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Abstract Background The COVID-19 pandemic has highlighted the crucial role of artificial intelligence (AI) in predicting mortality and guiding healthcare decisions. However, AI models may perpetuate or exacerbate existing health disparities due to demographic biases, particularly affecting racial and ethnic minorities. The objective of this study is to investigate the demographic biases in AI models predicting COVID-19 mortality and to assess the effectiveness of transfer learning in improving model fairness across diverse demographic groups. Methods This retrospective cohort study used a population-based dataset of COVID-19 cases from the Centers for Disease Control and Prevention (CDC), spanning the years 2020–2024. The study analyzed AI model performance across different racial and ethnic groups and employed transfer learning techniques to improve model fairness by adapting pre-trained models to the specific demographic and clinical characteristics of the population. Results Decision Tree (DT) and Random Forest (RF) models consistently showed improvements in accuracy, precision, and ROC-AUC scores for Non-Hispanic Black, Hispanic/Latino, and Asian populations. The most significant precision improvement was observed in the DT model for Hispanic/Latino individuals, which increased from 0.3805 to 0.5265. The precision for Asians or Pacific Islanders in the DT model increased from 0.4727 to 0.6071, and for Non-Hispanic Blacks, it rose from 0.5492 to 0.6657. Gradient Boosting Machines (GBM) produced mixed results, showing accuracy and precision improvements for Non-Hispanic Black and Asian groups, but declines for the Hispanic/Latino and American Indian groups, with the most significant decline in precision, which dropped from 0.4612 to 0.2406 in the American Indian group. Logistic Regression (LR) demonstrated minimal changes across all metrics and groups. For the Non-Hispanic American Indian group, most models showed limited benefits, with several performance metrics either remaining stable or declining. Conclusions This study demonstrates the potential of AI in predicting COVID-19 mortality while also underscoring the critical need to address demographic biases. The application of transfer learning significantly improved the predictive performance of models across various racial and ethnic groups, suggesting these techniques are effective in mitigating biases and promoting fairness in AI models.

Abstract In the musculoskeletal system, lymphatic vessels (LVs), which are interdigitated with blood vessels, travel and form an extensive transport network. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, we investigate the lymphatic draining function at the tibial fracture sites using near-infrared indocyanine green lymphatic imaging (NIR-ICG) and discover that lymphatic drainage insufficiency (LDI) starts on day one and persists for up to two weeks following the fracture in male mice. Sufficient lymphatic drainage facilitates fracture healing in male mice. Furthermore, we identify that lymphatic platelet thrombosis (LPT) blocks the draining lymphoid sinus and LVs, causes LDI, and inhibits fracture healing in male mice, which can be rescued by a blood thinner. Moreover, unblocked lymphatic drainage decreases neutrophils and increases M2-type macrophages of the hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs) in male rats. Lymphatic platelet thrombolysis also benefits senile fracture healing in female mice. These findings demonstrate that LPT limits bone regeneration by impeding lymphatic transporting DAMPs. Together, these findings represent a way forward in the treatment of bone repair.

Abstract Diabetic wounds are notoriously difficult to heal due to impaired cell repair mechanisms, reduced angiogenesis, and a heightened risk of infection. Fibroblasts play a vital role in wound healing by producing extracellular matrix (ECM) components and various growth factors, but their function is inhibited in diabetic wounds. Chitooligosaccharides (COS), intermediate products of chitosan degradation, have shown efficacy in promoting tissue repair, yet their role in diabetic wound healing remains underexplored. In a mouse model of diabetic wounds, COS treatment demonstrated substantial bioactivity in accelerating wound healing by enhancing fibroblast proliferation and migration. Additionally, COS increased collagen III deposition and angiogenesis at the wound sites. The COS also mitigated inflammatory responses by controlling leukocyte infiltration and bacterial infection. Mechanistically, COS regulated fibroblast activity via the PI3K/Akt signaling pathway, providing a novel bioactive material for chronic wound healing.

Ischemic stroke is a leading cause of death and disability worldwide, with an increasing trend and tendency for onset at a younger age. China, in particular, bears a high burden of stroke cases. In recent years, the inflammatory response after stroke has become a research hotspot: understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment. This review summarizes several major cells involved in the inflammatory response following ischemic stroke, including microglia, neutrophils, monocytes, lymphocytes, and astrocytes. Additionally, we have also highlighted the recent progress in various treatments for ischemic stroke, particularly in the field of stem cell therapy. Overall, understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes. Stem cell therapy may potentially become an important component of ischemic stroke treatment.

Abstract Background Epithelial ovarian cancer (EOC) is a lethal form of gynecological malignancy. Some EOC patients experience relapse after standard primary debulking surgery (PDS) and adjuvant chemotherapy (ACT). Identifying molecular residual disease (MRD) by circulating tumor DNA (ctDNA) detection can timely signal the potential for relapse. However, research on the usage of ctDNA for MRD detection in EOC is limited. Methods Fifty-one EOC patients who received standard PDS and ACT were included. Targeted sequencing based on a panel of 1021 cancer-related genes, along with further validation using Enrich-rare-mutation sequencing, was performed on tumor tissues acquired during PDS and on plasma samples collected before and after PDS/ACT to identify variants reflecting tumor signals. Results Post-surgery MRD was associated with relapse (Log-rank p = 0.0006) and was identified as an independent prognostic factor (HR, 3.4; 95% CI, 1.02–11.42; p = 0.047). The negative and positive predictive values were 0.83 and 0.62 respectively. Additionally, post-surgery MRD outperformed CA125 in predicting relapse, and integrating both parameters could provide more accurate risk stratification. Post-ACT MRD detection identified the patients with ctDNA clearance who were still at risk of relapse. Furthermore, baseline ctDNA detection could help determine patients who are not suitable for further tests after surgery. Conclusions Post-surgery MRD is superior to CA125 in predicting relapse in EOC. Patients exhibiting transient ctDNA clearance, as evaluated by post-ACT MRD, may require longitudinal monitoring. Baseline ctDNA detection could help determine whether post-surgery ctDNA monitoring should be performed.

Abstract Semantic segmentation in the context of 3D point clouds for the railway environment holds a significant economic value, but its development is severely hindered by the lack of suitable and specific datasets. Additionally, the models trained on existing urban road point cloud datasets demonstrate poor generalisation on railway data due to a large domain gap caused by non‐overlapping special/rare categories, for example, rail track, track bed etc. To harness the potential of supervised learning methods in the domain of 3D railway semantic segmentation, we introduce RailPC, a new point cloud benchmark. RailPC provides a large‐scale dataset with rich annotations for semantic segmentation in the railway environment. Notably, RailPC contains twice the number of annotated points compared to the largest available mobile laser scanning (MLS) point cloud dataset and is the first railway‐specific 3D dataset for semantic segmentation. It covers a total of nearly 25 km railway in two different scenes (urban and mountain), with 3 billion points that are finely labelled as 16 most typical classes with respect to railway, and the data acquisition process is completed in China by MLS systems. Through extensive experimentation, we evaluate the performance of advanced scene understanding methods on the annotated dataset and present a synthetic analysis of semantic segmentation results. Based on our findings, we establish some critical challenges towards railway‐scale point cloud semantic segmentation. The dataset is available at https://github.com/NNU‐GISA/GISA‐RailPC, and we will continuously update it based on community feedback.

Laser peen forming (LPF) is an appealing technique for forming metal sheets using high-energy, short-duration laser pulses. The deformation of the target metal plate is closely related to the magnitude and distribution of laser-induced residual stress. Consequently, the relationship between process parameters and residual stress is worth researching. In this research, two process parameters in LPF, laser energy and coverage ratio (spot distance essentially), and one workpiece parameter, plate thickness, were examined through an element method (FEM) of multiple square-spot laser shock peening (SSLSP). Corresponding experiments of SSLSP on aluminum alloy 2024-T351 test blocks were conducted, together with an X-ray diffraction (XRD) residual stress measurement and a surface morphology observation. The FEM simulation and experimental results show that congested laser spots had a significant influence on the magnitude of compressive residual stress; higher laser energy was beneficial to the depth of the compressive stress layer but could decrease its magnitude. Therefore, for better forming ability, higher laser energy and a higher coverage ratio are beneficial; for surface strengthening, laser energy should not be too large, and the coverage ratio should be larger than 100% to ensure that the residual stress on the treated surface is compressive, resulting in better surface integrity.

