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Abstract With the focus on the insufficient origin-based cold storage in China, this study investigates the location and routing problem (LRP) of origin-based cold storage for fresh agricultural products. This study considers the loss of fresh agricultural products in different environments during transportation and presents a cold storage LRP model. To address this issue, a hybrid whale algorithm with heuristic rules is designed, and the effectiveness of the algorithm is verified by standard instances. Finally, taking Chenggu County as a practical case, the influence of cold storage capacity and farmers’ demand for refrigeration are analysed. Experimental results show that the proposed algorithm has a good effect in solving medium-scale LRP. As the storage capacity increases, the total cost of the system can be increased by 0.086%. As farmers’ demand for refrigeration increases, the total cost of the system can be increased by 34.034%. Farmers’ demand has a greater impact on the system’s total costs than the cold storage capacity. When optimizing the cold storage layout, changes in fresh agricultural product output in the next few years can be roughly predicted, and the most economical optimization scheme can be obtained.

Abstract Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving “immune cell-gut microbes-bile acid metabolites” contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD. Graphical abstract

Abstract Streptococcus pneumoniae is a significant pathogen causing infectious diseases, including pneumonia, otitis media, septicemia, and meningitis. The introduction of multivalent vaccines has coincided with a remarkable decrease in the number of pneumococcal-related deaths. Despite this, pneumococcal infection remains a significant cause of death among children under 5 years old and adults aged 65 or older at a global level. Therefore, early detection of S. pneumoniae infection is crucial for prognosis of pneumococcal infection patients. In this study, we evaluated the utility of a real-time multienzyme isothermal rapid amplification (MIRA) assay for detecting S. pneumoniae and other non-S. pneumoniae bacterial species. A primer–probe set targeting the S. pneumoniae lytA gene was designed, followed by optimization of parameters for the MIRA assay. At the same time, we validated the real-time MIRA assay for detecting S. pneumoniae using 79 clinical isolates identified by VITEK MS. The results showed a detection sensitivity and specificity of 100%. These results demonstrate that the designed real-time MIRA assay is a promising, rapid, simple, and reliable method for detecting S. pneumoniae infection in resource-limited areas. It has great potential for application in detecting not only S. pneumoniae but also other non-S. pneumoniae bacterial species.

Abstract The benefits of physical exercise on human health make it desirable to identify new approaches that would mimic or potentiate the effects of exercise to treat metabolic diseases. However, whether far-infrared (FIR) hyperthermia therapy could be used as exercise mimetic to realize wide-ranging metabolic regulation, and its underling mechanisms remain unclear. Here, a specific far-infrared (FIR) rays generated from graphene-based hyperthermia devices might promote exercise capacity and metabolisms. The material characterization showed that the graphene synthesized by chemical vapour deposition (CVD) was different from carbon fiber, with single-layer structure and high electrothermal transform efficiency. The emission spectra generated by graphene-FIR device would maximize matching those adsorbed by tissues. Graphene-FIR enhanced both core and epidermal temperatures, leading to increased blood flow in the femoral muscle and the abdominal region. The combination of microbiomic and metabolomic analysis revealed that graphene-FIR modulates the metabolism of the gut-muscle axis. This modulation was characterized by an increased abundance of short-chain fatty acids (SCFA)-producing bacteria and AMP, while lactic acid levels decreased. Furthermore, the principal routes involved in glucose metabolism, such as glycolysis and gluconeogenesis, were found to be altered. Graphene-FIR managed to stimulate AMPK activity by activating GPR43, thus enhancing muscle glucose uptake. Furthermore, a microbiota disorder model also demonstrated that the graphene-FIR effectively restore the exercise endurance with enhanced p-AMPK and GLUT4. Our results provided convincing evidence that graphene-based FIR therapy promoted exercise capacity and glucose metabolism via AMPK in gut-muscle axis. These novel findings regarding the therapeutic effects of graphene-FIR suggested its potential utility as a mimetic agent in clinical management of metabolic disorders.

With the use of metagenomic next-generation sequencing, patients diagnosed with Whipple pneumonia are being increasingly correctly diagnosed. We report a series of 3 cases in China that showed a novel pattern of movable infiltrates and upper lung micronodules. After treatment, the 3 patients recovered, and lung infiltrates resolved.

Abstract Pyroptosis may play an important role in the resistance of ovarian cancer (OC) to chemotherapy. However, the mechanism by which pyroptosis modulation can attenuate chemotherapy resistance has not been comprehensively studied in OC. Here, we demonstrated that RAS‐associated C3 botulinum toxin substrate 1 (RAC1) is highly expressed in OC and is negatively correlated with patient outcomes. Through cell function tests and in vivo tumor formation tests, we found that RAC1 can promote tumor growth by mediating paclitaxel (PTX) resistance. RAC1 can mediate OC progression by inhibiting pyroptosis, as evidenced by high‐throughput automated confocal imaging, the release of lactate dehydrogenase (LDH), the expression of the inflammatory cytokines IL‐1β/IL‐18 and the nucleotide oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome. Mechanically, RNA‐seq, gene set enrichment analysis (GSEA), coimmunoprecipitation (Co‐IP), mass spectrometry (MS), and ubiquitination tests further confirmed that RAC1 inhibits caspase‐1/gasdermin D (GSDMD)‐mediated canonical pyroptosis through the P21‐activated kinase 4 (PAK4)/mitogen‐activated protein kinase (MAPK) pathway, thereby promoting PTX resistance in OC cells. Finally, the whole molecular pathway was verified by the results of in vivo drug combination tests, clinical specimen detection and the prognosis. In summary, our results suggest that the combination of RAC1 inhibitors with PTX can reverse PTX resistance by inducing pyroptosis through the PAK4/MAPK pathway.

We report a clinical isolate of Burkholderia thailandensis 2022DZh obtained from a patient with an infected wound in southwest China. Genomic analysis indicates that this isolate clusters with B. thailandensis BPM, a human isolate from Chongqing, China. We recommend enhancing monitoring and surveillance for B. thailandensis infection in both humans and livestock.

Introduction Thyroid cancer stem cells (TCSCs) play a crucial role in the pathogenesis, metastasis, and therapeutic response of thyroid cancer, making them promising biomarkers and potential targets for clinical intervention. This systematic review aims to qualitatively assess the impact of commonly used TCSC markers on the prognosis of thyroid cancer using qualitative methods. Material and methods In total, the analysis encompassed five articles. Results Six TCSC markers were involved, among which CD133, CD44, CD24, CD15 and ALDH1 were associated with the prognosis of thyroid cancer. Conclusions However, the utility of these TCSC markers in clinical practice for predicting the prognosis of thyroid cancer requires further research to provide additional evidence supporting their effectiveness.

