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Background/Objective: Active vitamin D insufficiency accelerates the development of osteoporosis, with senescent bone cells and the senescence-associated secretory phenotype (SASP) playing crucial roles. This study aimed to investigate whether the senolytic agent ABT263 could correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent cells. Methods: Bone marrow mesenchymal stem cells (BM-MSCs) from young and aged mice were treated with ABT263 in vitro, and 1,25(OH)2D-insufficient (Cyp27b1+/−) mice were administered ABT263 in vivo. Cellular, molecular, imaging, and histopathological analyses were performed to compare treated cells and mice with control groups. Results: ABT263 induced apoptosis in senescent BM-MSCs by downregulating Bcl2 and upregulating Bax expression. It also induced apoptosis in senescent BM-MSCs from 1,25(OH)2D-insufficient mice. ABT263 administration corrected bone loss caused by 1,25(OH)2D insufficiency by increasing bone density, bone volume, trabecular number, trabecular thickness, and collagen synthesis. It also enhanced osteoblastic bone formation and reduced osteoclastic bone resorption in vivo. ABT263 treatment corrected the impaired osteogenic action of BM-MSCs by promoting their proliferation and osteogenic differentiation. Furthermore, it corrected oxidative stress and DNA damage caused by 1,25(OH)2D insufficiency by increasing SOD-2 and decreasing γ-H2A.X expression. Finally, ABT263 corrected bone cell senescence and SASP caused by 1,25(OH)2D insufficiency by reducing the expression of senescence and SASP-related genes and proteins. Conclusion: ABT263 can correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent skeletal cells, reducing oxidative stress, DNA damage, and SASP, and promoting bone formation while inhibiting bone resorption. These findings provide new insights into the potential therapeutic application of senolytic agents in the treatment of osteoporosis associated with active vitamin D insufficiency. The translational potential of this article: This study highlights the therapeutic potential of ABT263, a senolytic compound, in treating osteoporosis caused by active vitamin D insufficiency. By selectively eliminating senescent bone cells and their associated SASP, ABT263 intervention demonstrates the ability to restore bone homeostasis, prevent further bone loss, and promote bone formation. These findings contribute to the growing body of research supporting the use of senolytic therapies for the prevention and treatment of age-related bone disorders. The translational potential of this study lies in the development of novel therapeutic strategies targeting cellular senescence to combat osteoporosis, particularly in cases where vitamin D insufficiency is a contributing factor. Further clinical studies are warranted to validate the efficacy and safety of ABT263 and other senolytic agents in the treatment of osteoporosis in humans.

Abstract Hypertension has become a major contributor to the morbidity and mortality of cardiovascular diseases worldwide. Despite the evidence of the anti‐hypertensive effect of gastrodia‐uncaria granules (GUG) in hypertensive patients, little is known about its potential therapeutic targets as well as the underlying mechanism. GUG components were sourced from TCMSP and HERB, with bioactive ingredients screened. Hypertension‐related targets were gathered from DisGeNET, OMIM, GeneCards, CTD, and GEO. The STRING database constructed a protein–protein interaction network, visualized by Cytoscape 3.7.1. Core targets were analyzed via GO and KEGG using R package ClusterProfiler. Molecular docking with AutodockVina 1.2.2 revealed favorable binding affinities. In vivo studies on hypertensive mice and rats validated network pharmacology findings. GUG yielded 228 active ingredients and 1190 targets, intersecting with 373 hypertension‐related genes. PPI network analysis identified five core genes: AKT1, TNF‐α, GAPDH, IL‐6, and ALB. Top enriched GO terms and KEGG pathways associated with the anti‐hypertensive properties of GUG were documented. Molecular docking indicated stable binding of core components to targets. In vivo study showed that GUG could improve vascular relaxation, alleviate vascular remodeling, and lower blood pressure in hypertensive animal models possibly through inhibiting inflammatory factors such as AKT1, mTOR, and CCND1. Integrated network pharmacology and in vivo experiment showed that GUG may exert anti‐hypertensive effects by inhibiting inflammation response, which provides some clues for understanding the effect and mechanisms of GUG in the treatment of hypertension.

Abstract Background Lung adenocarcinoma is a high-mortality rate cancer. Within this category, Lung mucinous adenocarcinoma (LMAC) is a rare and distinct subtype of lung adenocarcinoma necessitating further investigation. The study was launched to compare the difference of survival features between LMAC and lung non-mucinous adenocarcinoma (LNMAC) and to investigate the significance and demand for developing a new staging system tailored to LMAC. Methods This retrospective study assessed the suitableness of the current staging system for LMAC. It compared the overall survival (OS) between LMAC and LNMAC from 2004 to 2020 (LNMAC: 160,387; LMAC: 6,341) and instituted a novel classification framework for LMAC based on US population. Verification group consisting of patients from two Chinese medical centers from 2010 to 2018 (n = 392) was set to ascertain the applicability of this novel system. The primary endpoint was OS. To minimize the bias, propensity score match (PSM) was employed. Survival analysis and Log-rank test were executed to explore the survival features of LMAC. Results The results indicated that the existed staging system was not suitable for LMAC. Patients diagnosed with LMAC exhibited a superior OS compared to those with LNMAC in stage IA2 (P

