Search

Background: The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood.Methods: Proteasome activity, intracellular glutathione (GSH) and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR.Results: At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH) and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death.Conclusion: GSH protects cells from proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to proteasome inhibition-induced apoptosis. [ABSTRACT FROM AUTHOR]

Background: We did this study to better clarify the correlations of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)-G1958A (rs2236225) gene polymorphism with the risk of congenital heart diseases (CHD) and its subgroups., Methods: Relevant articles were searched in PubMed, Web of Science, Cochrane Library, Embase, CNKI, VIP database and Wanfang DATA until October 2023. We will use odds ratios (ORs) and 95% confidence intervals (CIs) to examine the potential associations of MTHFD1- G1958A gene polymorphism with CHD and its subgroups., Results: We included a total of 9 eligible studies, encompassing 1917 children with CHD, 1863 healthy children, 1717 mothers of the children with CHD and 1666 mothers of healthy children. In our study, the meta-analysis of fetal group revealed no significant association between any of the five genetic models for the MTHFD1-G1958A polymorphism and the risk of CHD. Subgroup analysis showed that associations between the MTHFD1-G1958A polymorphism and Tetralogy of Fallot (TOF) risk in the homozygote model (AA vs. GG, OR = 2.82, 95%CI [1.16, 6.86], P = 0.02) and recessive model (AA vs. GG + GA, OR = 3.09, 95%CI [1.36, 7.03], P = 0.007). In addition, the MTHFD1-G1958A polymorphism was associated with the risk of CHD in racial subgroup, increasing the risk of CHD in Caucasians. In maternal analysis, 2 genetic models of MTHFD1-G1958A polymorphism increased the risk of CHD: the heterozygote model (GA vs. GG, OR = 1.22, 95%CI [1.04, 1.42], P = 0.01), and the dominance model (GA + AA vs. GG, OR = 1.17, 95%CI [1.01, 1.34], P = 0.03)., Conclusions: The fetal MTHFD1-G1958A (rs2236225) gene polymorphism increase their risk of TOF. The maternal MTHFD1-G1958A polymorphism has a strong correlation with the risk of CHD, and there are racial differences in this correlation. Compared with GG genotype, the GA genotype increases the risk of CHD., Competing Interests: Declarations. Ethical approval: As a systematic review, there is no ethical approval is required. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The identification of oncogenic gene fusions in diffuse gliomas may serve as potential therapeutic targets and prognostic indicators, representing a novel strategy for treating gliomas consistent with the principles of personalized medicine. This study identified detectable oncogene fusions in glioma patients through an integrated analysis of genomic and transcriptomic data, which encompassed whole exon sequencing and next-generation RNA sequencing. In addition, this study also conducted a comparison of the genetic characteristics, tumor microenvironment, mutation burden and survival between glioma patients with or without gene fusions. A total of 68 glioma patients were enrolled in this study, including glioblastoma (GBM), low grade glioma (LGG) and diffuse midline glioma (DMG). 14 cases of GBM patients (51.9%, 14/27) were found to harbor the following 70 oncogenic gene fusions: ROS1 (n = 8), NTRK (n = 5), KIF5 (n = 5), RET (n = 3) and other infrequent gene fusions (n = 49). A total of 11 gene fusions were identified in 8 LGG patients (32.0%, 8/25) and seven gene fusions were identified in one DMG patient (16.7%, 1/6). In GBM patient group, five genes including HOXA3, ACTB, CDK5, GNA12 and CARD11 exhibited a statistically significant higher copy number amplification frequency in the GBM group without gene fusions compared to that in the GBM group with gene fusions. In LGG patient group, CDK5 gene was also found to exhibit a statistically significant higher amplification frequency in the LGG group without gene fusions. In addition, KMT2D exhibited a statistically significant higher mutation frequency in the LGG group with gene fusions compared to that in the LGG group without gene fusions. Comparison of the other genetic characteristics including immune cell infiltration score, tumor mutation burden (TMB), and microsatellite instability (MSI). The results showed no statistically significant differences were observed between fusion and non-fusion group of GBM and LGG. The survival analysis revealed that GBM patients without gene fusions exhibited a longer median survival (737 days) compared to GBM patients with gene fusions (642 days), but without a statistical significancy. Our study has identified a set of gene fusions present in gliomas, including a number of novel gene fusions that have not been previously reported. We have also elucidated the underlying genetic characteristics of glioma with gene fusions. Collectively, our findings have the potential to inform future clinical treatment strategies for patients with glioma., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Pathological neovascularization is a hallmark of many vision-threatening diseases. However, some patients exhibit poor responses to current anti-VEGF therapies due to resistance and limited efficacy. Recent studies have highlighted the roles of noncoding RNAs in various biological processes, paving the way for RNA-based therapeutics. In this study, we report a marked down-regulation of miR-205 under pathological conditions. miR-205 potently inhibits endothelial cell functions critical for pathological neovascularization, including proliferation, migration, and tube formation. Furthermore, miR-205 strengthens the endothelial barrier, thereby reducing vascular leakage. In mouse models of retinal and choroidal neovascularization, miR-205 administration effectively suppresses abnormal blood vessel formation and leakage. Mechanistically, miR-205 directly targets VEGFA and ANGPT2, which are key drivers of pathological neovascularization. To improve delivery, we successfully loaded miR-205 into exosomes derived from mesenchymal stem cells. This innovative approach avoids cytotoxicity while preserving therapeutic efficacy in both cellular and animal models. Collectively, our findings highlight miR-205 as a promising therapeutic for ocular neovascularization, with exosome delivery offering a novel and efficient strategy for treating vision-threatening vascular diseases., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were conducted according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Experimental Animal Center of Nanjing Medical University. Consent for publication: All authors agree to be published. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The exploration of chemical space holds promise for developing influential chemical entities. Molecular representations, which reflect features of molecular structure in silico, assist in navigating chemical space appropriately. Unlike atom-level molecular representations, such as SMILES and atom graph, which can sometimes lead to confusing interpretations about chemical substructures, substructure-level molecular representations encode important substructures into molecular features; they not only provide more information for predicting molecular properties and drug‒drug interactions but also help to interpret the correlations between molecular properties and substructures. However, it remains challenging to represent the entire molecular structure both intactly and simply with substructure-level molecular representations. In this study, we developed a novel substructure-level molecular representation and named it a group graph. The group graph offers three advantages: (a) the substructure of the group graph reflects the diversity and consistency of different molecular datasets; (b) the group graph retains molecular structural features with minimal information loss because the graph isomorphism network (GIN) of the group graph performs well in molecular properties and drug‒drug interactions prediction, showing higher accuracy and efficiency than the model of other molecular graphs, even without any pretraining; and (c) the molecular property may change when the substructure is substituted with another of differing importance in group graph, facilitating the detection of activity cliffs. In addition, we successfully predicted structural modifications to improve blood‒brain barrier permeability (BBBP) via the GIN of group graph. Therefore, the group graph takes advantages for simultaneously representing molecular local characteristics and global features.Scientific contribution The group graph, as a substructure-level molecular representation, has the ability to retain molecular structural features with minimal information loss. As a result, it shows superior performance in predicting molecular properties and drug‒drug interactions with enhanced efficiency and interpretability., Competing Interests: Declarations. Ethics, consent to participate, and consent to publish declarations: Not applicable. Competing interests: The author declares no competing interests., (© 2024. The Author(s).)

