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Abstract Aims To investigate the efficacy of the integrated data platform of cloud hospital combined with dietary management for adults with type 2 diabetes. Materials and Methods We conducted a randomized controlled clinical trial. One hundred eighty patients with type 2 diabetes were randomly allocated into a control group (Group A) and an experimental group (Group B). Routine standard diabetes care was applied to the patients in Group A. The integrated data platform with dietary management was applied to Group B. Individualized diabetes education videos were sent to the patients through the platform. The primary endpoint was the change in HbA1c and change in body weight from baseline to Week 12 during the follow‐up. Results At Week 12, HbA1c was 7.4 ± 0.7%, 6.9 ± 0.9% in Groups A and B, P

Imperialist competitive algorithm (ICA) is an efficient meta-heuristic algorithm by simulating the competitive behaviour among imperialist countries. However, it still suffers from slow convergence and deficiency in exploration. To address these issues, an improved ICA is proposed by combining ICA with a quasi-opposition-based learning (QOBL) strategy, which is named QOBL-ICA. The improvements include two aspects. First, the QOBL strategy is adopted to generate a population of fitter individuals. Second, a QOBL-assisted assimilation strategy is proposed to enhance the exploration ability of ICA. As a result, the proposed QOBL-ICA has more powerful exploration ability than ICA as well as faster convergence speed. The effectiveness of the proposed QOBL-ICA is verified by testing on 20 benchmark functions and 3 engineering design problems. Experimental results show that the performance of QOBL-ICA is superior to most state-of-the-art meta-heuristic algorithms in terms of global optimum reached and convergence speed.

Abstract Background Pullorum disease is a serious problem in many countries. Caused by Salmonella enterica serovar Gallinarum biovar Pullorum (S. Pullorum), it creates huge economic losses in the poultry industry. Although pullorum disease has been well-controlled in many developed countries, it is still a critical problem in developing countries. However, there is still a lack of information on S. Pullorum strains isolated from different regions and sources in China. The objective of this study was to supply the antimicrobial resistance patterns and clonal relationships of S. Pullorum from breeder chicken farms. Methods In this study, a total of 114 S. Pullorum strains recovered from 11 provinces and municipalities in China between 2020 and 2021 were selected. These 114 S. Pullorum strains were analyzed using whole genome sequencing (WGS). Antimicrobial resistance (AMR) was tested both by genotypic prediction using the WGS method and using disc diffusion to assess phenotypic AMR. Results These 114 sequenced S. Pullorum strains were divided into three sequence types (STs), the dominant STs was ST92 (104/114). Further core genome multi-locus sequence typing analysis indicated that 114 S. Pullorum strains may have a close relationship, which could be clonally transmitted among different provinces and municipalities. Our results showed a close relationship between the S. Pullorum strains found in different regions, indicating these strains may have been transmitted in China a long time ago. Nearly all S. Pullorum strains 94.74% (n = 108) were resistant to at least one antimicrobial class, and 35.96% of the examined Salmonella strains were considered multiple drug resistant. Conclusion Overall, this study showed that S. Pullorum strains in China have a close genetic relationship in terms of antimicrobial resistance, suggesting widespread clonal transmission.

Abstract Background Intracerebral hemorrhage (ICH) is a severe form of stroke characterized by high incidence and mortality rates. Currently, there is a significant lack of effective treatments aimed at improving clinical outcomes. Our research team has developed a three-dimensional (3D) biological scaffold that incorporates Bergenin, allowing for the sustained release of the compound. Methods This 3D biological scaffold was fabricated using a combination of photoinitiator, GEMA, silk fibroin, and decellularized brain matrix (dECM) to encapsulate Bergenin through advanced 3D bioprinting techniques. The kinetics of drug release were evaluated through both in vivo and in vitro studies. A cerebral hemorrhage model was established, and a 3D biological scaffold containing Bergenin was transplanted in situ. Levels of inflammatory response, oxidative stress, and apoptosis were quantified. The neurological function of rats with cerebral hemorrhage was assessed on days 1, 3, and 5 using the turning test, forelimb placement test, Longa score, and Bederson score. Results The 3D biological scaffold incorporating Bergenin significantly enhances the maintenance of drug concentration in the bloodstream, leading to a marked reduction in inflammatory markers such as IL-6, iNOS, and COX-2 levels in a cerebral hemorrhage model, primarily through the inhibition of the NF-κB pathway. Additionally, the scaffold effectively reduces the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in primary cultured astrocytes, which in turn decreases the production of reactive oxygen species (ROS) and inhibits IL-6 production induced by hemin. Subsequent experiments reveal that the 3D biological scaffold containing Bergenin promotes the activation of the Nrf-2/HO-1 signaling pathway, both in vivo and in vitro, thereby preventing cell death. Moreover, the application of this 3D biological scaffold has been demonstrated to improve drug retention in the bloodstream. Conclusion This strategy effectively mitigates inflammation, oxidative stress, and cell death in rats with cerebral hemorrhage by inhibiting the NF-κB pathway while concurrently activating the Nrf-2/HO-1 pathway.

Abstract Rosacea is a chronic inflammatory skin disease that typically affects the central facial area. Its main clinical symptoms include paroxysmal flushing, telangiectasia, and non-temporary erythema. Cell-free adipose tissue extracts (ATEs) are liquid components extracted from human adipose tissue that contain large amounts of growth factors. Despite the scar-reducing, anti-aging, and wound-healing effects of ATEs, the efficacy of ATEs in rosacea remains unknown. Therefore, the anti-rosacea effects of ATEs were investigated in human cathelicidin peptide (LL-37) induced rosacea mice and capsaicin (CAP)-stimulated HaCaT keratinocytes. In vitro, ATEs significantly reduced TRPV1 expression, intracellular calcium ions influx and the release of inflammatory factors (such as KLK5, IL-6, IL-8 and TNF-α) after intervening in CAP-stimulated cells. The in vivo results revealed that ATEs alleviated rosacea symptoms, such as erythema score, erythema area, transepidermal water loss, abnormal epidermal thickness, mast cell infiltration and telangiectasia upon downregulating TRPV1 and CD31 expression. Moreover, the up-regulated TRPV1 protein expression was also recovered by ATEs administration in vivo and in vitro. Meanwhile, ATEs demonstrated good biocompatibility. In summary, ATEs could be a potential therapeutic agent for rosacea by regulating inflammation and alleviating telangiectasia.