Colorectal cancer (CRC) has a postoperative recurrence rate of up to 50%. Local treatment at the surgical site offers a new strategy to prevent recurrence, minimizing systemic side effects. However, these treatments often face issues like poor stability, insufficient targeting, and significant local side effects. Research shows glucose starvation can induce disulfidptosis, a novel cell death pathway, in CRC cells, suitable for precise intervention in residual tumor cells postsurgery. This study develops a biocompatible 2D therapeutic platform using amyloid‐like protein nanofilm technology for precise local synergistic intervention in disulfidptosis and photodynamic therapy (PDT) after CRC surgery. The nanofilm boasts excellent drug‐loading capacity, enzyme activity retention, ultrathin dimensions, wet adhesion, and biocompatibility. A model simulating incomplete tumor resection post‐CRC surgery shows that the GCI@nanofilm effectively inhibits recurrence through an enzyme‐catalyzed cascade reaction inducing disulfidptosis and synergizing with PDT. In summary, GCI@nanofilm overcomes multiple challenges in local postsurgical intervention, providing a foundation for precise and efficient treatment of residual tumors.

Abstract It is still a huge challenge to introduce effective crack‐healing ability into energetic composites with a high oxidizer content. In this article, a poly(urea‐urethane) energetic elastomer was prepared by the polycondensation reaction of glycidyl azido polymer (GAP), isophorone diisocyanate (IPDI), and 2‐aminophenyl disulfide (2‐APD). In the poly(urea‐urethane) elastomer structure, the hybrid dynamic lock, including multilevel H‐bonds and disulfide bonds, not only provides abundant dynamic interactions and promotes chain diffusion, but also enhances physical crosslinking density. Such a unique design fabricated the energetic elastomer with robust tensile strength (0.72 MPa), high stretchability (1631%), and outstanding toughness (8.95 MJ/m3) in the field of energetic polymers. Meanwhile, this energetic elastomer exhibited high self‐healing efficiency (98.4% at 60 °C) and heat release (Q = 1750.46 J/g). Experimental and theoretical results adequately explain the self‐healing mechanism, particularly the role of azido units. The high‐solid content (80 wt%) energetic composites based on the energetic elastomer presented outstanding micro‐defect self‐healing (97.8%) and recycling without loss of mechanical performance. The development of smart energetic composites with excellent self‐healing and recyclable ability provides a meaningful way for a wide range of applications in the field of energetic materials.

Objective To report 3 cases of Guillain-Barré syndrome (GBS) caused by heat stroke (HS) and review the relevant literatures, and summarize the clinical characteristics of GBS caused by HS. Methods and Results The three patients were all diagnosed and treated by The Second Affiliated Hospital of Nanchang University in August 2022. The clinical manifestations were mainly weakness of limbs and dysarticulation after recovery of consciousness disorder of HS, disappearance of tendon reflex as shown by physical examination, extensive peripheral nerve damage mainly caused by axonal damage and motor nerve involvement as shown by EMG. Cerebrospinal fluid protein cell segregation phenomenon was present in Case 1 and Case 2, and the clinical diagnosis was GBS caused by HS. The muscle strength was better than before after immunotherapy, but obvious neurological dysfunction was still found after one year follow-up. Conclusions GBS caused by HS is a severe condition, often appearing within 3 weeks after HS. Immunotherapy leads to varying degrees of improvement in muscle strength; however, significant neurological dysfunction still persist, resulting in a poorer prognosis compared to general GBS.

Abstract Cancer models play critical roles in basic cancer research and precision medicine. However, current in vitro cancer models are limited by their inability to mimic the three-dimensional architecture and heterogeneous tumor microenvironments (TME) of in vivo tumors. Here, we develop an innovative patient-specific lung cancer assembloid (LCA) model by using droplet microfluidic technology based on a microinjection strategy. This method enables precise manipulation of clinical microsamples and rapid generation of LCAs with good intra-batch consistency in size and cell composition by evenly encapsulating patient tumor-derived TME cells and lung cancer organoids inside microgels. LCAs recapitulate the inter- and intratumoral heterogeneity, TME cellular diversity, and genomic and transcriptomic landscape of their parental tumors. LCA model could reconstruct the functional heterogeneity of cancer-associated fibroblasts and reflect the influence of TME on drug responses compared to cancer organoids. Notably, LCAs accurately replicate the clinical outcomes of patients, suggesting the potential of the LCA model to predict personalized treatments. Collectively, our studies provide a valuable method for precisely fabricating cancer assembloids and a promising LCA model for cancer research and personalized medicine.

Abstract Introduction The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. Method We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. Results In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P

BACKGROUND Thoracic paravertebral block (TPVB) and erector spinae plane block (ESPB) are widely used in video-assisted thoracic surgery (VATS). However, they have corresponding adverse effects, including hypotension for TPVB and unpredictable injectate spread in ESPB. An optimal perioperative analgesic strategy remains controversial. We investigated the effect of ultrasound-guided combined TPVB and ESPB (CTEB) for VATS. MATERIAL AND METHODS A total of 120 patients scheduled for thoracic surgery were randomized to receive either ultrasound-guided TPVB, ESPB, or CTEB preoperatively. Postoperative analgesia was achieved with sufentanil patient-controlled intravenous analgesia. The primary outcome was the static pain score at 2 h after surgery. RESULTS The static pain score 2 h postoperatively was significantly different among the 3 groups. This difference was statistically significant for Group ESPB vs Group TPVB (P=0.004), but not for Group ESPB vs Group CTEB (P=0.767), or Group TPVB vs Group CTEB (P=0.117). Group TPVB exhibited the highest incidence of hypotension among the 3 groups. More patients experienced a sensory loss in Groups TPVB and CTEB 30 min after the block performance. Patients receiving CTEB exhibited a lower incidence of chronic pain 6 months postoperatively than those in Group ESPB. CONCLUSIONS CTEB does not enhance the analgesic effect of ESPB in patients undergoing VATS; however, it may induce a faster sensory loss after nerve block and reduce the incidence of postoperative chronic pain compared with ESPB. CTEB may also help to reduce the incidence of intraoperative hypotension compared with TPVB.