Background and Objectives: Maintenance hemodialysis (MHD) patients are at a higher risk of cardiovascular disease (CVD), a common complication and leading cause of death. Persistent micro-inflammation is a unique feature of MHD. Given the established role of inflammation in the pathogenesis of atherosclerosis, this study aims to explore whether novel inflammatory markers (inflammation index) can serve as independent risk factors for CVD in MHD patients., Methods: A cross-sectional survey was conducted on patients from three dialysis centers, categorized into a CVD and non-CVD group based on medical history, laboratory tests, and physical examination. Fasting blood samples were collected from all participants for indicator testing., Results: The analysis of 209 patients revealed that 104 had concurrent CVD. Patients in the CVD group were significantly older and exhibited higher anxiety and depression scores. Forward stepwise multivariate logistic regression results identified the inflammation index neutrophil-to-lymphocyte ratio (NLR) (OR = 1.27, 95% CI 1.082-1.491, P < 0.05) and systemic immune-inflammation index (SII) (OR = 1.001, 95% CI 1.0001-1.002, P < 0.05) as independent risk factors for CVD in MHD patients. Receiver operating characteristic (ROC) curve analysis demonstrated that SII, platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and NLR all possess predictive diagnostic values for CVD events in this patient population., Conclusions: Hemodialysis centers can utilize simple and cost-effective inflammatory markers to proactively identify patients at risk of CVD. Future research into how inflammation contributes to CVD in MHD is required., Competing Interests: Declarations Ethics approval and informed consent The Ethics Committee of Dongzhimen Hospital, Affiliated with the Beijing University of Chinese Medicine, approved this study (2024DZMEC-313–02), and all enrolled patients signed valid informed consent forms. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Batten disease is a group of rare inherited neurodegenerative diseases. Juvenile CLN3 disease is the most prevalent type, and the most common pathogenic variant shared by most patients is the "1-kb" deletion which removes two internal coding exons (7 and 8) in CLN3. Previously, we identified two transcripts in patient fibroblasts homozygous for the 1-kb deletion: the 'major' and 'minor' transcripts. To understand the full variety of disease transcripts and their role in disease pathogenesis, it is necessary to first investigate CLN3 transcription in "healthy" samples without juvenile CLN3 disease., Methods: We leveraged PacBio long-read RNA sequencing datasets from ENCODE to investigate the full range of CLN3 transcripts across various tissues and cell types in human control samples. Then we sought to validate their existence using data from different sources., Results: We found that a readthrough gene affects the quantification and annotation of CLN3. After taking this into account, we detected over 100 novel CLN3 transcripts, with no dominantly expressed CLN3 transcript. The most abundant transcript has median usage of 42.9%. Surprisingly, the known disease-associated 'major' transcripts are detected. Together, they have median usage of 1.5% across 22 samples. Furthermore, we identified 48 CLN3 ORFs, of which 26 are novel. The predominant ORF that encodes the canonical CLN3 protein isoform has median usage of 66.7%, meaning around one-third of CLN3 transcripts encode protein isoforms with different stretches of amino acids. The same ORFs could be found with alternative UTRs. Moreover, we were able to validate the translational potential of certain transcripts using public mass spectrometry data., Conclusion: Overall, these findings provide valuable insights into the complexity of CLN3 transcription, highlighting the importance of studying both canonical and non-canonical CLN3 protein isoforms as well as the regulatory role of UTRs to fully comprehend the regulation and function(s) of CLN3. This knowledge is essential for investigating the impact of the 1-kb deletion and rare pathogenic variants on CLN3 transcription and disease pathogenesis., (© 2024. The Author(s).)

Background: Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes., Methods: A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data., Results: The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA., Conclusion: Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development., (© 2024. The Author(s).)

Background: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear., Methods: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values., Results: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause., Conclusion: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging., (© 2024. The Author(s).)

Ranula is a mucous cyst that occurs in the sublingual gland (SLG) in the floor of the mouth. It can be classified into two types based on origins: One is the the lesser sublingual gland (LSLG) in the anterior segment and the Rivini duct, which is connected to it, and the other is the greater sublingual gland (GSLG) in the posterior segment. Because of the anatomical characteristics, surgical resection of the cysts carries the risk of damaging adjacent tissues and has a high recurrence rate. Intralesional injection of sclerotherapy may be a better alternative treatment. We summarized 65 cases of ranula treated with intralesional injections of bleomycin(BML). According to the origin of the ranula, 60 cases were from the LSLG and the Rivini duct, and 5 cases were from the GSLG. The results showed that 60 cases of ranula from LSLG and Rivini ducts were 100% cured during the follow-up period. The median number of injections for all patients was 1.16. All 5 cases of ranula from the GSLG did not wholly recover. This study confirmed that BLM intralesional injection is a safe and effective treatment modality for cysts from LSLG or the ducts of Rivini rather than GSLG. Therefore, before treatment, it is necessary to determine the type and origin of the cyst by characterizing its morphology to ensure the effectiveness of the treatment., (© 2024. The Author(s).)

