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Abstract The Equilibrium Optimiser (EO) has been demonstrated to be one of the metaheuristic algorithms that can effectively solve global optimisation problems. Balancing the paradox between exploration and exploitation operations while enhancing the ability to jump out of the local optimum are two key points to be addressed in EO research. To alleviate these limitations, an EO variant named adaptive elite‐guided Equilibrium Optimiser (AEEO) is introduced. Specifically, the adaptive elite‐guided search mechanism enhances the balance between exploration and exploitation. The modified mutualism phase reinforces the information interaction among particles and local optima avoidance. The cooperation of these two mechanisms boosts the overall performance of the basic EO. The AEEO is subjected to competitive experiments with state‐of‐the‐art algorithms and modified algorithms on 23 classical benchmark functions and IEE CEC 2017 function test suite. Experimental results demonstrate that AEEO outperforms several well‐performing EO variants, DE variants, PSO variants, SSA variants, and GWO variants in terms of convergence speed and accuracy. In addition, the AEEO algorithm is used for the edge server (ES) placement problem in mobile edge computing (MEC) environments. The experimental results show that the author’s approach outperforms the representative approaches compared in terms of access latency and deployment cost.

Abstract Background Sarcopenia, a group of muscle‐related disorders, leads to the gradual decline and weakening of skeletal muscle over time. Recognizing the pivotal role of gastrointestinal conditions in maintaining metabolic homeostasis within skeletal muscle, we hypothesize that the effectiveness of the myogenic programme is influenced by the levels of gastrointestinal hormones in the bloodstream, and this connection is associated with the onset of sarcopenia. Methods We first categorized 145 individuals from the Emergency Room of Taipei Veterans General Hospital into sarcopenia and non‐sarcopenia groups, following the criteria established by the Asian Working Group for Sarcopenia. A thorough examination of specific gastrointestinal hormone levels in plasma was conducted to identify the one most closely associated with sarcopenia. Techniques, including immunofluorescence, western blotting, glucose uptake assays, seahorse real‐time cell metabolic analysis, flow cytometry analysis, kinesin‐1 activity assays and qPCR analysis, were applied to investigate its impacts and mechanisms on myogenic differentiation. Results Individuals in the sarcopenia group exhibited elevated plasma levels of glucagon‐like peptide 1 (GLP‐1) at 1021.5 ± 313.5 pg/mL, in contrast to non‐sarcopenic individuals with levels at 351.1 ± 39.0 pg/mL (P

Abstract Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained‐release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady‐state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20–50 kg. As a result, the PK characteristics of VPA were described using a one‐compartment model with first‐order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h−1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.

Abstract With a large number of film capacitors being deployed in critical locations in electrical and electronic systems, artificial intelligence (AI) technology is also expected to address the problems encountered in this process. According to our findings, AI applications can cover the entire lifecycle of film capacitors. However, the AI safety hazards in these applications have not received the attention they deserve. To meet this, the authors argue, with specific examples, risks that flawed, erratic, and unethical AI can introduce in the design, operation, and evaluation of film capacitors. Human‐AI common impact and more multi‐dimensional evaluation for AI are proposed to better cope with unknown, ambiguity, and known risks brought from AI in film capacitors now and in the future.

Abstract Long noncoding RNAs are key players in the development of lung adenocarcinoma (LUAD). The present study elucidated the role of LINC01087 in LUAD development. Cell vitality and apoptosis were assessed by the CCK‐8 assay and flow cytometry, respectively. The transwell assay was adopted to evaluate cell migration and invasion. Levels of m6A modification of LINC01087 were determined using the methylated RNA binding protein immunoprecipitation assay. The interactions among LINC01087, miR‐514a‐3p, and centrosome protein 55 (CEP55) were evaluated using dual‐luciferase reporter, RNA immunoprecipitation, and RNA–RNA pull‐down assays. LINC01087 was highly expressed in LUAD, and its downregulation restrained cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition in vitro as well as tumor growth in a xenograft tumor model. Overexpression of miR‐514a‐3p inhibited malignant phenotypes in LUAD cells by inactivating RhoA/ROCK1 signaling via the suppression of CEP55 expression. Mechanistically, RBM15 increased the expression and mRNA stability of LINC01087 by mediating its m6A modification and LINC01087 induced CEP55 expression by sponging miR‐514a‐3p. RBM15‐induced LINC01087 upregulation accelerated LUAD progression by regulating the miR‐514a‐3p/CEP55/RhoA/ROCK1 axis, illustrating the potential of LINC01087 as a novel target for LUAD therapy.

Abstract In recent years, the precisely controlled synthesis of chiral twisted molecular carbons has emerged as a forefront topic in the research of carbon materials. Molecular carbons refer to carbon nanomaterials synthesized with precision at the atomic level. Through rational design, rigid and stable chiral twisted structures can be synthesized. The exploration in the field of chiral twisted molecular carbons is key to fully understanding the various twisted configurations of carbon materials and delving into the relationship between structure design and functionality. This review explores chiral twisted configurations of carbon nanomaterials such as nanographene, carbon nanobelts, carbon nanosheets, graphdiyne, etc. It emphasizes the role of photocyclization, Scholl reaction, and Diels–Alder reactions in achieving precise chiral control and discusses a range of innovative design strategies. These strategies have led to the development of various twisted structures, such as helical, propeller, and Möbius strip configurations. The introduction of chirality, combined with the inherent exceptional optical properties of nanocarbon materials, has facilitated the creation of materials with superior chiroptical performances. This advancement is driving applications in fields such as optoelectronics and chiral optics.

Abstract Circadian rhythm disorder (CRD) is closely associated with hair regression and shedding, but whether this risk can be transmitted to the offspring is unknown. Whether Pu‐erh tea, with alleviating effects of CRD‐mediated syndrome, can act on the transmission of alopecia risk to offspring is also unproven. Here, we obtained CRD parental mice offspring and found that CRD‐mediated alopecia risk can be transmitted to offspring, especially male offspring. Parental consumption of Pu‐erh tea, especially in females or both parents, reduced the risk of CRD‐mediated alopecia transmitted to offspring by inhibiting subcutaneous fat accumulation (downregulation of Rab18, fat‐specific protein 27 (Fsp27), and perilipin 1 (Plin1)), reducing oxidative stress and inflammation in skin tissue (NADPH oxidase 4 (NOX4)/ nuclear factor kappa‐B (NF‐κB)), balancing androgen and hair growth factor release (hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), insulin‐like growth factor 1 (IGF‐1)), and restoring hair follicle DNA repair function (upregulation of Ku70, 8‐Oxoguanine DNA glycosylase 1 (OGG1), and Rad51). Transcriptomic analysis further clarified that the mechanism stemmed from the upregulation of gene expression in pathways such as the Wnt, Hippo, and other signaling pathways.

Abstract SARS‐CoV‐2 Omicron sublineages escape most preclinical/clinical neutralizing antibodies in development, suggesting that previously employed antibody screening strategies are not well suited to counteract the rapid mutation of SARS‐CoV‐2. Therefore, there is an urgent need to screen better broad‐spectrum neutralizing antibody. In this study, a comprehensive approach to design broad‐spectrum inhibitors against both SARS‐CoV‐1 and SARS‐CoV‐2 by leveraging the structural diversity of nanobodies is proposed. This includes the de novo design of a fully human nanobody library and the camel immunization‐based nanobody library, both targeting conserved epitopes, as well as the development of multivalent nanobodies that bind nonoverlapping epitopes. The results show that trivale B11‐E8‐F3, three nanobodies joined tandemly in trivalent form, have the broadest spectrum and efficient neutralization activity, which spans from SARS‐CoV‐1 to SARS‐CoV‐2 variants. It is also demonstrated that B11‐E8‐F3 has a very prominent preventive and some therapeutic effect in animal models of three authentic viruses. Therefore, B11‐E8‐F3 has an outstanding advantage in preventing SARS‐CoV‐1/SARS‐CoV‐2 infections, especially in immunocompromised populations or elderly people with high‐risk comorbidities.