Background Cushing’s syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters.Methods A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD.Results A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p

Background: The gut microbiota thrives in a complex ecological environment and its dynamic balance is closely related to host health. Recent studies have shown that the occurrence of various diseases including prostate inflammation is related to the dysregulation of the gut microbiome. Objective: This review focus on the mechanisms by which the gut microbiota induces prostate inflammation and benign prostatic hyperplasia and its therapeutic implications. Materials and methods: Publications related to gut microbiota, prostate inflammation, and benign prostatic hyperplasia (BPH) until April 2023 were systematically reviewed. The research questions were formulated using the Problem, Intervention, Comparison/Control, and Outcome (PICO) frameworks. Results: Fifteen articles covering the relationship between the gut microbiota and prostate inflammation/BPH, the mechanisms by which the gut microbiota influences prostate inflammation and BPH, and potential therapeutic approaches targeting the gut microbiota for these conditions were included. Conclusion: Short-chain fatty acids (SCFAs), which are metabolites of the intestinal microbiota, protect the integrity of the intestinal barrier, regulate immunity, and inhibit inflammation. However, dysregulation of the gut microbiota significantly reduces the SCFA content in feces and impairs the integrity of the gut barrier, leading to the translocation of bacteria and bacterial components such as lipopolysaccharide, mediating the development of prostate inflammation through microbe-associated molecular patterns (MAMPs).

Summary: In scenarios involving the treatment of complex or coexisting diseases with multiple drugs, the potential for severe adverse drug reactions in patients necessitates the identification of potential drug-drug interactions (DDIs). Most existing computational methods have not taken into account the asymmetry and relation types of drug interactions caused by the relation information between drugs, which may lead to missing information in embedded learning. Therefore, this paper proposes a directed relation graph attention aware network (DRGATAN) to predict asymmetric drug interactions. DRGATAN leverages an encoder to learn multi-relational role embeddings of drugs across different types of relations. The experimental results show that DRGATAN’s performance is superior to recognized advanced methods. The visualization demonstrates the effect of utilizing asymmetric information, and the case analysis validates the reliability of the proposed method. This study provides guidance for predicting asymmetric drug interactions.

Abstract. Background:. Dual regimen dolutegravir (DTG) plus lamivudine (3TC) has demonstrated non-inferior efficacy compared to DTG-based three-drug regimens (3DRs), yet directly comparative data regarding the efficacy and safety of DTG + 3TC and bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for therapy-naïve people with human immunodeficiency virus (HIV)-1 (PWH) are still limited. We aimed to assess the antiviral potency and safety profiles of DTG + 3TC vs. B/F/TAF based on antiretroviral therapy (ART)-naïve PWH in China. Methods:. This retrospective multicenter study enrolled PWH initiating ART with DTG + 3TC or B/F/TAF from 2020 to 2022 in Guangdong and Guangxi. We analyzed response rates based on target not detected (TND) status using intention-to-treat (ITT) analysis. Subgroups were formed based on baseline viral load (VL) (

Abstract Background Comorbidities of coronavirus disease 2019 (COVID-19)/coronary heart disease (CHD) pose great threats to disease outcomes, yet little is known about their shared pathology. The study aimed to examine whether comorbidities of COVID-19/CHD involved shared genetic pathology, as well as to clarify the shared genetic variants predisposing risks common to COVID-19 severity and CHD risks. Methods By leveraging publicly available summary statistics, we assessed the genetically determined causality between COVID-19 and CHD with bidirectional Mendelian randomization. To further quantify the causality contributed by shared genetic variants, we interrogated their genetic correlation with the linkage disequilibrium score regression method. Bayesian colocalization analysis coupled with conditional/conjunctional false discovery rate analysis was applied to decipher the shared causal single nucleotide polymorphisms (SNPs). Findings Briefly, we observed that the incident CHD risks post COVID-19 infection were partially determined by shared genetic variants. The shared genetic variants contributed to the causality at a proportion of 0.18 (95% CI 0.18–0.19) to 0.23 (95% CI 0.23–0.24). The SNP (rs10490770) located near LZTFL1 suggested direct causality (SNPs → COVID-19 → CHD), and SNPs in ABO (rs579459, rs495828), ILRUN(rs2744961), and CACFD1(rs4962153, rs3094379) may simultaneously influence COVID-19 severity and CHD risks. Interpretation Five SNPs located near LZTFL1 (rs10490770), ABO (rs579459, rs495828), ILRUN (rs2744961), and CACFD1 (rs4962153, rs3094379) may simultaneously influence their risks. The current study suggested that there may be shared mechanisms predisposing to both COVID-19 severity and CHD risks. Genetic predisposition to COVID-19 is a causal risk factor for CHD, supporting that reducing the COVID-19 infection risk or alleviating COVID-19 severity among those with specific genotypes might reduce their subsequent CHD adverse outcomes. Meanwhile, the shared genetic variants identified may be of clinical implications for identifying the target population who are more vulnerable to adverse CHD outcomes post COVID-19 and may also advance treatments of ‘Long COVID-19.’

Abstract Spinal dural arteriovenous fistulas (SDAVFs) are the most common type of spinal vascular malformations (AVMs), constituting approximately 70% of all spinal AVMs. The impact of various clinical and radiologic features on the outcomes in patients with SDAVFs is still controversial. The purpose of the study is to investigate the clinical outcomes and prognostic factors in patients with surgically treated SDAVFs in a single center. A retrospective review was performed for all patients with SDAVFs from January 2013 to September 2021 who underwent surgery at our institution. Medical records and pre- and postoperative imaging data were analyzed. Neurological function status was evaluated by modified Aminoff-Logue Scale (mALS). Student’s t-test, Wilcoxon rank sum test, χ2 test and logistic regression were used to find significant prognostic factors. P values

Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and their spatial location remain elusive. Recently, several studies have attempted to define the neuronal types and functional heterogeneity in the spinal cord using single-cell or single-nucleus RNA sequencing in animal models or developing humans. However, molecular evidence of cellular heterogeneity in the adult human spinal cord is limited. Here, we classified spinal cord neurons into 21 subclusters and determined their distribution from nine human donors using single-nucleus RNA sequencing and spatial transcriptomics. Moreover, we compared the human findings with previously published single-nucleus data of the adult mouse spinal cord, which revealed an overall similarity in the neuronal composition of the spinal cord between the two species while simultaneously highlighting some degree of heterogeneity. Additionally, we examined the sex differences in the spinal neuronal subclusters. Several genes, such as SCN10A and HCN1, showed sex differences in motor neurons. Finally, we classified human dorsal root ganglia (DRG) neurons using spatial transcriptomics and explored the putative interactions between DRG and spinal cord neuronal subclusters. In summary, these results illustrate the complexity and diversity of spinal neurons in humans and provide an important resource for future research to explore the molecular mechanisms underlying spinal cord physiology and diseases.

Objectives. This study aimed to use laboratory and clinical data of systemic lupus erythematosus (SLE) patients to construct prediction models for fundus complications in SLE. Methods. Routine blood test data and clinical information of 277 SLE patients were collected retrospectively. Based on their fundus examination, they were divided into two groups, with or without fundus lesions, defined as retinopathy and choroidopathy in this study. The data of the two groups were compared, and the prediction model was established using binary logistic regression analysis. Results. There were 85 patients in the fundus lesions’ group and 192 patients in the control group. Between the two groups, age, SLEDAI, serositis, hypertension, diabetes, anticardiolipin antibody (ACA), anti-Sm antibody, C-reactive protein (CRP), hemoglobin (Hb), platelet count (PLT), albumin (Alb), serum creatinine(Scr), urea, uric acid(UA), and immunoglobulin G(IgG) were significantly different (p

In the era of rapid product iteration, companies need simple and effective methods to guide the entire process of product innovation design and enhance their product innovation capabilities. Most research focused on improving one or several steps in the product design process. Although some scholars have proposed methods that guided the entire process, they combined more than three different theories, which increased the difficulty of theoretical learning and the complexity of practical implementation. This paper proposed a product innovation design process composed of three theoretical methods: Kano, Axiomatic Design (AD), and Theory of the Solution of Inventive Problems (TRIZ). This new process guided the entire product design process with fewer theoretical methods, reducing the difficulty of learning and implementation. The paper demonstrated the effectiveness of this method through the design practice of a portable two-wheeled self-balancing vehicle. Additionally, the discussion section explored the method's potential from the design management perspective.