Abstract Background Child dental anxiety is a prevalent issue in the field of pediatric dentistry. At present, several non-pharmacological interventions are employed to mitigate anxiety during dental treatments for children. The objective of this study is to assess the effectiveness of diverse non-pharmacological interventions in reducing dental anxiety, as well as enhancing heart rate during pediatric dental treatments. To achieve this, we conducted a systematic review and a network meta-analysis (NMA) to compare the efficacy of various outcome indicators. Methods A thorough search was conducted in the databases of PubMed, Embase, Web of Science, Cochrane Library, Scopus, APA PsycInfo, CINAHL, and AMED to identify all eligible randomized controlled trials (RCTs) from the beginning of the databases up to August 1, 2024. The quality assessment was carried out using the Cochrane Collaboration’s bias risk tool. The two outcome measures under consideration were dental anxiety and heart rate. Network graphs, league tables and SUCRA were constructed using R 4.2.3 software and Stata 16 software. This study is registered in PROSPERO under the registration number CRD42023467610. Results The study examined 12 different non-pharmacological approaches, drawing from a pool of 61 research studies involving 6,113 participants aged 4 to 16 years. The results of the network meta-analysis revealed that music (SUCRAs: 93.60%) proved to be the most effective measure in mitigating dental anxiety, followed by aromatherapy (SUCRAs: 78.58%) and game (SUCRAs: 70.99%). Moreover, hypnosis (SUCRAs: 98.80%), music (SUCRAs: 79.58%), and relaxation (SUCRAs: 72.41%) were identified as the top three interventions for decreasing heart rate. Conclusion In this NMA, when contemplating dental anxiety outcomes, music is recommended as a priority. For heart rate outcomes, hypnosis may be a preferred measure. However, owing to the limited number of articles, the conclusion of this study still requires additional confirmation or correction through more high-quality primary studies in the future.

This paper investigates the attitude tracking control problem for the cruise mode of a dual-system convertible unmanned aerial vehicle (UAV) in the presence of parameter uncertainties, unmodeled uncertainties and wind disturbances. First, a fixed-time disturbance observer (FXDO) based on the bi-limit homogeneity theory is designed to estimate the lumped disturbance of the convertible UAV model. Then, a fixed-time integral sliding mode control (FXISMC) is combined with the FXDO to achieve strong robustness and chattering reduction. Bi-limit homogeneity theory and Lyapunov theory are applied to provide detailed proof of the fixed-time stability. Finally, numerical simulation experimental results verify the robustness of the proposed algorithm to model parameter uncertainties and wind disturbances. In addition, the proposed algorithm is deployed in a open-source UAV autopilot and its effectiveness is further demonstrated by hardware-in-the-loop experimental results.

Platelet-rich plasma (PRP) has the capability of assisting in the recovery of damaged tissues by releasing a variety of biologically active factors to initiate a hemostatic cascade reaction and promote the synthesis of new connective tissue and revascularization. It is now widely used for tissue engineering repair. In addition, PRP has demonstrated nerve repair and pain relief, and has been studied and applied to the facial nerve, median nerve, sciatic nerve, and central nerve.These suggest that PRP injection therapy has a positive effect on nerve repair. This indicates that PRP has high clinical value and potential application in nerve repair. It is worthwhile for scientists and medical workers to further explore and study PRP to expand its application in nerve repair, and to provide a more reliable scientific basis for the opening of a new approach to nerve repair.

This paper presents a systematic methodology for analyzing and optimizing an innovative antenna mount designed for phased array antennas, implemented through a novel 2-PSS&1-RR circular-rail parallel mechanism. Initially, a comparative motion analysis between the 3D model of the mount and its full-scale prototype is conducted to validate effectiveness. Given the inherent complexity, a kinematic mapping model is established between the mount and the crank-slider linkage, providing a guiding framework for subsequent analysis and optimization. Guided by this model, feasible inverse and forward solutions are derived, enabling precise identification of stiffness singularities. The concept of singularity distance is thus introduced to reflect the structural stiffness of the mount. Subsequently, also guided by the mapping model, a heuristic algorithm incorporating two backtracking procedures is developed to reduce the mount's mass. Additionally, a parametric finite-element model is employed to explore the relation between singularity distance and structural stiffness. The results indicate a significant reduction (about 16%) in the antenna mount's mass through the developed algorithm, while highlighting the singularity distance as an effective stiffness indicator for this type of antenna mount.

Abstract Pressure ulcers (PU) are caused by persistent long-term pressure, which compromises the integrity of the epidermis, dermis, and subcutaneous adipose tissue layer by layer, making it difficult to heal. Platelet products such as platelet lysate (PL) can promote tissue regeneration by secreting numerous growth factors based on clinical studies on skin wound healing. However, the components of PL are difficult to retain in wounds. Gelatin methacrylate (GelMA) is a photopolymerizable hydrogel that has lately emerged as a promising material for tissue engineering and regenerative medicine. The PL liquid was extracted, flow cytometrically detected for CD41a markers, and evenly dispersed in the GelMA hydrogel to produce a surplus growth factor hydrogel system (PL@GM). The microstructure of the hydrogel system was observed under a scanning electron microscope, and its sustained release efficiency and biological safety were tested in vitro. Cell viability and migration of human dermal fibroblasts, and tube formation assays of human umbilical vein endothelial cells were applied to evaluate the ability of PL to promote wound healing and regeneration in vitro. Real-time polymerase chain reaction (PCR) and western blot analyses were performed to elucidate the skin regeneration mechanism of PL. We verified PL’s therapeutic effectiveness and histological analysis on the PU model. PL promoted cell viability, migration, wound healing and angiogenesis in vitro. Real-time PCR and western blot indicated PL suppressed inflammation and promoted collagen I synthesis by activating STAT3. PL@GM hydrogel system demonstrated optimal biocompatibility and favorable effects on essential cells for wound healing. PL@GM also significantly stimulated PU healing, skin regeneration, and the formation of subcutaneous collagen and blood vessels. PL@GM could accelerate PU healing by promoting fibroblasts to migrate and secrete collagen and endothelial cells to vascularize. PL@GM promises to be an effective and convenient treatment modality for PU, like chronic wound treatment.

Abstract Episyrphus balteatus can provide dual ecosystem services including pest control and pollination, which the larvae are excellent predators of aphid pest whereas adults are efficient pollinator. In this study, we assembled a high-quality genome of E. balteatus from northern China geographical population at the chromosome level by using Illumina, PacBio long reads, and Hi-C technologies. The 467.42 Mb genome was obtained from 723 contigs, with a contig N50 of 9.16 Mb and Scaffold N50 of 118.85 Mb, and 90.25% (431.75 Mb) of the assembly was anchored to 4 pseudo-autosomes and one pseudo-heterosome. In total, 14,848 protein-coding genes were annotated, and 95.14% of genes were fully represented in NR, GO, KEGG databases. Besides, we also obtained the mitochondrial genome of E. balteatus of 16, 837 bp in length with 37 typical mitochondrial genes. Overall, this high-quality genome is valuable for evolutionary and genetic studies of E. balteatus and other Syrphidae hoverfly species.