ABSTRACT Background Vaccination is one of the effective measures to prevent latent tuberculosis infection (LTBI) from developing into active tuberculosis (TB). Applying bioinformatics methods to pre‐evaluate the biological characteristics and immunogenicity of vaccines can improve the efficiency of vaccine development. Objectives To evaluate the immunogenicity of TB vaccine W541 and to explore the application of bioinformatics technology in TB vaccine research. Methods This study concatenated the immunodominant sequences of Ag85A, Ag85B, Rv3407, and Rv1733c to construct the W541 DNA vaccine. Then, bioinformatics methods were used to analyze the physicochemical properties, antigenicity, allergenicity, toxicity, and population coverage of the vaccine, to identify its epitopes, and to perform molecular docking with MHC alleles and Toll‐like receptor 4 (TLR4) of the host. Finally, the immunogenicity of the vaccine was evaluated in animal experiments. Results The W541 vaccine protein is a soluble cytoplasmic protein with a half‐life of 1.1 h in vivo and an instability index of 45.37. It has good antigenicity and wide population coverage without allergenicity and toxicity. It contains 138 HTL epitopes, 73 CTL epitopes, 8 linear and 14 discontinuous B cell epitopes, and has a strong affinity for TLR4. Immune simulations have shown that it can effectively stimulate innate and adaptive immune responses. Animal experiments confirmed that the W541 DNA vaccine could effectively activate Th1‐ and Th17‐type immune responses, producing high levels of IFN‐γ and IL‐17A, but could not significantly increase antibody levels. Conclusion The W541 DNA vaccine can induce strong cellular immune responses. However, further optimization of the vaccine design is needed to make the expressed protein more stable in vivo. Bioinformatics analysis could reveal the physicochemical and immunological information of vaccines, which is critical for guiding vaccine design and development.

Abstract Marine oil exploration is important yet greatly increases the risk of oil leakage, which will result in severe environment pollution and economic losses. It is an urgent need to develop effective underoil adhesives. However, realizing underoil adhesion is even harder than those underwater, due to the stubborn attachment of a highly viscous oil layer on target surface. Here, inspired by endocytosis, a tough gel tape composed of zwitterionic polymer network and zwitterionic surfactants is developed. The amphiphilic surfactants can form micelle to capture the oil droplets and transport them from the interface to gel via electrostatic attraction of polymer backbone, mimicking the endocytosis and achieving robust underoil adhesion. Benefiting from the oil‐resistance of polymer backbone, the gel further realizes a combination of i) long‐term adhesion with high durability, ii) repeated adhesion in oil, and iii) renewable adhesion efficiency after exhausted use. The tape exhibits an ultra‐high adhesive toughness of 2446.86 J m−2 to stainless steel in silicone oil after 30 days' oil‐exposure; such value of adhesive toughness surpasses many of those achieved in underwater adhesion and is greater than underoil adhesion performance of commercial tape. The strategy illustrated here will motivate the design of sustainable and efficient adhesives for wet environments.

Abstract Humans recognize and manipulate objects relying on the multidimensional force features captured by the tactile sense of skin during the manipulation. Since the current sensors integrated in robots cannot support the robots to sense the multiple interaction states between manipulator and objects, achieving human‐like perception and analytical capabilities remains a major challenge for service robots. Prompted by the tactile perception involved in robots performing complex tasks, a multimodal tactile sensory system is presented to provide in situ simultaneous sensing for robots when approaching, touching, and manipulating objects. The system comprises a capacitive sensor owning the high sensitivity of 1.11E‐2 pF mm−1, a triboelectricity nanogenerator with the fast response speed of 30 ms, and a pressure sensor array capable of 3D force detection. By Combining transfer learning models, which fuses multimodal tactile information to achieve high‐precision (up to 95%) recognition of the multi‐featured targets such as random hardness and texture information under random sampling conditions, including random grasp force and velocity. This sensory system is expected to enhance the intelligent recognition and behavior‐planning capabilities of autonomous robots when performing complex tasks in undefined surrounding environments.

Abstract Aims Few studies have investigated differences in sequential transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and simultaneous RFA‐TACE for the treatment of hepatocellular carcinoma (HCC) using the Milan criteria. This study explored the differences in safety and prognosis between sequential TACE‐RFA and simultaneous RFA‐TACE. Methods This retrospective real‐world study included 109 patients with HCC within the Milan criteria who underwent sequential TACE‐RFA (n = 75) or simultaneous RFA‐TACE (n = 34) at the Eastern Hepatobiliary Surgery Hospital between January 2017 and 2021. Postoperative complications, length of hospital stay, and long‐term prognosis were compared. The median follow‐up duration of these patients was 39.1 months. Overall survival (OS) and time to tumor recurrence (TTR) curves were plotted using the Kaplan−Meier method and were compared using the logarithmic rank test. Independent risk factors for OS and tumor recurrence (TR) were analyzed using the Cox risk regression model. Results Multivariate analysis showed that tumor diameter >3 cm (hazard ratio [HR]: 2.201, 95% confidence interval [CI]: 1.106–4.378, p = 0.025; HR: 2.236, 95% CI: 1.271–3.934, p = 0.005, respectively) and alpha‐fetoprotein (AFP) > 400 μg/L (HR: 2.362, 95% CI: 1.195–4.668, p = 0.013; HR: 1.798, 95% CI: 1.048–3.086, p = 0.033, respectively) were independent risk factors for OS and TTR, whereas the presence of multiple tumors (HR: 2.352, 95% CI: 1.127–4.907, p = 0.023) was an independent risk factor for TTR. Simultaneous RFA‐TACE did not have an effect on OS or TTR. After propensity score‐matched, comparable results were obtained and RFA‐TACE still had no effect on OS or TTR. No significant differences were observed in grade III/IV complications (2/75 [2.7%] vs. 1/34 [2.9%], p = 1.000) between the two groups. However, the RFA‐TACE group had fewer complications than the TACE‐RFA group (24/34 [70.6%] vs. 66/75 [88.0%], p = 0.026). The RFA‐TACE group had a shorter hospital stay and less total cost during hospitalization compared with the TACE‐RFA group (6.0 vs. 10.0 days, p