ABSTRACT Background The aim of this study is to investigate the radiological features of primary pulmonary invasive mucinous adenocarcinoma (IMA) in a relatively large population to help improve its further understanding and its accuracy of initial diagnosis. Methods This retrospective study included consecutive patients with pathologically confirmed primary pulmonary IMA from January 2019 to December 2021. According to tumor morphology, IMAs were divided into regular nodule/mass, irregular, and large consolidative types. According to tumor density, IMAs were divided into solid, halo, part‐solid, pure ground‐glass, and cystic types. ANOVA, chi‐square, or Fisher exact tests were used to analyze the differences in radiological and clinicopathological characteristics of IMA according to morphological and density subtypes. Results We analyzed 312 patients. Pulmonary IMA tended to occur in the elderly, with a slightly higher number of women than men. IMA showed a predominance in the lower lobe and adjacent to pleura. IMA of regular nodule/mass, irregular, and large consolidative types accounted for 80.8% (252/312), 13.8% (43/312), and 5.4% (17/312), respectively. Solid, halo, part‐solid, pure ground‐glass, and cystic IMAs accounted for 55.8% (174/312), 28.2% (88/312), 11.2% (35/312), 1.3% (4/312), and 3.5% (11/312), respectively. The lobulated (76.9%), spiculated (63.5%), and air bronchogram (56.7%) signs were common in IMA. Dead branch sign (88.2%), angiogram sign (88.2%), and satellite nodules/skipping lesions (47.1%) were common in large‐consolidative‐type IMA. Kirsten rat sarcoma viral oncogene mutations were common (56.1%), whereas epidermal growth factor receptor mutations were relatively rare (2.3%). Conclusions Pulmonary IMA of regular nodule/mass type and solid type were the most common at the initial diagnosis. Detailed radiological features can aid in the differential diagnosis of IMA.

Background Neoadjuvant anti-programmed cell death protein-1 (PD-1) therapy exhibits potential in treating resectable non-small cell lung cancer (NSCLC). Previously, we have reported the 3-year clinical outcomes of this trial, implying the effectiveness and feasibility of neoadjuvant sintilimab monotherapy. However, the long-term prognosis of patients receiving neoadjuvant mono-immunotherapy has yet to be elucidated.Methods For patients with stage IA-IIIB NSCLC, two doses of sintilimab (200 mg) were administered intravenously in the neoadjuvant setting. The 5-year event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) were assessed in these updated results. The predictive role of specific biomarkers in neoadjuvant immunotherapy was also explored.Results With a median follow-up of 61.0 months, 5-year DFS and OS rates of patients who underwent R0 resection were 65.7% and 80.4%, respectively. The 5-year DFS and OS rates of patients with positive programmed death-ligand 1 (PD-L1) expression were 71.9% and 90.9%, respectively. The presence of PD-L1 positivity (tumor proportion score ≥1%) showed a tendency toward the promising prognosis (OS, HR, 0.143; 95% CI: 0.027 to 0.743), especially for those who did not achieve pathological complete response (pCR). In addition, tumor mutation burden was positively correlated with a favorable prognosis. A total of 10 recurrences and 5 subsequent deaths were identified within the 5-year follow-up, with lung metastasis being the predominant.Conclusions These updated analyses were the first to unveil the 5-year survival benefits of neoadjuvant sintilimab monotherapy, implying the potential value of PD-1 inhibitors in neoadjuvant therapy.

Abstract Background This study aimed to investigate the radiological, pathological, and prognostic characteristics of large consolidative‐type pulmonary invasive mucinous adenocarcinomas (IMA). Methods We retrospectively reviewed 738 patients who confirmed IMA between January 2010 and August 2022, and two radiologists reviewed imaging data to determine subtypes. We included 41 patients with pathologically large consolidative‐type IMA. We analyzed their radiological, pathological, and prognostic characteristics. The recurrence‐free survival (RFS) and overall survival (OS) were determined using the Kaplan–Meier method. Results Most lesions were located in the lower lobe, with 46.3% patients showing multiple lesions. Halo, angiogram, vacuole, air bronchogram, and dead branch sign were observed in 97.6%, 73.2%, 63.4%, 61.0%, and 61.0% of the cases, respectively. Unevenly low enhancement was observed in 88.89% of patients. T3 and T4 pathological stages were observed in 50.0% and 30.6% of patients, respectively. Lymph node metastasis was observed in 16.7% patients, with no distant metastasis. Spread‐through air spaces and intrapulmonary dissemination were observed in 27.8% and 19.4% patients, respectively. Moreover, Kirsten rat sarcoma viral oncogene mutations were found in 68.6% of cases, and no epidermal growth factor receptor mutations were seen. Among all mutation sites, G12V mutation is the most common, accounting for 40%. The average RFS and OS were 19.4 and 66.4 months, respectively, with 3‐year RFS and OS rates of 30.0% and 75.0%, respectively. Pleural invasion and lymph node metastasis were independent risk factors for diagnosis. Conclusion Halo, vacuole, angiogram, and dead branch signs were frequently observed in consolidative‐type IMA. Kirsten rat sarcoma viral oncogene mutations are common in consolidative‐type IMA, especially site G12V, whereas epidermal growth factor receptor mutations were rare; therefore, gene immunotherapy was more difficult. Most patients were in stage T3–T4; however, lymph node metastasis was rare.