Abstract Necrotizing enterocolitis (NEC) involves intestinal epithelial damage and inflammatory response and is associated with high morbidity and mortality in infants. To improve therapeutic prospects, elucidating underlying molecular mechanisms of intestinal epithelial damage during NEC is of the essence. Poly (ADP-ribose) polymerase 1 (PARP1)-dependent parthanatos is a programmed inflammatory cell death. In the present study, the presence of parthanatos-associated proteins PARP1 and poly (ADP-ribose) (PAR), along with high expression of DNA damage-associated biomarkers, 8-hydroxy-2’-deoxyguanosine (8-OHdG) and phosphorylation of histone H2AX (γH2AX), were discovered in the intestinal tissues of NEC infants. Additionally, the upregulated expression of PARP1 and PAR in NEC intestinal tissues correlated distinctly with clinical indices indicative of NEC incidence and severity. Furthermore, we demonstrated that inhibiting the expression of parthanatos-associated proteins, by either pharmacological blockage using 3-aminobenzamide (3-AB), an inhibitor of PARP1, or genetic knockout using Parp1-deficient mice, resulted in substantial improvements in both histopathological severity scores associated with intestinal injury and inflammatory reactions. Moreover, in an in vitro NEC model, reactive oxygen species (ROS)-induced DNA damage promoted the formation of PAR and nuclear translocation of apoptosis-inducing factor (AIF), thus activating PARP1-dependent parthanatos in Caco-2 cells and human intestinal organoids. Our work verifies a previously unexplored role for parthanatos in intestinal epithelial damage during NEC and suggests that inhibition of parthanatos may serve as a potential therapeutic strategy for intervention of NEC.

Abstract Background Addressing presbyopia in the aging population, particularly in non-cataractous patients, remains a challenge. This study evaluates the outcomes of refractive lens exchange (RLE) with AT LISA tri 839MP trifocal intraocular lens (IOL) implantation in a Chinese presbyopic population without cataracts. Methods The study included 164 eyes from 82 patients undergoing bilateral RLE at Peking Union Medical College Hospital. Comprehensive evaluations encompassed visual acuities, refraction, ocular aberrometry, and subjective outcomes via the VF-14 questionnaire. The focus was on postoperative visual performance, refractive outcomes, safety, objective optical quality, and patient satisfaction. Results 100%, 90.2%, and 89.0% of patients achieved binocular UDVA, UNVA, and UIVA of logMAR 0.1 or better at 6 months postoperatively. 97.6% of eyes were within ± 1.00 D of emmetropia postoperatively. Optical quality assessments showed increases in modulation transfer function and Strehl ratios (p

Approximately 50% of patients with non-small-cell lung cancer (NSCLC) are diagnosed at advanced stages and face a challenging prognosis despite the integration of targeted therapies, immunotherapy, and systemic chemotherapy into current standard care. A key factor in this context is trophoblast cell-surface antigen 2 (TROP2), which is widely expressed in NSCLC and strongly associated with poor patient outcomes. This article examines the latest developments in the application of datopotamab deruxtecan (Dato-DXd, DS-1062), a novel antibody-drug conjugate targeting TROP2, in the treatment of NSCLC. It provides a detailed assessment of Dato-DXd’s technical design, evaluates its efficacy by using recent clinical trial data, and discusses its safety profile.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusion : s: In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Abstract Background the mortality associated with severe malaria due to Plasmodiun falciparum remains high despite improvements in malaria management. Case prensentation: this case series aims to describe the efficacy and safety of the exchange transfusion combined with artesunate (ET-AS) regimen in severe P. falciparum malaria. Eight patients diagnosed with severe P. falciparum malaria were included. All patients underwent ET using the COBE Spectra system. The aimed for a post-exchange hematocrit of 30%. Half the estimated blood volume was removed and replaced using fresh frozen plasma. The regimen was well-tolerated without complications. The parasite clearance time ranged from 1 ~ 5 days. Five patients with cerebral malaria exhibited full improved consciousness within 3 days, while patient2 with hemolysis improved on day 2. Liver function improved within 1 ~ 6 days, and patient 1 and patient 6 showed improvements renal function on days 18 and 19, respectively. The length of intensive care unit stay range from 2 ~ 10 days, and all patients treated with ET-AS remained in the hospital for 3 ~ 19 days. Conclusions: these preliminary results suggest that ET-AS regimens are a safe and effective therapy for severe P. falciparum malaria and can benefit patients in clinical settings.

Abstract Realizing spin transport between heavy metal and two‐dimensional (2D) magnetic materials at high Curie temperature (TC) is crucial to advanced spintronic information storage technology. Here, environmentally stable 2D nonlayered Fe3O4 nanosheets are successfully synthesized using a reproducible process and found that they exhibit vortex magnetic domains at room temperature. A Verwey phase transition temperature (TV) of ≈110 K is identified for ≈3 nm thick nanosheet through Raman characterization and spin Hall device measurement of the Pt/Fe3O4 bilayer. The anisotropic magnetoresistance ratio decreases near TV, while both the spin Hall magnetoresistance ratio and spin mixing conductance (Gr) increase at TV. As the temperature approaches 112 K, the anomalous Hall effect ratio tends to become zero. The maximum Gr reaches ≈5 × 1015 Ω−1m−2 due to the clean and flat interface between Pt and 2D nanosheet. The observed spin transport behavior in Pt/Fe3O4 spin Hall devices indicates that 2D Fe3O4 nanosheets possess potential for high‐power micro spintronic storage devices applications.

ObjectiveTo evaluate the diagnostic value of metagenomic next-generation sequencing (mNGS) in pulmonary cryptococcosis (PC) using bronchoalveolar lavage fluid (BALF) and lung biopsy tissue specimens.MethodsIn this retrospective study, 321 patients diagnosed with lower respiratory tract diseases who underwent mNGS using BALF and LBT samples, between January 2021 and December 2023 were included. Individuals were classified into PC and non-PC groups according to the diagnostic criteria for PC, and conventional fungal cultures were performed. A serum/BALF cryptococcal antigen (CrAg) test was performed in some patients with PC. The diagnostic efficiencies of three methods for PC (mNGS, conventional culture, and CrAg) were compared. Additionally, two mNGS methods were used in this study: original mNGS (OmNGS, testing time from January 2021 to December 2022) and modified mNGS (MmNGS, testing time from January to December 2023). The diagnostic efficiency of the two mNGS methods on PC was simultaneously compared.ResultsAmong the 321 patients, 23 (7.2%) had PC and 298 (92.8%) did not. Compared with the composite reference standard for PC diagnosis, the sensitivity, specificity, and accuracy of mNGS for PC were 78.3% (95% confidence interval [CI], 55.8%–91.7%), 98.7% (95% CI, 96.4%–99.6%), and 97.2% (95% CI, 94.7%–98.7%), respectively. The sensitivity of mNGS was similar to that of CrAg (80.0%, 12/15) (P > 0.05). The diagnostic sensitivity of both mNGS and CrAg was higher than that of conventional culture (35.0%, 7/20) (P = 0.006, P = 0.016), and the combined detection of mNGS and CrAg further improved the diagnostic sensitivity of PC (93.3%, 14/15). The area under the receiver operating characteristic curve of mNGS was superior to that of conventional culture (0.885 vs. 0.675). In addition, the diagnostic sensitivity of PC was higher than that of OmNGS (P = 0.046).ConclusionThe sensitivity of mNGS is better than that of conventional culture. The combination of mNGS and CrAg improves the testing sensitivity of Cryptococcus. MmNGS could further improve the detection of Cryptococcus. Conventional PC detection methods are indispensable and mNGS can be used as a rapid and accurate auxiliary diagnostic method for PC.