Abstract Background Prediction of short-term outcomes in young patients with acute ischemic stroke (AIS) may assist in making therapy decisions. Machine learning (ML) is increasingly used in healthcare due to its high accuracy. This study aims to use a ML-based predictive model for poor 3-month functional outcomes in young AIS patients and to compare the predictive performance of ML models with the logistic regression model. Methods We enrolled AIS patients aged between 18 and 50 years from the Third Chinese National Stroke Registry (CNSR-III), collected between 2015 and 2018. A modified Rankin Scale (mRS) ≥ 3 was a poor functional outcome at 3 months. Four ML tree models were developed: The extreme Gradient Boosting (XGBoost), Light Gradient Boosted Machine (lightGBM), Random Forest (RF), and The Gradient Boosting Decision Trees (GBDT), compared with logistic regression. We assess the model performance based on both discrimination and calibration. Results A total of 2268 young patients with a mean age of 44.3 ± 5.5 years were included. Among them, (9%) had poor functional outcomes. The mRS at admission, living alone conditions, and high National Institutes of Health Stroke Scale (NIHSS) at discharge remained independent predictors of poor 3-month outcomes. The best AUC in the test group was XGBoost (AUC = 0.801), followed by GBDT, RF, and lightGBM (AUCs of 0.795, 0, 794, and 0.792, respectively). The XGBoost, RF, and lightGBM models were significantly better than logistic regression (P

In order to study the stability of slopes containing weakly inter bedded rocks under dynamic disturbance, the dynamic response characteristics of rocks with different inclinations under dynamic cyclic disturbance are investigated through indoor experiments on rock specimens with different inclinations and the construction of a dynamic model of the structural surface of the rock body under dynamic disturbance. The results show that the stress-strain curve under cyclic disturbance is a closed hysteresis loop curve, and its general stage is characterized by: sparse-dense-sparse; when the disturbance amplitude is constant, the rock deformation increases with the increase of inclination angle. For the rock specimen with the same inclination angle under the same static load stress, there is a disturbance threshold for the disturbance destructive stress amplitude of the rock structural surface. In the case that the disturbance amplitude is less than this threshold, the plastic deformation of the rock body is relatively stable. Once the perturbation amplitude exceeds the threshold, the structural surface of the specimen is damaged and the plastic deformation is destabilized, which is manifested by the S-shaped curve of the plastic accumulation and the number of cycles. It is shown that when the inclination angle of the structural face is greater than 30°, the damage of the structural face is not only material damage, but also shear damage occurs at the junction position of the structural face of the rock body, leading to the destabilization of the entire structural face of the rock system.

Abstract Background The prognosis, recurrence rates, and secondary prevention strategies varied significantly among different subtypes of acute ischemic stroke (AIS). Machine learning (ML) techniques can uncover intricate, non-linear relationships within medical data, enabling the identification of factors associated with etiological classification. However, there is currently a lack of research utilizing ML algorithms for predicting AIS etiology. Objective We aimed to use interpretable ML algorithms to develop AIS etiology prediction models, identify critical factors in etiology classification, and enhance existing clinical categorization. Methods This study involved patients with the Third China National Stroke Registry (CNSR-III). Nine models, which included Natural Gradient Boosting (NGBoost), Categorical Boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Random Forest (RF), Light Gradient Boosting Machine (LGBM), Gradient Boosting Decision Tree (GBDT), Adaptive Boosting (AdaBoost), Support Vector Machine (SVM), and logistic regression (LR), were employed to predict large artery atherosclerosis (LAA), small vessel occlusion (SVO), and cardioembolism (CE) using an 80:20 randomly split training and test set. We designed an SFS-XGB with 10-fold cross-validation for feature selection. The primary evaluation metrics for the models included the area under the receiver operating characteristic curve (AUC) for discrimination and the Brier score (or calibration plots) for calibration. Results A total of 5,213 patients were included, comprising 2,471 (47.4%) with LAA, 2,153 (41.3%) with SVO, and 589 (11.3%) with CE. In both LAA and SVO models, the AUC values of the ML models were significantly higher than that of the LR model (P

Summary: Background: Central nervous system (CNS) accessibility constitutes a major hurdle for drug development to treat neurological diseases. Existing drug delivery methods rely on breaking the blood-brain barrier (BBB) for drugs to penetrate the CNS. Researchers have discovered natural microchannels between the skull bone marrow and the dura mater, providing a pathway for drug delivery through the skull bone marrow. However, there has been no research on the feasibility, safety, and efficacy of this delivery method for drug treatment of stroke. Methods: We used a microporous method for intracalvariosseous (ICO) injection to deliver drugs directly into brain parenchyma through skull bone marrow. Safety of ICO was assessed by monitoring changes in skull and peripheral blood neutrophil counts, and FITC-dextran extravasation across the BBB. Drug delivery pathways were observed through transparent skull-dura mater-brain tissue. In a rodent stroke model, NA-1 or Y-3 neuroprotective agents were administered via ICO to evaluate safety and efficacy by assessing neurological deficits, infarct size, neuroinflammatory factors, neuronal apoptosis, and liver/kidney function. Drug concentration in tissues was measured using fluorescence tracing and high-performance liquid chromatography to gauge ICO delivery efficiency. Findings: ICO injection delivers drugs to the brain parenchyma through microchannels between the skull bone marrow and the dura mater, offering higher delivery efficiency than intravenous injection. After ICO injection, there were no changes in neutrophil counts in the skull bone marrow and peripheral blood, and the amount of FITC-dextran passing through the BBB remained unchanged. This confirmed that ICO injection does not cause skull infection or break BBB, which suggested ICO injection is safe and feasible. In the treatment of stroke with neuroprotective agents, although the drug dosage of ICO injection was lower than intravenous injection, drug accumulation in the brain increased after ICO injection, which helped repair nerve damage, reduce neuronal apoptosis, and decrease the expression of inflammatory factors. Interpretation: ICO injection is a central nervous system drug delivery method that utilizes natural microchannels between the skull and dura mater for efficient drug delivery. Our results assessed the feasibility and safety of ICO injection at the preclinical level and evaluated its efficacy in animal models of stroke. The findings provided a foundation for the clinical translation of ICO injection. Funding: This study was supported by The National Natural Science Foundation of China (No. 82425101); Beijing Municipal Science & Technology Commission (No. Z231100004823036); Capital's Funds for Health Improvement and Research (2022-2-2045); National Key Research & Development Program of China (2022YFF1501500, 2022YFF1501501, 2022YFF1501502, 2022YFF1501503, 2022YFF1501504, 2022YFF1501505).

IntroductionThis study aims to assess the pattern of functional connectivity (FC) between cerebellar subregions, the basal ganglia (BG), and the cortex, and explore the relationship between FC patterns and cognitive function after stroke with BG infarcts.MethodsA total of 39 stroke patients and 29 healthy controls were recruited. Four cerebellar seed points were selected, and the FC of each seed point with other voxels in the whole brain was calculated. FC and cognitive performance were compared between the two groups, and their correlations were analyzed.ResultsStroke patients exhibited increased FC between the bilateral cerebellum IX and BG (particularly the head of the caudate nucleus), which was positively correlated with episodic memory, visuospatial ability, and attention. Increased FC was also observed between the right cerebellum Crus I/II and BG, as well as the bilateral cerebellum VI and BG, correlating positively with episodic memory. Conversely, decreased FC was identified between the bilateral cerebellum IX and the right caudal cuneus, which negatively correlated with episodic memory, language, and attention but positively correlated with executive function. Additionally, increased FC between the bilateral cerebellum VI and the bilateral inferior parietal lobule was associated with improvements in episodic memory, language, and attention. Decreased FC was observed between the right cerebellum VI and the left insula, as well as between the right cerebellum Crus I/II and the left insula, which negatively correlated with episodic memory.DiscussionThe enhanced FC between the cerebellum and BG, along with the reorganization of new neural circuits involving the cerebellar cortex, may contribute to cognitive recovery following stroke. These changes may represent compensatory mechanisms of the cerebellum in response to stroke injury.