Background and Aims: The impact of lipids on the overall survival (OS) of patients with malignancy has not yet been clarified. This study aimed to evaluate the effect of hyperlipidemia on the OS among Chinese patients based on Body Mass Index (BMI) stratifications and hyperlipidemia types., Method: The patients in this study were derived from the Investigation of the Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) trial. Kaplan-Meier was used to draw the survival curve, and the log-rank test was used to estimate the survival rates between each group. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI)., Results: A total of 9054 patients were included in the final study, with a median age of 59 years, and 55.3% (5004) of them were males. Regarding types of hyperlipidemia, only low high-density lipoprotein was an independent risk factor for the prognosis of all patients (HR = 1.35, 95% CI: 1.25-1.45, P < 0.001), while high total cholesterol (HR = 1.01, 95% CI: 0.90-1.15, P = 0.839) and high low-density lipoprotein (HR = 1.03, 95%CI: 0.91-1.16, P = 0.680) were not. In terms of BMI stratification, the effect of triglycerides on prognosis varied; high triglycerides were an independent risk factor for the prognosis of underweight patients (HR = 1.56, 95% CI:1.05-2.32, P = 0.027) and a protective factor for overweight patients (HR = 0.75, 95% CI: 0.63-0.89, P = 0.001). However, for normal-weight patients, there was no significant statistical difference (HR = 0.88, 95%CI: 0.75-1.03, P = 0.108)., Conclusions: The impact of hyperlipidemia on the OS among patients with cancer varied by different BMI and hyperlipidemia types. BMI and hyperlipidemia type ought to be considered in combination to estimate the prognosis of patients with malignancy., (© 2024. The Author(s).)

Background: Intravitreal injections of angiogenesis inhibitors have proved efficacious in the majority of patients with ocular angiogenesis. However, one-fourth of all treated patients fail to derive benefits from intravitreal injections. tRNA-derived small RNA (tsRNA) emerges as a crucial class of non-coding RNA molecules, orchestrating key roles in the progression of human diseases by modulating multiple targets. Through our prior sequencing analyses and bioinformatics predictions, tRNA-Cys-5-0007 has shown as a potential regulator of ocular angiogenesis. This study endeavors to elucidate the precise role of tRNA-Cys-5-0007 in the context of ocular angiogenesis., Methods: Quantitative reverse transcription PCR (qRT-PCR) assays were employed to detect tRNA-Cys-5-0007expression. EdU assays, sprouting assays, transwell assays, and Matrigel assays were conducted to elucidate the involvement of tRNA-Cys-5-0007 in endothelial angiogenic effects. STZ-induced diabetic model, OIR model, and laser-induced CNV model were utilized to replicate the pivotal features of ocular vascular diseases and evaluate the influence of tRNA-Cys-5-0007 on ocular angiogenesis and inflammatory responses. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were employed to elucidate the anti-angiogenic mechanism of tRNA-Cys-5-0007. Exosomal formulation was employed to enhance the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007., Results: tRNA-Cys-5-0007 expression was down-regulated under angiogenic conditions. Conversely, tRNA-Cys-5-0007 overexpression exhibited anti-angiogenic effects in retinal endothelial cells, as evidenced by reduced proliferation, sprouting, migration, and tube formation abilities. In diabetic, laser-induced CNV, and OIR models, tRNA-Cys-5-0007 overexpression led to decreased ocular vessel leakage, inhibited angiogenesis, and reduced ocular inflammation. Mechanistically, these effects were attributed to the targeting of vascular endothelial growth factor A (VEGFA) and TGF-β1 by tRNA-Cys-5-0007. The utilization of an exosomal formulation further potentiated the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007., Conclusions: Concurrent targeting of tRNA-Cys-5-0007 for anti-angiogenic and anti-inflammatory therapy holds promise for enhancing the effectiveness of current anti-angiogenic therapy., (© 2024. The Author(s).)

Background: The spleen plays a critical role in the immune response against malaria parasite infection, where splenic fibroblasts (SFs) are abundantly present and contribute to immune function by secreting type I collagen (collagen I). The protein family is characterized by Plasmodium vivax tryptophan-rich antigens (PvTRAgs), comprising 40 members. PvTRAg23 has been reported to bind to human SFs (HSFs) and affect collagen I levels. Given the role of type I collagen in splenic immune function, it is important to investigate the functions of the other members within the PvTRAg protein family., Methods: Protein structural prediction was conducted utilizing bioinformatics analysis tools and software. A total of 23 PvTRAgs were successfully expressed and purified using an Escherichia coli prokaryotic expression system, and the purified proteins were used for co-culture with HSFs. The collagen I levels and collagen-related signaling pathway protein levels were detected by immunoblotting, and the relative expression levels of inflammatory factors were determined by quantitative real-time PCR., Results: In silico analysis showed that P. vivax has 40 genes encoding the TRAg family. The C-terminal region of all PvTRAgs is characterized by the presence of a domain rich in tryptophan residues. A total of 23 recombinant PvTRAgs were successfully expressed and purified. Only five PvTRAgs (PvTRAg5, PvTRAg16, PvTRAg23, PvTRAg30, and PvTRAg32) mediated the activation of the NF-κBp65 signaling pathway, which resulted in the production of inflammatory molecules and ultimately a significant reduction in collagen I levels in HSFs., Conclusions: Our research contributes to the expansion of knowledge regarding the functional role of PvTRAgs, while it also enhances our understanding of the immune evasion mechanisms utilized by parasites., (© 2024. The Author(s).)

Background: Angiogenesis is a critical step in colorectal cancer growth, progression and metastasization. CT are routine imaging examinations for preoperative clinical evaluation in colorectal cancer patients. This study aimed to investigate the predictive value of preoperative CT enhancement rate (CER) and CT perfusion parameters on angiogenesis in colorectal cancer, as well as the association of preoperative CER and CT perfusion parameters with serum markers., Methods: This retrospective analysis included 42 patients with colorectal adenocarcinoma. Median of microvessel density (MVD) as the cut-off value, it divided 42 patients into high-density group (MVD ≥ 35/field, n = 24) and low-density group (MVD < 35/field, n = 18), and 25 patients with benign colorectal lesions were collected as the control group. Statistical analysis of CER, CT perfusion parameters, serum markers were performed in all groups. Receiver operating curves (ROC) were plotted to evaluate the diagnostic efficacy of relevant CT perfusion parameters for tumor angiogenesis; Pearson correlation analysis explored potential association between CER, CT perfusion parameters and serum markers., Results: CER, blood volume (BV), blood flow (BF), permeability surface (PS) and carbohydrate antigen 19 - 9 (CA19-9), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), trefoil factor 3 (TFF3), vascular endothelial growth factor (VEGF) in colorectal adenocarcinoma were significantly higher than those in the control group, the parameters in high-density group were significantly higher than those in the low-density group (P < 0.05); however, the time to peak (TTP) of patients in colorectal adenocarcinoma were significantly lower than those in the control group, and the high-density group showed a significantly lower level compared to the low-density group (P < 0.05). The combined parameters BF + TTP + PS and BV + BF + TTP + PS demonstrated the highest area under the curve (AUC), both at 0.991. Pearson correlation analysis showed that the serum levels of CA19-9, CA125, CEA, TFF3, and VEGF in patients showed positive correlations with CER, BV, BF, and PS (P < 0.05), while these indicators exhibited negative correlations with TTP (P < 0.05)., Conclusions: Some single and joint preoperative CT perfusion parameters can accurately predict tumor angiogenesis in colorectal adenocarcinoma. Preoperative CER and CT perfusion parameters have certain association with serum markers., (© 2024. The Author(s).)