ABSTRACT Background Immune checkpoint inhibitors (ICIs) have drastically shifted the current landscape toward a wide variety of malignancies. However, ICIs are interrupted owing immune‐related adverse events (irAEs), therapy completion, and disease progression. The risk–benefit of rechallenged ICIs remains inconclusive. Herein, a systematic review and meta‐analysis were conducted to evaluate the safety and efficacy of ICI rechallenge in the treatment of advanced solid tumor. Methods PubMed, Web of Science, Embase, and Cochrane Library were searched to analyze the efficacy and safety of ICI rechallenge. The study protocol was approved by the PROSPERO International Register of Systematic Reviews (CRD42022372222). The last updated search date was March 2, 2024. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence rates of all‐ and high‐grade irAEs were evaluated. Results A total of 41 retrospective studies comprising 2343 patients were ultimately enrolled for qualitative and quantitative assessments. A total of 1200 (51.2%) individuals were male and the median age was 66 years (range 18–97 years). The majority of the tumors was lung cancer (n = 898, 38.3%). The occurrence rates of all‐grade and high‐grade (grade 3 or 4) irAEs between initial and readministration ICIs were not significantly different (all‐grade: OR, 0.75, 95% CI: 0.39–1.45, p = 0.40; I2 = 87%; high‐grade: OR, 0.96, 95% CI: 0.62–1.49, p = 0.87, I2 = 65%). ICIs restart presented a decreased ORR and DCR compared to initial ICI administration (ORR: OR, 0.36, 95% CI: 0.23–0.56, p

ObjectiveThe aim of this study was to enhance the precision of categorization of endometrial lesions in ultrasound images via a data enhancement framework based on deep learning (DL), through addressing diagnostic accuracy challenges, contributing to future research.Materials and methodsUltrasound image datasets from 734 patients across six hospitals were collected. A data enhancement framework, including image features cleaning and soften label, was devised and validated across multiple DL models, including ResNet50, DenseNet169, DenseNet201, and ViT-B. A hybrid model, integrating convolutional neural network and transformer architectures for optimal performance, to predict lesion types was developed.ResultsImplementation of our novel strategies resulted in a substantial enhancement in model accuracy. The ensemble model achieved accuracy and macro-area under the receiver operating characteristic curve values of 0.809 of 0.911, respectively, underscoring the potential for use of DL in endometrial lesion ultrasound image classification.ConclusionWe successfully developed a data enhancement framework to accurately classify endometrial lesions in ultrasound images. Integration of anomaly detection, data cleaning, and soften label strategies enhanced the comprehension of lesion image features by the model, thereby boosting its classification capacity. Our research offers valuable insights for future studies and lays the foundation for creation of more precise diagnostic tools.

When readers encounter information conflicting with the predictive inferences made earlier, they may update the outdated ones with new ones, a process known as predictive inference revision. The current study examined the revision of disconfirmed predictive inferences by the primarily weakly activated, thus low-competitive inference alternatives during Chinese narrative text reading among Chinese native speakers. We conducted an event-related brain potential (ERP) experiment to study the predictive inference revision with increasingly supportive information for the low-competitive predictive inference alternatives. It serves as the very first attempts to study the predictive inference revision mechanisms by combining a larger range of ERP components, including frontal-Post-N400-Positivity (f-PNP) as an index of revision to examine the influences of the alternative inferences at later stages of reading comprehension. Our results showed that readers could detect inconsistent information (P300), disconfirm the incorrect predictive inferences before successfully integrating the low-competitive alternative predictive inferences with their current situation model (N400), engaging themselves in a second-pass reanalysis process incurring processing costs (P600), and revising the disconfirmed predictive inferences (f-PNP) at a later stage of reading comprehension. Results of this study are supportive of relevant theories in assuming that predictive inference revision does not happen immediately upon encountering conflicting information but happens slowly and incrementally. Our results also unfold the post-revision mechanisms by suggesting the remaining activation and lingering influences of the disconfirmed inferences in the forthcoming reading process.

Oxidative stress during sepsis could play a crucial role in the pathogenesis of several diseases, especially cardiovascular disorders. In fact, myocardial dysfunction during sepsis is caused by a number of chemicals, one of which is hydrogen peroxide (H2O2). Therefore, sepsis‐induced cardiomyopathy can be controlled through modulation of oxidative stress. Despite the encouraging pharmacological activities demonstrated by inorganic nanostructures, the mechanisms behind their blood protein interaction and antioxidant activity remain unclear. In order to advance the investigation for fabricating nanostructure platforms and studying their antioxidant effects as well as blood protein binding affinities, we explored the synthesis of manganese oxide (Mn3O4) nanorods via hydrothermal method and subsequent characterization using various techniques. The antioxidant effects against H2O2-induced oxidative stress in AC16 cardiomyocytes were then evaluated by different cellular and molecular assays. Additionally, the interaction of Mn3O4 nanorods with hemoglobin was investigated by experimental and and docking analyses. The results showed that synthesized Mn3O4 nanorods had an absorption peak in the range of 260 to 420 nm, vibration bands centered at 510 cm−1, 629 cm−1 and 410 cm−1, 13 distinct XRD peaks, a rod-like morphology with a diameter range of 10 to 75 nm, a hydrodynamic size of 371.7 nm, and a zeta potential of −43.3 mV. Moreover, the antioxidant assays indicated that synthesized Mn3O4 nanorods can trigger a protective effect against H2O2-induced oxidative stress in AC16 cardiomyocytes through inhibition of reactive oxygen species (ROS) overproduction, increased content of superoxide dismutase (SOD) and catalase and glutathione (GSH), and reduction of caspase-3 activity. Furthermore, the fluorescence quenching mechanism of hemoglobin by Mn3O4 nanorods was determined to be controlled by a spontaneous and static quenching process, involvement of hydrogen bonds, a binding affinity (Kb) value of 104 M−1, and number of binding site (n) of around 1.03. Additionally, it was found that Mn3O4 nanorods induced a slight conformational change in the hemoglobin structure, where Tyr35 and Trp37 move to a hydrophilic microenvironment. In conclusion, it can be suggested that Mn3O4 nanorods with a reasonable plasma protein binding affinity can be used as an antioxidant co-therapy in cardiac dysfunction during sepsis.

Pragmatic impairment has become a critical aspect of language development in autistic children and has gained significant academic attention over the past two decades. This study leverages bibliometric methods to conduct an exhaustive analysis of literature derived from Web of Science database. Utilizing CiteSpace software, we construct a knowledge map to dissect the academic hotspots in research related to pragmatic impairment in autistic children. This enables us to delineate the evolutionary trajectory of this research domain, analyze the prevailing research dimensions, and anticipate potential future dimensions. Our findings indicate that research hotspots in this field over the past two decades predominantly concentrate on assessing and diagnosing pragmatic impairment in autistic children, intervention strategies, and theory of mind. The research scope on pragmatic impairment in autistic children has progressively broadened and deepened. Research has evolved from initial descriptions and interpretations of autism to exploring the theory of mind in high-functioning, school-aged children. The current emphasis is on examining the specific skills that these children possess.