Abstract Background Metabolic reprograming and immune escape are two hallmarks of cancer. However, how metabolic disorders drive immune escape in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, the aim of the present study was to investigate the metabolic landscape of HNSCC and its mechanism of driving immune escape. Methods Analysis of paired tumor tissues and adjacent normal tissues from 69 HNSCC patients was performed using liquid/gas chromatography‐mass spectrometry and RNA‐sequencing. The tumor‐promoting function of kynurenine (Kyn) was explored in vitro and in vivo. The downstream target of Kyn was investigated in CD8+ T cells. The regulation of CD8+ T cells was investigated after Siglec‐15 overexpression in vivo. An engineering nanoparticle was established to deliver Siglec‐15 small interfering RNA (siS15), and its association with immunotherapy response were investigated. The association between Siglec‐15 and CD8+ programmed cell death 1 (PD‐1)+ T cells was analyzed in a HNSCC patient cohort. Results A total of 178 metabolites showed significant dysregulation in HNSCC, including carbohydrates, lipids and lipid‐like molecules, and amino acids. Among these, amino acid metabolism was the most significantly altered, especially Kyn, which promoted tumor proliferation and metastasis. In addition, most immune checkpoint molecules were upregulated in Kyn‐high patients based on RNA‐sequencing. Furthermore, tumor‐derived Kyn was transferred into CD8+ T cells and induced T cell functional exhaustion, and blocking Kyn transporters restored its killing activity. Accroding to the results, mechanistically, Kyn transcriptionally regulated the expression of Siglec‐15 via aryl hydrocarbon receptor (AhR), and overexpression of Siglec‐15 promoted immune escape by suppressing T cell infiltration and activation. Targeting AhR in vivo reduced Kyn‐mediated Siglec‐15 expression and promoted intratumoral CD8+ T cell infiltration and killing capacity. Finally, a NH2‐modified mesoporous silica nanoparticle was designed to deliver siS15, which restored CD8+ T cell function status and enhanced anti‐PD‐1 efficacy in tumor‐bearing immunocompetent mice. Clinically, Siglec‐15 was positively correlated with AhR expression and CD8+PD‐1+ T cell infiltration in HNSCC tissues. Conclusions The findings describe the metabolic landscape of HNSCC comprehensively and reveal that the Kyn/Siglec‐15 axis may be a novel potential immunometabolism mechanism, providing a promising therapeutic strategy for cancers.

Abstract Background Diabetic sarcopenia is a disease‐related skeletal muscle disorder that causes progressive symptoms. The complete understanding of its pathogenesis is yet to be unravelled, which makes it difficult to develop effective therapeutic strategies. This study investigates how MFG‐E8 affects mitophagy and the protective role of D‐pinitol (DP) in diabetic sarcopenia. Methods In vivo, streptozotocin‐induced diabetic SAM‐R1 (STZ‐R1) and SAM‐P8 (STZ‐P8) mice (16‐week‐old) were used, and STZ‐P8 mice were administrated of DP (150 mg/kg per day) for 6 weeks. Gastrocnemius muscles were harvested for histological analysis including transmission electron microscopy. Proteins were evaluated via immunohistochemistry (IHC), immunofluorescence (IF), and western blotting (WB) assay. In vitro, advanced glycation end products (AGEs) induced diabetic and D‐galactose (DG) induced senescent C2C12 models were established and received DP, MFG‐E8 plasmid (Mover)/siRNA (MsiRNA), or 3‐MA/Torin‐1 intervention. Proteins were evaluated by IF and WB assay. Immunoprecipitation (IP) and co‐immunoprecipitation (CO‐IP) were used for hunting the interacted proteins of MFG‐E8. Results In vivo, sarcopenia, mitophagy deficiency, and up‐regulated MFG‐E8 were confirmed in the STZ‐P8 group. DP exerted protective effects on sarcopenia and mitophagy (DP + STZ‐P8 vs. STZ‐P8; all P

Abstract Film capacitors are playing an increasingly important role in power‐related fields, driven by the continuous development of dielectric materials and practical needs. Long‐term accumulation has also led to an increasing wealth of data related to film capacitors. Sonification opens up a new way for people to make good use of data from film capacitors. A framework for sonifying film capacitors data based on TwoTone is presented. Based on the analysis and discussion, it is clear that the sonification results can easily represent the monotonic variation pattern of film capacitors data. What's more, the sonification results increase the possibility that people pay attention to the changing trend of film capacitors data when there is no significant difference in the visual perception of the data. In addition to providing a new way of music generation of electrical equipment, the method proposed is expected to contribute to theory reference in typical scenarios, such as factory calibration of film capacitors, monitoring of film capacitor operation status, and presentation of statistical data of film capacitors' dielectric materials, which will help us to better understand the distribution characteristics of polymer films.

Abstract Metallurgical slag such as solid waste generated in the steel industry carries environmental pollution risks, but it is rich in nutrients required by microalgae. Metallurgical slag used for carbon capture and biomass energy conversion has multiple benefits: (i) reduction and harmless treatment of metallurgical solid waste, (ii) assisting in carbon neutrality by efficient carbon fixation, and (iii) production of biodiesel from CO2. In this study, AOD, BOF, BFS, HVS, and VTS slag were applied to culture Chlorella pyrenoidosa (C. pyrenoidosa) with the regulation of growth, carbon fixation, and lipid synthesis. An excellent fixed amount of CO2 with 94.59 mg is obtained from C. pyrenoidosa biomass at BOF slag added (mass ratio of CO2 captured/microalgae/slag with 1.99/1.00/10.53) since high Ca/Mg mass ratio of 419 (8.38 mg/L Ca and 0.02 mg/L Mg), no Cr and low concentration of Al (0.04 mg/L) contribute to regulating antioxidant enzyme activity (SOD and POD) to resist ROS and improving PEPC activity to reduce carbon flux toward lipid to promote biomass synthesis. Both metal concentrations from Ca (5.86 mg/L), Mg (0.05 mg/L), Al (0.42 mg/L), and Cr (0.006 mg/L) and suitable pH (10.53) in AOD leaching solution at solid/liquid ratio of 0.5 g/L change carbon flow toward efficient lipid synthesis (47.07 wt%) by continuously providing raw materials and energy by regulating ACC, ME, and PEPC activities. High value‐added biodiesel with high concentrations of C16 and C18 methyl esters from lipid of C. pyrenoidosa is achieved, following other ecological and economic benefits including 197 mg CO2 captured and 2198 mg AOD applied with harmless. In this study, C. pyrenoidosa is cultured with elements from metallurgical slag solid waste, which promotes C. pyrenoidosa efficient carbon fixation to assist in carbon neutrality, and provides guidance for CO2 conversion to high‐value‐added products with low cost.

Abstract Postexercise blood pressure (BP) may be a better predictor of cardiovascular risk than office BP, but there is a lack of data supporting this claim. We hypothesized that postexercise BP may be an important prognostic marker. Our aim was to evaluate the association of postexercise BP with major adverse cardiovascular events (MACE) and all‐cause mortality. A total of 2581 participants (median age, 46 years; 55.9% women) from the Coronary Artery Risk Development in Young Adults study at year 20 (2005–2006) who underwent a graded exercise treadmill test using a modified Balke graded protocol were included. Postexercise BP was measured at baseline. Cox models were used to estimate the associations of postexercise BP with MACE and all‐cause mortality. Participants were followed up until December 31, 2021. In the entire population, postexercise systolic BP showed no significant association with MACE or all‐cause mortality, while postexercise diastolic BP was associated with MACE (hazard ratios [HR], 1.27 [95% CI, 1.06–1.52], per 10 mmHg increase) and all‐cause mortality (HR, 1.26 [95% CI, 1.05–1.51], per 10 mmHg increase). In the normal BP group, postexercise systolic BP was not significantly associated with MACE or all‐cause mortality, and postexercise diastolic BP was strongly associated with MACE (HR, 1.57 [95% CI, 1.18–2.09], per 10 mmHg increase). In this population‐based cohort study, postexercise diastolic BP was significantly associated with the risk of MACE and all‐cause mortality. Among individuals with normal BP, postexercise diastolic BP could identify those at a higher risk of cardiovascular events.