The COVID-19 pandemic caused by SARS-CoV-2 has brought great challenges to all countries. SARS-CoV-2 infection can bring damage to multiple organs of the human body. The impact of SARS-CoV-2 on fertility has become a focus of interest. This article reviews the mechanism of SARS-CoV-2 attacking the human body, and its impact on fertility, pregnancy and assisted reproductive technique, with the hope of providing reference for clinicians.

Abstract Background Cervical cancer is one of the most common gynecological cancers threatening women’s health worldwide. Double-stranded RNA-binding proteins (dsRBPs) regulate innate immunity and are therefore believed to be involved in virus-related malignancies, however, their role in cervical cancer is not well known. Methods We performed RNA-seq of tumor samples from cervical cancer patients in local cohort and also assessed the RNA-seq and clinical data derived from public datasets. By using single sample Gene Set Enrichment Analysis (ssGSEA) and univariate Cox analysis, patients were stratified into distinct dsRBP clusters. Stepwise Cox and CoxBoost were performed to construct a risk model based on optimal dsRBPs clusters-related differentially expressed genes (DEGs), and GSE44001 and CGCI-HTMCP-CC were employed as two external validation cohorts. Single cell RNA sequencing data from GSE168652 and Scissor algorithm were applied to evaluated the signature-related cell population. Results The expression of dsRBP features was found to be associated with HPV infection and carcinogenesis in CESC. However, only Adenosine deaminases acting on RNA (ADAR) and Dicer, Drosha, and Argonautes (DDR) exhibited significant correlations with the overall survival (OS) of CESC patients. Based on these findings, CESC patients were divided into three dsRBP clusters. Cluster 3 showed superior OS but lower levels of ADAR and DDR. Additionally, Cluster 3 demonstrated enhanced innate immunity, with significantly higher activity in cancer immunity cycles, immune scores, and levels of tumor-infiltrating immune cells, particularly CD8+ T cells. Furthermore, a risk model based on nine dsRBP cluster-related DEGs was established. The accuracy of survival prediction for 1 to 5 years was consistently above 0.78, and this model’s robust predictive capacity was confirmed by two external validation sets. The low-risk group exhibited significantly higher levels of immune checkpoints, such as PDCD1 and CTLA4, as well as a higher abundance of CD8+ T cells. Analysis of single-cell sequencing data revealed a significant association between the dsRBP signature and glycolysis. Importantly, low-risk patients showed improved OS and a higher response rate to immunotherapy, along with enduring clinical benefits from concurrent chemoradiotherapy. Conclusions dsRBP played a crucial role in the regulation of prognosis and tumor immunology in cervical cancer, and its prognostic signature provides a strategy for risk stratification and immunotherapy evaluation.

Abstract Background IFN-λ has been shown to have a dual function in cancer, with its tumor-suppressive roles being well-established. However, the potential existence of a negative ‘‘tumor-promoting’’ effect of endogenous IFN-λ is still not fully understood. Methods We conducted a comprehensive review and analysis of the perturbation of IFN-λ genes across various cancer types. Correlation coefficients were utilized to examine the relationship between endogenous IFN-λ expression and clinical factors, immune cell infiltration, tumor microenvironment, and response to immunotherapy. Genes working together with IFN-λ were obtained by constructing the correlation-based network related to IFN-λ and the gene interaction network in the KEGG pathway and IFN-λ-related genes obtained from the networks were integrated as candidate markers for the prognosis model. We then applied univariate and multivariate COX regression models to select cancer-specific independent prognostic markers associated with IFN-λ and to investigate risk factors for these genes by survival analysis. Additionally, computational methods were used to analyze the transcriptome, copy number variations, genetic mutations, and methylation of IFN-λ-related patient groups. Result Endogenous expression of IFN-λ has been linked to poor prognosis in cancer patients, with the genes IFN-λ2 and IFN-λ3 serving as independent prognostic markers. IFN-λ acts in conjunction with related genes such as STAT1, STAT2, and STAT3 to affect the JAK-STAT signaling pathway, which promotes tumor progression. Abnormalities in IFN-λ genes are associated with changes in immune checkpoints and immune cell infiltration, which in turn affects cancer- and immune-related pathways. While there is increased immune cell infiltration in patients with IFN-λ expression, this does not improve survival prognosis, as T-cell dysfunction and an inflammatory environment are also present. The amplification of IFNL2 and IFNL3 copy number variants drives specific endogenous expression of IFN-λ in patients, and those with this specific expression have been found to have more mutations in the TP53 gene and lower levels of DNA methylation. Conclusion Our study integrated multi-omics data to provide a comprehensive insight into the dark side of endogenous IFN-λ, providing a fundamental resource for further discovery and therapeutic exploration in cancer.

Abstract Sepsis is the uncontrolled reaction of the body to infection-induced inflammation, which results in life-threatening multiple-organ dysfunction (MODS). Although the research on sepsis has advanced significantly in recent years, its pathophysiology remains entirely unknown. Ferroptosis is a new-fashioned type of programmed cell death that may have an impact on sepsis development. However, the precise mechanism still needs to be explored. In this paper, Four pediatric sepsis datasets [training datasets (GSE26378 and GSE26440) and validation datasets (GSE11755 and GSE11281)] were chosen through the GEO (Gene Expression Omnibus) database, and 63 differentially expressions of ferroptosis-relation-genes (DE-FRGs) were eventually discovered using bioinformatics investigation. Functional annotation was performed using GO and KEGG pathway enrichment analysis. Then, four Core-FRGs (FTH1, GPX4, ACSL1, and ACSL6) were extracted after the construction of the protein–protein interaction (PPI) network and the research of the MCODE module. Consequently, Hub-FRG (GPX4) was found using the validation datasets, and correlation exploration of immunity populations (neutrophils, r = − 0.52; CD8 T-cells, r = 0.43) and immunity checkpoints (CD274, r = − 0.42) was implemented. The usefulness of GPX4 as a marker in sepsis was assessed in a mouse model of sepsis. The findings demonstrate that GPX4 is a crucial biomarker and a new latent immunotherapy target for the prediction and therapy of pediatric sepsis.