The state preparation is a crucial procedure in atom interferometry; however, there is a shortage of detailed experimental studies on determining the optimal method for achieving this. This paper investigates and compares two methods for state preparation: the combined use of microwave and Raman light (M-R) and the combined use of optical pumping, microwave, and Raman light (O-M-W). The experimental results demonstrate that the M-R method improves the efficiency of Raman transitions for atom interference, which is helpful in enhancing the contrast of the interference fringes. The O-M-R method increases the quantity of prepared atoms, thereby enhancing the signal-to-noise ratio of the detected signals. This work helps provide a useful experimental basis and reference for researchers to design a suitable state preparation scheme.

Abstract Clinical studies have demonstrated an association between high myopia (HM) and neuropsychiatric disorders; however, the underlying mechanism of the association is not clear. We used whole exome sequencing (WES) in combination with the Genetic Variants Classification Criteria and Guidelines published by the American College of Medical Genetics (ACMG) and bioinformatics analysis to clarify the interrelationship between candidate genes. Causative genes for ocular diseases (45.38%) followed by neuropsychiatric disorders (22.69%) accounted for the highest proportion of genes that exhibited high pathogenicity in HM patients were found. Four pathogenic gene mutations were identified according to ACMG guidelines: c.164_165insACAGCA and c.C1760T in POLG, c.G1291A in COL5A1, and c.G10242T in ZNF469. Three causative genes for neuropsychiatric diseases, PTPRN2, PCDH15 and CDH23, were found to fall at the HM locus. The above results suggest that these genes may interact in high myopia and neuropsychiatric diseases.

Objective To retrospectively analyze the clinical sign and symptom, pathological and genetic characteristics of a case of hereditary myopathy with early respiratory failure (HMERF). Methods and Results A 26‑year‑old female patient presented with muscle weakness (including the proximal and distal arms and lower legs) and myalgia, typical daytime and nighttime respiratory failure symptoms. The serum creatine kinase (CK, 258 U/L) and creatine kinase isoenzyme (CK ‑ MB, 17.80 ng/ml) levels were increased. The EMG showed myogenic changes, and thigh muscle MRI showed selective semitendinous muscle involvement. The skeletal muscle biopsy showed the formation of cytoplasm arranged in the submuscular membrane like a "necklace". Gene test revealed a mutation of TTN gene with c.90211T > C (p. Cys30071Arg). The final diagnosis was HMERF. Conclusions The possibility of HMERF should be considered in patients with unexplained respiratory failure, especially with muscle weakness. Skeletal muscle biopsy and genetic test can make a definitive diagnosis.

Magnetometer towfish can be utilized for underwater and aerial towed magnetic field measurements. Although they lack propulsion systems, significant magnetic interference persists, necessitating magnetic interference compensation. However, as towfish possess no maneuverability, they cannot employ calibration methods akin to those of airborne platforms for determining magnetic compensation parameters. This article proposed a ground calibration method of magnetic compensation parameters for magnetometer towfish and designed a ground magnetic interference calibration device to impose certain constraints on the magnetic field environment. Based on the equivalence analysis with the aeromagnetic compensation parameter calibration scheme, a ground calibration method tailored for magnetometer towfish was designed and subsequently subjected to ground calibration experiments and dynamic noise validation in actual environments. Experimental results reveal that the method possesses remarkable efficacy for calibrating magnetic compensation parameters of towfish by using towed magnetic field measurement devices, yielding a quality akin to that of aircraft platforms. The improvement ratio for magnetic compensation calibration exceeds 16.

Abstract Introduction We investigated the frequency of uveitic macular edema (UME) in patients with different types of noninfectious uveitis and present the primary treatment methods for UME at a specialized eye center in Shaanxi Province, China. Methods We conducted a retrospective, noninterventional, observational survey involving 1946 patients with noninfectious uveitis (2816 eyes). The collected data included sex, age of uveitis onset, age of UME onset, anatomical classification of uveitis, and the treatment administered to UME patients. Results Of the 1946 patients with noninfectious uveitis, 929 (47.74%) were male and 1017 (52.26%) were female. The average age of all participants in the study was 42.19 ± 15.34 years, with average age at uveitis onset of 39.50 ± 15.52 years. Among the patients, 1003 (51.54%), 239 (12.28%), 410 (21.07%), and 294 (15.11%) had anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis, respectively. UME was observed in 134 (6.89%) of the uveitis patients. The average age of UME patients was 47.33 ± 17.17 years, with average age at uveitis onset of 45.78 ± 17.20 years. Out of the 134 UME patients, 3 (0.30%), 15 (6.28%), 47 (11.46%), and 69 (23.47%) had anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis, respectively. Among them, 37 were lost to follow-up, 44 received adalimumab (ADA) combined with low-dose prednisone and with or without conventional immunosuppressants, 19 received interferon-α2a therapy, 14 received intravitreal corticosteroid injections (such as dexamethasone implant or fluocinolone acetonide), 11 received low-dose corticosteroids combined with conventional immunosuppressants, 5 received only oral prednisone, and 4 received repeated peribulbar or subconjunctival injections of triamcinolone acetonide. Conclusions At our tertiary ophthalmic center in Shaanxi Province, China, only 6.89% of patients with noninfectious uveitis were diagnosed with UME. The primary treatment modality for UME in our center is ADA, in accordance with treatment guidelines and the Chinese medical insurance reimbursement system.

