT549 cells, it was confirmed that LDHA promoted cell proliferation, migration and invasion. LDH5 isoenzyme activity in patients with BC was higher than healthy controls. The increased activity of LDH5 isoenzymes was induced by overexpression of LDHA in BC. High expression of LDHA was found to be associated with poor prognosis in BC.Conclusion: LDHA plays a critical role in the progression of BC through the regulation of the activity of LDH5 isoenzyme, indicating that LDHA may serve as a valuable target for BC treatment.Keywords: LDHA, LDH5 isoenzyme, breast cancer, progression, prognosis

Siyu Wu,1,&ast; Yumeng Hu,1,&ast; Bowen Sui2 1Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China; 2First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bowen Sui, Email suibowen79@126.comAbstract: Lung cancer, with its high incidence and mortality rates, has garnered significant attention in the medical community. The tumor microenvironment (TME), composed of tumor cells, stromal cells, extracellular matrix, surrounding blood vessels, and other signaling molecules, plays a pivotal role in the development of lung cancer. Stromal cells within the TME hold potential as therapeutic targets for lung cancer treatment. However, the precise and comprehensive mechanisms by which stromal cells contribute to lung cancer progression have not been fully elucidated. This review aims to explore the mechanisms through which stromal cells in the tumor microenvironment promote lung cancer development, with a particular focus on how immune cells, tumor-associated fibroblasts, and endothelial cells contribute to immune suppression, inflammation, and angiogenesis. The goal is to provide new insights and potential strategies for the diagnosis and treatment of lung cancer.Keywords: tumor microenvironment, lung cancer, stromal cells, immune cells, cancer-associated fibroblasts, endothelial cells

Yilu Zheng,1 Gareth R Williams,2 Ran Hu,1 Sen Tong,3 Jianxiang Xu,1 Tong Wang,1 Yanyan Zhang,1 Junzi Wu,3 Fan Li,4 Yingyu Cai,4 Li-Min Zhu1 1College of Biological Science and Medical Engineering, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai, 201620, People’s Republic of China; 2UCL School of Pharmacy, University College London, London, WC1N 1AX, UK; 3The Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Yunnan University of Chinese Medicine, Kunming, 650500, People’s Republic of China; 4Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, People’s Republic of ChinaCorrespondence: Yingyu Cai, Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, People’s Republic of China, Email yingyu.cai@shgh.cn Li-Min Zhu, College of Biological Science and Medical Engineering, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai, 201620, People’s Republic of China, Email lzhu@dhu.edu.cnBackground: The development of selective formulations able to target and kill tumor cells without the application of external energy has shown great promise for anti-tumor therapy.Methods: Here, we report a “nanobomb” that explosively increases Ca content within cells. It can selectively release Ca2+ and generate H2O2 in the tumor microenvironment (TME) by acid-triggered degradation of the two-layer protective shell (ie, unlocking the “double-lock”). This material, termed CaO2@ZIF8:CUR@PAA, comprises a CaO2 core coated with the ZIF-8 framework, which was then loaded with curcumin (CUR) and coated again with polyacrylic acid (PAA).Results: Under the slightly acidic conditions of the TME, the PAA shell (first lock) breaks down first exposing CaO2@ZIF8 and CUR inside the cell. Then, ZIF8 (second lock) is degraded in response to acid to deposit Ca2+, and H2O2. CUR can promote the release of Ca2+ from the endoplasmic reticulum to the cytoplasm, inhibit the outflow of Ca2+, and accumulates a large amount of Ca2+ intracellularly together with exogenous Ca2+ (calcium storms). The powerful calcium storm that causes mitochondrial dysfunction. The presence of a large amount of exogenous H2O2 causes further oxidative damage to tumor cell membranes and mitochondria where intracellular ROS production far exceeds clearance. CaO2@ZIF8:CUR@PAA NPs can induce cell S cycle arrest and apoptosis to inhibit tumor multiplication and growth. Oxidative damage-triggered immunogenic cell death (ICD) in turn leads to the polarization of macrophages to the M1 phenotype, inducing immunogenic cell death and inhibiting tumor cell proliferation and metastasis.Discussion: The acid two-step unlocking nanoplatform is a therapeutic modality that combines calcium storm and oxidative damage. The mode triggers apoptosis leading to ICD of tumor cells. The material induces cycle blockade during treatment to inhibit cell proliferation. Robust in vitro and in vivo data demonstrate the efficacy of this approach and CaO2@ZIF8:CUR@PAA as an anticancer platform, paving the way for nanomaterials in immune-triggered cancer therapy.Highlights: - A new calcium accumulation nanoplatform plays a role in activate antitumor immunity.- Double-locked structure slows down the premature decomposition of CaO2.- The platform allows Ca2+ and H2O2 to accumulate in tumor cells.- This leads to mitochondrial dysfunction, apoptosis, and M1 macrophage polarization.- Potent anti-tumor effects are seen both in vitro and in vivo.Keywords: Calcium ion load, controlled-release nanomaterials, two-layer protective shell, pH responsive drug release, reactive oxygen species, anti-cancer

Xiangming Hu,1,&ast; Zhenyan Zhao,1,&ast; Can Wang,1,&ast; Dejing Feng,1 Yang Chen,2 Guannan Niu,1 Zheng Zhou,1 Hongliang Zhang,1 Zhe Li,1 Yunqing Ye,1 Moyang Wang,1 Yongjian Wu1 1Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Cardiology, Peking University People’s Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Moyang Wang; Yongjian Wu, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China, Email wangmoyang1983@vip.sina.com; fuwaiwyj@163.comPurpose: The impact of periprocedural myocardial injury (PPMI) according to VARC-3 criteria in patients undergoing transcatheter aortic valve replacement (TAVR) remains unclear. This study aimed to investigate the incidence, risk factors, and prognosis of PPMI in patients with severe aortic who underwent TAVR in China.Materials and Methods: Between September 2012 and November 2021, 516 patients with severe aortic stenosis who underwent TAVR at the Fuwai Hospital were consecutively enrolled. PPMI was defined according to the VARC-3 criteria as a 70-fold increase of upper reference limit in cardiac troponin I (cTnI) levels. We compared the baseline characteristics, perioperative conditions, and in-hospital and long-term endpoints between the PPMI and non-PPMI groups. Logistic regression analysis was used to determine the predictors of PPMI. Survival probabilities for outcomes between the PPMI and non-PPMI groups were estimated using the Kaplan-Meier method.Results: Of the enrolled patients (mean age: 75.5± 7.2 years, 57.5% male), the incidence of PPMI was 20.5%. The median cTnI was 24.9 (interquartile range: 11.4− 60.2) times the upper reference limit. After multivariable adjustment, female sex (odds ratio [OR]: 3.01, 95% confidence interval [CI]: 1.88− 4.82, P < 0.001), anticoagulant use (OR: 0.27, 95% CI: 0.08− 0.96, P = 0.043), balloon-expandable valve (OR: 0.27, 95% CI: 0.09− 0.79, P = 0.017), and secondary valve implantation (OR: 2.66, 95% CI: 1.40− 5.03, P = 0.003) were significantly associated with PPMI. Patients with PPMI had short- and long-term outcomes similar to those without PPMI.Conclusion: Female sex and secondary valve implantation are predictors of an increased risk of PPMI, whereas baseline anticoagulant use and the use of balloon-expandable valves are protective factors. The presence of PPMI does not seem to indicate poor short- or long-term prognosis in patients undergoing TAVR.Keywords: aortic stenosis, transcatheter aortic valve replacement, myocardial injury, risk factor, prognosis