Background The impact of long‐term renal function change on stroke outcomes remains unclear. This study used the CNSR‐III (Third China National Stroke Registry) cohort to determine whether changes in estimated glomerular filtration rate based on creatinine and cystatin C (eGFRCr+CysC) during the first year post stroke were associated with 5‐year stroke outcomes. Methods and Results We included 4270 patients with centrally tested serum creatinine and cystatin C at admission and 1 year post admission and evaluated 5‐year follow‐up data. Patients were stratified into quintiles based on the 1‐year changes in eGFR. The primary outcomes included all‐cause mortality, stroke disability, and stroke recurrence. In patients with acute ischemic stroke, the mean baseline eGFRCr+CysC was 88.6±22.6 mL/min per 1.73 m2, which decreased by 5.6% to 83.6±20.7 mL/min per 1.73 m2 at 1 year. Compared with patients with relatively stable eGFRCr+CysC (Q3), those with decreased eGFRCr+CysC (Q1) exhibited significantly increased adjusted risk of death (hazard ratio [HR], 1.96 [95% CI, 1.27–3.04], P=0.003) and those with increased eGFRCr+CysC (Q5) exhibited borderline significance (HR, 1.51 [95% CI, 0.94–2.42], P=0.09), after adjusting for confounders, including baseline eGFRCr+CysC and albumin‐to‐creatinine ratio. Patients with a significant decrease (odds ratio [OR], 1.74 [95% CI, 1.25–2.42], P=0.001) or increase (OR, 1.51 [95% CI, 1.06–2.15], P=0.02) in eGFRCr+CysC also experienced a higher risk of disability. Conclusions Both the decline and increase in eGFRCr+CysC levels in the first year post stroke were independently associated with all‐cause mortality and stroke disability. These findings indicate that monitoring eGFRCr+CysC changes could be important for predicting long‐term outcomes and informing poststroke care strategies.

Summary: Background: Existing studies have not provided robust evidence about the CVD risk of non-smoking patients with restrictive spirometric pattern (RSP) or airflow obstruction (AFO), and how the risk is modified by body shape. We aimed to bridge the gap. Methods: We used never-smokers' data from the China Kadoorie Biobank (CKB) and performed Cox models by sex (278,953 females and 50,845 males). Spirometry was used to assess the baseline spirometric pattern. CVD outcomes were captured through multiple sources. Findings: Females’ results were presented primarily, though males' results were similar. During a median 12-year (maximum 14.5 years) follow-up, both RSP and AFO patients had increased risks of acute myocardial infarction (AMI), other ischaemic heart disease (other IHD), heart failure, pulmonary heart disease, arrhythmia, and intracerebral haemorrhage (ICH). RSP was also associated with ischaemic stroke (IS). The HRs (95% CIs) for AFO in females ranged from 1.29 (1.15–1.45) for ICH to 8.84 (7.79–10.03) for pulmonary heart disease, while those for RSP ranged from 1.11 (1.08–1.15) for IS to 3.17 (2.80–3.59) for pulmonary heart disease. These risks increased with the severity of AFO and reduced FVC. RSP/AFO was more strongly associated with other IHD, heart failure, and pulmonary heart disease in underweight females than in normal and obese counterparts, respectively. Interpretation: With the confounding of smoking fully controlled, both RSP and AFO were associated with higher risks of various CVD outcomes, which further increased with the severity of AFO and reduced FVC. These associations were even stronger in underweight individuals. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Ministry of Science and Technology of the People's Republic of China, Kadoorie Charitable Foundation, UK Wellcome Trust, UK Medical Research Council, Cancer Research UK, and British Heart Foundation.

Background and purpose Recombinant human prourokinase (rhPro-UK) is a new generation of specific plasminogen activator, that is non-inferior to alteplase in acute ischemic stroke. We aimed to investigate the efficacy and safety of rhPro-UK compared with standard medical treatment in acute mild ischemic stroke within 4.5 hours of symptom onset.Methods and design Prourokinase in mild ischemic stroke is a multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial. Patients who had an acute ischemic stroke within 4.5 hours from symptom onset and with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 will be recruited. Patients will be randomly assigned (1:1) to receive intravenous rhPro-UK (35 mg) or standard medical treatment. The follow-up duration will be 90 days. The calculated sample size is 1446.Study outcomes Primary efficacy outcome is an excellent functional outcome, defined as a modified Rankin Scale (mRS) score ≤ 1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, mRS score ≤ 2 at 90 days, early neurological improvement at 24 hours (a decrease of NIHSS score ≥ 4 points compared with baseline or NIHSS score ≤ 1 point), Barthel index of 75–100 points at 90 days, quality of life at 90 days, and activities of daily living at 90 days. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours, mortality at 90 days, moderate and severe systematic bleeding at 90 days, and adverse events/serious adverse events within 90 days.Discussion This large phase III randomised clinical trial will answer the question of whether thrombolysis is beneficial for acute mild ischemic stroke, and may provide evidence for rhPro-UK in patients had an acute mild ischemic stroke within 4.5 hours of symptom onset.Trial registration number NCT05507645

Background The benefit of intravenous alteplase in acute ischaemic stroke (AIS) is time-dependent. Tenecteplase is non-inferior to alteplase among patients with AIS. We aimed to delineate the association of the stroke onset to treatment time (OTT) with tenecteplase compared with alteplase on therapeutic benefit and clinical risks.Methods This is a post hoc analysis of the Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-2 an open-label, randomised, controlled, non-inferior trial. A total of 1430 AIS within 4.5 hours onset at 53 sites in China from 12 June 2021 to 29 May 2022 were randomly assigned (1:1) to receive either tenecteplase 0.25 mg/kg or alteplase 0.9 mg/kg. The primary efficacy outcome was the proportion of participants with a modified Rankin Scale score of 0–1 at 90 days. A post hoc subgroup analysis was conducted with the OTT divided into three intervals (0–90 min, 91–180 min and 181–270 min). The primary safety outcome was symptomatic intracranial haemorrhage within 36 hours post-thrombolytic treatment.Results Treatment was initiated within 270 min of stroke onset in 1412 patients who were randomly allocated to either tenecteplase (n=707) or alteplase (n=705). The OR of primary efficacy outcome was similar as OTT increased (p=0.84). Adjusted odds of an excellent functional outcome were 0.99 (95% CI 0.37 to 2.67) for 0–90 min, 1.23 (95% CI 0.88 to 1.71) for 91–180 min and 1.21 (95% CI 0.88 to 1.65) for 181–270 min. All were in favour of the tenecteplase group. Meta-analysis of 2949 patients yielded a pooled risk difference of 5.54 (95% CI −0.18 to 11.26; p=0.82) in favour of tenecteplase for more than 180 min and 1.77 (95% CI −2.66 to 6.20; p=0.58) for 0–180 min.Conclusions In AIS patients who were treated with either tenecteplase or alteplase within 4.5 hours onset, there was no difference observed in the efficacy and safety between the two groups at the three different OTT time intervals.