SRY‐box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell‐cycle‐arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFβ2–Smad2/3–p53–p21WAF1/CIP1–Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4–MAPK (JNK/ERK/p38)–ATF2 and WT1–ATF2 pathways, which is dependent on its high‐mobility group (HMG) domain. In addition, the SOX6‐induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT‐263 (navitoclax) and ABT‐199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6‐induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin‐resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1–ATF2–TGFβ2 axis mediates SOX6‐induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.

Abstract Background The aim of the present study was to compare the predictive accuracy of PD‐L1 immunohistochemistry (IHC), tissue or blood tumor mutation burden (tTMB, bTMB), gene expression profile (GEP), driver gene mutation, and combined biomarkers for immunotherapy response of advanced non‐small cell lung cancer (NSCLC). Methods In part 1, clinical trials involved with predictive biomarker exploration for immunotherapy in advanced NSCLC were included. The area under the curve (AUC) of the summary receiver operating characteristic (SROC), sensitivity, specificity, likelihood ratio and predictive value of the biomarkers were evaluated. In part 2, public datasets of immune checkpoint inhibitor (ICI)‐treated NSCLC involved with biomarkers were curated (N = 871). Odds ratio (OR) of the positive versus negative biomarker group for objective response rate (ORR) was measured. Results In part 1, the AUC of combined biomarkers (0.75) was higher than PD‐L1 (0.64), tTMB (0.64), bTMB (0.68), GEP (0.67), and driver gene mutation (0.51). Combined biomarkers also had higher specificity, positive likelihood ratio and positive predictive value than single biomarkers. In part 2, the OR of combined biomarkers of PD‐L1 plus TMB (PD‐L1 cutoff 1%, 0.14; cutoff 50% 0.13) was lower than that of PD‐L1 (cutoff 1%, 0.33; cutoff 50% 0.24), tTMB (0.28), bTMB (0.48), EGFR mutation (0.17) and KRAS mutation (0.47), for distinguishing ORR of patients after immunotherapy. Furthermore, positive PD‐L1, tTMB‐high, wild‐type EGFR, and positive PD‐L1 plus TMB were associated with prolonged progression‐free survival (PFS). Conclusion Combined biomarkers have superior predictive accuracy than single biomarkers for immunotherapy response of NSCLC. Further investigation is warranted to select optimal biomarkers for various clinical settings.

Objective Geographic defect reconstruction in load‐bearing bones presents formidable challenges for orthopaedic surgeon. The use of 3D‐printed personalized implants presents a compelling opportunity to address this issue. This study aims to design, manufacture, and evaluate 3D‐printed personalized implants with irregular lattice porous structures for geographic defect reconstruction in load‐bearing bones, focusing on feasibility, osseointegration, and patient outcomes. Methods This retrospective study involved seven patients who received 3D‐printed personalized lattice implants for the reconstruction of geographic defects in load‐bearing bones. Personalized implants were customized for each patient. Randomized dodecahedron unit cells were incorporated within the implants to create the porous structure. The pore size and porosity were analyzed. Patient outcomes were assessed through a combination of clinical and radiological evaluations. Tomosynthesis‐Shimadzu metal artifact reduction technology (T‐SMART) was utilized to evaluate osseointegration. Functional outcomes were assessed according to the Musculoskeletal Tumor Society (MSTS) 93 score. Results Multiple pore sizes were observed in porous structures of the implant, with a wide distribution range (approximately 300–900 um). The porosity analysis results showed that the average porosity of irregular porous structures was around 75.03%. The average follow‐up time was 38.4 months, ranging from 25 to 50 months. Postoperative X‐rays showed that the implants matched the geographic bone defect well. Osseointegration assessments according to T‐SMART images indicated a high degree of bone‐to‐implant contact, along with favorable bone density around the implants. Patient outcomes assessments revealed significant improvements in functional outcomes, with the average MSTS score of 27.3 (range, 26–29). There was no implant‐related complication, such as aseptic loosening or structure failure. Conclusion 3D‐printed personalized lattice implants offer an innovative and promising strategy for geographic defect reconstruction in load‐bearing bones. This approach has the potential to match the unique contours and geometry of the geographic bone defect and facilitate osteointegration.

Abstract Introduction Maternal stress and trauma during pregnancy have been shown to influence cortisol levels and epigenetic patterns, including DNA methylation, in the offspring. This study aimed to determine whether a tailor‐made family intervention could help reduce cortisol levels in children born to traumatized mothers, and to determine whether it effected offspring DNA methylation. The secondary aim was to determine whether the family intervention influenced DNA methylation aging, a marker of biological aging. Methods A needs‐based family intervention was designed to help address relational difficulties and family functioning, and included a focus on family strengths and problem‐solving patterns. Women survivors of sexual violence during the Kosovar war in 1998–1999, and their families (children with or without partners) were randomly assigned to 10 sessions of a family therapy over a 3–5‐month period, or to a waitlist control group. Both mothers and children completed assessments prior to and after the intervention phase. Children's blood samples collected at these two time points were used to measure cortisol and epigenome‐wide DNA methylation patterns (Illumina EPIC array). Cortisol levels, and genome‐wide DNA methylation changes pre‐/postintervention were compared between children in the intervention and the waitlist groups. DNA methylation age and accelerated biological aging were calculated. Results Sixty‐two women–child dyads completed the study, 30 were assigned first to the intervention group, and 32 to the waitlist control group. In adjusted linear regression, the family intervention was associated with a significant decline in cortisol levels compared to the waitlist control (β = −124.72, 95% confidence interval [CI]: −197.4 to −52.1, p = .001). Children in the intervention group, compared to the waitlist control group, showed >1% differential methylation degree at 5819 CpG (5'—C—phosphate—G—3') sites across the genome (p

Abstract In this letter, we address the problem of designing the joint waveform of radar detection, wireless communication and jamming. In the current most powerful filter‐bank multi‐carrier comb spectrum framework, a parameter‐agile time–frequency structure between symbols is elaborated to improve the uncertainty of waveform generation architecture. Furthermore, a novel composite modulation strategy that combines intra‐symbol chaos‐based radar frequency modulation and inter‐symbol chaos‐based phase modulation is proposed for a substantial jamming performance improvement. Simulation results verify that the proposed joint waveform produces a superior jamming performance while satisfying the requirements of radar detection and wireless communication.

Abstract Melatonin (N‐acetyl‐5‐methoxytryptamine) is reported to improve mood disorders in perimenopausal women and gut microbiome composition is altered during menopausal period. The possible role of microbiome in the treatment effect of melatonin on menopausal depression remains unknown. Here, it is shown that melatonin treatment reverses the gut microbiota dysbiosis and depressive‐like behaviors in ovariectomy (OVX) operated mice. This effect of melatonin is prevented by antibiotic cocktails (ABX) treatment. Transferring microbiota harvested from adolescent female mice to OVX‐operated mice is sufficient to ameliorate depressive‐like behaviors. Conversely, microbiota transplantation from OVX‐operated mice or melatonin‐treated OVX‐operated mice to naïve recipient mice exhibits similar phenotypes to donors. The colonization of Alistipes Inops, which is abundant in OVX‐operated mice, confers the recipient with depressive‐like behaviors. Further investigation indicates that the expansion of Alistipes Inops induced by OVX leads to the degradation of intestinal tryptophan, which destroys systemic tryptophan availability. Melatonin supplementation restores systemic tryptophan metabolic disorders by suppressing the growth of Alistipes Inops, which ameliorates depressive‐like behaviors. These results highlight the previously unrecognized role of Alistipes Inops in the modulation of OVX‐induced behavioral disorders and suggest that the application of melatonin to inhibit Alistipes Inops may serve as a potential strategy for preventing menopausal depressive symptoms.