Micropsalliota is a relatively small genus, with 97 names recorded in previous research. In this study, two new species of Micropsalliota, M. bispora and M. vulgaris, have been identified based on morphological and phylogenetic evidence from subtropical regions of China. Morphologically, M. bispora is characterized by very small basidiomata, cymbiform basidiospores up to 9.0 μm long, white to cream pileus with fawn to dull red center, and tibiiform cheilocystidia; M. vulgaris is recognized by small basidiomata, medium-sized spores, white to cream pileus, covered with reddish brown to dark brown fibrils, various cheilocystidia that are up to 60 μm long, and hyphae of fibrils exhibiting pale brown vacuolar pigmentation. Their distinct taxonomic status is confirmed by the positions of the two new species in 4-locus (ITS, LSU, rpb2, tef-1α) phylogenetic trees. Detailed descriptions and morphological photographs of two new species are presented. To aid in diagnosis, a key to 35 species of Micropsalliota in China is provided.

Abstract Advances in cancer genomics have significantly expanded our understanding of cancer biology. However, the high cost of drug development limits our ability to translate this knowledge into precise treatments. Approved non-oncology drugs, comprising a large repository of chemical entities, offer a promising avenue for repurposing in cancer therapy. Herein we present CHANCE, a supervised machine learning model designed to predict the anticancer activities of non-oncology drugs for specific patients by simultaneously considering personalized coding and non-coding mutations. Utilizing protein–protein interaction networks, CHANCE harmonizes multilevel mutation annotations and integrates pharmacological information across different drugs into a single model. We systematically benchmarked the performance of CHANCE and show its predictions are better than previous model and highly interpretable. Applying CHANCE to approximately 5000 cancer samples indicated that >30% might respond to at least one non-oncology drug, with 11% non-oncology drugs predicted to have anticancer activities. Moreover, CHANCE predictions suggested an association between SMAD7 mutations and aspirin treatment response. Experimental validation using tumor cells derived from seven patients with pancreatic or esophageal cancer confirmed the potential anticancer activity of at least one non-oncology drug for five of these patients. To summarize, CHANCE offers a personalized and interpretable approach, serving as a valuable tool for mining non-oncology drugs in the precision oncology era.

Abstract The Hawaiian flower thrips, Thrips hawaiiensis, is a common flower inhabiting pest of various horticultural plant species. It damages flowers and fruits by puncturing. T. hawaiiensis shows a rapidly developed resistance to chemical control. The lack of a high-quality reference genome limits our understanding of the genetics of T. hawaiiensis. Here, we sequenced the genome of T. hawaiiensis using Oxford Nanopore sequencing technology, Illumina, and Hi-C technology, yielding a genome assembly of 287.59 Mb with scaffold N50 of 13.84 Mb. BUSCO analysis demonstrated the T. hawaiiensis genome assembly has a high-level completeness of 98.7%. In total, 18,289 protein-coding genes were annotated and 26.69% of the genome were annotated as repeats. Our study presents the first high-quality genome assembly of T. hawaiiensis and lays the foundation for further studies on thrips genetic characteristics and pest management.

Abstract Background Diabetic encephalopathy (DE) is considered as one of the complications of diabetes,which is associated with cognitive impairment in the pathological process of development. Up to now, phospholipid phosphatase related 4 (Plppr4), also known as plasticity related gene 1 (PRG-1) has been revealed its important role in neuroplasticity. However, the underlying mechanisms of Plppr4 on the basis of diabetic-induced cognitive dysfunction (DCD) are still unknown. The aim of current study was to provide insight into molecular mechanism and cellular heterogeneity underlying DCD, and investigate the functional role of PRG-1 involved in this process. Methods Combined Single-cell RNA sequencing (scRNA-seq) and RNA transcriptome analysis, the distinct sub-populations, functional heterogeneity as well as potential enriched signaling pathways of hippocampal cells could be elucidated. Results We identified the sub-cluster of type I spiral ganglion neurons expressed marker gene as Amigo2 in cluster8 and Cnr1 in cluster 9 of hippocampal cells from DCD and the effect of those on neuronal cells interaction. We also found that PRG-1 was involved in the synaptic plasticity regulation of hippocampus via NGF\BDNF-Trkb signaling pathway. In high glucose induced HT22 cells injury model in vitro, we investigated that down-regulated PRG-1 along with down-regulated BDNF and also decreased expression of synapsin-1, PSD-95, SYN which are related to synaptic plasticity; Meanwhile, the Prg-1 targeted miR-18a-LncRNA NONRATG-022419 pairs related with significantly down-regulated expression of PRG-1. Conclusion This study revealed the synaptic plasticity regulation of PRG-1 in DCD, and might provide the therapeutic target and potential biomarkers for early interventions in DCD patients.

Abstract Background China is actively responding to low birth rates by developing childcare institutions to alleviate the parenting pressures on families. However, despite strong childcare demand, the enrollment rate remains low. Few studies have explored the role of social influence in parents' childcare decisions. Therefore, this study will construct a research model to explore the mechanisms of social influence on parents' intentions to use childcare institutions. Methods This study used parents of infants and toddlers in mainland China as the study population. Questionnaires were collected through electronic surveys created on a professional website, with 554 responses gathered through purposive sampling. The data were analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM) and Importance-Performance Map Analysis (IPMA). Results The results indicate that perceived benefits are the significant driving variable for parents' intention to use childcare institutions, while price sensitivity and perceived risk are significant barriers. Normative influence and perceived childcare policy significantly affect perceived benefits and price sensitivity, while informational influence has a significant positive effect on perceived risk. Additionally, the Importance-Performance Map Analysis (IPMA) shows that improvements should focus more on price sensitivity given the current low performance. Conclusions These findings provide insights for childcare policymakers and institutional childcare managers and will generate a management basis for developing China’s childcare service industry.