Abstract Background Recent studies have discovered an emerging role of IL11 in various colitis-associated cancers, suggesting that IL11 mainly promotes tumor cell survival and proliferation in regulating tumorigenesis. Herein we aimed to reveal a novel function of IL-11 through STAT3 signaling in regulating tumor immune evasion. Methods AOM/DSS model in Il11 −/− and Apc min/+/Il11 −/− mice were used to detect tumor growth and CD8+ T infiltration. STAT1/3 phosphorylation and MHC-I, CXCL9, H2-K1 and H2-D1 expression were detected in MC38 cells and intestine organoids treated with/without recombinant IL11 to explore effect of IL11/STAT3 signaling, with IL11 mutein used to competitively inhibit IL11 and rescue inhibited STAT1 activation. Correlation between IL11 and CD8+ T infiltration was analyzed using TIMER2.0 website. IL11 expression and survival prognosis was analyzed in clinical data of patient cohort from Nanfang Hospital. Results IL11 is highly expressed in CRC and indicates unfavorable prognosis. IL11 knockout increased CD8+ T cell infiltration and reduced intestinal and colon formation. Tumors were significantly suppressed while MHC-I and CXCL9 expression for CD8+ T infiltration were remarkably increased in the tumor tissues of Apc min/+/Il11 −/− mice or Il11 −/− mice induced by AOM/DSS. IL11/STAT3 signaling downregulated MHC-I and CXCL9 by inhibiting IFNγ-induced STAT1 phosphorylation. IL11 mutein competitively inhibit IL11 to upregulate CXCL9 and MHC-I in tumor and attenuated tumor growth. Conclusions This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.

Background: Cases of treatment failure in patients developing the R263K mutation have been previously reported. Here we present a patient who developed resistance to dolutegravir due to the R263K mutation during rifampicin treatment. Case presentation: A patient with human immunodeficiency virus (HIV) had a virological failure of HIV when he used dolutegravir (DTG, once a day) and rifampicin at the same time. After treatment failure the dose of dolutegravir was increased (50mg, twice daily), but expected response was not achieved. The R263K mutation was identified and rifampicin was stopped. The treatment regimen was changed to zidovudine combined with lamivudine and lopinavir/ritonavir. Along with the regimen changes, the HIV-RNA, CD4, and CD8 of the patient improved. Due to the DTG drug-drug interactions with rifampicin, the dose of DTG should be doubled when used with rifampicin. Otherwise the patient might be at risk of developing treatment failure and the INSTI drug resistance R263K mutation. Conclusion: This case report discusses a possibility of developing resistance to dolutegravir due to the R263K mutation during rifampicin treatment, stressing the importance of detailed medical history and adherence, as well as the problem of drug-drug interactions in the follow-up process.

Abstract Background Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. Methods Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan–Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. Results Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6–5.4%), and DCR was 35.8% (95% CI, 33.7–38.0%). The median PFS was 2.7 months (95% CI 2.2–2.8), and the median OS was 5.8 months (95% CI 5.4–6.1). Conclusions The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. Trial registration This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

Abstract Septic cardiomyopathy is a serious complication of sepsis. The mechanism of disease pathogenesis, which is caused by infection, is well researched. Despite ongoing efforts, there are no viable biological markers in the peripheral blood for early detection and diagnosis of septic cardiomyopathy. We aimed to uncover potential biomarkers of septic cardiomyopathy by comparing the covaried genes and pathways in the blood and myocardium of sepsis patients. Gene expression profiling of GSE79962, GSE65682, GSE54514, and GSE134364 was retrieved from the GEO database. Student’s t-test was used for differential expression analysis. K-means clustering analysis was applied for subgroup identification. Least absolute shrinkage and selection operator (LASSO) and logistic regression were utilized for screening characteristic genes and model construction. Receiver operating characteristic (ROC) curves were generated for estimating the diagnostic efficacy. For ceRNA information prediction, miWalk and lncBase were applied. Cytoscape was used for ceRNA network construction. Inflammation-associated genes were upregulated, while genes related to mitochondria and aerobic metabolism were downregulated in both blood and the myocardium. Three groups with a significantly different mortality were identified by these covaried genes, using clustering analysis. Five characteristic genes—BCL2A1, CD44, ADGRG1, TGIF1, and ING3—were identified, which enabled the prediction of mortality of sepsis. The pathophysiological changes in the myocardium of patients with sepsis were also reflected in peripheral blood to some extent. The co-occurring pathological processes can affect the prognosis of sepsis. Thus, the genes we identified have the potential to become biomarkers for septic cardiomyopathy.

AbstractBackground The prevalence of hypertension (HTN) is higher in patients with non-alcoholic fatty liver disease (NAFLD). Inflammation is the key link between HTN and NAFLD. Systemic inflammation can be dramatically increased by inflammatory diet intake. However, whether controlling the inflammatory diet intake in NAFLD patients could affect the occurrence of HTN still remains unknown. Our aim here is to evaluate the effect of the dietary inflammatory index (DII) on blood pressure in patients with different grades of hepatic steatosis.Materials and Methods The data were collected from the National Health and Nutrition Examination Survey (NHANES) (2017-2018). DII was calculated based on the data of 24-h dietary recall interviews. The severity of liver steatosis was assessed by a controlled attenuation parameter. Multivariable logistic regression, multivariable linear regression and subgroup analyses were conducted to determine the association between DII and blood pressure in patients with different degrees of hepatic steatosis.Results A total of 5449 participants were included in this analysis. In male participants with severe liver steatosis (S3), the highest DII tertile group was more likely to have higher systolic blood pressure (SBP) compared with the lowest tertile group (Tertile1: 128.31(125.31,131.31), Tertile3: 133.12(129.40,136.85), P for trend =0.03551). DII was positively correlated with SBP and the prevalence of HTN in males with hepatic steatosis grade S3 (≥ 67% steatosis) (SBP: P for trend = 0.011, HTN: P for trend = 0.039). Regarding the association of DII with SBP and HTN, the tests for interaction were significant for hepatic steatosis (SBP: interaction for p = 0.0015, HTN: interaction for p = 0.0202).Conclusions In the present study, we demonstrated that DII was a risk factor for increased SBP and the prevalence of HTN in males with severe hepatic steatosis S3, indicating that anti-inflammatory dietary management should be considered in these individuals to reduce the risk of developing HTN.

Abstract The hydrogen storage cylinder lining was taken as the research object. The injection model of the cylinder liner was developed employing 3D software, a two-cavity injection molding system was built, and Moldflow was utilized for analysis to determine the best combination of injection molding process parameters. The effects of injection process parameters (melt temperature, mold temperature, holding pressure, holding time and cooling time) on the evaluation index were analyzed by orthogonal experiment L16(45). The prediction data of IV hydrogen storage cylinder lining under different parameters were obtained by the range analysis method. The multi-objective optimization problem of injection molding process was transformed into a single-objective optimization problem by using the grey correlation analysis method. The optimal parameters such as melt temperature 270 °C, mold temperature 80 °C, packing pressure 55 MPa, packing time 20 s and cooling time 13 s were obtained. Taguchi method was adopted to obtain SNR (signal-to-noise ratio), while range and variance methods were used for analysis. The results showed that warpage was 0.4892 mm, the volume shrinkage was 12.31%, the residual stress in the first direction was 98.13 MPa, and the residual stress in the second direction was 108.1 MPa. The comprehensive index was simultaneously most impacted by the melt temperature.