Abstract Telemedicine has gained tremendous development during the COVID‐19 pandemic. With deblocking and opening, telemedicine accelerates the evolvution of the medical “snack community” and undermines the perception of medical students and staff, which promotes the incidence of psychosocial‐related disorders. Moreover, the inconsistent telemedicine adaptability between medical workers and patients aggravates the doctor–patient conflict due to the aging population and COVID‐19 squeal. Telemedicine is colliding with the national healthcare system, whose synchronization with conventional medical service is crucial to coordinate the relationship among medical payment, patient privacy and qualifications of clinicians. This study puts more emphasis on the double‐edged sword role of telemedicine in clinical practice and medical education during the COVID‐19 pandemic and beyond. Overall, while telemedicine has demonstrated its utility in health care throughout the COVID pandemic, it is pretty critical to continue evaluating the efficacy and limitations of telemedicine in order to maintain equal access to medical service and high‐quality medical education. A new concept as telemedicine‐medical “snack community”‐PHS ecosystem, where the psychological health education system and partners healthcare system with enough bandwidth, especially 5G technology, could optimize the effect of telemedicine on medical practice and education, is proposed.

Abstract Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) degeneration and vision loss. Since irreversible neurodegeneration occurs before diagnosable, early diagnosis and effective neuroprotection are critical for glaucoma management. Small extracellular vesicles (sEVs) are demonstrated to be potential novel biomarkers and therapeutics for a variety of diseases. In this study, it is found that intravitreal injection of circulating plasma‐derived sEVs (PDEV) from glaucoma patients ameliorated retinal degeneration in chronic ocular hypertension (COH) mice. Moreover, it is found that PDEV‐miR‐29s are significantly upregulated in glaucoma patients and are associated with visual field defects in progressed glaucoma. Subsequently, in vivo and in vitro experiments are conducted to investigate the possible function of miR‐29s in RGC pathophysiology. It is showed that the overexpression of miR‐29b‐3p effectively prevents RGC degeneration in COH mice and promotes the neuronal differentiation of human induced pluripotent stem cells (hiPSCs). Interestingly, engineered sEVs with sufficient miR‐29b‐3p delivery exhibit more effective RGC protection and neuronal differentiation efficiency. Thus, elevated PDEV‐miR‐29s may imply systemic regulation to prevent RGC degeneration in glaucoma patients. This study provides new insights into PDEV‐based glaucoma diagnosis and therapeutic strategies for neurodegenerative diseases.

Abstract Background Previous studies have shown that the red cell distribution width (RDW)/serum albumin ratio (RA) is an integrative and new inflammatory marker. RA is associated with clinical outcomes in a variety of diseases, but the clinical value of RDW/RA in the assessment of diabetic kidney disease (DKD) has not been elucidated. We examined the link between diabetic RA and DKD while controlling for a wide variety of possible confounders. Methods Retrospective cohort analysis of the National Health and Nutrition Examination Survey (NHANES: 2009–2018) database from the Second Affiliated Hospital and Yuying Children's Hospital and the Wenzhou Medical University (WMU) database was conducted. Multivariate logistic regression analysis was used to assess the association between RA and DKD. Results Overall, 4513 diabetic patients from the NHANES database (n = 2839) and the WMU (n = 1412) were included in this study; 974 patients were diagnosed with DKD in NHANES and 462 in WMU. In the NHANES cohort, diabetes mellitus (DM) patients with higher RA level had a higher risk of DKD (odds ratio = 1.461, 95% confidence interval: 1.250–1.707, p < 0.00001). After adjusting for confounders and propensity score‐matched (PSM) analysis, both shown RA levels were independently linked to DKD (pAdjust = 0.00994, pPSM = 0.02889). Similar results were also observed in the WMU cohort (p

Abstract Transformation optics (TO) provides a powerful tool to manipulate electromagnetic waves, enabling the design of invisibility cloaks, which can render objects invisible. Despite many years of research, however, invisibility cloaks experimentally realized thus far can only operate at a single frequency. The narrow bandwidth significantly restricts the practical applications of invisibility cloaks and other TO devices. Here, a general design strategy is proposed to realize a multiband anisotropic metamaterial characterized by two principal permittivity components, i.e., one infinite and the other spatially gradient. Through a proper transformation and combination of such metamaterials, an omnidirectional invisibility cloak is experimentally implemented, which is impedance‐matched to free space at multiple frequencies. Both far‐field numerical simulations and near‐field experimental mappings confirm that this cloak can successfully suppress scattering from multiple large‐scale objects simultaneously at 5 and 10 GHz. The design strategy and corresponding practical realization bring multiband transformation optical devices one step closer to reality.

Abstract The engineering of ferroic orders, which involves the evolution of atomic structure and local ferroic configuration in the development of next‐generation electronic devices. Until now, diverse polarization structures and topological domains are obtained in ferroelectric thin films or heterostructures, and the polarization switching and subsequent domain nucleation are found to be more conducive to building energy‐efficient and multifunctional polarization structures. In this work, a continuous and periodic strain in a flexible freestanding BaTiO3 membrane to achieve a zigzag morphology is introduced. The polar head/tail boundaries and vortex/anti‐vortex domains are constructed by a compressive strain as low as ≈0.5%, which is extremely lower than that used in epitaxial rigid ferroelectrics. Overall, this study c efficient polarization structures, which is of both theoretical value and practical significance for the development of next‐generation flexible multifunctional devices.

Abstract Few studies have reported the timing and amount of gestational weight gain (GWG) to prevent large‐for‐gestational‐age (LGA) or small‐for‐gestational‐age (SGA). This study aimed to evaluate the association of GWG velocity in each trimester with LGA or SGA based on data from the Taicang and Wuqiang cohort study (TAWS, n = 2008). We used a linear mixed model to evaluate the association of trimester‐specific GWG velocity with birthweight categories and stratified by prepregnancy body mass index category and parity. For normal‐weight pregnant women, mothers with LGA births had higher GWG velocities than mothers with appropriate‐for‐gestational‐age (AGA) births in the first trimester (0.108 vs. 0.031 kg/week, p

Abstract Common federated learning (FL) lacks consideration of clients' personalized requirements, which performs poorly for the scenario with data and resource heterogeneity. In order to overcome the challenge of heterogeneous characteristics, this letter proposes a novel decentralized personalized federated learning (PFL) architecture that first utilizes a directed acyclic graph (DAG) blockchain technology to achieve PFL efficiently, which is called PFLDAG. Simulation results demonstrate that PFLDAG approximately improves accuracy by 80% compared with the classic Google FedAvg algorithm, and by 10% compared with IFCA cluster PFL which considers personalized requirements. In addition, the approach also substantially improves the convergence speed.