Abstract Nocturia is an increasingly prevalent chronic disease that affects the quality of an individual’s life. The prevalence of nocturia exceeds 50% among older adults in the U.S. Inflammation and oxidative stress are considered potential factors affecting nocturia, according to prior research. Flavonoids have attracted considerable interest due to their anti-inflammatory, antioxidant, and anti-aging properties. The association between flavonoid consumption and nocturia has been rarely investigated. For this cross-sectional study, we selected 5926 middle-aged and older adults over 40 from the 2007–2010 National Health and Nutrition Examination Survey (NHANES). Daily dietary flavonoid consumption was assessed through two 24-hour dietary recall interviews and the principal outcome was assessed based on a standardized questionnaire administered by trained interviewers. Weighted multivariate logistic regression and stratified analysis were employed to evaluate the impact of dietary total flavonoid consumption on nocturia. Restricted cubic spline (RCS) was utilized to explore whether there is a non-linear association between total flavonoid intake and nocturia. In addition, we performed weighted logistic regression and weighted quantile sum (WQS) regression by six flavonoid species (isoflavones, anthocyanins, flavan-3-ols, flavanones, flavonoids and flavonols) to estimate a combined mixture sum effect as well as the contribution of each mixture component. Subgroup analysis help us identify heterogeneity in these relationships and enhances the applicability of the research findings across different groups. After fully adjusting for confounders, weighted logistic regression models indicated that dietary flavonoid intake was significantly associated with a decreased prevalence of nocturia (OR: 0.93; 95% CI: 0.88-1.00, P-value = 0.036). This trend remained significant in the analysis stratified by quartile level of flavonoid intake. RCS analysis demonstrated an inverse linear correlation between total flavonoid consumption and nocturia. Analysis conducted through quartile stratification of six flavonoid species and WQS regressions showed that anthocyanins, flavan-3-ols, and flavonols were crucial elements. Within these subclasses, Peonidin in anthocyanins, Catechin and Theaflavin-3,3’-digallate in flavan-3-ols, and Isorhamnetin, Kaempferol, and Quercetin in flavonols were also investigated and may have contributed significantly. Our study revealed an inverse association between dietary flavonoid intake and nocturia in middle-aged and older adults, and anthocyanins, flavan-3-ols and flavonols were protectively associated with nocturia.

Abstract To explore the neurobiological heterogeneity within the Clinical High-Risk (CHR) for psychosis population, this study aimed to identify and characterize distinct neurobiological biotypes within CHR using features from resting-state functional networks. A total of 239 participants from the Shanghai At Risk for Psychosis (SHARP) program were enrolled, consisting of 151 CHR individuals and 88 matched healthy controls (HCs). Functional connectivity (FC) features that were correlated with symptom severity were subjected to the single-cell interpretation through multikernel learning (SIMLR) algorithm in order to identify latent homogeneous subgroups. The cognitive function, clinical symptoms, FC patterns, and correlation with neurotransmitter systems of biotype profiles were compared. Three distinct CHR biotypes were identified based on 646 significant ROI-ROI connectivity features, comprising 29.8%, 19.2%, and 51.0% of the CHR sample, respectively. Despite the absence of overall FC differences between CHR and HC groups, each CHR biotype demonstrated unique FC abnormalities. Biotype 1 displayed augmented somatomotor connection, Biotype 2 shown compromised working memory with heightened subcortical and network-specific connectivity, and Biotype 3, characterized by significant negative symptoms, revealed extensive connectivity reductions along with increased limbic-subcortical connectivity. The neurotransmitter correlates differed across biotypes. Biotype 2 revealed an inverse trend to Biotype 3, as increased neurotransmitter concentrations improved functional connectivity in Biotype 2 but reduced it in Biotype 3. The identification of CHR biotypes provides compelling evidence for the early manifestation of heterogeneity within the psychosis spectrum, suggesting that distinct pathophysiological mechanisms may underlie these subgroups.

Abstract Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid (DHA). An increased level of circulating DHA inhibits PD-L1 expression in tumor cells by binding the PD-L1 promoter and subsequently prevents c-myc-initiated transcription of PD-L1. Colonization of germ-free male mice with gut bacteria from anti-PD-L1 non-responding patients supplemented with DHA enhances the efficacy of anti-PD-L1 therapy compared to controls. Our findings reveal a previously unknown mechanistic impact of PNP on human tumor immunotherapy by modulating gut bacterial metabolic pathways.

Abstract Despite numerous efforts involving surface coating, doping, and alloying, maintaining surface stability of metal at high temperatures without compromising intrinsic properties has remained challenging. Here, we present a pragmatic method to address the accelerated oxidation of Cu, Ni, and Fe at temperatures exceeding 200 °C. Inspired by the concept that oxygen (O) itself can effectively obstruct the pathway of O infiltration, this study proposes the immobilization of O on the metal surface. Through extensive calculations considering various elements (C, Al, Si, Ge, Ga, In, and Sn) to anchor O on Cu surfaces, Si emerges as the optimal element. The theoretical findings are validated through systematic sputtering deposition experiments. The introduction of anchoring elements to reinforce Cu–O bonds enables the formation of an atomically thin barrier on the Cu surface, rendering it impermeable to O even at high temperatures (400 °C) while preserving its intrinsic conductivity. This oxidation resistance, facilitated by the impermeable atomic monolayer, opens promising opportunities for researchers and industries to overcome limitations associated with the use of oxidizable metal films.

Abstract The literature documenting the value of drug-like molecules found in natural products is vast. Although many dietary and herbal remedies have been found to be effective for treating intestinal inflammation, the identification of their active components has lagged behind. In this study, we find that a major ginger component, furanodienone (FDN), is a selective pregnane X receptor (PXR) ligand with agonistic transcriptional outcomes. We show that FDN binds within a sub-pocket of the PXR ligand binding domain (LBD), with subsequent alterations in LBD structure. Using male mice, we show that orally provided FDN has potent PXR-dependant anti-inflammatory outcomes that are colon-specific. Increased affinity and target gene activation in the presence of synergistically acting agonists indicates further opportunities for augmenting FDN activity, efficacy and safety. Collectively, these results support the translational potential of FDN as a therapeutic agent for the treatment and prevention of colonic diseases.