Background: The neural cells in the brains of patients with Parkinson's disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson's disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson's disease based on the central-peripheral-central theory., Methods: The present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson's disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes., Discussion: The objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP., Trial Registration: Chinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023., (© 2024. The Author(s).)

Since limb bleeding has been well managed by extremity tourniquets, the management of exsanguinating torso hemorrhage (TH) has become a hot issue both in military and civilian medicine. Conventional hemostatic techniques are ineffective for managing traumatic bleeding of organs and vessels within the torso due to the anatomical features. The designation of noncompressible torso hemorrhage (NCTH) marks a significant step in investigating the injury mechanisms and developing effective methods for bleeding control. Special tourniquets such as abdominal aortic and junctional tourniquet and SAM junctional tourniquet designed for NCTH have been approved by FDA for clinical use. Combat ready clamp and junctional emergency treatment tool also exhibit potential for external NCTH control. In addition, resuscitative endovascular balloon occlusion of the aorta (REBOA) further provides an endovascular solution to alleviate the challenges of NCTH treatment. Notably, NCTH cognitive surveys have revealed that medical staff have deficiencies in understanding relevant concepts and treatment abilities. The stereotypical interpretation of NCTH naming, particularly the term noncompressible, is the root cause of this issue. This review discusses the dynamic relationship between TH and NCTH by tracing the development of external NCTH control techniques. The authors propose to further subdivide the existing NCTH into compressible torso hemorrhage and NCTH' (noncompressible but REBOA controllable) based on whether hemostasis is available via external compression. Finally, due to the irreplaceability of special tourniquets during the prehospital stage, the authors emphasize the importance of a package program to improve the efficacy and safety of external NCTH control. This program includes the promotion of tourniquet redesign and hemostatic strategies, personnel reeducation, and complications prevention., (© 2024. The Author(s).)

Background: Diabetic kidney disease (DKD) is a prevalent complication of diabetes and the leading cause of end-stage renal disease. Recent evidence suggests that total flavonoids of Astragalus (TFA) has promising effects on diabetes; however, its influence on DKD and the underlying mechanism remains unclear., Methods: In this study, we induced the DKD model using streptozotocin (STZ) in male C57BL/6J mice and utilized glomerular endothelial cell (GEC) lines for in vitro investigations. We constructed a network pharmacology analysis to understand the mechanism of TFA in DKD. The mechanism of TFA action on DKD was investigated through Western blot analysis and multi-immunological methods., Results: Our findings revealed that TFA significantly reduced levels of urinary albumin (ALB). Network pharmacology and intracellular pathway experiments indicated the crucial involvement of the PI3K/AKT signaling pathway in mediating these effects. In vitro experiments showed that TFA can preserve the integrity of the glomerular filtration barrier by inhibiting the expression of inflammatory factors TNF-alpha and IL-8, reducing oxidative stress., Conclusion: Our findings demonstrated that TFA can ameliorates the progression of DKD by ameliorating renal fibrosis and preserving the integrity of the kidney filtration barrier. These results provide pharmacological evidence supporting the use of TFA in the treatment of kidney diseases., (© 2024. The Author(s).)

Background: The C-reactive protein (CRP)-triglyceride-glucose (TyG) index (CTI), which is a measure representing the level of inflammation and insulin resistance (IR), is related to poor cancer prognosis; however, the CTI has not been validated in patients with cancer cachexia. Thus, this study aimed to explore the potential clinical value of the CTI in patients with cancer cachexia., Methods: In this study, our prospective multicenter cohort included 1411 patients with cancer cachexia (mean age 59.45 ± 11.38, 63.3% male), which was a combined analysis of multiple cancer types. We randomly selected 30% of the patients for the internal test cohort (mean age 58.90 ± 11.22% 61.4% male). Additionally, we included 307 patients with cancer cachexia in the external validation cohort (mean age 61.16 ± 11, 58.5% male). Receiver operating characteristic (ROC) and calibration curves were performed to investigate the prognostic value of CTI. The prognostic value of the CTI was also investigated performing univariate and multivariate survival analyses., Results: The survival curve indicated that the CTI showed a significant prognostic value in the total, internal, and external validation cohorts. Prognostic ROC curves and calibration curves revealed that the CTI showed good consistency in predicting the survival of patients with cancer cachexia. Multivariate survival analysis showed that an elevated CTI increased the risk of death by 22% (total cohort, 95% confidence interval [CI] = 1.13-1.33), 34% (internal test cohort, 95%CI = 1.11-1.62), and 35% (external validation cohort, 95%CI = 1.14-1.59) for each increase in the standard deviation of CTI. High CTI reliably predicted shorter survival (total cohort, hazard ratio [HR] = 1.45, 95%CI = 1.22-1.71; internal test cohort, HR = 1.62, 95%CI = 1.12-2.36; external validation cohort, HR = 1.61, 95%CI = 1.15-2.26). High CTI significantly predicted shorter survival in different tumor subgroups, such as esophageal [HR = 2.11, 95%CI = 1.05-4.21] and colorectal cancer [HR = 2.29, 95%CI = 1.42-3.71]. The mediating effects analysis found that the mediating proportions of PGSGA, ECOG PS, and EORTC QLQ-C30 on the direct effects of CTI were 21.72%, 19.63%, and 11.61%, respectively We found that there was a significant positive correlation between the CTI and 90-day [HR = 2.48, 95%CI = 1.52-4.14] and 180-day mortality [HR = 1.77,95%CI = 1.24-2.55] in patients with cancer cachexia., Conclusion: The CTI can predict the short- and long-term survival of patients with cancer cachexia and provide a useful prognostic tool for clinical practice., (© 2024. The Author(s).)