BackgroundTension-type headache (TTH) is among the most common primary headache disorders, characterized by recurrent episodes that are difficult to manage, thus posing a significant public health challenge. Acupuncture, a well-recognized non-pharmacological treatment, is frequently employed for pain management, including TTH. However, the variety of acupuncture techniques and inconsistent treatment outcomes underscore the need for a thorough evaluation. This study aims to update the current evidence on acupuncture and related therapies for TTH, evaluate the efficacy and safety of various acupuncture therapies, and identify the most effective therapeutic strategies, providing valuable guidance for clinical practice.MethodsWe systematically searched randomized controlled trials (RCTs) from four English databases (PubMed, Embase, Cochrane Library, and Web of Science) and four Chinese databases (Wanfang, VIP, CNKI, and SinoMed), including gray literature, up to April 19, 2024. The outcome measures included headache frequency, duration, pain intensity, and responder rate. A Bayesian network meta-analysis was conducted using Stata 17.0 to assess the relative effectiveness and safety of the different acupuncture therapies. This study was registered with the Prospective Register of Systematic Reviews (CRD42024537187).ResultsA total of 42 RCTs, encompassing 4,103 participants and 21 distinct treatment therapies, were included in the analysis. The network meta-analysis yielded the following findings: (1) regarding responder rate, several acupuncture or combined acupuncture and medication approaches, such as electro-acupuncture (EA) + cupping therapy (CT) [odds ratio (OR) = 28.66, 95% CI: 1.68 to 487.35], manual acupuncture (MA) + bloodletting therapy (BT) (OR = 6.07, 95% CI: 1.81 to 20.29), plum blossom needle tapping (PBNT) (OR = 3.76, 95% CI: 1.04 to 13.65), and scalp acupuncture (SPA) (OR = 3.65, 95% CI: 2.29 to 5.83), were significantly more effective than western medicine (WM) alone, with EA + CT (92.1%) being the most effective. (2) In terms of reducing headache frequency, EA (85.9%) was the most effective, followed by MA + PBNT (80.9%) and MA + WM (78.4%). Compared to WM, both MA + PBNT (SMD = −1.76, 95% CI: −3.31 to −0.22) and EA (SMD = −1.75, 95% CI: −3.30 to −0.20) significantly reduced headache frequency. (3) For shortening headache duration, EA (83.9%) emerged as the most effective treatment, followed by MA + WM (73.5%) and laser acupuncture (LA) (68.5%). (4) In terms of pain intensity reduction, the MA + WM combination (89.4%) was superior to other treatments, with SPA + WM (77.7%) being the next most effective. Compared to herbal medicine (HM), both MA + WM (SMD = −2.37, 95% CI: −4.20 to −0.55) and MA alone (SMD = −1.00, 95% CI: −1.75 to −0.24) significantly alleviated pain intensity.ConclusionThis comprehensive analysis of 21 acupuncture and related therapies demonstrates that EA is the most effective in reducing headache frequency and shortening headache duration, while EA + CT and MA + WM are the optimal therapies for enhancing responder rate and reducing pain intensity, respectively. However, clinical decisions should be individualized based on the specific needs of each patient.Systematic review registrationThe study protocol was registered on the PROSPERO database under registration number CRD42024537187 (https://www.crd.york.ac.uk/prospero/#recordDetails).

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination occurring in the central nervous system (CNS). Inulin is a common prebiotic that can improve metabolic disorders by modulating the gut microbiota. However, its capacity to affect CNS autoimmunity is poorly recognized. Experimental autoimmune encephalomyelitis (EAE) is a classical mouse model of MS. Herein, we found that oral administration of inulin ameliorated the severity EAE in mice, accompanied by reductions in inflammatory cell infiltration and demyelination in the CNS. These reductions were associated with decreased proportion and numbers of Th17 cells in brain and spleen. Consistent with the findings, the serum concentrations of IL-17, IL-6, and TNF-α were reduced in inulin treated EAE mice. Moreover, the proliferation of auto-reactive lymphocytes, against MOG35-55 antigen, was attenuated ex vivo. Mechanistically, inulin treatment altered the composition of gut microbiota. It increased Lactobacillus and Dubosiella whereas decreased g_Prevotellaceae_NK3B31_group at the genus level, alongside with elevated concentration of butyric acid in fecal content and serum. In vitro, butyrate, but not inulin, could inhibit the activation of MOG35-55 stimulated lymphocytes. Furthermore, fecal microbiota transplantation assay confirmed that fecal contents of inulin-treated normal mice had an ameliorative effect on EAE mice. In contrast, antibiotic cocktail (ABX) treatment diminished the therapeutic effect of inulin in EAE mice as well as the reduction of Th17 cells, while supplementation with Lactobacillus reuteri restored the amelioration effect. These results confirmed that the attenuation of inulin on Th17 cells and inflammatory demyelination in EAE mice was dependent on its modulation on gut microbiota and metabolites. Our findings provide a potential therapeutic regimen for prebiotic inulin supplementation in patients with multiple sclerosis.

Abstract Abandoned coal mine goaf is affected by air leakages and prone to spontaneous combustion, resulting in environmental pollution and geological disasters. Haizhou Open-pit Mine adopts both underground and open-pit mining methods. During the long-term mining process, the original stable stratum structure is constantly destroyed, and the slope slides, increasing cracks and severe air leakage around the goaf and roadway. The spontaneous combustion of coal is particularly prominent after the mine shut down. At present, there is no suitable indirect monitoring method to effectively explore the spontaneous combustion area in goaf. The study developed an all-weather monitoring plan and conducted multi-point continuous long-term measurements of the spontaneous combustion state in one abandoned coal mine goaf located in the eastern part of the Haizhou Open-pit Mine. We evaluated the dynamic correlation between surface CO2 flux (SCF) and changes in the underground fire areas, determined the scope and evolution trend of the fire areas, and identified the distribution and change laws of SCF. The results show a significant positive correlation between SCF and soil temperature; moreover, the SCF value was found to reflect the CO2 emission intensity of the goaf. The high SCF in the test area showed month-wise expansion and increase, while the CO2 emission gradually increased monthly, and the calculated annual total emission was approximately 7017 t. Hence, the study can further provide guidance for the monitoring of spontaneous combustion in shallow coal seams, goaf and the assessment of CO2 emissions from underground coal fires through the on-site monitoring and analysis results.

Abstract Background Stroke-associated pneumonia (SAP) and gastrointestinal bleeding (GIB) are common medical complications after stroke. The previous study suggested a strong association between SAP and GIB after stroke. However, little is known about the time sequence of SAP and GIB. In the present study, we aimed to verify the association and clarify the temporal sequence of SAP and GIB after ischemic stroke. Methods Patients with ischemic stroke from in-hospital Medical Complication after Acute Stroke study were analyzed. Data on occurrences of SAP and GIB during hospitalization and the intervals from stroke onset to diagnosis of SAP and GIB were collected. Multiple logistic regression was used to evaluate the association between SAP and GIB. Kruskal-Wallis test was used to compare the time intervals from stroke onset to diagnosis of SAP and GIB. Results A total of 1129 patients with ischemic stroke were included. The median length of hospitalization was 14 days. Overall, 86 patients (7.6%; 95% CI, 6.1-9.2%) developed SAP and 47 patients (4.3%; 95% CI, 3.0-5.3%) developed GIB during hospitalization. After adjusting potential confounders, SAP was significantly associated with the development of GIB after ischemic stroke (OR = 5.13; 95% CI, 2.02-13.00; P

Abstract Background Previous research on ABO blood types and stroke has been controversial, predominantly suggesting heightened risk of stroke in non-O blood types. Nonetheless, investigations into the correlation and underlying mechanisms between ABO blood groups and stroke subtypes, especially within Chinese cohorts, remain limited. Methods The ABO blood types of 9,542 ischaemic stroke (IS) patients were inferred using two ABO gene loci (c.261G > del; c.802G > A). The healthy population was derived from the 1000 Genomes Project. Patients were classified by the causative classification system (CCS). Volcano plot and gene ontology (GO) analysis were employed to explore protein differential expression among blood types. Additionally, HT29 and SW480 cell lines with downregulated ABO expression were generated to evaluate its impact on cholesterol uptake and efflux. Results A greater proportion of stroke patients had non-O blood types (70.46%) than did healthy individuals (61.54%). Notable differences in blood type distributions were observed among stroke subtypes, with non-O blood type patients mainly classified as having large artery atherosclerosis (LAA). Clinical baseline characteristics, such as the low-density lipoprotein cholesterol level, activated partial thromboplastin time and thrombin time, varied significantly among blood types. A volcano plot revealed 17 upregulated and 42 downregulated proteins in the O blood type. GO term analysis indicated that downregulated proteins were primarily associated with lipid metabolism pathways. In vitro experiments revealed that reducing ABO gene expression decreased cholesterol uptake and increased cholesterol efflux. Conclusions This study revealed that the non-O blood type increased the risk of LAA stroke through cholesterol metabolism.