Abstract Introduction Anemia is a prevalent complication of chronic kidney disease (CKD), primarily due to insufficient erythropoietin (EPO). Pegmolesatide (by Hansoh Pharma) is currently the only marketed long-acting EPO mimetic peptide (EMP) for the treatment of anemia in both dialysis and non-dialysis CKD patients. This paper aimed to explore the long-acting erythropoiesis stimulating molecular mechanism of Pegmolesatide. Methods In vitro assays were utilized to assess Pegmolesatide erythropoietin receptor (EPOR) affinity, competitive binding, cell proliferation/survival, apoptosis, cell surface receptor expression, and signal transduction. Pharmacokinetics (PK) and Pharmacodynamics (PD) parameters were evaluated in BALB/c mice following single administration. Furthermore, two Phase II clinical trials in dialysis and non-dialysis chronic kidney disease (CKD) patients with anemia, respectively CTR20140533 and CTR20140539, assessed PK-PD and safety following repeated administration. Results In vitro Pegmolesatide demonstrated enhanced binding stability and prolonged residency at EPOR, surpassing erythropoiesis-stimulating agents (ESAs) rHuEPO and Darbepoetin. This sustained EPOR binding facilitated heightened endogenous EPOR expression post-drug withdrawal, maintaining downstream signal transduction pathways (JAK2/STAT5, ERK1/2 MAPK) for erythropoiesis. Pegmolesatide promoted UT-7 cell proliferation & survival and suppressed apoptosis. Following a single 0.08 mg/kg dose of Pegmolesatide in BALB/c mice, reticulocyte count, red blood cells, hemoglobin, and hematocrit persisted at elevated levels 4-6 days after administration. In the two clinical Phase II studies dose-dependent increases in hemoglobin and prolonged response duration were independently observed. Pegmolesatide showed significant PK-PD dual prolongation effects and was well tolerated. Adverse events were mild and manageable, with no reports of severe anaphylaxis. Discussion Preclinical and clinical evidence signifies that Pegmolesatide is a unique, potent PEGylated EPO-memetic peptide (EMP) with a prolonged PD efficacy and PK half-life and a good safety-tolerability profile. To elucidate further, future studies will address the endocytosis, intracellular degradation, and ligand release of EPOR subsequent to Pegmolesatide binding, thereby supplementing our understanding of the molecular mechanism at play. Trial registration: Phase IIa clinical study of Pegmolesatide on renal anemia, CTR20140533. Initial Public Notice 14 Jan 2015, http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml . Phase II clinical study of Pegmolesatide on renal anemia, CTR20140539. Initial Public Notice 26 Jan 2015, http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml .

Abstract Background Prostate Tumor Overexpressed 1 (PTOV1) is overexpressed and associated with malignant phenotypes in various types of tumors. However, the detailed roles of PTOV1 and its underlying mechanism in CRC remain unclear. Methods The clinical significance of PTOV1 was assessed in clinical databases and CRC samples. The effects of PTOV1 on the tumor-associated phenotypes of CRC were detected by several in vitro assays and in vivo mouse models. Immunoprecipitation (IP) combined with protein mass spectrometry and Co-Immunoprecipitation (Co-IP) was used to identify p53 interacting with PTOV1. Immunofluorescence assay, western blot and transmission electron microscopy (TEM) analysis were used to evaluated the effects of PTOV1 on autophagy. Results Here, we revealed that PTOV1 was highly expressed in human CRC tissues, especially at advanced stages, and associated with reduced survival time among CRC patients. The upregulated PTOV1 promoted cell proliferation, migration, invasion, tumor growth and metastasis of CRC cells in vitro and in vivo. At the molecular level, PTOV1 destabilized p53 by activating autophagy and recruiting p53 for the cargo receptor SQSTM1 directed autophagic degradation. There was a negative expression correlation between PTOV1 and p53 in CRC tissues. Moreover, p53 overexpression or SQSTM1 knockdown reversed the pro-tumor phenotypes of PTOV1 in CRC. Conclusion Our study unveils the oncogenic role of PTOV1 in CRC progression, which was achieved by promoting SQSTM1 directed autophagic degradation of p53. These findings highlight the potential of targeting the PTOV1-SQSTM1-p53 axis as a therapeutic approach for CRC.

Abstract Background Postoperative venous thromboembolism (VTE) following hip arthroscopy is associated with increased hospital readmissions and significant medical costs. However, the risk factors for postoperative VTE after hip arthroscopy remain a topic of debate. In this study, we aimed to quantitatively and comprehensively identify risk factors for postoperative VTE after hip arthroscopy, providing evidence for the development of clinical prevention strategies. Methods A systematic search was conducted using PubMed, Embase, Web of Science, Scopus, and the Cochrane Library databases from their inception to December 10, 2024. The search was limited to English-language articles that evaluated risk factors for postoperative VTE after hip arthroscopy. The quality of the included studies was assessed using the Newcastle–Ottawa Scale. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relationship between various risk factors and the incidence of postoperative VTE after hip arthroscopy. This protocol was registered with PROSPERO (registration number: CRD42024601636). Results Five studies, encompassing 71,815 patients who underwent hip arthroscopy, were included in the meta-analysis. The analysis identified obesity (OR: 1.41, 95% CI: 1.23–1.61), smoking (OR: 1.23, 95% CI: 1.04–1.45), and age > 45 years (OR: 1.49, 95% CI: 1.03–2.15) as significant risk factors for postoperative VTE. Conclusion Obesity, smoking, and age > 45 years are found to be significant risk factors for postoperative VTE after hip arthroscopy.

Abstract Purpose Open-label phase Ib/II study to investigate the safety and efficacy of LBL-007, an anti-LAG-3 antibody, plus toripalimab, an anti-PD-1 antibody, in patients with previously treated advanced nasopharyngeal carcinoma (NPC) and other solid tumors. Methods Patients with advanced tumors refractory to prior standard therapies were enrolled. In phase Ib, patients received LBL-007 200 mg or 400 mg and toripalimab 240 mg intravenously once every 3 weeks. In phase II, all patients received LBL-007 at the recommended phase II dose (RP2D) and toripalimab 240 mg intravenously once every 3 weeks. The primary end points were safety in phase Ib and objective response rate (ORR) in phase II. The exploratory end point was the predictive capability of LAG-3 and PD-L1 expression for efficacy. Results Between November 30, 2021, and December 1, 2023, 80 patients were enrolled, including 30 (37.5%) with NPC and 50 (62.5%) with other tumors. Median follow-up was 26.0 months. In Phase Ib, LBL-007 was administered at 200 mg to four patients and 400 mg to six patients, with no dose-limiting toxicities observed. Therefore, the 400 mg dose of LBL-007 was established as the RP2D and administered to 70 patients in phase II. Nine (11.3%) of 80 patients had grade 3 or 4 treatment-related adverse events, the most common of which included anemia (2.5%), hyponatremia (2.5%), increased alanine aminotransferase (2.5%), increased aspartate aminotransferase (1.3%), and fatigue (1.3%). Eight patients (10.0%) had treatment-related serious adverse events. No treatment-related deaths were reported. In immunotherapy-naive NPC patients (n = 12), ORR was 33.3%, disease control rate (DCR) was 75%, and median progression-free survival (PFS) was 10.8 months (95% CI, 1.3 to not estimated). In IO-treated NPC patients (n = 17), ORR was 11.8%, DCR was 64.7%, and median PFS was 2.7 months (95% CI, 1.4 to 4.9). For other tumors, ORRs were 15.8% in immunotherapy-naive patients and 3.7% in immunotherapy-treated patients. Patients with ≥ 2 + LAG-3 expression had a higher ORR of 28.0%, compared to 7.7% in those with