IntroductionSymbiotic bacteria play key roles in a variety of important life processes of insects such as development, reproduction and environmental adaptation, and the elucidation of symbiont population structure and dynamics is crucial for revealing the underlying regulatory mechanisms. The marmalade hoverfly (Episyrphus balteatus) is not only a remarkable aphid predator, but also a worldwide pollinator second to honeybees. However, its symbiont composition and dynamics remain unclear.MethodsHerein, we investigate the symbiotic bacterial dynamics in marmalade hoverfly throughout whole life cycle, across two sexes, and in its prey Megoura crassicauda by 16S rRNA sequencing.ResultsIn general, the dominant phyla were Proteobacteria and Firmicutes, and the dominant genera were Serratia and Wolbachia. Serratia mainly existed in the larval stage of hoverfly with the highest relative abundance of 86.24% in the 1st instar larvae. Wolbachia was found in adults and eggs with the highest relative abundance of 62.80% in eggs. Significant difference in species diversity was observed between the adults feeding on pollen and larvae feeding on M. crassicauda, in which the dominant symbiotic bacteria were Asaia and Serratia, respectively. However, between two sexes, the symbionts exhibited high similarity in species composition. In addition, our results suggested that E. balteatus obtainded Serratia mainly through horizontal transmission by feeding on prey aphids, whereas it acquired Wolbachia mainly through intergeneration vertical transmission. Taken together, our study revealed the effects of development stages, diet types and genders of E. balteatus on symbionts, and explored transmission modes of dominant bacteria Serratia and Wolbachia.DiscussionOur findings lay a foundation for further studying the roles of symbiotic bacteria in E. balteatus life cycle, which will benefit for revealing the co-adaptation mechanisms of insects and symbiotic bacteria.

Nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) and nicotinamide adenine dinucleotide phosphate (NADP+)/reduced NADP+ (NADPH) are essential metabolites involved in multiple metabolic pathways and cellular processes. NAD+ and NADH redox couple plays a vital role in catabolic redox reactions, while NADPH is crucial for cellular anabolism and antioxidant responses. Maintaining NAD(H) and NADP(H) homeostasis is crucial for normal physiological activity and is tightly regulated through various mechanisms, such as biosynthesis, consumption, recycling, and conversion between NAD(H) and NADP(H). The conversions between NAD(H) and NADP(H) are controlled by NAD kinases (NADKs) and NADP(H) phosphatases [specifically, metazoan SpoT homolog-1 (MESH1) and nocturnin (NOCT)]. NADKs facilitate the synthesis of NADP+ from NAD+, while MESH1 and NOCT convert NADP(H) into NAD(H). In this review, we summarize the physiological roles of NAD(H) and NADP(H) and discuss the regulatory mechanisms governing NAD(H) and NADP(H) homeostasis in three key aspects: the transcriptional and posttranslational regulation of NADKs, the role of MESH1 and NOCT in maintaining NAD(H) and NADP(H) homeostasis, and the influence of the circadian clock on NAD(H) and NADP(H) homeostasis. In conclusion, NADKs, MESH1, and NOCT are integral to various cellular processes, regulating NAD(H) and NADP(H) homeostasis. Dysregulation of these enzymes results in various human diseases, such as cancers and metabolic disorders. Hence, strategies aiming to restore NAD(H) and NADP(H) homeostasis hold promise as novel therapeutic approaches for these diseases.

As one of the high-demand horticultural crops, chili peppers have a significant impact on the economy of Indonesia. However, despite the growing demand and interest in chili peppers, their production often faces disruptions due to crop failures. One of the leading causes of such failures is pests and diseases. Among all parts of the chili plant, chili leaves are the most susceptible to damage. Distinguishing between healthy and unhealthy chili leaves can serve as an early detection step for chili diseases and preventive measures to contain their spread. Convolutional Neural Network (CNN) are effective algorithms for image classification. The development of CNN has led to the use of models previously trained on large datasets to accurately classify relatively small datasets. One such pretrained model known for its exceptional classification capabilities is Xception. By utilizing the pretrained Xception model trained on the ImageNet dataset for the classification of healthy and unhealthy chili leaf images, our model achieved an accuracy of 91% on a dataset containing 2136 images. Furthermore, the model achieved a 100% success rate by correctly predicting all 10 out of 10 given images.

Abstract Gaussian bare-bone imperialist competitive algorithm (GBB-ICA) is an effective variant of imperialist competitive algorithm (ICA), which updates the position of colonies by sampling a Gaussian distribution. However, the mean and standard deviation adopted by GBB-ICA is calculated only using the positions of imperialist and the colony itself, making the searching tends to trap into local optimum. To overcome this drawback, a new double Gaussian sampling strategy is proposed in this paper. An extra Gaussian sampling point, whose mean and standard is calculated using the positions of the second best colony and the current colony itself, is introduced into GBB-ICA. To further speed up the convergence and explore informative region, the quasi-oppositional learning technique is incorporated into GBB-ICA to produce more potential candidates in the assimilation step as well as generating a higher quality initial population. The proposed algorithm is called quasi-oppositional learning-based double Gaussian sampling bare-bone imperialist competitive algorithm (QOLBDGSBB-ICA) and is tested on 20 benchmark functions and four engineering design problems. Experimental results show that the proposed algorithm outperforms over other referenced ICA variants on 19 benchmark functions, which well validates the effectiveness of the proposed algorithm.

Abstract Limited information is available on the cardiovascular health (CVH) index and risk of high-normal blood pressure (HNBP) in elderly people. Randomized cluster sampling, multivariate logistic regression, and mediating effects analysis were used in this study analyze the relationship between CVH index and HNBP in the elderly. 1089 non-hypertensive residents aged 65 years or older completed the study. The positive rate of HNBP was 75.85% (male vs. female: 76.13% vs. 75.64%, P = 0.852); The ideal rate of CVH (ideal CVH index ≥ 5 items) was 14.51% (male vs. female: 15.91% vs. 13.46%, P = 0.256). Compared with people with 0–2 ideal CVH index, the risk of HNBP in people with 4 ideal indexes and ≥ 5 ideal indexes decreased by 50% and 63%, respectively, and their OR (95% CI) were 0.50 (0.31, 0.81) and 0.37 (0.21, 0.66), respectively. The results of the trend test showed that the risk of HNBP decreased by 32% for every increase in the ideal CVH index (trend P

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy. Here, a new type of spatiotemporal biomimetic “Gemini nanoimmunoregulators” was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death (ICD), tumor-associated macrophages (TAMs) phenotype reprogramming and programmed cell death ligand 1 (PD-L1) degradation. The “Gemini nanoimmunoregulators” PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine (mPDA) as nanovectors to deliver metformin (Met) and toll-like receptor 7/8 agonist resiquimod (R848) to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane (RM) inlaid with T7 or M2 peptides. mPDA/Met@RM-T7 (abbreviated as PM@RM-T7) was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity. Meanwhile, PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion. Subsequently, mPDA/R848@RM-M2 (abbreviated as PR@RM-M2) specifically recognized TAMs and reset the phenotype from M2 to M1 state, thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes. This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity, which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis. This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