Background: Elastin-driven genetic diseases are a group of complex diseases driven by elastin protein insufficiency and dominant-negative production of aberrant protein, including supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa. Here, a Chinese boy with a novel nonsense mutation in the ELN gene is reported., Case Presentation: We report a 1-year-old boy who presented with exercise intolerance, weight growth restriction with age, a 1-year history of heart murmur, and inguinal hernia. Gene sequencing revealed a novel nonsense mutation in the ELN gene (c.757 C > T (p.Gln253Ter), NM&#95;000501.4). Due to severe branch pulmonary artery stenosis, the reconstruction of the branch pulmonary artery with autologous pericardium was performed. The inguinal hernia repair was performed 3 months postoperatively. After six months of outpatient follow-up, the child recovered well, gained weight with age, and had no special clinical symptoms., Conclusion: We identified a de novo nonsense mutation in the ELN gene leading to mild SVAS and severe branch pulmonary artery stenosis. A new phenotype of inguinal hernia was also needed to be considered for possible association with the ELN gene. Still, further confirmation will be necessary., (© 2023. The Author(s).)

Objective: To estimate the prevalence and risk factors associated with tuberculosis (TB) among people living with human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) in China., Methods: A systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. After the literature was screened based on the inclusion and exclusion criteria, STATA ® version 17.0 software was used for the meta-analysis. The heterogeneity among study data was assessed using I 2 statistics. Subgroup analysis and meta-regressions were performed to further explore the source of heterogeneity., Results: A total of 5241 studies were retrieved. Of these, 44 studies were found to be eligible. The pooled prevalence of HIV/TB co-infection was 6.0%. The risk factors for HIV/TB co-infection included a low CD4 + T cell count, smoking, intravenous drug use and several other sociodemographic and clinical factors. Bacillus Calmette-Guérin (BCG) vaccination history was a protective factor., Conclusion: A high prevalence of TB was observed among people living with HIV/AIDS in China. Low CD4 + T cell count, smoking, and intravenous drug use were the primary risk factors for HIV/TB co-infection, whereas BCG vaccination history was a protective factor. Checking for TB should be prioritized in HIV screening and healthcare access., Systematic Review Registration: Registered on PROSPERO, Identifier: CRD42022297754., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Primary failure of tooth eruption (PFE) is a rare autosome genetic disorder that causes open bite. This work aimed to report a small family of PFE(OMIM: # 125,350) with a novel PTH1R variant. One of the patients has a rare clinical phenotype of the anterior tooth involved only., Case Presentation: The proband was a 13-year-old young man with an incomplete eruption of the right upper anterior teeth, resulting in a significant open-bite. His left first molar partially erupted. Family history revealed that the proband's 12-year-old brother and father also had teeth eruption disorders. Genetic testing found a novel PTH1R variant (NM&#95;000316.3 c.1325-1336del), which has never been reported before. The diagnosis of PFE was based on clinical and radiographic characteristics and the result of genetic testing. Bioinformatic analysis predicted this variant would result in the truncation of the G protein-coupled receptor encoded by the PTH1R, affecting its structure and function., Conclusion: A novel PTH1R variant identified through whole-exome sequencing further expands the mutation spectrum of PFE. Patients in this family have different phenotypes, which reflects the characteristics of variable phenotypic expression of PFE., (© 2023. The Author(s).)

Background: As one of the most critical proteins in the JAK/STAT signaling pathway, Janus kinase 2 (JAK2) is involved in many biological processes and diseases. Several observational studies have reported the role of JAK2 in erectile dysfunction. However, the causal relationship between JAK2 and erectile dysfunction remains unclear. Here we investigated the causal relationship between JAK2 and erectile dysfunction., Results: Genetically predicted JAK2 was causally associated with erectile dysfunction in inverse variance weighting (OR = 1.109, 95% CI = 1.029-1.196, p = 0.007) and weighted median method (OR = 1.117, 95% CI = 1.003-1.245, p = 0.044). No heterogeneity was observed in Cochran Q-test (p = 0.855) and MR-PRESSO (p = 0.866). Pleiotropy was not observed in our study (p = 0.617)., Conclusions: These findings highlighted JAK2 as a risk factor for erectile dysfunction and proved the causal relationship between JAK2 and erectile dysfunction, suggesting that targeting JAK2 signaling might be a novel and promising therapeutic candidate in the treatment of erectile dysfunction., (© 2023. The Author(s).)

Background: The emergence of SARS-CoV-2 Omicron subvariants has raised questions regarding resistance to immunity by natural infection or immunization. We examined the sensitivity of Delta and Omicron subvariants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4/5, and BA.3) to neutralizing antibodies from BBIBP-CorV-vaccinated and BBIBP-CorV- or ZF2001-boosted individuals, as well as individuals with Delta and BA.1 breakthrough infections, and determined their fusogenicity and infectivity., Methods: In this cross-sectional study, serum samples from two doses of BBIBP-CorV-vaccinated individuals 1 (n = 36), 3 (n = 36), and 7 (n = 37) months after the second dose; BBIBP-CorV- (n = 25) or ZF2001-boosted (n = 30) individuals; and fully vaccinated individuals with Delta (n = 30) or BA.1 (n = 26) infection were collected. The serum-neutralizing reactivity and potency of bebtelovimab were assessed against D614G, Delta, and Omicron subvariants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4/5, and BA.3) through a pseudovirus neutralization assay. The fusogenicity and infectivity of D614G, Delta, and Omicron subvariants were determined by cell-cell fusion assay and pseudovirus infection assay, respectively., Results: Omicron subvariants markedly escaped vaccine-elicited neutralizing antibodies after two doses of BBIBP-CorV with comparable efficiency. A third dose vaccination of BBIBP-CorV or ZF2001 increased neutralizing antibody titers and breadth against Delta and three Omicron subvariants. Delta and BA.1 breakthrough infections induced comparable neutralizing antibody titers against D614G and Delta variants, whereas BA.1 breakthrough infections elicited a stronger and broader antibody response against three Omicron subvariants than Delta breakthrough infections. BA.2.12.1 and BA.4/5 are more resistant to immunity induced by breakthrough infections. Bebtelovimab had no significant loss of potency against the Delta and Omicron subvariants. Cell culture experiments showed Omicron subvariants to be less fusogenic and have higher infectivity than D614G and Delta with comparable efficiency., Conclusions: These findings have important public health implications and highlight the importance of repeated exposure to SARS-CoV-2 antigens to broaden the neutralizing antibody response against Omicron subvariants., (© 2022. The Author(s).)