Bingxin Ma,1 Gang Wu,1 Haohui Zhu,1 Yifei Liu,1 Wenjia Hu,1 Jing Zhao,1 Yinlong Liu,1 Qiuyu Liu2 1Department of Ultrasound, Henan Provincial People’s Hospital, Zhengzhou, 450000, People’s Republic of China; 2Department of Pathology, Henan Provincial People’s Hospital, Zhengzhou, 450000, People’s Republic of ChinaCorrespondence: Gang Wu, Email drwugang325@126.com; Haohui Zhu, Email zhh761126@163.comObjective: The study aimed to apply an artificial intelligence (AI)-assisted scoring system, and improve the diagnostic efficiency of Sclerosing adenosis and early breast cancer.Methods: This study retrospectively collected adenopathy patients (156 cases) and early breast cancer patients (150 cases) in Henan Provincial People’s Hospital from August 2020 to April 2023.Results: The area under the curve of the model constructed by clinical ultrasound features and combined AI features to predict and identify the two in the training group was 0.89 and 0.94, respectively. The combined AI model with the best performance (training AUC, 0.94, 95% CI, 0.91– 0.97 and validation AUC, 0.95, 95% CI, 0.90– 0.99) was superior to the clinical ultrasound feature model, and the decision curve also showed that the clinical ultrasound combined with AI Nomogram had good clinical practicability. In the training group, the AUC of the sonographer and AI in differential diagnosis was 0.67(95% CI, 0.62– 0.71) and 0.89(95% CI, 0.84– 0.93), respectively, and the sonographer’s assessment showed better sensitivity (1.00 VS 0.73), but AI showed a higher accuracy rate (0.66 VS 0.80).Conclusion: Age, lesion size, burr, blood flow, and AI risk score are independent predictors of sclerosing adenosis and early breast cancer. The combined clinical ultrasound feature and AI model are correlated with AI risk score, US routine features, and clinical data, superior to the clinical ultrasound model and BI-RADS grading, and have good diagnostic performance, which can provide clinicians with a more effective diagnostic tool.Keywords: sclerosing adenosis, breast tumor, ultrasound, AI, computer-aided diagnosis

Yue Wang,1– 5 Jiang Fang,1– 5 Qiang Yuan,1– 5 Jian Yu,1– 5 Jin Hu1– 5 1Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 2National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 3Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 4Neurosurgical Institute of Fudan University, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 5Shanghai Clinical Medical Center of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Jian Yu; Jin Hu, Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, People’s Republic of China, Tel +86 21 52889999, Email hujin@fudan.edu.cn; lance2000@hotmail.comBackground: Traumatic brain injury (TBI) is a prevalent neurological disorder associated with significant public health burdens and long-term risks, including neurodegenerative diseases such as Parkinson’s disease (PD). Emerging evidence suggests a strong link between moderate to severe TBI and an elevated risk of PD, though the underlying mechanisms remain poorly understood.Materials and Methods: Common differentially expressed genes (DEGs) were identified in GEO datasets of patients with traumatic brain injury (TBI) and Parkinson’s disease (PD). Further analyses, including GO and KEGG pathway enrichment, protein-protein interaction (PPI) network construction, hub gene identification, as well as miRNA and transcription factor prediction and drug candidate screening, were conducted. Subsequently, the expression of hub genes was validated using additional TBI- and PD-related GEO datasets and the Comparative Toxicogenomics Database (CTD). Finally, the expression of hub genes was further validated in a mouse model of TBI induced by controlled cortical impact (CCI).Results: Shared transcriptional signatures between TBI and PD were uncovered, highlighting overlapping molecular networks and pathways. The glutathione peroxidase 3 (GPX3) gene emerged as a pivotal hub gene, with its expression significantly altered in both TBI and PD datasets.Conclusion: This study underscores the critical role of GPX3 in the molecular intersection of TBI and PD, suggesting it as a novel and potential therapeutic target, offering new insights into potential therapeutic strategies.Keywords: traumatic brain injury, Parkinson’s disease, bioinformatics, oxidative stress, mitochondrial dysfunction, neurodegenerative diseases

YuZhou Shen,1 LingHan Leng,2 YingChun Hu1 1Department of Emergency Medicine, the Affiliated Hospital of Southwest Medical University, Lu Zhou, Sichuan, People’s Republic of China; 2Department of Intensive Care Unit, Chengdu Fifth People’s Hospital, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: YingChun Hu, Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiang Yang District, Lu Zhou, Sichuan, People’s Republic of China, Tel +86-15228232720, Fax +86-830-3165120, Email huyingchun913@swmu.edu.cnPurpose: As a crucial aspect of emergency critical medicine, sepsis has been in a difficult stage. As its ”preparatory stage”, SIRS has attracted the attention of the medical workers all over the world. The frequency of occurrence is on the rise, but there is a lack of certain indicators for the timely detection and recognition of illnesses.Methods: By virtue of scRNA-seq, this research has analyzed single-cell transcriptome data from samples taken from groups with septic death and systemic inflammatory response syndrome so as to identify the unique markers and patterns in immune response.Results: By revealing the status of twelve cell clusters of four major cell types in blood samples through UMAP cell clustering and the differences of major cell populations between the dead and SIRS patients, the results have elucidated the components of different cells and their marker genes in two disease states, and the response mechanism beneficial to disease diagnosis in blood samples.Conclusion: By establishing a theoretical framework centered on cellular and molecular regulation, the study has introduced a novel approach for diagnosing and treating sepsis death group and SIRS patients early, as well as differentiating and preventing these conditions.Keywords: sepsis, SIRS, single cell sequencing, biomarkers, single cell transcriptome