Abstract Background Routine coagulation tests are not widely accepted diagnostic criteria of trauma-induced hypercoagulopathy (TIH) due to insensitivity. Lymphatic vessels drain approximately 10% of the interstitial fluid into the lymphatic system and form lymph. Subjective The purpose of this study was to identify the potential lymph biomarkers for TIH. Methods Eighteen male Sprague-Dawley rats were randomly assigned to the sham (non-fractured rats with sham surgery and vehicle treatment), the VEH (fractured rats with vehicle treatment) and the CLO (fractured rats with clopidogrel treatment) group. Thoracic duct lymph was obtained to perform proteomics and untargeted metabolomics. Results A total of 1207 proteins and 16,695 metabolites were identified. The top 5 GO terms of lymph proteomics indicated that oxidative stress and innate immunity were closely associated with TIH and antithrombotic therapy. The top 5 GO terms of lymph metabolomics showed that homocystine and lysophosphatidylcholine were the differential expressed metabolites (DEMs) between the sham and VEH groups, while cholic acid, docosahexaenoic acid, N1-Methyl-2-pyridone-5-carboxamide, isoleucine and testosterone are the DEMs between the VEH and CLO group. Conclusions This study presents the first proteomic and metabolomic profiling of lymph after TIH and antithrombotic therapy, and predicts the possible lymph biomarkers for TIH.

Abstract Background Life’s Essential 8 (LE8), the recently updated construct for quantifying cardiovascular health, is related to the risks of cardiovascular events. The present study aimed to evaluate associations of LE8 score with the multi-territorial extent of atherosclerosis in a community-dwelling population. Methods Data were derived from the baseline cross-sectional survey of the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in Lishui City. The LE8 included overall, medical and behavior LE8 scores, and were categorized as low (

Increased efforts in neuroscience seek to understand how macro-anatomical and physiological connectomes cooperatively work to generate cognitive behaviors. However, the structure-function coupling characteristics in normal aging individuals remain unclear. Here, we developed an index, the Coupling in Brain Structural connectome and Functional connectome (C-BSF) index, to quantify regional structure-function coupling in a large community-based cohort. C-BSF used diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (fMRI) data from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events study (PRECISE) cohort (2007 individuals, age: 61.15 ± 6.49 years) and the Sydney Memory and Ageing Study (MAS) cohort (254 individuals, age: 83.45 ± 4.33 years). We observed that structure-function coupling was the strongest in the visual network and the weakest in the ventral attention network. We also observed that the weaker structure-function coupling was associated with increased age and worse cognitive level of the participant. Meanwhile, the structure-function coupling in the visual network was associated with the visuospatial performance and partially mediated the connections between age and the visuospatial function. This work contributes to our understanding of the underlying brain mechanisms by which aging affects cognition and also help establish early diagnosis and treatment approaches for neurological diseases in the elderly.

Summary: Background: Guidelines recommend low-dose colchicine for secondary prevention in cardiovascular disease, but uncertainty remains concerning its efficacy for stroke, efficacy in key subgroups and about uncommon but serious safety outcomes. Methods: In this trial-level meta-analysis, we searched bibliographic databases and trial registries form inception to May 16, 2024. We included randomised trials of colchicine for secondary prevention of ischaemic stroke and major adverse cardiovascular events (MACE: ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death). Secondary outcomes were serious safety outcomes and mortality. A fixed-effect inverse-variance model was used to generate a pooled estimate of relative risk (RR) with 95% confidence intervals (CI). This study is registered with PROSPERO, CRD42024540320. Findings: Six trials involving 14,934 patients with prior stroke or coronary disease were included. In all patients, colchicine compared with placebo or no colchicine reduced the risk for ischaemic stroke by 27% (132 [1.8%] events versus 186 [2.5%] events, RR 0.73 [95% CI 0.58–0.90]) and MACE by 27% (505 [6.8%] events versus 693 [9.4%] events, with RR 0.73 [0.65–0.81]). Efficacy was consistent in key subgroups (females versus males, age below versus above 70, with versus without diabetes, statin versus non-statin users). Colchicine was not associated with an increase in serious safety outcomes: hospitalisation for pneumonia (109 [1.5%] versus 106 [1.5%], RR 0.99 [0.76–1.30]), cancer (247 [3.5%] versus 255 [3.6%], RR 0.97 [0.82–1.15]), and gastro-intestinal events (153 [2.1%] versus 135 [1.9%]), RR 1.15 [0.91–1.44]. There was no difference in all-cause death (201 [2.7%] versus 181 [2.4%], RR 1.09 [0.89–1.33]), cardiovascular death (70 [0.9%] versus 80 [1.1%], RR 0.89 [0.65–1.23]), or non-cardiovascular death (131 [1.8%] versus 101 [1.4%], RR 1.26 [0.98–1.64]). Interpretation: In patients with prior stroke or coronary disease, colchicine reduced ischaemic stroke and MACE, with consistent treatment effect in key subgroups, and did not increase serious safety events or death. Funding: There was no funding source for this study.

Background The aim of this study was to investigate the efficacy and safety of tenecteplase versus alteplase in patients with acute ischemic stroke, considering their diabetes history and admission hyperglycemia status. Methods and Results This was a post hoc analysis of the TRACE‐2 (Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events‐2) randomized clinical trial that enrolled patients in China between June 2021 and May 2022. Eligible patients with acute ischemic stroke for standard intravenous thrombolysis, but ineligible for endovascular thrombectomy, were randomly assigned (1:1) to tenecteplase or alteplase within 4.5 hours of symptom onset. Admission hyperglycemia was defined as plasma glucose >7.8 mmol/L. The primary efficacy and safety outcome were excellent functional outcome at 90 days (modified Rankin Scale score of 0–1) and symptomatic intracranial hemorrhage within 36 hours, respectively. The Cochran–Mantel–Haenszel χ2 test was used for the outcomes. Of the 1382 patients included, 369 (26.7%) had a history of diabetes, and 482 (34.9%) experienced admission hyperglycemia. The primary efficacy outcome, comparing tenecteplase to alteplase, was achieved in 93 (56.7%) versus 97 (48.3%) among patients with a history of diabetes (P=0.11) and 335 (64.6%) versus 300 (62.2%) among those without diabetes (P=0.45), respectively. The primary efficacy outcome for tenecteplase versus alteplase was comparable among patients with and without admission hyperglycemia (57.5% versus 53.9%, P = 0.44; 65.4% versus 60.4%, P=0.12, respectively). No significant difference in the risk of symptomatic intracranial hemorrhage within 36 hours was observed between tenecteplase and alteplase, regardless of diabetes history or admission hyperglycemia. Conclusions This study demonstrated that intravenous tenecteplase exhibits similar clinical outcomes compared with alteplase, irrespective of the patient's glucose metabolism status. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT04797013.

The consumption of chemical fertilizers has increased eight-fold since the 19th century, outstripping crop yields increases and, emphasizing the need for precise nitrogen (N) assessment in crops to optimize fertilization and mitigate environmental impacts. This study developed a model using chlorophyll fluorescence technology to accurately evaluate the N status in maize leaves while addressing the limitations of current labor-intensive and environmentally sensitive methods. Based on a long-term experiment initiated in 2011, maize hybrid Fumin 985 was sampled in 2021 and 2022 under two crop-straw management strategies (SM: no tillage with surface straw mulch, SP: plough tillage with straw incorporation) and six N application rates. Partial least squares regression (PLSR) models were formulated using chlorophyll fluorescence parameters (ChlF) to assess leaf N content (N leaf). The results indicated that a N application rate of 270 kg ha−1 sufficed to meet crop N requirements. Leaf characteristics such as N leaf, total pigment content (TP), and leaf dry weight (DW leaf) changed significantly with increasing N application rates, influencing rapid chlorophyll fluorescence (OJIP) dynamics. Principal component analysis (PCA) reduced ChlF from 35 to 21, and four models were developed, among which, the model using ChlF and TP was more accurate than the model using DW alone. Key ChlF parameters for PLSR model performance included ABS/RC, φ(Eo), ETo/CSm, and δ(Ro)/(1–δ(Ro)). Although non-destructive N leaf detection using chlorophyll fluorescence technology proved feasible, additional leaf characteristics, such as TP, are necessary to improve model accuracy. Considering local field conditions is essential for the application of this technology at a larger scale. Precise evaluation of N status using chlorophyll fluorescence is beneficial for a more efficient N management and sustainable agriculture.