Abstract Objective To assess the prevalence and factors associated with early cognitive impairment in intracerebral hemorrhage (ICH) patients and to describe short‐term recovery trajectories among ICH patients with early cognitive impairment. Methods We prospectively enrolled ICH patients without baseline dementia in our institutions. Cognitive function was assessed using mini‐mental state examination (MMSE), and functional outcome was evaluated at discharge, 3, and 6 months after symptoms onset using the modified Rankin Scale (mRS). We used multinomial logistic regression models to investigate potential risk factors and generalized linear models to analyze the functional outcome data. Results Out of 181 patients with ICH, 167 were included in the final analysis. Early cognitive impairment occurred in 60.48% of patients with ICH. Age (odds ratio [OR] per 1‐year increase, 1.037; 95% confidence interval [CI], 1.003–1.071; p = 0.034), National Institutes of Health Stroke Scale (NIHSS) score (OR per 1‐point increase, 1.146; 95% CI, 1.065–1.233; p

Abstract Objective To evaluate the effectiveness and safety of perampanel (PER) monotherapy (MT) or add‐on therapy (AT) in Chinese children with epilepsy, as well as to evaluate the data from routine therapeutic drug monitoring (TDM) of PER for these pediatric patients. Methods This retrospective and observational study was carried out on children with epilepsy (n = 340) from 2020 to 2022 at the Children's Hospital of Nanjing Medical University. Outcome measures were the responder rate (50% or greater seizure reduction), long‐term efficacy, and tolerability (number and types of adverse events) in MT and AT groups. Concentrations of plasma PER obtained from these patients, if available, were analyzed too. Results A total of 279 patients achieved at least 3 months of therapy, and 58.1% responded to PER therapy. 53 of the responders were seizure‐free (32.7%). The retention rate dropped from 88.0% at 3 months to 40.6% at 12 months after treatment. Patients with MT achieved better seizure control than those with AT (P < 0.001). Intriguingly, PER exerted a very weak effect on patients who took more than 2 ASMs or were diagnosed with drug‐resistant epilepsy. There were no significant differences in tolerability between the two groups. In addition, 179 patients were routinely monitored for PER, and the trough concentrations (C0) for these patients ranged from 30.0 to 992.0 ng/mL. However, no significant difference in C0 was observed between responders and nonresponders (333 ng/mL vs 325.5 ng/mL, P = 0.264). Significance This study provides effectiveness and safety data on Chinese children with epilepsy treated with PER either as MT or as AT. The efficacy of patients receiving MT was much better than cases administered with more than 2 ASMs or diagnosed with drug‐resistant epilepsy. In addition, no association was found between the plasma PER concentration and efficacy or safety. Plain Language Summary The study reports the effects of perampanel on seizures and adverse effects in Chinese patients with epilepsy younger than 18 years. Seizures decreased in 58.1% of patients (responders); in a third of these responders, seizures stopped. After treatment was started, 88% of patients were still on perampanel at 3 months and 40.6% at 12 months. People who were treated with perampanel only were more likely to respond than those who received perampanel and other antiseizure treatments, although perampanel was tolerated equally well in these groups. Plasma perampanel concentration did not predict seizure response or adverse effects.

Background Intercalary reconstruction for patients with short residual bone segments remains challenging. Three‐dimensional (3D)‐printed custom‐made porous implants are a promising technique for short‐segment fixation in these patients. This study aims to evaluate the efficiency of 3D‐printed custom‐made porous components (3DCPCs) for short‐segment fixation, focusing on prosthesis survivorship, radiographic results, and potential complications. Methods This retrospective study involved 39 patients who underwent intercalary prosthetic reconstruction with 3DCPCs after tumor resection of the femur, tibia, or humerus from June 2015 to October 2020. Segment bone loss involved the femur (n = 15), tibia (n = 16), and humerus (n = 8), leaving 78 residual bone segments. There were 46 short segments requiring 46 3DCPCs and 32 segments with the ability to accommodate 32 off‐the‐shelf standard uncemented stems for prosthesis fixation. Clinical and functional outcomes were evaluated. Prosthesis‐overall survivorship and prosthesis‐specific survivorship were analyzed using Kaplan–Meier survival analysis. Radiographic results and modes of failure of using this technique were also examined. Results The mean follow‐up was 41 months. The prosthesis‐overall survivorship was 87.2% and 84.6% at 2 and 5 years, respectively. The prosthesis‐specific survivorship was 92.1% and 89.5% at 2 and 5 years, respectively. There was not a substantial difference in prosthesis survivorship among the femur, tibia, and humerus. The average MSTS score was 26.2, ranging from 22 to 28. The radiographic evaluation results revealed excellent or good interface (38/46) in most of the 46 porous components. A total of 38 of 46 bone segments’ remolding demonstrated no change. In total, seven patients (16.3%) had complications requiring further surgery. Conclusion The prosthesis survivorship of using 3DCPCs for short‐segment fixation is similar or better compared to other studies involving intercalary prosthetic reconstruction with short‐segment fixation. Radiographic evaluation revealed good osteointegration and avoidance of stress shielding. Overall, intercalary prosthetic reconstruction with 3DCPC is a feasible modality for patients with short residual bone segments after tumor resection.

Abstract Although MXene has attracted great interest in diverse fields, it is susceptible to oxidation in water (H2O) with transition metal ions such as Co2+, Fe2+, and Cu2+, which is pronounced at high temperatures. This impedes the preparation of MXene‐based composites and their functional applications. Here, this study revealed that Co2+ increases the maximum and average atomic charge of H in H2O to improve the reactivity of H2O, which leads to the fact that Co2+ catalyzes the oxidation of Ti3C2Tx MXene. Furthermore, the addition of N,N‐dimethyl formamide (DMF) reduces the H2O activity and improves the oxidation stability of Ti3C2Tx in the presence of Co2+ via preferentially forming coordination bonds with Co2+. This strategy is also effective in enhancing the oxidation tolerance of Ti3C2Tx to Fe2+ in H2O. Moreover, it is feasible to enhance the oxidation stability of Ti2CTx MXene in H2O with the existence of Co2+. By virtue of these, the CoO/Ti3C2Tx composite was successfully prepared without obvious Ti3C2Tx oxidation, which is desirable to harness the advantages of Ti3C2Tx as the complementary component for lithium‐ion batteries. This work provides a straightforward paradigm to enhance the oxidation resistance of MXene in H2O in the presence of transition metal ions and at high temperatures, which opens a new vista to use MXene for target applications.

Background We aim to identify the distinct lesion patterns and regions associated with functional outcome and inflammation in patients with acute ischemic stroke, and investigate whether the association between lesion patterns and functional outcome was mediated by inflammation. Methods and Results We performed nonnegative matrix factorization to derived low‐dimensional lesion patterns (atoms), and Bayesian linear regression models were applied to explore the associations of lesion patterns with inflammatory factors including high‐sensitivity C‐reactive protein and interleukin‐6, as well as functional outcome (defined as modified Rankin Scale score at 3 months). The difference distribution mean and 95% highest probability density interval (HPDI) were calculated. Mediation analysis was used to examine the mediating effects of inflammation on the relationships between lesion patterns and functional outcome. Seven lesion patterns were derived from 5914 patients with acute ischemic stroke. Lesion patterns distributed in the cortical regions were associated with inflammatory response, including atom 1 (interleukin‐6: mean, 0.113 [95% HPDI, 0.073–0.162]; high‐sensitivity C‐reactive protein: mean, 0.082 [95% HPDI, 0.038–0.123]) and atom 4 (interleukin‐6: mean, 0.113 [95% HPDI, 0.071–0.167]; high‐sensitivity C‐reactive protein: mean, 0.108 [95% HPDI, 0.058–0.165]). These lesion patterns were also significantly associated with functional outcome (atom 1: mean, 1.958 [95% HPDI, 1.538–2.383]; atom 4: mean, 2.245 [95% HPDI, 1.773–2.741]). Mediation analysis suggested that interleukin‐6 explained 15.34% and 7.47% in the association of atom 1 and atom 4 with functional outcome, respectively. Conclusions Certain lesion patterns that are associated with both inflammation and functional outcome of acute ischemic stroke, especially cortical infarction, may play a role in functional outcome through modulating inflammatory reactions.