Purpose – The bridge expansion joint (BEJ) is a key device for accommodating spatial displacement at the beam end, and for providing vertical support for running trains passing over the gap between the main bridge and the approach bridge. For long-span railway bridges, it must also be coordinated with rail expansion joint (REJ), which is necessary to accommodate the expansion and contraction of, and reducing longitudinal stress in, the rails. The main aim of this study is to present analysis of recent developments in the research and application of BEJs in high-speed railway (HSR) long-span bridges in China, and to propose a performance-based integral design method for BEJs used with REJs, from both theoretical and engineering perspectives. Design/methodology/approach – The study first presents a summary on the application and maintenance of BEJs in HSR long-span bridges in China representing an overview of their state of development. Results of a survey of typical BEJ faults were analyzed, and field testing was conducted on a railway cable-stayed bridge in order to obtain information on the major mechanical characteristics of its BEJ under train load. Based on the above, a performance-based integral design method for BEJs with maximum expansion range 1600 mm (±800 mm), was proposed, covering all stages from overall conceptual design to consideration of detailed structural design issues. The performance of the novel BEJ design thus derived was then verified via theoretical analysis under different scenarios, full-scale model testing, and field testing and commissioning. Findings – Two major types of BEJs, deck-type and through-type, are used in HSR long-span bridges in China. Typical BEJ faults were found to mainly include skewness of steel sleepers at the bridge gap, abnormally large longitudinal frictional resistance, and flexural deformation of the scissor mechanisms. These faults influence BEJ functioning, and thus adversely affect track quality and train running performance at the beam end. Due to their simple and integral structure, deck-type BEJs with expansion range 1200 mm (± 600 mm) or less have been favored as a solution offering improved operational conditions, and have emerged as a standard design. However, when the expansion range exceeds the above-mentioned value, special design work becomes necessary. Therefore, based on engineering practice, a performance-based integral design method for BEJs used with REJs was proposed, taking into account four major categories of performance requirements, i.e., mechanical characteristics, train running quality, durability and insulation performance. Overall BEJ design must mainly consider component strength and the overall stiffness of BEJ; the latter factor in particular has a decisive influence on train running performance at the beam end. Detailed BEJ structural design must stress minimization of the frictional resistance of its sliding surface. The static and dynamic performance of the newly-designed BEJ with expansion range 1600 mm have been confirmed to be satisfactory, via numerical simulation, full-scale model testing, and field testing and commissioning. Originality/value – This research provides a broad overview of the status of BEJs with large expansion range in HSR long-span bridges in China, along with novel insights into their design.

Di Shen,1,&ast; Xintian Cai,2,&ast; Junli Hu,2 Shuaiwei Song,1 Qing Zhu,2 Huimin Ma,2 Yingying Zhang,2 Rui Ma,2 Pan Zhou,2 Wenbo Yang,2 Jing Hong,2 Delian Zhang,2 Nanfang Li2 1Graduate School, Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Hypertension Research Laboratory, Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region “Hypertension Research Laboratory”, Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, No. 91 Tianchi Road, Urumuqi, Xinjiang, 830001, People’s Republic of China, Tel +86 8564818, Email lnanfang2016@sina.comObjective: Hypertension development and progression are largely influenced by inflammation, which plays a critical role by activating the immune system and causing damage to the vascular endothelium. Metabolic dysfunction-associated fatty liver disease (MAFLD) is also associated with chronic low-grade inflammation, which drives disease progression via metabolic imbalances and adipose tissue dysfunction. This study investigates the relationship between inflammatory indices and MAFLD in hypertensive patients and assesses the predictive accuracy of these indices for MAFLD.Methods: We performed a cross-sectional analysis involving 34,303 hypertensive patients from a Chinese hospital-based registry. The diagnosis of MAFLD was established using metabolic dysfunction criteria alongside evidence of hepatic steatosis confirmed through imaging. Complete blood counts were used to calculate inflammatory indices, including the monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic inflammatory response index (SIRI), systemic immune-inflammation index (SII), and aggregate index of systemic inflammation (AISI). To assess the relationship between inflammatory indices and MAFLD, multivariable logistic regression was performed with adjustments for potential confounders. The diagnostic performance of these indices was analyzed using receiver operating characteristic (ROC) curves and area under the curve (AUC) calculations.Results: Patients with MAFLD exhibited significantly elevated levels of all inflammatory indices compared to those without. After multivariable adjustment, each standard deviation increase in AISI, SIRI, and SII was associated with a 74%, 62%, and 58% increased odds of MAFLD, respectively. The AUC for AISI was 0.659, indicating moderate diagnostic accuracy. The AUCs for SIRI and SII were 0.626 and 0.619, respectively, while NLR, PLR, and MLR had lower AUCs of 0.593, 0.558, and 0.589, respectively.Conclusion: In hypertensive patients, inflammatory indices, especially AISI, show a strong association with MAFLD, indicating their potential utility in risk stratification within clinical settings. Further research is needed to evaluate the effectiveness of these markers in the management of MAFLD. Keywords: metabolic-dysfunction-associated fatty liver disease, inflammatory indices, hypertension, diagnostic accuracy

Ruoyu Lu,1,&ast; Ye Zhang,1,&ast; Yiting Chen,1 Jiajun Lyu,1 Rong Li,1 Wenhui Kang,1 Anda Zhao,1,2 Zidi Ning,1 Yabin Hu,3 Xiaya Lin,4 Shilu Tong,3 Zhaohui Lu,3 Shenghui Li1,5 1School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Huadong Hospital, Fudan University, Shanghai, People’s Republic of China; 3National Children’s Medical Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Hainan Branch, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya, Hainan Province, People’s Republic of China; 5MOE-Shanghai Key Laboratory of Children’s Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaohui Lu, National Children’s Medical Center; Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dongfang Road, Pudong District, Shanghai, 200127, People’s Republic of China, Tel +86-18930830796, Email luzhaohui@sjtu.edu.cn Shenghui Li, School of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Huangpu District, Shanghai, 200025, People’s Republic of China, Tel +86-21-63846590, Email lsh9907@163.com; submission9907@163.comPurpose: Aiming to investigate the combined association of sleep quality and outdoor activity with the risk of asthma and allergic rhinitis in children.Patients and Methods: 16,936 children from kindergartens and primary schools in 13 administrative districts of Shanghai, China were involved in the analyses. The Children’s Sleep Habits Questionnaire (CSHQ) and the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire were respectively used to evaluate the sleep quality, allergic rhinitis and asthma. Multivariable logistic regression models were used to analyze the correlation of sleep quality, outdoor activities and their combination with children’s asthma and allergic rhinitis.Results: The overall prevalence of asthma and allergic rhinitis in our sampled children were 10.2% and 17.6%, respectively. Poor sleep quality (asthma: aOR, 1.45; 95% CI: 1.23 to 1.73; allergic rhinitis: aOR, 1.16; 95% CI: 1.03 to 1.31) and low outdoor activity (asthma: aOR, 1.30; 95% CI: 1.14 to 1.49, allergic rhinitis: aOR, 1.18; 95% CI: 1.07 to 1.32) were separately associated with higher risk of asthma and allergic rhinitis, and when the two were superimposed, an additive effect (asthma: aOR, 1.76; 95% CI: 1.30 to 2.39; allergic rhinitis: aOR, 1.46; 95% CI: 1.17 to 1.82) was revealed. These associations were independent of sleep duration, but being stronger in sleep sufficiency group. And after stratification by gender, premature birth and family history of allergy, similar associations were validated in general.Conclusion: Poor sleep quality and low levels of outdoor activity, when combined, have a stronger association with asthma and allergic rhinitis than each factor independently, and this relationship is not influenced by sleep duration. Our findings highlight the need for public health interventions that simultaneously address multiple lifestyle factors to reduce the risk of allergic diseases.Keywords: asthma, allergic rhinitis, sleep quality, physical activity