Background/Aims Chronic hepatitis B (CHB) and fatty liver (FL) often co-exist, but natural history data of this dual condition (CHB-FL) are sparse. Via a systematic review, conventional meta-analysis (MA) and individual patient-level data MA (IPDMA), we compared liver-related outcomes and mortality between CHB-FL and CHB-no FL patients. Methods We searched 4 databases from inception to December 2021 and pooled study-level estimates using a random-effects model for conventional MA. For IPDMA, we evaluated outcomes after balancing the two study groups with inverse probability treatment weighting (IPTW) on age, sex, cirrhosis, diabetes, ALT, HBeAg, HBV DNA, and antiviral treatment. Results We screened 2,157 articles and included 19 eligible studies (17,955 patients: 11,908 CHB-no FL; 6,047 CHB-FL) in conventional MA, which found severe heterogeneity (I2=88–95%) and no significant differences in HCC, cirrhosis, mortality, or HBsAg seroclearance incidence (P=0.27–0.93). IPDMA included 13,262 patients: 8,625 CHB-no FL and 4,637 CHB-FL patients who differed in several characteristics. The IPTW cohort included 6,955 CHB-no FL and 3,346 CHB-FL well-matched patients. CHB-FL patients (vs. CHB-no FL) had significantly lower HCC, cirrhosis, mortality and higher HBsAg seroclearance incidence (all P≤0.002), with consistent results in subgroups. CHB-FL diagnosed by liver biopsy had a higher 10-year cumulative HCC incidence than CHB-FL diagnosed with non-invasive methods (63.6% vs. 4.3%, P

Summary: Background: With increasingly prevalent coexistence of chronic hepatitis B (CHB) and hepatic steatosis (HS), simple, non-invasive diagnostic methods to accurately assess the severity of hepatic inflammation are needed. We aimed to build a machine learning (ML) based model to detect hepatic inflammation in patients with CHB and concurrent HS. Methods: We conducted a multicenter, retrospective cohort study in China. Treatment-naive CHB patients with biopsy-proven HS between April 2004 and September 2022 were included. The optimal features for model development were selected by SHapley Additive explanations, and an ML algorithm with the best accuracy to diagnose moderate to severe hepatic inflammation (Scheuer's system ≥ G3) was determined and assessed by decision curve analysis (DCA) and calibration curve. This study is registered with ClinicalTrials.gov (NCT05766449). Findings: From a pool of 1,787 treatment-naive patients with CHB and HS across eleven hospitals, 689 patients from nine of these hospitals were chosen for the development of the diagnostic model. The remaining two hospitals contributed to two independent external validation cohorts, comprising 509 patients in validation cohort 1 and 589 in validation cohort 2. Eleven features regarding inflammation, hepatic and metabolic functions were identified. The gradient boosting classifier (GBC) model showed the best performance in predicting moderate to severe hepatic inflammation, with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI 0.83–0.88) in the training cohort, and 0.89 (95% CI 0.86–0.92), 0.76 (95% CI 0.73–0.80) in the first and second external validation cohorts, respectively. A publicly accessible web tool was generated for the model. Interpretation: Using simple parameters, the GBC model predicted hepatic inflammation in CHB patients with concurrent HS. It holds promise for guiding clinical management and improving patient outcomes. Funding: This research was supported by the National Natural Science Foundation of China (No. 82170609, 81970545), Natural Science Foundation of Shandong Province (Major Project) (No. ZR2020KH006), Natural Science Foundation of Jiangsu Province (No.BK20231118), Tianjin Key Medical Discipline (Specialty), Construction Project, TJYXZDXK-059B, Tianjin Health Science and Technology Project key discipline special, TJWJ2022XK034, and Research project of Chinese traditional medicine and Chinese traditional medicine combined with Western medicine of Tianjin municipal health and Family Planning Commission (2021022).

Four-dimensional (4D) printing is a promising technology that provides solutions for compelling needs in various fields. Most of the reported 4D printed systems are based on the temporal shape transformation of printed subjects. Induction of temporal heterogenicity in functions in addition to shape may extend the scope of 4D printing. Herein, we report a 4D printing approach using plant protein (zein) gel inspired by the amyloid fibrils formation mechanism. The printing of zein gel in a specialized layered-Carbopol supporting bath with different water concentrations in an ethanol-water mixture modulates hydrophobic and hydrogen bonding that causes temporal changes in functions. The part of the construct printed in a supporting bath with higher water content exhibits higher drug loading, faster drug release and degradation than those printed in the supporting bath with lower water content. Tri-segment conduit and butterfly-shaped construct with two asymmetrical wings are printed using this system to evaluate biomedical function as nerve conduit and drug delivery system. 4D printed conduits are also effective as a drug-eluting urethral stent in the porcine model. Overall, this study extends the concept of 4D printing beyond shape transformation and presents an approach of fabricating specialized baths for 4D printing that can also be extended to other materials to obtain 4D printed medical devices with translational potential.