Abstract Tumor mRNA vaccines have been developed for over 20 years. Whether mRNA vaccines could promote a clinical benefit to advanced cancer patients is highly unknown. PubMed and Embase were retrieved from January 1, 2000 to January 4, 2023. Random effects models were employed. Clinical benefit (objective response rate [ORR], disease control rate [DCR], 1‐year/2‐year progression‐free survival [PFS], and overall survival [OS]) and safety (vaccine‐related grade 3–5 adverse events [AEs]) were evaluated. Overall, 984 patients (32 trials) were enrolled. The most typical cancer types were melanoma (13 trials), non‐small cell lung cancer (5 trials), renal cell carcinoma (4 trials), and prostate adenocarcinoma (4 trials). The pooled ORR and DCR estimates were 10.0% (95%CI, 4.6–17.0%) and 34.6% (95%CI, 24.1–45.9%). The estimates for 1‐year and 2‐year PFS were 38.4% (95%CI, 24.8−53.0%) and 20.0% (95%CI, 10.4–31.7%), respectively. The estimates for 1‐year and 2‐year OS were 75.3% (95%CI, 62.4–86.3%) and 45.5% (95%CI, 34.0–57.2%), respectively. The estimate for vaccine‐related grade 3–5 AEs was 1.0% (95%CI, 0.2–2.4%). Conclusively, mRNA vaccines seem to demonstrate modest clinical response rates, with acceptable survival rates and rare grade 3–5 AEs.

Objective To investigate the prevalence of occult hepatitis C virus infection (OCI) in Shaanxi blood donors and characterize the occult hepatitis C virus in this cohort. Methods Between July and September of 2019, 112, 117, 46, and 75 blood samples were obtained from eligible donors, alanine aminotransferase (ALT) elevated donors(ALT>50 U/L), hepatitis B virus surface antigen (HBsAg) positive donors, and anti-hepatitis C virus (anti-HCV) positive donors, respectively. Peripheral blood lymphocytes (PBMCs) were isolated from all the samples. HCV 5′UTR was amplified from total RNA of PBMCs using reverse transcription nested PCR (RT-Nested PCR) to detect the infection status of OCI in blood donors. HCV RNA core/E2 region was amplified from HCV RNA positive samples with RT-Nested PCR to determine HCV genotypes and subtypes via sequencing. Results Two (2.67%, 2/75) cases of OCI were identified in anti-HCV positive samples, 1(0.85%, 1/117) case of OCI was identified in abnormal ALT samples, and all OCI were genotyped as 1b. OCI was not found in HBsAg positive and eligible blood donors. Conclusions Our findings suggest that OCI does exist among Shaanxi blood donors and that ALT may be useful in diagnosing OCI.

Abstract Background Plasmablastic lymphoma (PBL) is a rare but aggressive B-cell lymphoma subtype with poor prognosis. Knowledge about the etiology, clinicopathologic and molecular features, and outcomes of PBL is limited. This study aimed to examine the clinicopathologic characteristics, therapeutic approaches, and clinical outcomes of PBL patients in a Chinese population. Methods A total of 102 PBL patients were recruited from three cancer centers. The pathologic features and clinical outcomes of 56 patients with available treatment details and follow-up data were reviewed and analyzed. RNA sequencing was performed in 6 PBL and 11 diffuse large B-cell lymphoma (DLBCL) patients. Results Most patients in our cohort were male (n = 36, 64.3%), and 35 patients presented with Ann Arbor stage I/II disease at diagnosis. All these patients showed negative findings for human immunodeficiency virus, and the vast majority of patients in our cohort were immunocompetent. Lymph nodes (n = 13, 23.2%) and gastrointestinal tract (n = 10, 17.9%) were the most commonly involved site at presentation. Post-treatment complete remission (CR) was the only prognostic factor affecting overall survival (OS) and progression-free survival (PFS) in the multivariate analysis. RNA-seq demonstrated that B-cell receptor (BCR), T-cell receptor (TCR), P53, calcium signaling, and Wnt signaling pathways were significantly downregulated in PBLs compared with GCB (or non-GCB) DLBCLs. Conclusions In this multicenter study in the Chinese population, PBL mainly occurred in immunocompetent individuals and most patients present with early-stage disease at diagnosis. Post-treatment CR was an important prognostic factor affecting OS and PFS. RNA-seq showed that the B-cell receptor (BCR), P53, calcium signaling, cell adhesion molecules, and Wnt signaling pathways significantly differed between PBL and GCB (or non-GCB) DLBCL, which provided theoretical basis for its pathogenesis and future treatment.

Abstract This study aimed to investigate the factors affecting the success rate of full pulpotomy in permanent posterior teeth with pulpitis. The study included 105 permanent posterior teeth clinically diagnosed as reversible or irreversible pulpitis in 92 patients aged 18–82 years. All teeth underwent a full pulpotomy using mineral trioxide aggregate as a capping material and were recalled for clinical and radiographic evaluation at 3, 6, 12, and 24 months postoperatively. The overall success rate after the 12-month review was above 90%, and failed cases mainly occurred during the first 12 months after treatment. In this study, the treatment outcome of pulpotomy was not related to sex, or tooth position and the cause of pulpitis. To analyze the influence of age on the treatment outcome, all the teeth were allocated to three groups: group 1 (18–39 years); group 2 (40–59 years); and group 3 (≥ 60 years). A significant difference in success rate was found between groups 1 and 3 (P = 0.014). These results suggest that pulpotomy can be used as an alternative treatment for permanent mature teeth diagnosed with pulpitis and that aging is one factor affecting the treatment outcome.

Abstract Background Birth weight is considered not only to undermine future growth, but also to induce lifelong diseases; the aim of this study is to explore the relationship between birth weight and adult bone mass. Methods We performed multivariable regression analyses to assess the association of birth weight with bone parameters measured by dual-energy X-ray absorptiometry (DXA) and by quantitative ultrasound (QUS), independently. We also implemented a systemic Mendelian randomization (MR) analysis to explore the causal association between them with both fetal-specific and maternal-specific instrumental variables. Results In the observational analyses, we found that higher birth weight could increase the adult bone area (lumbar spine, β-coefficient= 0.17, P < 2.00 × 10−16; lateral spine, β-coefficient = 0.02, P = 0.04), decrease bone mineral content-adjusted bone area (BMCadjArea) (lumbar spine, β-coefficient= − 0.01, P = 2.27 × 10−14; lateral spine, β-coefficient = − 0.05, P = 0.001), and decrease adult bone mineral density (BMD) (lumbar spine, β-coefficient = − 0.04, P = 0.007; lateral spine; β-coefficient = − 0.03, P = 0.02; heel, β-coefficient = − 0.06, P < 2.00 × 10−16), and we observed that the effect of birth weight on bone size was larger than that on BMC. In MR analyses, the higher fetal-specific genetically determined birth weight was identified to be associated with higher bone area (lumbar spine; β-coefficient = 0.15, P = 1.26 × 10−6, total hip, β-coefficient = 0.15, P = 0.005; intertrochanteric area, β-coefficient = 0.13, P = 0.0009; trochanter area, β-coefficient = 0.11, P = 0.03) but lower BMD (lumbar spine, β-coefficient = − 0.10, P = 0.01; lateral spine, β-coefficient = − 0.12, P = 0.0003, and heel β-coefficient = − 0.11, P = 3.33 × 10−13). In addition, we found that the higher maternal-specific genetically determined offspring birth weight was associated with lower offspring adult heel BMD (β-coefficient = − 0.001, P = 0.04). Conclusions The observational analyses suggested that higher birth weight was associated with the increased adult bone area but decreased BMD. By leveraging the genetic instrumental variables with maternal- and fetal-specific effects on birth weight, the observed relationship could be reflected by both the direct fetal and indirect maternal genetic effects.