Wenqi Wu,1,2,&ast; Xiaohao Hu,1,2,&ast; Linyang Yan,3,&ast; Zhiyin Li,4 Bo Li,5 Xinpeng Chen,6 Zexun Lin,7 Huiqiong Zeng,8 Chun Li,9 Yingqian Mo,10 Yalin Wu,3 Qingwen Wang1,2 1Department of Rheumatology and Immunology, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China; 2Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, People’s Republic of China; 3Department of Ultrasound, Institute of Ultrasonic Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, People’s Republic of China; 4Department of Information Systems, City University of Hong Kong, Hong Kong, People’s Republic of China; 5Department of Rheumatology and Immunology, People’s Hospital of Longhua District, Shenzhen, People’s Republic of China; 6Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, People’s Republic of China; 7Shenzhen Nanshan Medical Group HQ Taohuayuan Community Health Service Center, Shenzhen, People’s Republic of China; 8Traditional Chinese Medicine Department of Rheumatism, Women & Children Health Institute, Shenzhen, People’s Republic of China; 9Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, People’s Republic of China; 10Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yalin Wu; Qingwen Wang, Email yalinwu@jj.ac.kr; wangqingwen@pkuszh.comObjective: In primary healthcare, diagnosing rheumatoid arthritis (RA) is challenging due to a general lack of in-depth knowledge of RA by general practitioners (GPs) and the lack of effective tools, leading to high rates of missed diagnosis. This study focuses on a screening model for primary healthcare, aiming to improve early RA screening accuracy and efficiency at a relatively lower cost, reducing delays in GPs’ recognition of RA.Methods: We randomly selected 2106 participants from the RA group or combined control group (comprising healthy individuals and patients with non-RA rheumatic diseases) at Peking University Shenzhen Hospital as the developing cohort. Guided by experienced rheumatologists, we built a comprehensive database with 26 clinical features. Using 10 classical machine learning algorithms, we developed screening models. Evaluation metrics determined the best model. Employing multivariatelogistic regression results and the best-performing model to identify the least costly features, ensuring applicability in primary healthcare clinics. Subsequently, we retrained and validated our proposed model based on two primary healthcare validation cohorts.Results: In experiments, the algorithms achieved over 88% accuracy on training and test sets. Random Forest (RF) excelled with 96.20% (95% CI 95.39% to 97.02%) accuracy, 96.22% (95% CI 95.40% to 97.03%) specificity, 96.18% (95% CI 95.37% to 97.00%) sensitivity, and 96.20% (95% CI 95.39% to 97.02%) Areas Under Curves (AUC). A meticulous feature selection identified 11 key features for RA screening. In an external test on two primary healthcare datasets with these features, RF demonstrated an accuracy of 88.435% (95% CI 85.55% to 91.32%), sensitivity of 98.55% (95% CI 97.47% to 99.63%), specificity of 85.56% (95% CI 82.39% to 88.73%), and an AUC of 92.055% (95% CI 89.62% to 94.49%).Conclusion: The screening model excels in automating prompt identification of RA in primary healthcare, improving the early detection of RA, and reducing delays and associated costs. Our findings contribute positively and are poised to elevate prospective RA management, fostering improvements in healthcare sector responsiveness and resource efficiency.Keywords: rheumatoid arthritis, machine learning, primary health care

Objective: This meta-analysis aims to assess the impact of robotic and open-cut forms on postoperative complications in knee replacement surgeries. Method: A comprehensive and systematic search was conducted on four significant databases using keywords derived from 'robot,' 'robot-assisted knee replacement (TAKR),' 'osteoarthritis,' 'knee arthroplasty,' 'wound healing,' 'knee replacement,' and 'postoperation' from the earliest available records until March 2024. A total of 590 publications were explored, and 16 related randomized clinical trials (RCTs) were analyzed in depth to unveil the role of robots in knee replacement surgery. In this meta-review, different parameters were adopted to evaluate various aspects: operation duration was used to measure the time from the primary incision to the wound closure after the surgery; Knee Society Score (KSS) and Hip Knee Ankle Angle (HKA) were used to evaluate the recovery and imaging features of the knees. Results: Data suggests there was little difference between the two methods except that the operation duration was higher in the robot-assisted group than in the conventional ones. Conclusions: In broad terms, this meta-analysis indicates that employing robotics does not decrease specific post-surgical complications, such as wound infections and painful feelings. However, this advanced medical technology of robots' application helps reduce blood loss and drainage compared to patients with conventional surgery. Consequently, utilizing a robotic approach for knee replacement surgeries may only provide moderate promotion for wound recovery after the surgery. This insight is valuable for surgeons when choosing the most appropriate operative approach.

Abstract Aims Nutrition and inflammation status play a vital role in the prognosis of patients with heart failure (HF). This study aimed to investigate the association between the advanced lung cancer inflammation index (ALI), a novel composite indicator of inflammation and nutrition, and short‐term mortality among critically ill patients with HF. Methods This retrospective study included 548 critically ill patients with HF from the MIMIC‐IV database. ALI was computed using body mass index, serum albumin and neutrophil–lymphocyte ratio. The primary endpoint was all‐cause in‐hospital mortality, and the secondary endpoint was 90 day mortality. Kaplan–Meier survival curve analysis with long‐rank test and Cox proportional hazards regression models were employed to assess the relationship between baseline ALI and short‐term mortality risk. The incremental predictive ability of ALI was evaluated by C‐statistic, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results The average age of 548 patients was 72.2 (61.9, 82.1) years, with 60% being male. Sixty‐three patients (11.5%) died in the hospital, and 114 patients (20.8%) died within 90 days of intensive care unit admission. The Kaplan–Meier analysis revealed that the cumulative incidences of both in‐hospital and 90 day mortality were significantly higher in patients with lower ALI (log‐rank test, in‐hospital mortality: P