Background/Aims The aim of this study was to analyze the chronological changes in postoperative complications in surgical ulcerative colitis patients over the past decade in China and to investigate the potential parameters that contributed to the changes. Methods Ulcerative colitis patients who underwent surgery during 2008–2017 were retrospectively enrolled from 13 hospitals in China. Postoperative complications were compared among different operation years. Risk factors for complications were identified by logistic regression analysis. Results A total of 446 surgical ulcerative colitis patients were analyzed. Fewer short-term complications (24.8% vs. 41.0%, P=0.001) and more laparoscopic surgeries (66.4% vs. 25.0%, P

Taking X100 and X80 pipeline steels as research objects，their stress-strain curves in air and under different applied potentials were obtained through the slow strain rate tensile test (SSRT).The stress corrosion sensitivity analysis showed that the applied potential had a significant effect on the SCC sensitivity and corrosion cracking mechanism of X100 and X80 pipeline steels in 3.5%NaCl neutral solution.Under the same stress corrosion conditions，the SCC sensitivity of X100 pipeline steel was lower than that of X80 pipeline steel.The characteristics and differences of the corrosion resistance of X100 and X80 pipeline steels were analyzed by combing the observation of fracture morphology and fast/slow scan tests of polarization curves，the stress corrosion mechanism type of X100 and X80 pipeline steel materials under different applied potential conditions could be obtained，when the applied potential was higher than -395 mV，the metal was in the state of activation dissolution；when the applied potential was -395～-462 mV(X80 steel) or -395～-504 mV(X100 steel)，the mechanisms were membrane crackinganodic dissolution(AD) and hydrogen induced crack.If the applied potential further decreased，the mechanism was hydrogen induced crack.

Abstract Objectives This study aims to characterize the specific organ metastatic rates in lung adenocarcinoma (LUAD) patients and identify the prognosis‐associated factors. Methods Using the Surveillance, Epidemiology and End Results database, 40 117 patients diagnosed with positive histology as the only primary LUAD were included. We stratified patients by diagnosed year, age, sex, race/ethnicity, marital status, insurance, location, TNM stage, organ‐specific metastases, surgery, chemotherapy, and radiation therapy. We performed multivariable logistic and Cox regression to identify the factors associated with the presence of specific organ metastases and prognosis predictors. Results For the 40 117 LUAD patients, 43.69%, 26.25%, 19.66%, 10.60%, and 17.89% had specific organ, bone, brain, liver, and lung metastases, respectively. The average survival in patients with organ metastases was 12.19 months, compared to 36.40 months in patients without metastases. In different kinds of metastatic organ cohorts, the longest average survival was 12.60 months in the lung metastases cohort, and the shortest was 8.43 months in liver metastases cohort. In total, 571 patients with metastases received surgery, which was significantly associated with decreased mortality (hazard ratio 1.82, 95% confidence interval 1.65–2.01, p

Two novel energetic compounds, 3-nitroxymethyl-5-(4-nitro-furazan-3-yl)-1,2,4-oxadiazole (4) and 3-nitroxymethyl-5-(4-azido-furazan-3-yl)-1,2,4-oxadiazole (5), were synthesized. Both of them were fully characterized, and the structure of 4 was further confirmed by X-ray single crystal diffraction. The thermal behaviors, detonation performances and the sensitivities of 4 and 5 were also investigated by differential scanning calorimetry (DSC), EXPLO5 program and BAM standard techniques. In addition, the electrostatic potential energy surface (ESP) was studied by Multiwfn program and density functional theory at B3LPY/6-31G (d, p). Both compounds have low melt-point, good energetic performance and mechanical sensitivity, which endow them with promising properties as plasticizing ingredients in propellant formulations.

BackgroundIn the era of immunotherapy, the optimal combination of immune checkpoint inhibitors (ICIs) and chemoradiotherapy (CRT) for stage III non-small cell lung cancer (NSCLC) is not defined. The current study investigated the efficacy and safety of definitive CRT(dCRT) plus consolidation ICIs with or without induction ICIs in stage III NSCLC.Methods123 consecutive patients treated with dCRT followed by consolidation ICIs at our institution from 2018 to 2022 were retrospectively reviewed. Failure patterns, survival outcomes, and toxicity profiles were analyzed.ResultsThe 1- and 2- year PFS rates were 75.3% and 56.9%, respectively, and median PFS was 30.83 months from the start of treatment. In-field failure (18.7%) was the most common failure pattern. The most common adverse event (AE) was pneumonitis caused by ICIs or RT. The incidence of Grade 3-4 and Grade 5 pneumonitis was 5.7% and 1.6%, respectively. Further analysis showed that the induction plus consolidation ICIs group has significantly lower cumulative incidence of distant metastasis rates (HR: 0.30, 95%CI: 0.09-1.00, p=0.043) and higher incidence of pneumonitis (p=0.039) compared with patients in the consolidation ICIs group.ConclusionsCombined CRT and consolidation ICIs achieved encouraging efficacy and manageable toxicity in patients with stage III NSCLC in China. Induction plus consolidation ICIs might reduce distant metastasis and deserve further investigation.