A patient with SARS-CoV-2 infection was adimitted to Shanghai Shibei hospital of Jing'an District in early 2023. According to the patient's complaits， clinical manifestations， physical symptoms， laboratory examination， radiological image results， plus lumbar puncture， the patient was diagnosed with novel coronavirus encephalitis. The patient was discharged from the hospital after a combined treatment of Chinese and western medicine.

Objective To evaluate the quality of platelet concentrates (PCs) prepared by traditional and modified buffy coat centrifugal canning methods, and to explore the effect of modified buffy coat centrifugal canning method on improving the quality of PCs. Methods The buffy coat centrifugal canning methods was divided into traditional group and modified group. In the traditional group, the buffy coat component bag and empty bag were directly combined layer by layer and vertically canned for light centrifugation. In the modified group, a foam spacer was added between the buffy coat component bag and the empty bag for light centrifugation layer by layer. The effects of the two groups of centrifugal canning methods on the preparation quality of PCs were observed. Results The platelet content in PCs prepared by the modified buffy coat centrifugal canning method was significantly higher than that in the traditional group, and the mixed amount of red blood cells was lower than that in the traditional group (P0.05), the qualified rates of platelet content and mixed red blood cell in the modified group were higher than those in the traditional group (P

Abstract Dicarboxylic acids are one of the important water-soluble organic compounds in atmospheric aerosols, causing adverse effects to both climate and human health. More attention has therefore been paid to organic acids in aerosols. In this study, the molecular distribution and diurnal variations of wintertime dicarboxylic acids in a rural site of Guanzhong Plain, Northwest China, were explored. Oxalic acid (C2, day: 438.9 ± 346.8 ng m−3, night: 398.8 ± 392.3 ng m−3) is the most abundant compound followed by methylglyoxal (mGly, day: 207.8 ± 281.1 ng m−3, night: 222.9 ± 231.0 ng m−3) and azelaic (C9, day: 212.8 ± 269.1 ng m−3, night: 211.4 ± 136.7 ng m−3) acid. The ratios of C9/C6 and C9/Ph indicating that atmospheric dicarboxylic acids in winter in the region mainly come from biomass burning. Furthermore, secondary inorganic ions (NO3 −, SO4 2−, and NH4 +), relative humidity, liquid water content, and in-situ pH of aerosols are highly linearly correlated with C2, suggesting that liquid phase oxidation is an important pathway for the formation of dicarboxylic acids. The δ13C analysis of C2 suggested that lighter carbon isotope compositions tend to be oxidized to form aqueous-phase secondary organic aerosols (aqSOA), leading to the decay of 13C in aqSOA products rather than aerosol aging. This study provides a theoretical basis for the mechanism of formation of dicarboxylic acid.

Chronic diseases have become a major public health issue that seriously affects people's health. In China, chronic disease prevalence is increasingly serious as population aging progresses, which poses great challenges to the management of chronic diseases. Chronic disease management in rural primary care is a weak part of domestic chronic disease management, the improvement of which will contribute to the achievement of goals of healthy China and rural vitalization. We performed comparisons between three foreign typical chronic disease management models (chronic care model, innovative care for chronic conditions framework, chronic disease self-management program) , and between three domestic typical ones (chronic disease self-management model, community general practice chronic disease health management model, Xiamen "three division co management" chronic disease management model) , in terms of features, service providers, merits and limitations. On this basis, we proposed recommendations on improving rural chronic disease management in China from four aspects: talent team building, multi-sectoral cooperation, government responsibility, and patient self-management.

Abstract Combined with one-time pad encryption scheme, quantum key distribution guarantees the unconditional security of communication in theory. However, error correction and privacy amplification in the post-processing phase of quantum key distribution result in high time delay, which limits the final secret key generation rate and the practicability of quantum key distribution systems. To alleviate this limitation, this paper proposes an efficient post-processing algorithm based on polar codes for quantum key distribution. In this algorithm, by analyzing the channel capacity of the main channel and the wiretap channel respectively under the Wyner’s wiretap channel model, we design a codeword structure of polar codes, so that the error correction and privacy amplification could be completed synchronously in a single step. Through combining error correction and privacy amplification into one single step, this efficient post-processing algorithm reduces complexity of the system and lower the post-processing delay. Besides, the reliable and secure communicaiton conditions for this algorithm has been given in this paper. Simulation results show that this post-processing algorithm satisfies the reliable and secure communication conditions well.

Abstract Screening of mRNAs and lncRNAs associated with prognosis and immunity of lung adenocarcinoma (LUAD) and used to construct a prognostic risk scoring model (PRS-model) for LUAD. To analyze the differences in tumor immune microenvironment between distinct risk groups of LUAD based on the model classification. The CMap database was also used to screen potential therapeutic compounds for LUAD based on the differential genes between distinct risk groups. he data from the Cancer Genome Atlas (TCGA) database. We divided the transcriptome data into a mRNA subset and a lncRNA subset, and use multiple methods to extract mRNAs and lncRNAs associated with immunity and prognosis. We further integrated the mRNA and lncRNA subsets and the corresponding clinical information, randomly divided them into training and test set according to the ratio of 5:5. Then, we performed the Cox risk proportional analysis and cross-validation on the training set to construct a LUAD risk scoring model. Based on the risk scoring model, patients were divided into distinct risk group. Moreover, we evaluate the prognostic performance of the model from the aspects of Area Under Curve (AUC) analysis, survival difference analysis, and independent prognostic analysis. We analyzed the differences in the expression of immune cells between the distinct risk groups, and also discuss the connection between immune cells and patient survival. Finally, we screened the potential therapeutic compounds of LUAD in the Connectivity Map (CMap) database based on differential gene expression profiles, and verified the compound activity by cytostatic assays. We extracted 26 mRNAs and 74 lncRNAs related to prognosis and immunity by using different screening methods. Two mRNAs (i.e., KLRC3 and RAET1E) and two lncRNAs (i.e., AL590226.1 and LINC00941) and their risk coefficients were finally used to construct the PRS-model. The risk score positions of the training and test set were 1.01056590 and 1.00925190, respectively. The expression of mRNAs involved in model construction differed significantly between the distinct risk population. The one-year ROC areas on the training and test sets were 0.735 and 0.681. There was a significant difference in the survival rate of the two groups of patients. The PRS-model had independent predictive capabilities in both training and test sets. Among them, in the group with low expression of M1 macrophages and resting NK cells, LUAD patients survived longer. In contrast, the monocyte expression up-regulated group survived longer. In the CMap drug screening, three LUAD therapeutic compounds, such as resveratrol, methotrexate, and phenoxybenzamine, scored the highest. In addition, these compounds had significant inhibitory effects on the LUAD A549 cell lines. The LUAD risk score model constructed using the expression of KLRC3, RAET1E, AL590226.1, LINC00941 and their risk coefficients had a good independent prognostic power. The optimal LUAD therapeutic compounds screened in the CMap database: resveratrol, methotrexate and phenoxybenzamine, all showed significant inhibitory effects on LUAD A549 cell lines.