Abstract Background En‐Bloc transurethral resection of bladder tumor (ERBT) was clinically used to resect non‐muscle‐invasive bladder cancer (NMIBC). However, discrepancies persist regarding the comparisons between ERBT and conventional transurethral resection of bladder tumor (cTURBT). Methods We conducted a comprehensive search in PubMed, Embase, Web of Science, Cochrane Database of Systematic Reviews, and performed manual searches of reference lists to collect and extract data. Data evaluation was carried out using Review Manager 5.4.0, Rx64 4.1.3, and relevant packages. Results There were nine eligible meta‐analyses and nine eligible RCTs in our study. NMIBC patients undergoing ERBT were significant associated with a lower rate of bladder perforation and obturator nerve reflex compared to those receiving cTURBT. Our pooled result indicated that ERBT and cTURBT required similar operation time. Regarding postoperative outcomes, ERBT demonstrated superior performance compared to cTURBT in terms of detrusor muscle presence, catheterization time, and residual tumor. ERBT exhibited a higher rate of three‐month recurrence‐free survival (RFS) compared to those receiving cTURBT (p

Abstract Earthworms, long utilized in traditional medicine, serve as a source of inspiration for modern therapeutics. Lysenin, a defensive factor in the coelom fluid of the earthworm Eisenia fetida, has multiple bioactivities. However, the inherent toxicity of Lysenin as a pore‐forming protein (PFP) restricts its application in therapy. Here, a gene therapy strategy based on Lysenin for cancer treatment is presented. The formulation consists of polymeric nanoparticles complexed with the plasmid encoding Lysenin. After transfection in vitro, melanoma cells can express Lysenin, resulting in necrosis, autophagy, and immunogenic cell death. The secretory signal peptide alters the intracellular distribution of the expressed product of Lysenin, thereby potentiating its anticancer efficacy. The intratumor injection of Lysenin gene formulation can efficiently kill the transfected melanoma cells and activate the antitumor immune response. Notably, no obvious systemic toxicity is observed during the treatment. Non‐viral gene therapy based on Lysenin derived from Eisenia foetida exhibits potential in cancer therapy, which can inspire future cancer therapeutics.

Abstract Radical difunctionalization of aliphatic alkynes provides direct access to valuable multi‐substituted alkenes, but achieving a high level of chemo‐ and stereo‐control remains a formidable challenge. Herein a novel photoredox neutral alkyne di‐functionalization is reported through functional group migration followed by a radical‐polar crossover and energy transfer‐enabled stereoconvergent isomerization of alkenes. In this sequence, a hydroxyalkyl and an aryl group are incorporated concomitantly into an alkyne, leading to diversely functionalized E‐allyl alcohols. The scope of alkynes is noteworthy, and the reaction tolerates aliphatic alkynes containing hydrogen donating C─H bonds that are prone to intramolecular hydrogen atom transfer. The protocol features broad functional group compatibility, high product diversity, and exclusive chemo‐ and stereoselectivity, thus providing a practical strategy for the elusive radical di‐functionalization of unactivated alkynes.

Abstract Macrophage therapy for liver fibrosis is on the cusp of meaningful clinical utility. Due to the heterogeneities of macrophages, it is urgent to develop safer macrophages with a more stable and defined phenotype for the treatment of liver fibrosis. Herein, a new macrophage‐based immunotherapy using macrophages stably expressing a pivotal cytokine from Toxoplasma gondii, a parasite that infects ≈ 2 billion people is developed. It is found that Toxoplasma gondii macrophage migration inhibitory factor‐transgenic macrophage (Mφtgmif) shows stable fibrinolysis and strong chemotactic capacity. Mφtgmif effectively ameliorates liver fibrosis and deactivates aHSCs by recruiting Ly6Chi macrophages via paracrine CCL2 and polarizing them into the restorative Ly6Clo macrophage through the secretion of CX3CL1. Remarkably, Mφtgmif exhibits even higher chemotactic potential, lower grade of inflammation, and better therapeutic effects than LPS/IFN‐γ‐treated macrophages, making macrophage‐based immune therapy more efficient and safer. Mechanistically, TgMIF promotes CCL2 expression by activating the ERK/HMGB1/NF‐κB pathway, and this event is associated with recruiting endogenous macrophages into the fibrosis liver. The findings do not merely identify viable immunotherapy for liver fibrosis but also suggest a therapeutic strategy based on the evolutionarily designed immunomodulator to treat human diseases by modifying the immune microenvironment.

Abstract Background Latent tuberculosis infection (LTBI) often progresses to active tuberculosis, necessitating the development of novel vaccine to prevent LTBI. In this study, we aimed to design a Mycobacterium tuberculosis (M. tuberculosis) vaccine that could elicit a potent immune response to prevent LTBI. Methods We used bioinformatics and immunoinformatics techniques to develop a multi‐epitope vaccine (MEV) called C624P. The vaccine contained six cytotoxic T lymphocytes (CTL), two helper T lymphocytes (HTL), and four B‐cell epitopes derived from six antigens associated with LTBI and the Mycobacterium tuberculosis region of difference. We added Toll‐like receptor (TLR) agonists and PADRE peptide to the MEV to enhance its immunogenicity. We then analyzed the C624P vaccine's physical and chemical properties, spatial structure, molecular docking with TLRs, and immunological features. Results The C624P vaccine displayed good antigenicity and immunogenicity scores of 0.901398 and 3.65609, respectively. The vaccine structure was stable, with 42.82% α‐helix content, a Z‐value of −7.84, and a favored Ramachandran plot area of 85.84% after majorization. Molecular docking analysis showed that the C624P vaccine could bind tightly to TLR2 (−1011.0 kcal/mol) and TLR4 (−941.4 kcal/mol). Furthermore, the C624P vaccine effectively stimulated T and B lymphocytes, resulting in high levels of Th1 cytokines such as IFN‐γ and IL‐2. Conclusions The C624P vaccine represents a promising MEV for preventing LTBI. The vaccine's good antigenicity, immunogenicity, stability, and ability to activate immune responses suggest its effectiveness in preventing LTBI. Our study demonstrated the utility of bioinformatics and immunoinformatics techniques in designing safe and effective tuberculosis vaccines.

Abstract The importance of uncommon/rare oncogenic drivers in non‐small cell lung cancer (NSCLC) was underscored during the 20th China Lung Cancer Summit. These drivers, while present in a significant proportion of NSCLC patients, remain a challenge for diagnosis and therapeutic targeting. In the never‐smokers/low smokers category with mutations such as EGFR and HER2, the efficacy of immune checkpoint inhibitors (ICIs) remains suboptimal, attributed to lower PD‐L1 expression and tumor mutation burden (TMB). However, heavy smokers, often with mutations like KRAS, may derive benefits from ICIs, as supported by trials like CheckMate‐057. With the complex landscape of these drivers and their clinical implications, the summit culminated in six pivotal consensus points, aiming to guide future research and clinical decisions. Despite the advancements, the detection, interpretation, and therapeutic strategies involving these drivers necessitate further exploration and standardization.