Background/Aims: Necrotizing pancreatitis (NP) presents a more severe clinical trajectory and increased mortality compared to edematous pancreatitis. Prompt identification of NP is vital for patient prognosis. A risk prediction model for NP among Chinese patients has been developed and validated to aid in early detection. Methods: A retrospective analysis was performed on 218 patients with acute pancreatitis (AP) to examine the association of various clinical variables with NP. The least absolute shrinkage and selection operator (LASSO) regression was utilized to refine variables and select predictors. Subsequently, a multivariate logistic regression was employed to construct a predictive nomogram. The model's accuracy was validated using bootstrap resampling (n=500) and its calibration assessed via a calibration curve. The model's clinical utility was evaluated through decision curve analysis. Results: Of the 28 potential predictors analyzed in 218 AP patients, the incidence of NP was 25.2%. LASSO regression identified 14 variables, with procalcitonin, triglyceride, white blood cell count at 48 hours post-admission, calcium at 48 hours post-admission, and hematocrit at 48 hours post-admission emerging as independent risk factors for NP. The resulting nomogram accurately predicted NP risk with an area under the curve of 0.822, sensitivity of 82.8%, and specificity of 76.4%. The bootstrap-validated area under the curve remained at 0.822 (95% confidence interval, 0.737 to 0.892). This model exhibited excellent calibration and demonstrated greater predictive efficacy and clinical utility for NP than APACHE II, Ranson, and BISAP. Conclusions: We have developed a prediction nomogram of NP that is of great value in guiding clinical decision.

Alpine meadow patchiness is the starting point and an important feature of the formation of ‘Black Beach’ on the Tibetan Plateau, which directly threatens regional ecological security and economic development. Therefore, exploring an efficient, rapid and accurate method for identifying bald patches in degraded alpine meadows is of great significance for the dynamic monitoring and rational utilization in the grassland region. In this study, high-resolution remote sensing image data of degraded alpine meadows was obtained using a low-altitude Unmanned Aerial Vehicle (UAV)-mounted imager. Afterwards, a standardized dataset was constructed through data screening and normalization, combined with expert experience to manually annotate the bald patches in the images. Then, based on deep learning techniques, four classical network frameworks, Hrnet, Deeplabv3+, PSPnet and Unet, were built and paired with different backbone networks for model training respectively. The final results showed that Hrnet had the best recognition results, with the highest mean values of 68.27%, 75.90%, 78.22% and 99.22% for the Mean Intersection over Union, Mean Pixel Accuracy, Recall and Accuracy, respectively. In summary, the results showed that it is effective to combine low-altitude UAV remote sensing platform with deep learning technology. This study provides a new method for the identification of alpine meadow bald patches.

ABSTRACTIn order to develop nutritious and healthy fermented fig juice, foure samples fermented were made using natural fermentation and fermentation by lactobacillus. Then the total acidity, total sugar, reducing sugar, total phenols, total flavones and characteristic organic acids, antioxidant activity, and inhibition of enzyme activity in fermented fig juice were compared. The results showed that natural fermentation could produce more reducing sugar, lactic acid, flavonoids, and exhibit stronger DPPH radical scavenging capacity and total reducing power. Inhibition of tyrosinase and pancreatic lipase was detected in fermented fig juice, of which the inhibition rate of tyrosinase by natural fermentation was 81.80%, and the inhibition rate of pancreatic lipase by mixed cultures was 38.72%, which was higher than that of other groups. The results indicated the functional activity of fermented fig juice could be improved by fermentation, and the natural fermentation method was found superior.

AbstractObjective Accumulating evidence suggests that differentially expressed circular RNAs (circRNAs) play critical roles in immune cells of systemic lupus erythematosus (SLE) patients. Hsa_circ_0000479 has been studied in the field of cancer and infection, whereas seldom studied in autoimmune diseases. The aim of this study was to investigate the role and clinical value of neutrophil hsa_circ_0000479 in SLE.Methods The expression levels of hsa_circ_0000479 in both healthy individuals and SLE patients’ neutrophils were detected by qPCR and compared with those in peripheral blood mononuclear cells (PBMCs) . In addition, the correlation of hsa_circ_0000479 levels in neutrophils with the clinical and immunological features of SLE patients was also analysed.Results The expression levels of hsa_circ_0000479 in the patients with SLE were significantly higher in neutrophils than that of PBMCs, and also significantly higher than that in healthy controls (HCs). Moreover, the expression levels of hsa_circ_0000479 in neutrophils were negatively associated with absolute neutrophil count and complement 3 (C3), whereas positively correlated with anti-dsDNA and anti-nucleosome antibodies in SLE. In addition, SLE patients with higher levels of hsa_circ_0000479 demonstrated more several clinical manifestations, including Raynaud’s phenomenon, alopecia and leucopenia.Conclusions Hsa_circ_0000479 is up-regulated in neutrophils of SLE patients, and is also associated with several important laboratory indicators and clinical manifestations, suggesting that hsa_circ_0000479 in neutrophils was one of probable factors involved in the pathogenesis of SLE with potential clinical value.

Abstract BackgroundCardiovascular-kidney-metabolic (CKM) health is affected by social determinants of health, especially education. CKM syndrome has not been evaluated in Chinese population, and the association of education with CKM syndrome in different sexes and its intertwined relation with lifestyles have not been explored. ObjectiveWe aimed to explore the association between educational attainment and the prevalence of CKM syndrome stages in middle-aged and older Chinese men and women as well as the potential role of health behavior based on Life’s Essential 8 construct. MethodsThis study used data from the nationwide, community-based REACTION (Risk Evaluation of Cancers in Chinese diabetic individuals: a longitudinal study). A total of 132,085 participants with complete information to determine CKM syndrome stage and education level were included. Educational attainment was assessed by the self-reported highest educational level achieved by the participants and recategorized as low (elementary school or no formal education) or high (middle school, high school, technical school/college, or above). CKM syndrome was ascertained and classified into 5 stages according to the American Heart Association presidential advisory released in 2023. ResultsAmong 132,085 participants (mean age 56.95, SD 9.19 years; n=86,675, 65.62% women) included, most had moderate-risk CKM syndrome (stages 1 and 2), and a lower proportion were at higher risk of CKM (stages 3 and 4). Along the CKM continuum, low education was associated with 34% increased odds of moderate-risk CKM syndrome for women (odds ratio 1.36, 95% CI 1.23-1.49) with a significant sex disparity, but was positively correlated with high-risk CKM for both sexes. The association between low education and high-risk CKM was more evident in women with poor health behavior but not in men, which was also interactive with and partly mediated by behavior. ConclusionsLow education was associated with adverse CKM health for both sexes but was especially detrimental to women. Such sex-specific educational disparity was closely correlated with health behavior but could not be completely attenuated by behavior modification. These findings highlight the disadvantage faced by women in CKM health ascribed to low education, underscoring the need for public health support to address this inequality.