This study investigated whether artemisinin (ART) exerts a neuroprotective effect against cerebral ischemia/reperfusion (I/R) injury. Hypoxia-glucose deprivation and reoxygenation (OGD/R) of SH-SY5Y cells were used as the I/R injury model in vitro. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and lactate dehydrogenase (LDH) release was measured. Cell apoptosis and apoptosis-associated protein expression were determined via flow cytometry and western blotting, respectively. The levels of glutathione peroxidase, superoxide dismutase, catalase, and malondialdehyde were determined. The secretion of tumor necrosis factor-α and interleukin-1β was measured using ELISA. The activation of the nuclear factor kappa B (NF-κB) pathway was also determined. The indicated ART concentrations (0, 25, 50, 75, and 100 μM) had no significant effect on SH-SY5Y cell viability and LDH activity. ART promoted cell viability, reduced cell apoptosis, repressed cellular inflammation, and inhibited cellular oxidative stress and NF-κB signaling pathway in OGD/R-induced SH-SY5Y cells. In addition, all the protective effects of ART on OGD/R-induced SH-SY5Y cell injury were significantly reversed by an NF-κB agonist. In conclusion, ART protects neurons from OGD/R-induced damage in vitro by inhibiting the NF-κB signaling pathway. These results suggest that ART may be a potential agent for the treatment of cerebral I/R injury.

Abstract Existed classifications of congenital proximal radioulnar synostosis (PRUS) mainly focus on osseous changes and do not cover all types of congenital PRUS, ignoring the role and developing status of the supinator. This study aims to explore the correlation between supinator development and radiographic deformity of congenital PRUS. Pediatric patients diagnosed with congenital PRUS in two pediatric Orthopedic centers were evaluated retrospectively. MRI and radiographic images of their bilateral forearms (including normal ones) were collected. The area of supinator, extensor carpi radialis longus (ECRL), extensor carpi radialis brevis (ECRB), brachioradialis (BRAR) muscle and extensor indicis (EI) muscle were measured on each forearm. The ratios of these muscles were calculated and regarded as an indicator of the developing status of supinator muscle. Twenty-seven congenital PRUS forearms of 16 patients (average 3.45 years) were included. A new MRI & X-ray classification system was proposed to cover all types of radiographic deformity and provide a comprehensive description of supinator development. This study revealed the relation between MRI measured supinator volume and radiographic deformity of congenital PRUS. Supinator muscles were observed in all congenital PRUS cases. A novel classification was proposed, providing a more comprehensive understanding of congenital PRUS.

Abstract Cubitus varus deformity is the most common late complication of malunited supracondylar fracture that requires corrective osteotomy and fixation. From 2009 to 2017, 40 consecutive patients with cubitus varus deformity were included. Twenty patients underwent the conventional closing-wedge osteotomy (conventional group), while the other twenty patients underwent the 3D-printed model and osteotomy template osteotomy (3D-printed template group). The functional outcome was evaluated using the Mayo Elbow Performance Index (MEPI) Score and Flynn criteria. There were no statistically significant differences were observed regarding the humerus-elbow-wrist angle and tilting angle between the two groups, both preoperatively and postoperatively at 24 months. No statistically significant differences were observed regarding the elbow ROM (127.0 ± 4.7° VS 128.9 ± 3.8°) and MEPI score (93.5 ± 3.3 VS 94.3 ± 4.1) between the groups. All patients were satisfied both cosmetically and functionally as per the Flynn criteria and MEPI score. The conventional osteotomy and 3D-printed model and osteotomy template techniques both met the treatment requirements of cubitus varus deformity. The 3D-printed template technique showed better osteotomy accuracy, but no significant advantage regarding the functional and cosmetic results than conventional osteotomy.

Abstract Background Calcific aortic valve disease (CAVD) is the most commonly valvular disease in the western countries initiated by inflammation and abnormal calcium deposition. Currently, there is no clinical drug for CAVD. Neutrophil elastase (NE) plays a causal role in inflammation and participates actively in cardiovascular diseases. However, the effect of NE on valve calcification remains unclear. So we next explore whether it is involved in valve calcification and the molecular mechanisms involved. Methods NE expression and activity in calcific aortic valve stenosis (CAVD) patients (n = 58) and healthy patients (n = 30) were measured by enzyme-linked immunosorbent assay (ELISA), western blot and immunohistochemistry (IHC). Porcine aortic valve interstitial cells (pVICs) were isolated and used in vitro expriments. The effects of NE on pVICs inflammation, apoptosis and calcification were detected by TUNEL assay, MTT assay, reverse transcription polymerase chain reaction (RT-PCR) and western blot. The effects of NE knockdown and NE activity inhibitor Alvelestat on pVICs inflammation, apoptosis and calcification under osteogenic medium induction were also detected by RT-PCR, western blot, alkaline phosphatase staining and alizarin red staining. Changes of Intracellular signaling pathways after NE treatment were measured by western blot. Apolipoprotein E−/− (APOE−/−) mice were employed in this study to establish the important role of Alvelestat in valve calcification. HE was used to detected the thickness of valve. IHC was used to detected the NE and α-SMA expression in APOE−/− mice. Echocardiography was employed to assess the heat function of APOE−/− mice. Results The level and activity of NE were evaluated in patients with CAVD and calcified valve tissues. NE promoted inflammation, apoptosis and phenotype transition in pVICs in the presence or absence of osteogenic medium. Under osteogenic medium induction, NE silencing or NE inhibitor Alvelestat both suppressed the osteogenic differentiation of pVICs. Mechanically, NE played its role in promoting osteogenic differentiation of pVICs by activating the NF-κB and AKT signaling pathway. Alvelestat alleviated valve thickening and decreased the expression of NE and α-SMA in western diet-induced APOE−/− mice. Alvelestat also reduced NE activity and partially improved the heart function of APOE−/−mice. Conclusions Collectively, NE is highly involved in the pathogenesis of valve calcification. Targeting NE such as Alvelestat may be a potential treatment for CAVD.

BackgroundDialect Attitude is conceptualized as an individual's cognitive and affective evaluation of a dialect and its speakers. In the contemporary China, dialect is suffering from significant stigmatization, resulting in social inequalities, which hinder sustainable development. This study aims to reveal the Chinese public attitudes towards dialects, and clarify the potential determinants related to heterogeneous attitudes at a macro level.MethodsWe combine the crawler technology and sentiment analysis to conduct a provincial cross-sectional study. We collect 1,650,480 microblogs about public attitudes towards dialects from Microblog across 31 specific Chinese provinces. Spatial regression models are utilized to clarify the influence of macro-level determinants on differences in public attitudes.ResultsThe present study reveals that: (1) The Chinese public generally holds positive attitudes towards dialects, with significant variation between provinces. (2) Political Resource (β = 0.076, SD = 0.036, PConclusionsBasing on the combination of crawler technology and sentiment analysis, the present study develops the most comprehensive database which takes 1,650,480 dialects-related microblogs from 31 Chinese provinces, and describes the following scenario: (1) Overall, the Chinese public shares a relatively positive attitude towards dialects with significant variations among different provinces, (2) Political Resource, Economic Development and Culture Resource pose positive effects on Chinese public attitudes towards dialects and (3) Political Resource and Culture Resource influence more significant in the relatively disadvantaged regions, and Economic Development poses a higher influence in the relatively advantaged regions.