Accurate recognition of working conditions can optimize the zinc flotation process and improve its efficiency. Traditionally, this recognition heavily relies on manual observations of froth appearance, a method prone to human error and subjective judgment. To address this issue and improve recognition accuracy, a sparse attention convolution-ViT model is proposed. This model leverages machine vision techniques to investigate the relationship between froth visual features and the working conditions using real-time froth images from industrial sites. The model aims to recognize zinc flotation working conditions in real time, thereby providing guidance for operations. First, it combines the strengths of convolutional neural networks (CNNs) and vision transformers (ViT) to effectively extract both local and global features from froth images. Specifically, CNNs are adept at capturing local features, such as texture, color, and fine details of the froth, while ViT excels at identifying global features, such as the froth size distribution. By combining these two architectures, the sparse attention convolution-ViT model comprehensively analyzes the froth images. To enhance the global feature processing of froth images, a sparse multi-head attention mechanism is introduced into the ViT component. This mechanism allows the model to process global features with different sparsity levels, reducing computational costs and improving the model’s adaptability to different froth appearances. Each attention head in the sparse multi-head attention mechanism targets different aspects of global features, allowing the model to extract various information from the froth images while maintaining efficiency. Furthermore, an attention gated unit is introduced to refine the feature processing. This unit allows adaptive weighting of extracted features in the image, enhancing model interpretability and optimizing feature transfer. By effectively capturing the relevant features, the attention-gated unit helps the model to focus on critical features of the froth images that can indicate the working conditions. Experimental results demonstrated the effectiveness of the proposed sparse attention convolution-ViT model in recognizing zinc flotation working conditions. The model achieved a recognition accuracy of 88.62% on the zinc flotation froth image dataset, surpassing traditional CNN and ViT models. Ablation experiments highlighted the critical role of the sparse multi-head attention mechanism and the attention-gated unit, contributing to accuracy improvements of 0.92% and 2.63%, respectively. Moreover, gradient-weighted class activation mapping was used to visualize feature weights, confirming the model’s capability to effectively characterize froth images by identifying both local and global features. This accurate recognition of zinc flotation conditions underscores the potential of the model in providing reliable real-time recognition, supporting the optimization of the flotation process, thereby improving efficiency and resource utilization in zinc flotation.

The ability to predict tunnel deformation holds great significance for ensuring the reliability, safety, and sustainability of tunnel structures. However, existing deformation prediction models often simplify or overlook the impact of spatial characteristics on deformation by treating it as a time series prediction issue. This study utilizes monitoring data from the Grand Canyon Tunnel and introduces an effective data-driven method for predicting tunnel deformation based on the spatio-temporal characteristics of the historical deformation of adjacent sections. The proposed model, a combination of graph attention network (GAT) and bidirectional long and short-term memory network (Bi-LSTM), is equipped with robust spatio-temporal predictive capabilities. Additionally, the study explores other possible spatial connections and the scalability of the model. The results indicate that the proposed model outperforms other deep learning models, achieving favorable root mean square error (RMSE), mean absolute error (MAE), and coefficient of determination (R2) values of 0.34 mm, 0.23 mm, and 0.94, respectively. The graph structure based on intuitive spatial connections proves more suitable for meeting the challenges of predicting deformation. Integrating GAT-LSTM with transfer learning technology, remains stable performance when extended to other tunnels with limited data.

Introduction Existing research suggests an association between smoking and the incidence of recurrent aphthous stomatitis (RAS); however, the causal relationship remains ambiguous. We employed Mendelian randomization (MR) to clarify the potential causal association between smoking and the risk of developing RAS. Methods We utilized genome-wide association study (GWAS) sequencing data related to smoking from the Finnish database as instrumental variables (IVs) and GWAS data for RAS from the UK Biobank (UKB) as the outcome to perform a two-sample MR analysis. The selection of IVs was rigorously controlled according to the three principal assumptions of relevance, independence, and exclusivity. The primary analytical methods utilized were inverse variance weighting (IVW) and weighted median (WM), supplemented by MR-Egger, simple mode, and weighted mode techniques to infer causality between smoking and RAS. Sensitivity analyses were conducted using MR-PRESSO, Cochran's Q, and the MR-Egger intercept to ensure the robustness of the findings. Results The findings from the IVW and WM analyses suggest a causal association between smoking and an elevated risk of RAS (IVW: OR=1.003; 95% CI: 1.0002– 1.005, p=0.033; WM: OR=1.003; 95% CI: 1.00006–1.007, p=0.044). Compared to non-smokers, smokers have a 0.3% increase in the risk of RAS. Furthermore, the sensitivity analysis did not reveal any inconsistencies that would contradict the MR results. Conclusions Our findings provide preliminary evidence of a potential causal relationship between smoking and the risk of RAS, which may contribute to a deeper understanding of the underlying mechanisms. Further research is needed to confirm these results and explore their implications for clinical practice.

In order to improve the global search ability of PSO and avoid falling into local extreme value, an improved self-regulating tabu annealing PSO was proposed to study the impact of foreign trade on economic resilience model (China Yangtze River Delta as an example). Firstly, improving the inertial adaptive weights and introducing adjustment factors to constrain the learning particles can make the algorithm have stronger searching ability. The improved algorithm can realize the self-adjustment of inertia weights. Secondly, the improved simulated annealing particle swarm optimization algorithm is verified and compared with the former algorithm through two different functions, and the results show that the convergence speed and accuracy are improved. According to the sensitivity calculation, the compensation node is determined for reactive power compensation. The final results show that the resilience of tourism economy in the Yangtze River Delta urban agglomerations presents a changing trend of "rising first and then decreasing", and the resilience level of all cities is on the rise. The cities with high resilience are mainly distributed in the central and eastern regions, and the resilience level of tourism economy in each city has a certain spatial agglomeration characteristic. The resilience of tourism economy is comprehensively affected by economic development level, economic development structure, infrastructure and government intervention, among which the speed of tourism development has a significant negative impact on the resilience of tourism economy, and other factors have a significant promoting effect.

The high labor demand during rice seedling cultivation and transplantation poses a significant challenge in advancing machine-transplanted rice cultivation. This problem may be solved by increasing the seeding rate during seedling production while reducing the number of seedling trays. This study conducted field experiments from 2021 to 2022, using transplanting seedling ages of 10 and 15 days to explore the effects of 250, 300, and 350 g/tray on the seedling quality, mechanical transplantation quality, yields, and economic benefits of rice. The commonly used combination of 150 g/tray with a 20-day seedling age in rice production was used as CK. The cultivation of seedlings under a high seeding rate and short seedling age significantly affected seedling characteristics, but there was no significant difference in seedling vitality compared to CK. The minimum number of rice trays used in the experiment was observed in the treatment of 350–10 (300 g/tray and 10-day seedling age), only 152–155 trays ha–1, resulting in a 62% reduction in the number of trays needed. By increasing the seeding rate of rice, missed holes during mechanical transplantation decreased by 2.8 to 4%. The treatment of 300–15 (300 g/tray and 15-day seedling age) achieved the highest yields and economic gains. These results indicated that using crop straw boards can reduce the application of seedling trays. On that basis, rice yields can be increased by raising the seeding rate and shortening the seedling age of rice without compromising seedling quality.