Abstract Background Not many large‐sample investigations are available that compare the potency of the relationship of remnant cholesterol (RC) and other lipid parameters with diabetes and prediabetes. The goals of our study are to discover the relationship between RC and prediabetes, diabetes, and insulin resistance (IR) and to investigate RC, high‐density lipoprotein cholesterol (HDL‐C), non‐HDL‐C, triglycerides (TG), low‐density lipoprotein cholesterol (LDL‐C), total cholesterol (TC), TC/HDL‐C, LDL‐C/HDL‐C, and TG/HDL‐C, which are the lipid parameters that are most positively related to diabetes, prediabetes, and IR. Methods This research enrolled 36 684 subjects from China's eight provinces. We employed multiple logistic regression analysis for testing the relationship between lipid parameters and diabetes, prediabetes, and IR. Results After adjusting for potential confounders, and comparing the results with other lipid parameters, the positive relationship between RC and diabetes (odds ratio [OR] 1.417, 95% confidence interval [CI]: 1.345–1.492), prediabetes (OR 1.555, 95% CI: 1.438–1.628), and IR (OR 1.488, 95% CI: 1.404–1.577) was highest. RC was still related to diabetes, prediabetes, and IR even when TG

Abstract Background Novel diabetes phenotypes were proposed by the Europeans through cluster analysis, but Chinese community diabetes populations might exhibit different characteristics. This study aims to explore the clinical characteristics of novel diabetes subgroups under data‐driven analysis in Chinese community diabetes populations. Methods We used K‐means cluster analysis in 6369 newly diagnosed diabetic patients from eight centers of the REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study. The cluster analysis was performed based on age, body mass index, glycosylated hemoglobin, homeostatic modeled insulin resistance index, and homeostatic modeled pancreatic β‐cell functionality index. The clinical features were evaluated with the analysis of variance (ANOVA) and chi‐square test. Logistic regression analysis was done to compare chronic kidney disease and cardiovascular disease risks between subgroups. Results Overall, 2063 (32.39%), 658 (10.33%), 1769 (27.78%), and 1879 (29.50%) populations were assigned to severe obesity‐related and insulin‐resistant diabetes (SOIRD), severe insulin‐deficient diabetes (SIDD), mild age‐associated diabetes mellitus (MARD), and mild insulin‐deficient diabetes (MIDD) subgroups, respectively. Individuals in the MIDD subgroup had a low risk burden equivalent to prediabetes, but with reduced insulin secretion. Individuals in the SOIRD subgroup were obese, had insulin resistance, and a high prevalence of fatty liver, tumors, family history of diabetes, and tumors. Individuals in the SIDD subgroup had severe insulin deficiency, the poorest glycemic control, and the highest prevalence of dyslipidemia and diabetic nephropathy. Individuals in MARD subgroup were the oldest, had moderate metabolic dysregulation and the highest risk of cardiovascular disease. Conclusion The data‐driven approach to differentiating the status of new‐onset diabetes in the Chinese community was feasible. Patients in different clusters presented different characteristics and risks of complications.

Abstract Background Serotonin (5‐hydroxytryptamine) is a multifunctional bioamine serving as a neurotransmitter, peripheral hormone and mitogen in the vertebrate system. It has pleiotropic activities in central nervous system and gastrointestinal function via an orchestrated action of serotonergic elements, particularly serotonin receptor‐mediated signalling cascades. The mitogenic properties of serotonin have garnered recognition for years and have been exploited for repurposing serotonergic‐targeted drugs in cancer therapy. However, emerging conflicting findings necessitate a more comprehensive elucidation of serotonin's role in cancer pathogenesis. Main body and conclusion Here, we provide an overview of the biosynthesis, metabolism and action modes of serotonin. We summarise our current knowledge regarding the effects of the peripheral serotonergic system on tumourigenesis, with a specific emphasis on its immunomodulatory activities in human cancers. We also discuss the dual roles of serotonin in tumour pathogenesis and elucidate the potential of serotonergic drugs, some of which display favourable safety profiles and impressive efficacy in clinical trials, as a promising avenue in cancer treatment. Key points Primary synthesis and metabolic routes of peripheral 5‐hydroxytryptamine in the gastrointestinal tract. Advanced research has established a strong association between the serotonergic components and carcinogenic mechanisms. The interplay between serotonergic signalling and the immune system within the tumour microenvironment orchestrates antitumour immune responses. Serotonergic‐targeted drugs offer valuable clinical options for cancer therapy.

Objective The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.Methods and analysis In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti−PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).Results A total of 107 patients received INCB001158 50–150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50–100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti–PD-1/PD-L1–naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response.Conclusions INCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted.Trial registration number NCT02903914.

BackgroundVascular cognitive impairment (VCI) persistently impairs cognition and the ability to perform activities of daily living, seriously compromising patients’ quality of life. Previous studies have reported that disorders of serum iron metabolism and iron deposition in the brain can lead to inflammation, abnormal protein aggregation and degeneration, and massive neuronal apoptosis in the central nervous system, which in turn leads to a progressive decline in cognitive processes. Our previous clinical studies have found acupuncture to be a safe and effective intervention for treating VCI, but the specific mechanisms require further exploration. ObjectiveThe objective of the trial is to evaluate the clinical efficacy of Tongdu Xingshen acupuncture and to investigate whether it can improve VCI by regulating brain iron deposition and body iron metabolism. MethodsIn total, 42 patients with VCI and 21 healthy individuals will participate in this clinical trial. The 42 patients with VCI will be randomized into acupuncture and control groups, while the 21 healthy individuals will be in the healthy control group. Both the control and acupuncture groups will receive conventional medical treatment and cognitive rehabilitation training. In addition, the acupuncture group will receive electroacupuncture treatment with Tongdu Xingshen for 30 minutes each time, 6 times a week for 4 weeks. Meanwhile, the healthy control group will not receive any intervention. All 3 groups will undergo baseline assessments of brain iron deposition, serum iron metabolism, and neuropsychological tests after enrollment. The acupuncture and control groups will be evaluated again at the end of 4 weeks of treatment, as described earlier. By comparing neuropsychological test scores between groups, we will examine the efficacy of Tongdu Xingshen acupuncture in treating VCI. Additionally, we will test the correlations between neuropsychological test scores, brain iron deposition, and body iron metabolism indexes to explore the possible mechanisms of Tongdu Xingshen acupuncture in treating VCI. ResultsParticipants are currently being recruited. The first participant was enrolled in June 2023, which marked the official start of the experiment. As of the submission of the paper, there were 23 participants. The recruitment process is expected to continue until June 2025, at which point the processing and analysis of data will begin. As of May 15, 2024, up to 30 people have been enrolled in this clinical trial. ConclusionsThis study will provide data on the effects of Tongdu Xingshen acupuncture on cerebral iron deposition as well as somatic iron metabolism in patients with VCI. These results will help to prove whether Tongdu Xingshen acupuncture can improve VCI by regulating brain iron deposition and body iron metabolism, which will provide the clinical and theoretical basis for the wide application of acupuncture therapy in VCI rehabilitation. Trial RegistrationChina Clinical Registration Agency ChiCTR2300072188; https://tinyurl.com/5fcydtkv International Registered Report Identifier (IRRID)PRR1-10.2196/56484