Background Diabetic foot ulcers (DFUs) are a common and serious complication of diabetes, often leading to amputation and decreased quality of life. Current treatment methods have limited success rates, highlighting the need for new approaches. This study investigates the potential of tibial transverse transport (TTT) to promote wound healing in DFUs.Methods To test this hypothesis, the study used New Zealand White rabbits to establish a diabetic model and simulate foot ulcers, followed by the treatment of unilateral TTT or bilateral TTT. The study employed histological analysis, flow cytometry, ELISA, and qPCR to assess the impact of TTT on tissue repair and endothelial progenitor cell (EPC) mobilization and homing, aiming to understand the underlying biological processes in wound healing.Results TTT significantly enhanced wound healing in diabetic rabbit foot ulcers. Specifically, bilateral TTT led to complete wound healing by day 19, faster than the unilateral TTT group, which healed by day 26, and the sham operation group, which nearly healed by day 37. Histological analysis showed improved tissue architecture, collagen deposition, and neovascularization in TTT-treated groups. Furthermore, TTT treatment resulted in a significant increase in VEGFR2 expression and VEGFR2/Tie-2 positive cells, particularly in the bilateral group. These findings were corroborated by qPCR results, which showed increased expression of VEGFA and CXCL12 by TTT. Conclusions: TTT may be a promising treatment for DFUs, significantly enhancing wound healing by stimulating EPC mobilization and homing mediated angiogenesis. This novel approach could substantially improve treatment outcomes for diabetic patients with chronic foot ulcers.

Liquid-liquid phase separation (LLPS) is integral to various biological processes, facilitating signal transduction by creating a condensed, membrane-less environment that plays crucial roles in diverse physiological and pathological processes. Recent evidence has underscored the significance of LLPS in human health and disease. However, its implications in respiratory diseases remain poorly understood. This review explores current insights into the mechanisms and biological roles of LLPS, focusing particularly on its relevance to respiratory diseases, aiming to deepen our understanding and propose a new paradigm for studying phase separation in this context.

Abstract Background and Aim Glycated albumin (GA) is a biomarker monitoring glycemia 2–4 weeks before stroke onset. This study was designed to explore the association between GA levels with poststroke outcomes in patients with acute ischemic stroke or transient ischemic attack (TIA). Method Participants with ischemic stroke or TIA who had a baseline GA measurement were included in the Third China National Stroke Registry study. The effect of GA on stroke recurrence, poor functional outcomes, and combined vascular events was examined during the 1‐year follow‐up period. Multivariate Cox and logistic regression models were performed to evaluate the association. Discrimination tests were used to examine the incremental predictive value of GA when incorporating it into the conventional model. Results A total of 3861 participants were enrolled. At the 3‐month follow‐up, the elevated GA level was associated with an increased risk of poor functional outcomes (adjusted odds ratio [OR], 1.45; 95% confidence interval [CI], 1.01–2.09). A similar increase was observed for stroke recurrence (adjusted hazard ratio [HR], 1.56; 95% CI, 1.09–2.24), poor functional outcomes (adjusted OR, 1.62; 95% CI, 1.07–2.45), and combined vascular events (adjusted HR, 1.55; 95% CI, 1.09–2.20) at the 1‐year follow‐up. In nondiabetic patients, the association between GA and poor functional outcomes was more pronounced (adjusted OR, 1.62; 95% CI, 1.05–2.50). Adding GA into the conventional model resulted in slight improvements in predicting poor functional outcomes (net reclassification improvement [NRI]: 12.30% at 1 year). Conclusion This study demonstrated that elevated GA levels in serum were associated with stroke adverse outcomes, including stroke recurrence, poor functional outcomes, and combined vascular events, in patients with ischemic stroke or TIA.

Abstract Current harmonics are generated at the switching frequency and its multiples when the traction converters are modulated. To address this, multi-trap filters are introduced, which are capable of selectively eliminating these specific harmonics to the limits set by IEEE 519-2014. This targeted removal significantly reduces the need for high total inductance, thereby allowing for a more compact filter design. Comparatively, to traditional inductor-capacitor-inductor (LCL) filters, more magnetic cores are needed for trap inductors. Furthermore, the traction systems have not been examined in conjunction with multi-trap filters. To reduce the filter size and investigate its application in traction converters, this paper presents an integrated double-trap LCL (DTLCL) filter. A tiny capacitor is connected in parallel with the grid-side inductor to form one LC-trap. In addition, another LC-trap is formed by connecting the equivalent trap inductor, introduced through the magnetic coupling between inverter-side and grid-side inductors, in series with the filter capacitor. The presented filters' features are thoroughly analyzed, and the design method has been developed. Finally, the simulation and hardware-in-the-loop (HIL) experiment results validate the proposed method's viability and efficacy. Compared to the discrete windings, the integrated ones enable a size decrease of two cores. Furthermore, the proposed filters can meet IEEE 519-2014 criteria with 0.3% for all the current switching harmonics and total harmonic distortion (THD) of 2.36% of the grid‐side current.

Abstract Lupus nephritis (LN) occurs in 50% of cases of systemic lupus erythematosus (SLE) and is one of the most serious complications that can occur during lupus progression. Mesangial cells (MCs) are intrinsic cells in the kidney that can regulate capillary blood flow, phagocytose apoptotic cells, and secrete vasoactive substances and growth factors. Previous studies have shown that various types of inflammatory cells can activate MCs for hyperproliferation, leading to disruption of the filtration barrier and impairment of renal function in LN. Here, we characterized the heterogeneity of kidney cells of LN mice by single-nucleus RNA sequencing (snRNA-seq) and revealed the interaction between macrophages and MCs through the CXC motif chemokine ligand 12 (CXCL12)/dipeptidyl peptidase 4 (DPP4) axis. In culture, macrophages modulated the proliferation and migration of MCs through this ligand–receptor interaction. In LN mice, treatment with linagliptin, a DPP4 inhibitor, effectively inhibited MC proliferation and reduced urinary protein levels. Together, our findings indicated that targeting the CXCL12/DPP4 axis with linagliptin treatment may serve as a novel strategy for the treatment of LN via the CXCL12/DPP4 axis.

Abstract Background Elderly patients suffering from osteoporotic fractures are more susceptible to delayed union or nonunion, and their bodies then are in a state of low-grade chronic inflammation with decreased antioxidant capacity. Tanshinone IIA is widely used in treating cardiovascular and cerebrovascular diseases in China and has anti-inflammatory and antioxidant effects. We aimed to observe the antioxidant effects of Tanshinone IIA on mesenchymal stem cells (MSCs), which play important roles in bone repair, and the effects of local application of Tanshinone IIA using an injectable biodegradable hydrogel on osteoporotic fracture healing. Methods MSCs were pretreated with or without different concentrations of Tanshinone IIA followed by H2O2 treatment. Ovariectomized (OVX) C57BL/6 mice received a mid-shaft transverse osteotomy fracture on the left tibia, and Tanshinone IIA was applied to the fracture site using an injectable hydrogel. Results Tanshinone IIA pretreatment promoted the expression of nuclear factor erythroid 2-related factor 2 and antioxidant enzymes, and inhibited H2O2-induced reactive oxygen species accumulation in MSCs. Furthermore, Tanshinone IIA reversed H2O2-induced apoptosis and decrease in osteogenic differentiation in MSCs. After 4 weeks of treatment with Tanshinone IIA in OVX mice, the bone mineral density of the callus was significantly increased and the biomechanical properties of the healed tibias were improved. Cell apoptosis was decreased and Nrf2 expression was increased in the early stage of callus formation. Conclusions Taken together, these results indicate that Tanshinone IIA can activate antioxidant enzymes to protect MSCs from H2O2-induced cell apoptosis and osteogenic differentiation inhibition. Local application of Tanshinone IIA accelerates fracture healing in ovariectomized mice.