Abstract This paper summarizes key features of the dose‐finding strategies used in the development of 11 approved new molecular entities that are first‐in‐class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose‐finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in in vitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose‐finding in early phase clinical studies in a well‐defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial. Two important considerations for successful dose selection include (1) identifying appropriate disease‐specific endpoints, including pharmacodynamic (PD) end points and intermediate clinical end points or clinical end points, and (2) designing a study with adequate treatment durations for evaluating these end points. Appropriately selected PD biomarkers is useful for dose selection, and early development of these biomarkers can facilitate the overall clinical development program. Optimization of ERT doses, as well as evaluations of patient intrinsic factors and/or immune tolerance strategies may be necessary to overcome antibody responses or increase efficacy in IEM.

Background Aseptic loosening is considered to be a rather uncommon complication in proximal humerus endoprosthetic replacement (PHER). However, patients with aseptic loosening often suffer severe bone loss, which poses a great challenge in following revision. Under this situation, a standard stemmed endoprosthesis is unavailable for revision limb salvage. Computer‐aided design and 3D‐printed personalized implants are an emerging solution for reconstructing complex bone defects. Case Presentation Here, we present a 67‐year‐old male who underwent PHER after tumor resection and developed aseptic loosening with severe periprosthetic osteolysis around the stem. Computer‐aided design and 3D‐printed personalized stem‐plate composite was used for the precision revision of this patient. During the follow‐up, encouraging results were observed, with good endoprosthetic stability and satisfactory limb function. Conclusion Computer‐aid design and 3D‐printed personalized stem‐plate composite used in the present case could help to achieve good endoprosthetic stability and satisfactory limb function. This 3D‐printed personalized stem‐plate composite seems to be an effective method for the precise revision of PHER in patients with severe periprosthetic osteolysis. In addition, it also provides a novel method for similar revision surgery of other joints or primary endoprosthetic replacement with severe bone defects.

Abstract The association of various air pollutants exposure during adolescence with blood pressure (BP) in young adulthood is uncertain. We intended to evaluate the long‐term association of individual and joint air pollutants exposure during adolescence with BP in young adulthood. This cross‐sectional study of incoming students was conducted in five geographically disperse universities in China during September and October 2018. Mean concentrations of particulate matter with diameters ≤2.5 μm (PM2.5), ≤10 μm (PM10), nitrogen dioxides (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3) at participants’ residential addresses during 2013–2018 were collected from the Chinese Air Quality Reanalysis dataset. Generalized linear mixed models (GLM) and quantile g‐computation (QgC) models were utilized to estimate the association between individual and joint air pollutants exposure and systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP). A total of 16,242 participants were included in the analysis. The GLM analyses showed that PM2.5, PM10, NO2, CO, and SO2 were significantly positively associated with SBP and PP, while O3 was positively associated with DBP. The QgC analyses indicated that long‐term exposure to a mixture of the six air pollutants had a significant positive joint association with SBP and PP. In conclusion, air pollutant co‐exposure during adolescence may influence BP in young adulthood. The findings of this study emphasized the impacts of multiple air pollutants interactions on potential health and the need of minimizing pollution exposures in the environment.

Abstract Background Evidence on the influence of programmed death‐ligand 1 (PD‐L1) expression on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) in EGFR‐mutant non‐small cell lung cancer (NSCLC) patients is at variance. Methods A single‐center retrospective study was conducted to evaluate the influence of PD‐L1 expression on the efficacy of EGFR‐TKIs for NSCLC patients with EGFR mutation. Clinical information was retrieved from electronic medical records. The patients were divided into three subgroups according to PD‐L1 expression level: PD‐L1

Abstract Background Osimertinib is the first‐line treatment for patients with epidermal growth factor receptor (EGFR) mutations, but the treatment options after drug resistance are limited. Previous studies have suggested that EGFR is in an immunosuppressive tumor immune microenvironment (TIME). However, the evolution of TIME after osimertinib resistance and whether this resistance can be overcome by targeting TIME needs to be further investigated. Methods The remodeling process and mechanism of TIME during the treatment with osimertinib were studied. Results The proportion of EGFRL858R+T790M mutant tumor immune infiltrating cells was extremely low. Osimertinib treatment transiently triggered inflammatory cells, but several immunosuppressive cells infiltrated after drug resistance and formed a myeloid‐derived suppressor cell (MDSC)‐enriched TIME. The programmed cell death protein‐1 monoclonal antibody was not able to reverse the MDSC‐enriched TIME. Further analysis revealed that the activation of nuclear factor‐kappa B (NF‐κB) and mitogen‐activated protein kinase (MAPK) pathways recruited a large number of MDSCs via cytokines. Finally, MDSC secreted high levels of interleukin‐10 and arginase‐1 and created an immunosuppressive TIME. Conclusions Thus, our findings lay the foundation for the evolution of TIME in osimertinib treatment, establish the mechanism of immunosuppressive TIME after osimertinib resistance, and propose potential solutions.

Abstract Background Surgical resection remains the primary treatment option for gallbladder carcinoma (GBC). However, there is a pressing demand for prognostic tools that can refine patients' treatment choices and tailor personalized therapies accordingly. Aims The nomograms were constructed using the data of a training cohort (n = 378) of GBC patients at Eastern Hepatobiliary Surgery Hospital (EHBH) between 2008 and 2018. The model's performance was validated in GBC patients (n = 108) at Guangzhou Centre from 2007 to 2018. Methods and results The 5‐year overall survival (OS) rate in the training cohort was 24.4%. Multivariate analyses were performed using preoperative and postoperative data to identify independent predictors of OS. These predictors were then incorporated into preoperative and postoperative nomograms, respectively. The C‐index of the preoperative nomogram was 0.661 (95% CI, 0.627 to 0.694) for OS prediction and correctly delineated four subgroups (5‐year OS rates: 48.1%, 19.0%, 15.6%, and 8.1%, p

Abstract Objective To investigate the risk factors for gastrointestinal perforation in metastatic colorectal cancer patients receiving bevacizumab. Methods We retrospectively reviewed 217 patients with metastatic colorectal cancer receiving bevacizumab to investigate the risk factors for gastrointestinal perforation. Three patients occurred intestinal perforation after receiving bevacizumab. We analyzed the clinical characteristics of three patients with intestinal perforation. Results All patients receiving bevacizumab. Three of 217 patients occurred intestinal perforation after receiving bevacizumab. Patient no. 1 was 70 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Patient no. 2 was 59 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation after receiving bevacizumab, and recovered smoothly after symptomatic treatment. Patient no. 3 was 60 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Conclusions Patients with advanced colorectal cancer receiving bevacizumab are at risk of gastrointestinal perforation. The patient's age, gender and history of bowel obstruction may be associated with gastrointestinal perforation.

There have been many M≥3.0 earthquakes in and around the Jiangling Depression in history, and the stress variation can directly affect the preparation of surrounding earthquakes. This paper innovatively uses the variation characteristics of Jingzhou well water level and GNSS data to analyze the stress variation in the Jiangling Depression. The results show that (1) the long-term decline trend of Jingzhou well water level has little correlation with rainfall and is mainly from deep source, which is different from the recharge source of the surrounding water system. The long-term decline trend of Jingzhou well water level is mainly affected by the tension state of the region. (2) The strain rate in the northern part of the study area is relatively high, and the tension state in the NNW direction is dominant. The slope of HBJM-HBJL stations baseline time series is positive, indicating that the NNW-SSE is in a tension state as a whole, which is consistent with the trend of Jingzhou well water level. (3) Jingzhou well water level and GNSS baseline time series have good synchronization, which directly reflects that the stress field in and around Jiangling Depression is in a state of tension in recent years. There have been many ≥ 3.0 earthquakes in and around the Jiangling depression in history. In the future, it is worth noting when the stress–strain state of the study area changes.