Most mammals tolerate exposure to hypobaric hypoxia poorly as it may affect multiple regulatory mechanisms and inhibit cell proliferation, promote apoptosis, limit tissue vascularization, and disrupt the acid–base equilibrium. Here, we quantified the functional state of germ cell development and demonstrated the interaction between the germ and somatic cells via single-cell RNA sequencing (scRNA-seq). The present study elucidated the regulatory effects of hypobaric hypoxia exposure on germ cell formation and sperm differentiation by applying enrichment analysis to genomic regions. Hypobaric hypoxia downregulates the genes controlling granule secretion and organic matter biosynthesis, upregulates tektin 1 (TEKT1) and kinesin family member 2C (KIF2C), and downregulates 60S ribosomal protein 11 (RPL11) and cilia- and flagella-associated protein 206 (CFAP206). Our research indicated that prosaposin-G protein-coupled receptor 37 (PSAP-GPR37) ligands mediate the damage to supporting cells caused by hypobaric hypoxic exposure. The present work revealed that hypoxia injures peritubular myoid (PTM) cells and spermatocytes in the S phase. It also showed that elongating spermatids promote maturation toward the G2 phase and increase their functional reserve for sperm–egg binding. The results of this study provide a theoretical basis for future investigations on prophylactic and therapeutic approaches toward protecting the reproductive system against the harmful effects of hypobaric hypoxic exposure.

Abstract Introduction With the advancements in early diagnosis, more and more patients with multiple primary lung cancer (MPLC) have been identified. However, the progression of MPLC involves complex changes in cell composition and metabolic function, which remains largely controversial. Objective Our study aims to comprehensively reveal the cellular characteristics and inter‐cellular connections of MPLC. Methods We performed scRNA‐seq from 23 samples of six MPLC patients, combined with bulk whole‐exome sequencing. We performed trajectory analysis to investigate the transition of different cell types during the development of MPLC. Results A total of 1 67 397 cells were sequenced derived from tumour and adjacent tissues of MPLC patients, and tumour, normal, immune and stromal cells were identified. Two states of epithelial cells were identified, which were associated with immune response and cell death, respectively. Furthermore, both CD8+ naïve and memory T cells participated in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells were exhausted T cells and cytotoxic T cells, which positively regulated cell death and were implicated in the regulation of cytokine production, respectively. Two main subpopulations of B cells with distinct functions were identified, which participate in the regulation of the immune response and antigen presentation, respectively. In addition, we found a specific type of endothelial cells that were abundant in tumour samples, with an increasing trend from normal to tumour samples. Conclusions Our study showed the comprehensive landscape of different cells of MPLC, which might reveal the key cellular mechanisms and, therefore, may provide new insights into the early diagnosis and treatment of MPLC.

Neoadjuvant immunotherapy has brought new hope for patients with non-small cell lung cancer (NSCLC). However, limited by the lack of clinically feasible markers, it is still difficult to select NSCLC patients who respond well and to predict patients’ clinical outcomes before the treatment. Before the treatment, we isolated plasma extracellular vesicles (EVs) from three cohorts (discovery, training and validation) of 78 NSCLC patients treated with neoadjuvant immunotherapy. To identify differentially-expressed EV long RNAs (exLRs), we employed RNA-seq in the discovery cohort. And we subsequently used qRT-PCR to establish and validate the predictive signature in the other two cohorts. We have identified 8 candidate exLRs from 27 top-ranked exLRs differentially expressed between responders and non-responders, and tested their expression with qRT-PCR in the training cohort. We finally identified H3C2 (P = 0.029), MALAT1 (P = 0.043) and RPS3 (P = 0.0086) significantly expressed in responders for establishing the predictive signature. Integrated with PD-L1 expression, our signature performed well in predicting immunotherapeutic responses in the training (AUC=0.892) and validation cohorts (AUC=0.747). Furthermore, our signature was proven to be a predictor for favorable prognosis of patients treated with neoadjuvant immunotherapy, which demonstrates the feasibility of our signature in clinical practices (P = 0.048). Our results demonstrate that the exLR-based signature could accurately predict responses to neoadjuvant immunotherapy and prognosis in NSCLC patients.

Objective The debate on the superiority of single‐ or double‐bundle for anterior cruciate ligament reconstruction has not ceased. The comparative studies on intra‐articular biomechanics after different surgical reconstructions are rare. This study is to evaluate the biomechanical stress distribution intra‐knee after single‐ and double‐bundle anterior cruciate ligament reconstruction by three‐dimensional finite element analysis, and to observe the change of stress concentration under the condition of vertical gradient loads. Methods In this study, magnetic resonance imaging data were extracted from patients and healthy controls for biomechanical analysis. Patients included in the three models were matched in age and sex. The strength and distribution of induced stresses were analyzed in two frequently used procedures, anatomical single‐bundle anterior cruciate ligament reconstruction and anatomical double‐bundle anterior cruciate ligament reconstruction, using femoral‐graft‐tibial system under different loads, to mimic a post‐operation mechanical motion. The three‐dimensional finite‐element models for normal ligament and two surgical methods were applied. A vertical force simulating daily walking was performed on the models to assess the interfacial stresses and displacements of intra‐articular tissues and ligaments. The evaluation results mainly included the stress of each part of ligament and meniscus. The stress values of different parts of three models were extracted and compared. Results The stress of ligament/graft at femoral side of three finite‐element models was significantly higher than at tibial side, while the highest level was observed in single‐bundle reconstruction finite‐element model. With the increase of force, the maximum stress in the medial (7.1–7.1 MPa) and lateral (4.9–7.4 MPa) meniscus of single‐bundle reconstruction finite‐element model shifted from the anterior horn to the central area (p = 0.0161, 0.0479, respectively). The stress was shown to be at a lower level at femoral side and posterior cruciate ligament of intra‐knee in two reconstruction finite‐element models than that in normal finite‐element models, while presented higher level at the tibial side than normal knee (p = 0.3528). The displacement of the femoral side and intra‐knee areas in reconstruction finite‐element models was greater than that in normal finite‐element model (p = 0.0855). Conclusion Compared with the single‐bundle technique, the graft of double‐bundle anterior cruciate ligament reconstruction has better stress dissipation effect and can prevent postoperative meniscus tear more effectively.