Background and Purpose Non-high-density lipoprotein cholesterol (non-HDL-C), which represents the total cholesterol content of all pro-atherogenic lipoproteins, has recently been included as a new target for lipid-lowering therapy in high-risk atherosclerotic patients in multiple guidelines. Herein, we aimed to explore the relationship between non-HDL-C level and the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing stroke recurrence. Methods This study comprised a post hoc analysis of the CHANCE-2 (Ticagrelor or Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II) trial, from which 5,901 patients with complete data on non-HDL-C were included and categorized by median non-HDL-C levels, using a cutoff of 3.5 mmol/L. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days. Results Ticagrelor-aspirin significantly reduced the risk of recurrent stroke in patients with low non-HDL-C (71 [4.8%] vs. 119 [7.7%]; adjusted hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.40–0.74), but not in those with high non-HDL-C (107 [7.3%] vs. 108 [7.6%]; adjusted HR, 0.88; 95% CI, 0.67–1.16), compared with clopidogrel-aspirin (P for interaction=0.010). When analyzed as a continuous variable, the benefit of ticagrelor-aspirin for recurrent stroke decreased as non-HDL-C levels increased. No significant differences in the treatment assignments across the non-HDL-C groups were observed in terms of the rate of severe or moderate bleeding (5 [0.3%] vs. 8 [0.5%] in the low non-HDL-C group; 4 [0.3%] vs. 2 [0.1%] in the high non-HDL-C group; P for interaction=0.425). Conclusion CHANCE-2 participants with low non-HDL-C levels received more clinical benefit from ticagrelor-aspirin versus clopidogrel-aspirin compared to those with high non-HDL-C, following minor ischemic stroke or transient ischemic attack.

Knowledge of the function of growth-regulating factors (GRFs) in sugarcane (Saccharum officinarum and S. spontaneum) growth and development could assist breeders in selecting desirable plant architectures. However, limited information about GRFs is available in Saccharum due to their polyploidy. In this study, 22 GRFs were identified in the two species and their conserved domains, gene structures, chromosome location, and synteny were characterized. GRF7 expression varied among tissues and responded to diurnal rhythm. SsGRF7-YFP was localized preferentially in the nucleus and appears to act as a transcriptional cofactor. SsGRF7 positively regulated the size and length of rice leaves, possibly by regulating cell size and plant hormones. Of seven potential transcription factors binding to the SsGRF7 promoter in S. spontaneum, four showed positive expression patterns, and two showed negative expression patterns relative to SsGRF7.

Background: The musculoskeletal system contains an extensive network of lymphatic vessels. Decreased lymph flow of the draining collecting lymphatics usually occurs in clinic after traumatic fractures. However, whether defects in lymphatic drainage can affect fracture healing is unclear. Methods: To investigate the effect of lymphatic dysfunction on fracture healing, we used a selective VEGFR3 tyrosine kinase inhibitor to treat tibial fractured mice for 5 weeks versus a vehicle-treated control. To ensure successfully establishing deceased lymphatic drainage model for fractured mice, we measured lymphatic clearance by near infrared indocyanine green lymphatic imaging (NIR-ICG) and the volume of the draining popliteal lymph nodes (PLNs) by ultrasound at the whole phases of fracture healing. In addition, hindlimb edema from day 0 to day 7 post-fracture, pain sensation by Hargreaves test at day 1 post-fracture, bone histomorphometry by micro-CT and callus composition by Alcian Blue-Hematoxylin/Orange G staining at day 14 post-fracture, and bone quality by biomechanical testing at day 35 post-fracture were applied to evaluate fracture healing. To promote fracture healing via increasing lymphatic drainage, we then treated fractured mice with anti-mouse podoplanin (PDPN) neutralizing antibody or isotype IgG antibody for 1 week to observe lymphatic drainage function and assess bone repair as methods described above. Results: Compared to vehicle-treated group, SAR-treatment group significantly decreased lymphatic clearance and the volume of draining PLNs. SAR-treatment group significantly increased soft tissue swelling, and reduced bone volume (BV)/tissue volume (TV), trabecular number (Tb.N), woven bone and biomechanical properties of fracture callus. In addition, anti-PDPN treated group significantly reduced the number of CD41+ platelets in PLNs and increased the number of pulsatile lymphatic vessels, lymphatic clearance and the volume of PLNs. Moreover, anti-PDPN treated group significantly reduced hindlimb edema and pain sensation and increased BV/TV, trabecular number (Tb.Th), woven bone and biomechanical properties of fracture callus. Conclusions: Inhibition of proper lymphatic drainage function delayed fracture healing. Use of a anti-PDPN neutralizing antibody reduced lymphatic platelet thrombosis (LPT), increased lymphatic drainage and improved fracture healing. The translational potential of this article: (1) We demonstrated lymphatic drainage function is crucial for fracture healing. (2) To unblock the lymphatic drainage and prevent the risk of bleeding and mortality by blood thinner, we demonstrated PDPN neutralizing antibody is a novel and safe way forward in the treatment of bone fracture healing by eliminating LPT and increasing lymphatic drainage.

Objective The Dayingezhuang gold deposit in the middle of the Zhaoping metallogenic belt represents a typical altered-rock type deposit with a giant Au reserve of 283 tons on the Jiaodong Peninsula. The genetic type of the deposit is still controversial. Methods Based on detailed field observations, ore genesis and variations in ore-forming fluids from different depths were investigated in this study. Results Fluid inclusion studies show that the ore-forming fluids formed an H2O-CO2-NaCl±CH4 system with moderate temperature, low salinity, and moderate-low density. Furthermore, the temperatures and salinities decrease gradually from the early to late mineralization stages(Ⅰ-Ⅳ), but the opposite occurs at densities. Hydrogen and O isotopic compositions show that the ore fluids were dominated by magmatic water in the early stage, with subordinate meteoric water input during the late stages. Fluid boiling occurred possibly during the main mineralization stages. Sulfur and Pb isotopes of pyrite indicate that the ore-forming materials were derived from deep crust-mantle mixed magma. Overall, the mineralization process and tectonic setting are similar to those of the other Jiaodong gold deposits in a craton-destruction environment. Conclusion Comprehensive comparisons of ore fluids, Au and Ag contents, and gold fineness between shallow and deep ores show that ore fluids and mineralization intensity are consistent throughout the deposit. Gold precipitation has a broad and stable environment, indicating the great potential for mineral exploration in deep spaces.

Osteoarthritis (OA) is a common chronic inflammatory disorder. Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA. However, current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints. Bortezomib (BTZ), a proteasome inhibitor, could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues. To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy, herein, we designed a novel nanomedicine (denoted as BTZ@PTK) by the co-assembly of BTZ and an amphiphilic copolymer (denoted as PTK) with ROS-cleaved thioketal (TK) linkages. The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites, and then triggered the controlled release of BTZ, resulting in the accurate delivery and the inflammatory microenvironment remodeling. Accordingly, BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide (LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages, which leads to a better effect than BTZ. In OA mice, BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality. Importantly, BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium, thereby delaying cartilage damage. Collectively, BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.