BackgroundPrevious neuroimaging studies have revealed structural and functional brain abnormalities in patients with cervical spondylosis (CS). However, the results are divergent and inconsistent. Therefore, the present study conducted a multi-modal meta-analysis to investigate the consistent structural and functional brain alterations in CS patients.MethodsA comprehensive literature search was conducted in five databases to retrieve relevant resting-state functional magnetic resonance imaging (rs-fMRI), structural MRI and diffusion tensor imaging (DTI) studies that measured brain functional and structural differences between CS patients and healthy controls (HCs). Separate and multimodal meta-analyses were implemented, respectively, by employing Anisotropic Effect-size Signed Differential Mapping software.Results13 rs-fMRI studies that used regional homogeneity, amplitude of low-frequency fluctuations (ALFF) and fractional ALFF, seven voxel-based morphometry (VBM) studies and one DTI study were finally included in the present research. However, no studies on surface-based morphometry (SBM) analysis were included in this research. Due to the insufficient number of SBM and DTI studies, only rs-fMRI and VBM meta-analyses were conducted. The results of rs-fMRI meta-analysis showed that compared to HCs, CS patients demonstrated decreased regional spontaneous brain activities in the right lingual gyrus, right middle temporal gyrus (MTG), left inferior parietal gyrus and right postcentral gyrus (PoCG), while increased activities in the right medial superior frontal gyrus, bilateral middle frontal gyrus and right precuneus. VBM meta-analysis detected increased GMV in the right superior temporal gyrus (STG) and right paracentral lobule (PCL), while decreased GMV in the left supplementary motor area and left MTG in CS patients. The multi-modal meta-analysis revealed increased GMV together with decreased regional spontaneous brain activity in the left PoCG, right STG and PCL among CS patients.ConclusionThis meta-analysis revealed that compared to HCs, CS patients had significant alterations in GMV and regional spontaneous brain activity. The altered brain regions mainly included the primary visual cortex, the default mode network and the sensorimotor area, which may be associated with CS patients' symptoms of sensory deficits, blurred vision, cognitive impairment and motor dysfunction. The findings may contribute to understanding the underlying pathophysiology of brain dysfunction and provide references for early diagnosis and treatment of CS.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, CRD42022370967.

BackgroundThe triglyceride glucose (TyG) index has been associated with an increased risk in breast cancer. However, this association remains unclear among the Chinese population. This study aimed to investigate whether the TyG index is associated with the risk of prevalent breast cancer in Chinese women.MethodsThis cross-sectional study included 142,184 women from the REACTION (Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal) Study, which recruited adults aged 40 years or older from 25 centers across mainland China between 2011 and 2012. The TyG index was calculated according to the formula: Ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). Multivariable-adjusted logistic regression models were used to evaluate odds ratios (ORs) and 95% confidence intervals (CIs) regarding the associations between the TyG index and breast cancer.ResultsMultivariable-adjusted logistic regression analysis showed that compared with the lowest quartile of the TyG index, the highest quartile of the TyG index was significantly associated with an increased risk of prevalent breast cancer, with an OR (95% CI) of 1.61 (1.19–2.17). In the stratified analysis, the association of each 1 SD increase in the TyG index with risk of prevalent breast cancer was more dominant in individuals with menarche at age 13–17, those who were postmenopausal, those with a history of breastfeeding, and those who had two to four children, with the ORs (95% CIs) of 1.35 (1.09–1.68), 1.27 (1.05–1.54), 1.26 (1.05–1.52), and 1.32 (1.08–1.62), respectively. Moreover, among those without discernible insulin resistance (homeostatic model assessment-insulin resistance [HOMA-IR] ≥2.5), hyperglycemia and dyslipidemia, each 1 SD increase in the TyG index was associated with a 1.36-fold increase in breast cancer risk, with an OR (95% CI) of 2.36 (1.44–3.87).ConclusionThe TyG index is significantly associated with the prevalent breast cancer risk among middle-aged and elderly Chinese women.

Abstract This single-arm, multi-center clinical trial aimed to evaluate the safety, tolerability, DLT, recommended dose (RD), preliminary efficacy, and pharmacokinetics (PK) characteristics of lurbinectedin, a selective inhibitor of oncogenic transcription, in Chinese patients with advanced solid tumors, including relapsed SCLC. Patients with advanced solid tumors were recruited in the dose-escalation stage and received lurbinectedin in a 3 + 3 design (two cohorts: 2.5 mg/m2 and 3.2 mg/m2, IV, q3wk). The RD was expanded in the following dose-expansion stage, including relapsed SCLC patients after first-line platinum-based chemotherapy. The primary endpoints included safety profile, tolerability, DLT, RD, and preliminary efficacy profile, while the secondary endpoints included PK characteristics. In the dose-escalation stage, ten patients were included, while one patient had DLT in the 3.2 mg/m2 cohort, which was also the RD for the dose-expansion stage. At cutoff (May 31, 2022), 22 SCLC patients were treated in the ongoing dose-expansion stage, and the median follow-up was 8.1 months (range 3.0–11.7). The most common grade ≥ 3 treatment-related adverse events (TRAEs) included neutropenia (77.3%), leukopenia (63.6%), thrombocytopenia (40.9%), anemia (18.2%), and ALT increased (18.2%). The most common severe adverse events (SAEs) included neutropenia (27.3%), leukopenia (22.7%), thrombocytopenia (18.2%), and vomiting (9.1%). No treatment-related deaths occurred. The Independent Review Committee (IRC)-assessed ORR was 45.5% (95% CI 26.9–65.3). Lurbinectedin at the RD (3.2 mg/m2) showed manageable safety and acceptable tolerability in Chinese patients with advanced solid tumors, and demonstrates promising efficacy in Chinese patients with SCLC as second-line therapy. Trial registration: This study was registered with ClinicalTrials.gov NCT04638491, 20/11/2020.

Abstract Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.

Abstract Potassium (K+) is the main intracellular cation in the body. Elevated K+ levels (hyperkalemia) increase the risk of life‐threatening arrhythmias and sudden cardiac death. However, the details of K+ homeostasis and the effects of orally administered K+ binders, such as sodium zirconium cyclosilicate (SZC), on K+ redistribution and excretion in patients remain incompletely understood. We built a fit‐for‐purpose systems pharmacology model to describe K+ homeostasis in hyperkalemic subjects and capture serum K+ (sK+) dynamics in response to acute and chronic administration of SZC. The resulting model describes K+ distribution in the gastrointestinal (GI) tract, blood, and extracellular and intracellular spaces of tissue, renal clearance of K+, and K+–SZC binding and excretion in the GI tract. The model, which was fit to time‐course sK+ data for individual patients from two clinical trials, accounts for bolus delivery of K+ in meals and oral doses of SZC. The virtual population of patients derived from fitting the model to these trials was then modified to predict the SZC dose–response and inform clinical trial design in two new applications: emergency lowering of sK+ in severe hyperkalemia and prevention of hyperkalemia between dialysis sessions in patients with end‐stage chronic kidney disease. In both cases, the model provided novel and useful insight that was borne out by the now completed clinical trials, providing a concrete case study of fit‐for‐purpose, model‐informed drug development after initial approval of a drug.