This article aims to test a causal nexus between bitcoin market and economic policy uncertainty. We use the continuous wavelet analysis to investigate lead-lag relationship between bitcoin market and economic policy uncertainty in different time-frequency domains. Our findings show the negative relationship between bitcoin returns and economic policy uncertainty around the period of bitcoin’s currency recognition and COVIC-19 pandemic crisis both daily and monthly time series test. Furthermore, we find that the causality relationship between bitcoin and economic policy uncertainty is relatively indistinct around the period of bitcoin’s currency recognition, while bitcoin returns are leading economic policy uncertainty changes during COVID-19 pandemic crisis, indicating the economic policy uncertainty fluctuation trend can refer to the fluctuation of bitcoin, bitcoin can be viewed as a leading indicator, but it could not be employed as a safe-haven asset hedge against uncertainty during the period of COVID-19 pandemic.

ABSTRACT: Milk fat globule membrane (MFGM) proteins surround the triacylglycerol core comprising milk fat globules (MFG). We previously detected a decrease in the size of fat globules during conjugated linoleic acid (CLA)-induced milk fat depression (MFD), and other studies have reported that some MFGM proteins play a central role in regulating mammary cellular lipid droplet size. However, little is known about the relationship between MFD, MFG size, and MFGM proteins in bovine milk. The aim of this study was to investigate the profile of MFGM proteins during MFD induced by CLA. Sixteen mid-lactating Holstein cows (145 ± 24 d in milk) with similar body condition and parity were divided into control and CLA groups over a 10-d period. Cows were fed a basal diet (control, n = 8) or control plus 15 g/kg of dry matter (DM) CLA (n = 8) to induce MFD. Cow performance, milk composition, and MFG size were measured daily. On d 10, MFGM proteins were extracted and identified by quantitative proteomic analysis, and western blotting was used to verify a subset of the identified MFGM proteins. Compared with controls, supplemental CLA did not affect milk production, DM intake, or milk protein and lactose contents. However, CLA reduced milk fat content (3.73 g/100 mL vs. 2.47 g/100 mL) and the size parameters volume-related diameter D[4,3] (3.72 μm vs. 3.35 μm) and surface area-related diameter D[3,2] (3.13 μm vs. 2.80 μm), but increased specific surface area of MFG (1,905 m2/kg vs. 2,188 m2/kg). In total, 177 differentially expressed proteins were detected in milk from cows with CLA-induced MFD, 60 of which were upregulated and 117 downregulated. Correlation analysis showed that MFG size was negatively correlated with various proteins, including XDH and FABP3, and positively correlated with MFG-E8, RAB19, and APOA1. The results provide evidence for an important role of MFGM proteins in regulating MFG diameter, and they facilitate a mechanistic understanding of diet-induced MFD.

1,1,4,4-Tetramethyl-2-tetrazene (TMTZ), a potential candidate for replacing 1,1-dimethylhydrazine (UDMH), has excellent properties including a high specific impulse, non-toxicity and non-volatility. However, most synthetic methods depicted in the literature use stoichiometric oxidative coupling, and the oxidizing agents are usually heavy metals or halogens, leading to low synthetic efficiency and high environmental pollution. In order to overcome these problems, it is necessary to explore more environmentally friendly and catalytic synthetic methods. In this paper, a method of photocatalytic oxidative coupling for the preparation of TMTZ was reported for the first time. By using an organic photocatalyst Eosin Y, TMTZ was synthesized rapidly and efficiently. The thermal decomposition properties of TMTZ were studied, and different performance characteristics between TMTZ and UDMH were determined and analyzed, which provided a basis for the application of TMTZ based new liquid propellant.

Abstract Background Although immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 have demonstrated potency towards treating patients with non‐small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism. Methods The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort (n = 74), and confirmed with a mouse model. In addition, the tumor immune microenvironment (TIME) of KRAS‐mutant NSCLC, such as CD8+ tumor‐infiltrating lymphocytes (TILs) and PD‐L1 level, was investigated. Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME. Furthermore, interventions that improved TIME were developed to increase responsiveness to ICIs. Results We observed the inferior efficacy of ICIs in KRAS‐G12D‐mutant NSCLC. Based upon transcriptome data and immunostaining results from KRAS‐mutant NSCLC, KRAS‐G12D point mutation negatively correlated with PD‐L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+ TILs, which in turn yielded an immunosuppressive TIME. The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS‐G12D mutation suppressed PD‐L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down‐regulating high mobility group protein A2 (HMGA2) level. Notably, paclitaxel, a chemotherapeutic agent, upregulated HMGA2 level, and in turn, stimulated the secretion of CXCL10/CXCL11. Moreover, PD‐L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD‐L1 inhibitor monotherapy in a mouse model with KRAS‐G12D‐mutant lung adenocarcinoma. Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+ TILs via the up‐regulation of CXCL10/CXCL11 levels. Results of clinical study also revealed the superior efficacy of chemo‐immunotherapy in patients with KRAS‐G12D‐mutant NSCLC compared with ICI monotherapy. Conclusions Our study elucidated the molecular mechanism by which KRAS‐G12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC. Importantly, our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS‐G12D‐mutant NSCLC.