A central question in neural tissue engineering is how the tissue-engineered nerve (TEN) translates detailed transcriptional signals associated with peripheral nerve regeneration into meaningful biological processes. Here, we report a skin-derived precursor-induced Schwann cell (SKP-SC)-mediated chitosan/silk fibroin-fabricated tissue-engineered nerve graft (SKP–SCs-TEN) that can promote sciatic nerve regeneration and functional restoration nearly to the levels achieved by autologous nerve grafts according to behavioral, histological, and electrophysiological evidence. For achieving better effect of neuroregeneration, this is the first time to jointly apply a dynamic perfusion bioreactor and the ascorbic acid to stimulate the SKP-SCs secretion of extracellular matrix (ECM). To overcome the limitation of traditional tissue-engineered nerve grafts, jointly utilizing SKP-SCs and their ECM components were motivated by the thought of prolongating the effect of support cells and their bioactive cues that promote peripheral nerve regeneration. To further explore the regulatory model of gene expression and the related molecular mechanisms involved in tissue engineering-aided peripheral nerve regeneration, we performed a cDNA microarray analysis of gene expression profiling, a comprehensive bioinformatics analysis and a validation study on the grafted segments and dorsal root ganglia tissues. A wealth of transcriptomic and bioinformatics data has revealed complex molecular networks and orchestrated functional regulation that may be responsible for the effects of SKP-SCs-TEN on promoting peripheral nerve regeneration. Our work provides new insights into transcriptomic features and patterns of molecular regulation in nerve functional recovery aided by SKP-SCs-TEN that sheds light on the broader possibilities for novel repair strategies of peripheral nerve injury.

This paper introduces magnetic integrated high-order trap–trap–inductor (TTL) and inductor–trap–trap (LTT) filters featuring two LC-traps designed for grid-tied inverters, aimed at reducing the size of output-power multi-trap filters. The proposed filters exhibit excellent harmonic absorption capabilities alongside a compact design. Building on the conventional integrated inductor–capacitor–inductor (LCL) filter, the approach involves connecting a small capacitor in parallel with either the inverter-side or grid-side inductors to create an LC trap. Additionally, a second LC trap can be achieved by integrating the filter capacitor in series with the equivalent trap inductance, established by the magnetic coupling between the grid-side inductor and inverter-side one. This paper thoroughly analyzes the characteristics of the proposed filters. Moreover, a design method is presented to further minimize the size of the output filter components. Finally, validation through simulations and hardware-in-the-loop (HIL) experiments confirms the proposed approach’s effectiveness and feasibility. The integrated designs achieve a size reduction of 35.4% in comparison with the discrete windings. Moreover, these designed filters comply with IEEE standards, maintaining a grid-side current total harmonic distortion (THD) of less than 0.9%, with all current harmonics below 0.3% of the fundamental current.

Background Recent Mendelian randomization and meta‐analysis highlight the relevance of MCP‐1 (monocyte chemoattractant protein‐1) in stroke. We aimed to investigate the associations between MCP‐1 and clinical outcomes in patients with ischemic stroke or transient ischemic attack and test whether inflammation mediates or jointly contributes to the relationships. Methods and Results A total of 10 700 patients from the Third China National Stroke Registry study were included. Multivariable Cox regression was used for recurrent stroke and all‐cause death, and logistic regression was used for poor functional outcome. Mediation analyses were performed to clarify whether inflammation mediates the associations. After adjusting for potential confounders, low MCP‐1 level (

Background Tenecteplase, a bioengineered variant of alteplase, is a new alternative thrombolytic agent. The ORIGINAL study aims to evaluate the efficacy and safety of tenecteplase versus standard care in Chinese patients with acute ischemic stroke within 4.5 hours of symptom onset. Methods This is a multicenter phase III study that employs a randomized (1:1), active‐controlled, parallel‐group, prospective, open‐label, blinded–end point design. Adult participants (aged ≥18 years) with acute ischemic stroke who are eligible for intravenous thrombolysis within 4.5 hours of symptom onset according to current guideline recommendations are recruited from ≈55 neurology clinics/stroke centers throughout China. Results The primary objective of the ORIGINAL study is to demonstrate the noninferiority of tenecteplase (0.25 mg/kg) to alteplase (0.9 mg/kg) on the basis of the proportion of patients who achieve a modified Rankin Scale score of 0 or 1 on day 90, that is, a favorable functional outcome. The prespecified noninferiority risk ratio margin is 0.937. Secondary end points include other functional outcomes and the following safety end points: adjudicated symptomatic intracerebral hemorrhage (up to 36 hours after the end of study drug administration) based on the European Cooperative Acute Stroke Study III definition; all‐cause death within 90 days; and the proportion of patients with a modified Rankin Scale score of 5 or 6 on day 90. Conclusions It is anticipated that the results of this study will contribute to the growing body of evidence for the noninferiority of tenecteplase to alteplase given within 4.5 hours of acute ischemic stroke symptom onset and support a new indication for tenecteplase in China. Clinical Trial Registration Information NCT04915729 (https://clinicaltrials.gov/study/NCT04915729)

Abstract Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well‐characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A‐driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.

Summary: Background: Endovascular therapy (EVT) was demonstrated effective in acute large vessel occlusion (LVO) with large infarction. Revealing subgroups of patients who would or would not benefit from EVT will further inform patient selection for EVT. Methods: This post-hoc analysis of the ANGEL-ASPECT trial, a randomised controlled trial of 456 adult patients with acute anterior-circulation LVO and large infarction, defined by ASPECTS 3–5 or infarct core volume 70–100 mL, enrolled from 46 centres across China, between October 2, 2020 and May 18, 2022. Patients were randomly assigned (1:1) to receiving EVT and medical management or medical management alone. One patient withdrew consent, 455 patients were included in this post-hoc analysis and categorised into 4 subgroups by lower or higher NIHSS (< or ≥16) and smaller or larger infarct core (< or ≥70 mL). Those with lower NIHSS & smaller core, and higher NIHSS & larger core were considered clinical-radiological matched subgroups; otherwise clinical-radiological mismatched subgroups. Primary outcome was 90-day modified Rankin Scale (mRS). ANGEL-ASPECT is registered with ClinicalTrials.gov, NCT04551664. Findings: Overall, 139 (30.5%) patients had lower NIHSS & smaller core, 106 (23.3%) higher NIHSS & larger core, 130 (28.6%) higher NIHSS & smaller core, and 80 (17.6%) lower NIHSS & larger core. There was significant ordinal shift in the 90-day mRS toward a better outcome with EVT in clinical-radiological matched subgroups: lower NIHSS & smaller core (generalised OR, 1.76; 95% CI, 1.18–2.62; p = 0.01) and higher NIHSS & larger core (1.64; 1.06–2.54; 0.01); but not in the two clinical-radiological mismatched subgroups. Interpretation: Our findings suggested that in patients with anterior-circulation LVO and large infarction, EVT was associated with improved 90-day functional outcomes in those with matched clinical and radiological severities, but not in those with mismatched clinical and radiological severities. Simultaneous consideration of stroke severity and infarct core volume may inform patient selection for EVT. Funding: Unrestricted grants from industry [Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology].

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.

ObjectiveThis study aimed to examine the relationship between lipoprotein (a) (Lp[a]) and other blood lipid indexes and carotid artery atherosclerosis in patients with acute ischemic stroke (AIS).MethodsA total of 2,018 patients were selected from the hospital “acute stroke intervention and secondary prevention registration database” by identifying blood fat indexes (cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and Lp[a]). Based on the results of carotid artery ultrasound examinations, the patients were divided into a “no plaque” group, comprising 400 patients, a “plaque and no stenosis” group, comprising 1,122 patients and a “carotid stenosis” group, comprising 496 patients. The relationship between Lp(a) and blood lipid indexes and carotid artery atherosclerosis was then investigated using multi-factor logistics regression analysis.ResultsThere were 400 patients (19.8%) with no carotid plaque, 1,122 patients (55.6%) with plaque and no carotid stenosis and 496 patients (24.6%) with carotid stenosis. As the degree of carotid artery atherosclerosis increased, the Lp(a) level gradually increased; Lp(a) and cholesterol were identified as independent risk factors for carotid atherosclerosis.ConclusionLipoprotein (a) and cholesterol are independent risk factors for patients with AIS with carotid atherosclerosis, and their levels increase with the degree of carotid artery atherosclerosis; therefore, attention should focus on levels of cholesterol and Lp(a) in acute stroke patients to control atherosclerosis effectively.

Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.