Background: In the past few decades, globalization has rendered more frequent and intensive population movement between countries, which has changed the original disease spectrum and brought a huge health impact on the global population including China. This study aims to describe the spectrum and epidemiological characteristics of imported infections among foreign travelers travelling to China., Methods: The data on imported infections among foreign travelers were obtained from Custom Inbound Screening System (CISS) and the National Notifiable Infectious Disease Reporting System (NNIDRS). All the infections were classified into respiratory, gastrointestinal, vector-borne, blood/sex-transmitted and mucocutaneous diseases, of which case numbers and incidences were calculated and the proportions were compared among subgroups., Results: In total, 17,189 travelers diagnosed with 58 imported infectious diseases were reported from 2014 to 2018, with an overall incidence of 122.59 per million. Respiratory infection (7,351 cases, mainly influenza) and blood/sex-transmitted diseases (6,114 cases mainly Hepatitis B and HIV infection) were the most frequently diagnosed diseases, followed by vector-borne infections (3,128 cases, mainly dengue fever and malaria). The highest case number was from Asia and Europe, while the highest incidence rate was from Africa (296.00 per million). When specific diagnosis was compared, both the highest absolute case number and incidence were observed for influenza. An obvious seasonal pattern was observed for vector-borne diseases, with the annual epidemic spanning from July to November. The origin-destination matrices disclosed the movement of imported infection followed specific routes., Conclusions: Our study provided a profile of infectious diseases among foreign travelers travelling to China and pinpointed the target regions, seasons and populations for prevention and control, to attain an informed control of imported infections in China., (© 2022. The Author(s).)

Background: Systemic inflammation is currently regarded as a hallmark of cancer. This study aimed to accurately clarify the prognostic value of various inflammatory markers in patients with stage IV cancer., Methods: This study assessed 2,424 patients with cancer diagnosed with cancer in tumor, node, metastasis (TNM) stage IV. After evaluating the predictive value of 13 inflammatory indicators for patient prognosis using the C index, the lymphocyte C-reactive protein ratio (LCR) was selected to elucidate the prognostic and predictive values in patients with stage IV cancer. Kaplan-Meier and Cox proportional hazards regression models were used to analyze long-term survival., Results: A total of 1,457 men (60.1%) and 967 women (39.9%) diagnosed with TNM stage IV cancer were enrolled. A ratio of 2,814 was defined as the optimal cut-off value for the LCR. The LCR was the most accurate prognosis predictor for patients with stage IV cancer among the 13 inflammatory nutritional markers evaluated. The multivariate-adjusted restricted cubic spline plot suggested that LCR had an L-shaped dose-response association with all-cause mortality risk. Patients with lower LCR levels tended to present with worse prognoses. Kaplan-Meier curves and log-rank test results showed that the high LCR groups (LCR ≥ 2,814) exhibited a better prognosis, whereas patients with stage IV cancer of different sex and tumor types (for example, gastrointestinal tumor, non-gastrointestinal tumor, and lung cancer) had a worse survival time., Conclusion: The LCR score can be regarded as a stable and useful biomarker to predict prognosis in patients with TNM stage IV compared to other evaluated inflammation indicators., (© 2022. The Author(s).)

Background: To quantitatively assess the impact of the onset-to-diagnosis interval (ODI) on severity and death for coronavirus disease 2019 (COVID-19) patients., Methods: This retrospective study was conducted based on the data on COVID-19 cases of China over the age of 40 years reported through China's National Notifiable Infectious Disease Surveillance System from February 5, 2020 to October 8, 2020. The impacts of ODI on severe rate (SR) and case fatality rate (CFR) were evaluated at individual and population levels, which was further disaggregated by sex, age and geographic origin., Results: As the rapid decline of ODI from around 40 days in early January to < 3 days in early March, both CFR and SR of COVID-19 largely dropped below 5% in China. After adjusting for age, sex, and region, an effect of ODI on SR was observed with the highest OR of 2.95 (95% CI 2.37‒3.66) at Day 10-11 and attributable fraction (AF) of 29.1% (95% CI 22.2‒36.1%) at Day 8-9. However, little effect of ODI on CFR was observed. Moreover, discrepancy of effect magnitude was found, showing a greater effect from ODI on SR among patients of male sex, younger age, and those cases in Wuhan., Conclusion: The ODI was significantly associated with the severity of COVID-19, highlighting the importance of timely diagnosis, especially for patients who were confirmed to gain increased benefit from early diagnosis to some extent., (© 2022. The Author(s).)

Background: Systemic inflammation and insulin resistance (IR) are often associated with poor prognosis in cancer. This study aimed to investigate the prognostic value of surrogate systemic inflammation and IR indices in patients with cancer., Methods: This multicenter prospective study included 5,221 patients with cancer, with a mean age of 59.41±11.15 years, of whom 3,061 (58.6%) were male. The surrogate IR indices included low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LHR) ratio, total cholesterol to high-density lipoprotein cholesterol (TC/ HDL-c) ratio, triglyceride to high-density lipoprotein cholesterol (TG/HDL-c) ratio, and fasting triglyceride glucose (TyG). Prognostic receiver operator characteristic (ROC) curves and C-indices were used to select a better surrogate IR index in patients with cancer. The prognostic value of the indicators was evaluated using univariate and multivariate survival analyses., Results: In this study, the median survival time of patients was 44.5 (40.5-51.4) months, and the overall mortality in the 12-month period was 1,115 (53.7%), with 196 mortality events per 1,000 patient-years of patients' follow-up. The prognostic ROC curve and C-index suggested that the prognostic value of LHR was better than that of the other IR indices. The multivariate-adjusted hazard ratios (HRs) for overall survival (OS) were higher in patients with high C-reactive protein (CRP) (HR, 1.51; 95% confidence interval [CI]: 1.38-1.65) and high LHR (HR, 1.20; 95% CI: 1.06-1.37), respectively. The mortality rate of patients with both high CRP and LHR was 1.75-fold higher than that of patients with both low CRP and LHR., Conclusion: Both CRP and LHR showed good survival predictions in patients with cancer. CRP combined with LHR can improve the predictive power of patients with cancer., (© 2022. The Author(s).)