Trajectory planning is an important issue for manipulators and robots. To get a optimal trajectory, many constraints including actuators specifications, motion range of joints, workspace limitations, etc, and many objectives including the shortest time, the shortest distance, the lowest energy consumption, the minimum oscillations, obstacles-avoiding, etc, should be considered both. In this paper, firstly, the forward kinematics and inverse kinematics of a five axis manipulator are deduced. And, a simple method to choose one appropriate solution from multi solutions of inverse kinematics is proposed. Secondly, an easy-implemented optimization method of trajectory planning is proposed based on seventh order polynomial interpolation, event-trigger mechanism and conditional proportional control (P control). The proposed optimization method can capture the time optimal trajectory, and the actuators specifications including velocity, acceleration of motor can be guaranteed as well. Thirdly, comparative simulations and experiments validate the effectiveness and efficiency of proposed optimization method. The research provides an insight for the application of trajectory optimization on the micro controller with low computing capability and high real-time performance requirement.

Abstract Background Chronic migraine places a disabling burden on patients, which is extensively modeled by the nitroglycerin (NTG)-treated animal model. Although the NF-κB pathway is involved in an increase in CGRP levels and activation of the trigeminal system in the NTG model, the relationship between NTG and neuroinflammation remains unclear. This study aimed to optimize a chronic NTG rat model with hyperalgesia and the ethological capacity for estimating migraine therapies and to further explore the underlying mechanism of NTG-induced migraine. Methods Rats were administered different doses of NTG s.c. daily or every 2 d; 30 min and 2 h later, the mechanical threshold was tested. After 9 d, the rats were injected with EB or Cy5.5 for the permeability assay. The other animals were sacrificed, and then, brainstem and caudal trigeminal ganglion were removed to test CGRP, c-Fos and NOS activity; Cytokines levels in the tissue and serum were measured by ELISA; and NF-κB pathway and blood–brain barrier (BBB)-related indicators were analyzed using western blotting. Immunohistochemistry was performed to observe microglial polarization and IL-17A+ T cell migration in the medulla oblongata. Results NTG (10 mg/kg, s.c., every 2 d for a total of 5 injections) was the optimal condition, resulting in progressive hyperalgesia and migraine behavior. TNC neuroinflammation with increases in cytokines, CGRP and c-Fos and activation of the NF-κB pathway was observed, and these changes were alleviated by ibuprofen. Furthermore, NTG administration increased BBB permeability by altering the levels functional proteins (RAGE, LRP1, AQP4 and MFSD2A) and structural proteins (ZO-1, Occludin and VE-cadherin-2) to increase peripheral IL-17A permeation into the medulla oblongata, activating microglia and neuroinflammation, and eventually causing hyperalgesia and migraine attack. Conclusions This study confirmed that NTG (10 mg/kg, s.c., every 2 d for a total of 5 injections) was the optimal condition to provoke migraine, resulting in mechanical hyperalgesia and observable migraine-like behavior. Furthermore, IL-17A crossed the blood–brain barrier into the medulla oblongata, triggering TNC activation through microglia-mediated neuroinflammation. This process was a novel mechanism in NTG-induced chronic migraine, suggesting that IL-17A might be a novel target in the treatment of migraine.

In arthroscopic shoulder surgery, general anesthesia (GA) is the common method of anesthesia. Recently, the combined usage of interscalene brachial plexus block with general anesthesia (ISB/GA) was reported to have a lower incidence of adverse side effects than GA alone. However, to date, no study has compared stress and inflammatory responses between these two methods. Since stress and inflammatory responses are critical on intraoperative management and postoperative recovery, we integrated the laboratory and clinical methods and compared the stress and inflammatory factors, such as epinephrine, norepinephrine, glucose, lactate, inflammatory factors tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), as well as the clinical outcomes to determine whether ISB/GA provides an advantage on stress and inflammatory inhibition. Data showed that ISB/GA resulted in significantly lower epinephrine, norepinephrine, and glucose levels perioperatively. Six hours after operation, the TNF-α and IL-6 levels were also significantly lower in the ISB/GA group. ISB/GA patients had lower blood pressure, a more stable heart rate, lower visual analog scale score, and less opioid consumption during and after surgery. Our results indicate that ISB/GA is a better choice for arthroscopic shoulder surgery, owing to less stress and inflammatory responses during and after operation, which provides better clinical outcomes. Therefore, we recommend ISB/GA as a preferred anesthesia method for arthroscopic shoulder surgery.

Abstract Circulating tumor DNA (ctDNA) is a potential biomarker of prognosis and therapeutic response. We conducted this study to explore the role of the molecular tumor burden index (mTBI) in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study. We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study (NCT01917279). Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples. The pretreatment mTBI value was correlated with tumor burden (P = 0.025). Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI, and the median overall survival was 40.9 months and 68.4 months, respectively (P = 0.011). Patients with mTBI decrease to less than 0.02% at the first tumor evaluation had longer progression-free survival and overall survival (P

Summary: Background: Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed. Methods: The expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d. Findings: miR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes. Interpretation: Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy. Funding: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the “Dawn” Program of Shanghai Education Commission (19SG34 to J Xiao), the “Chen Guang” project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).

Abstract. Postmenopausal osteoporosis (PMOP) has become one of most frequent chronic disease worldwide with aging population. Eucommia ulmoides cortex (EU), a traditional Chinese medicine, has long since been used to treat PMOP. The aim of this study is to explore pharmacological mechanisms of EU against PMOP through using network pharmacology approach. The active ingredients of EU were obtained from Traditional Chinese Medicine System Pharmacology database, and target fishing was performed on these ingredients in UniProt database for identification of their relative targets. Then, we screened the targets of PMOP using GeneCards database and DisGeNET database. The overlapping genes between PMOP and EU were obtained to performed protein–protein interaction, Gene Ontology analysis, Kyoto encyclopedia of genes, and genomes analysis. Twenty-eight active ingredients were identified in EU, and corresponded to 207 targets. Also, 292 targets were closely associated with PMOP, and 50 of them matched with the targets of EU were considered as therapeutically relevant. Gene ontology enrichment analysis suggested that EU exerted anti-PMOP effects via modulating multiple biological processes including cell proliferation, angiogenesis, and inflammatory response. Kyoto encyclopedia of genes and genomes enrichment analysis revealed several pathways, such as PI3K-AKT pathway, mitogen-activated protein kinase pathway, hypoxia-inducible factors-1 pathway, tumor necrosis factor pathway, and interleukin-17 pathway that might be involved in regulating the above biological processes. Through the method of network pharmacology, we systematically investigated the mechanisms of EU against PMOP. The multi-targets and multi-pathways identified here could provide new insights for further determination of more exact mechanisms of EU.