Background: COVID-19 patients with long incubation period were reported in clinical practice and tracing of close contacts, but their epidemiological or clinical features remained vague., Methods: We analyzed 11,425 COVID-19 cases reported between January-August, 2020 in China. The accelerated failure time model, Logistic and modified Poisson regression models were used to investigate the determinants of prolonged incubation period, as well as their association with clinical severity and transmissibility, respectively., Result: Among local cases, 268 (10.2%) had a prolonged incubation period of > 14 days, which was more frequently seen among elderly patients, those residing in South China, with disease onset after Level I response measures administration, or being exposed in public places. Patients with prolonged incubation period had lower risk of severe illness (OR adjusted  = 0.386, 95% CI: 0.203-0.677). A reduced transmissibility was observed for the primary patients with prolonged incubation period (50.4, 95% CI: 32.3-78.6%) than those with an incubation period of ≤14 days., Conclusions: The study provides evidence supporting a prolonged incubation period that exceeded 2 weeks in over 10% for COVID-19. Longer monitoring periods than 14 days for quarantine or persons potentially exposed to SARS-CoV-2 should be justified in extreme cases, especially for those elderly., (© 2021. The Author(s).)

Background: Severe fever with thrombocytopenia (SFTS) caused by SFTS virus (SFTSV) was a tick-borne hemorrhagic fever that posed significant threat to human health in Eastern Asia. The study was designed to measure the seroprevalence of SFTSV antibody in healthy population residing in a high endemic region., Methods: A cohort study was performed on healthy residents in Shangcheng County in Xinyang City from April to December in 2018, where the highest SFTS incidence in China was reported. Anti-SFTSV IgG was measured by indirect enzyme-linked immunosorbent assay and neutralizing antibody (NAb) was detected by using PRNT50. The logistic regression models were performed to analyze the variables that were associated with seropositive rates., Results: Totally 886 individuals were recruited. The baseline seroprevalence that was tested before the epidemic season was 11.9% (70/587) for IgG and 6.8% (40/587) for NAb, which was increased to 13.4% (47/350) and 7.7% (27/350) during the epidemic season, and further to 15.8% (80/508) and 9.8% (50/508) post epidemic. The IgG antibody-based seropositivity was significantly related to the patients aged ≥ 70 years old [adjusted odds ratio (OR) = 2.440, 95% confidence interval (CI): 1.334-4.461 compared to the group of < 50 years old, P = 0.004], recent contact with cats (adjusted OR = 2.195, 95% CI: 1.261-3.818, P = 0.005), and working in tea garden (adjusted OR = 1.698, 95% CI: 1.002-2.880, P = 0.049) by applying multivariate logistic regression model. The NAb based seropositivity was similarly related to the patients aged ≥ 70 years old (adjusted OR = 2.691, 95% CI: 1.271-5.695 compared to the group of < 50 years old, P = 0.010), and recent contact with cats (OR = 2.648, 95% CI: 1.419-4.941, P = 0.002). For a cohort of individuals continually sampled with 1-year apart, the anti-SFTSV IgG were maintained at a stable level, while the NAb level reduced., Conclusions: Subclinical infection might not provide adequate immunity to protect reinfection of SFTSV, thus highlighting the ongoing threats of SFTS in endemic regions, which called for an imperative need for vaccine development. Identification of risk factors might help to target high-risk population for public health education and vaccination in the future., (© 2021. The Author(s).)

Background: Tuberculosis (TB) caused Mycobacterium tuberculosis (M.tb) is one of infectious disease that lead a large number of morbidity and mortality all over the world. Although no reliable evidence has been found, it is considered that combining chemotherapeutic drugs with Chinese herbs can significantly improves the cure rate and the clinical therapeutic effect., Methods: Multi-drug resistant pulmonary tuberculosis (MDR-PTB, n = 258) patients with Qi-yin deficiency syndrome will be randomly assigned into a treatment group (n = 172) or control/placebo group (n = 86). The treatment group will receive the chemotherapeutic drugs combined with Chinese herbs granules (1 + 3 granules), while the control group will receive the chemotherapeutic drugs combined with Chinese herbs placebo (1 + 3 placebo granules). In addition, MDR-PTB (n = 312) patients with Yin deficiency lung heat syndrome will be randomly assigned to a treatment (n = 208) or control/placebo (n = 104) group. The treatment group will receive the chemotherapeutic regimen combined with Chinese herbs granules (2 + 4 granules), while the control group will receive the chemotherapeutic drugs and Chinese herbs placebo (2 + 4 placebo granules). The primary outcome is cure rate, the secondary outcomes included time to sputum culture conversion, lesion absorption rate and cavity closure rate. BACTEC™ MGIT™ automated mycobacterial detection system will be used to evaluate the M.tb infection and drug resistance. Chi-square test and Cox regression will be conducted with SAS 9.4 Statistical software to analyze the data., Discussion: The treatment cycle for MDR-PTB using standardized modern medicine could cause lengthy substantial side effects. Chinese herbs have been used for many years to treat MDR-PTB, but are without high-quality evidence. Hence, it is unknown whether Chinese herbs enhances the clinical therapeutic effect of synthetic drugs for treating MDR-PTB. Therefore, this study will be conducted to evaluate the clinical therapeutic effect of combining Chinese herbs and chemotherapeutic drugs to treat MDR-PTB cases. It will assist in screening new therapeutic drugs and establishing treatment plan that aims to improve the clinical therapeutic effect for MDR-PTB patients., Trial Registration: This trial was registered at ClinicalTrials.gov (ChiCTR1900027720) on 24 November 2019 (prospective registered)., (© 2021. The Author(s).)

Background: Both simulation-based training and video-based training serve as educational adjuncts for learning TEE among medical students. In the present study, we hypothesized that simulation-based training would better enhance the performance of medical students in the interpretation of 20 cross-sectional views compared to video-based training., Methods: A total of 120 4th-year undergraduate medical students were enrolled in the present study. The study began with a pre-test of all the participants, followed by a 90-min theoretical lecture and a post-test. Subsequently, the participants were randomly divided into the video-based group (Group V) and simulation-based group (Group S). Next, Group V received 60 min of TEE video learning, while Group S received 60 min of TEE simulator training. After the respective training, both the groups undertook the retention-test 1 and retention-test 2, 1 week and 1 month later, respectively. The performance for each test was evaluated by five views, which were selected randomly and, respectively, from a set of 20 cross-sectional views. The primary outcome was the performance of the retention-test 1. Secondary outcomes included: (1) comparison the performances of the pre-test, post-test, and retention-test 2 between two groups; (2) comparison the performances of pre-test and post-test in the same group; (3) comparison the performances of retention-test 1, and retention-test 2 in the same group., Results: Better performances were observed in Group S in both retention-test 1 (Group V: 63.2 [52.6, 77.6] vs. Group S: 89.5 [68.4, 100.0], P < 0.001) and retention-test 2 (Group V: 58.0 [48.0, 72.0] vs. Group S: 74.0 [64.0, 80.0], P < 0.001) compared to Group V. No statistically significant differences were observed in the performances of pre-test (Group V: 8.3 [4.2, 12.5] vs. Group S: 8.3 [4.2, 12.5], P = 0.825) or post-test (Group V: 46.2 [38.5, 57.7] vs. Group S: 44.2 [38.5, 56.7], P = 0.694) between the two groups. The improvement had been observed in the post-test, compared with pre-test in the same group, respectively (Group V in post-test: 46.2 [38.5, 57.7] vs. Group V in pre-test: 8.3 [4.2, 12.5], P < 0.001; Group S in post-test: 44.2 [38.5, 56.7] vs. Group S in pre-test: 8.3 [4.2, 12.5], P < 0.001). However, the performance in retention-test 2 was significantly reduced, compared with retention-test 1 in the same group, respectively (Group V in retention-test 2: 58.0 [48.0, 72.0] vs. Group V in retention-test 1: 63.2 [52.6, 77.6] P = 0.005; Group S in retention-test 2: 74.0 [64.0, 80.0] vs. Group S in retention-test 1: 89.5 [68.4, 100.0], P < 0.001)., Conclusions: Following a 90-min theoretical lecture, simulation-based training better enhanced the performance of medical students in the interpretation and short-term retention of 20 cross-sectional views compared to video-based training., Trial Registration: http://www.chictr.org.cn ( ChiCTR2000033519 , 3/June/2020).

Background: The coronavirus disease 2019 (COVID-19) epidemic has been largely controlled in China, to the point where case fatality rate (CFR) data can be comprehensively evaluated., Methods: Data on confirmed patients, with a final outcome reported as of 29 March 2020, were obtained from official websites and other internet sources. The hospitalized CFR (HCFR) was estimated, epidemiological features described, and risk factors for a fatal outcome identified., Results: The overall HCFR in China was estimated to be 4.6% (95% CI 4.5-4.8%, P < 0.001). It increased with age and was higher in males than females. Although the highest HCFR observed was in male patients ≥70 years old, the relative risks for death outcome by sex varied across age groups, and the greatest HCFR risk ratio for males vs. females was shown in the age group of 50-60 years, higher than age groups of 60-70 and ≥ 70 years. Differential age/sex HCFR patterns across geographical regions were found: the age effect on HCFR was greater in other provinces outside Hubei than in Wuhan. An effect of longer interval from symptom onset to admission was only observed outside Hubei, not in Wuhan. By performing multivariate analysis and survival analysis, the higher HCFR was associated with older age (both P < 0.001), and male sex (both P < 0.001). Only in regions outside Hubei, longer interval from symptom onset to admission, were associated with higher HCFR., Conclusions: This up-to-date and comprehensive picture of COVID-19 HCFR and its drivers will help healthcare givers target limited medical resources to patients with high risk of fatality.

Background: COVID-19 has impacted populations around the world, with the fatality rate varying dramatically across countries. Selenium, as one of the important micronutrients implicated in viral infections, was suggested to play roles., Methods: An ecological study was performed to assess the association between the COVID-19 related fatality and the selenium content both from crops and topsoil, in China., Results: Totally, 14,045 COVID-19 cases were reported from 147 cities during 8 December 2019-13 December 2020 were included. Based on selenium content in crops, the case fatality rates (CFRs) gradually increased from 1.17% in non-selenium-deficient areas, to 1.28% in moderate-selenium-deficient areas, and further to 3.16% in severe-selenium-deficient areas (P = 0.002). Based on selenium content in topsoil, the CFRs gradually increased from 0.76% in non-selenium-deficient areas, to 1.70% in moderate-selenium-deficient areas, and further to 1.85% in severe-selenium-deficient areas (P < 0.001). The zero-inflated negative binomial regression model showed a significantly higher fatality risk in cities with severe-selenium-deficient selenium content in crops than non-selenium-deficient cities, with incidence rate ratio (IRR) of 3.88 (95% CIs: 1.21-12.52), which was further confirmed by regression fitting the association between CFR of COVID-19 and selenium content in topsoil, with the IRR of 2.38 (95% CIs: 1.14-4.98) for moderate-selenium-deficient cities and 3.06 (1.49-6.27) for severe-selenium-deficient cities., Conclusions: Regional selenium deficiency might be related to an increased CFR of COVID-19. Future studies are needed to explore the associations between selenium status and disease outcome at individual-level.

Background: Previous study indicated that transversus abdominis plane (TAP) block could be the principal anesthetic technique for peritoneal dialysis catheter (PDC) implantations. However, a TAP block could not provide an optimal anesthetic effect on catheter exit site during PDC implantation. We hypothesized that single-injection ultrasound-guided thoracic paravertebral block (US-TPVB) could be the principal anesthetic technique with better pain relief at catheter exit site during PDC implantation, compared to a TAP block. And anesthesia quality of a single-injection US-TPVB was compared with that of a TAP block and local anesthetic infiltration (LAI)., Methods: Patients undergoing PDC implantations were randomized into groups TPVB or TAP or LAI. In group TPVB, single-injection US-TPVB at T10-T11 level was performed with 20 ml of 0.25% ropivacaine. In group TAP, oblique subcostal TAP block was performed with 20 ml of 0.25% ropivacaine. In group LAI, 40 ml of 0.25% ropivacaine was used. Anesthesia quality was compared among the three groups, including general anesthesia conversion rate, cumulative rescuing sufentanil consumption, and satisfaction rate by nephrologists and patients., Results: Eighty-eight eligible patients were enrolled. Visual analogue scale (VAS) at most time points (except for the catheter exit site) were lower in group TAP, compared with group TPVB. VAS at parietal peritoneum manipulation was 6 (5, 7), 3 (0, 6), and 7 (4.75, 9) in groups TPVB, TAP, and LAI, respectively (P < 0.001). VAS at catheter exit site was 4 (3, 4), 5.5 (4, 8), and 5 (3, 7.25) in groups TPVB, TAP, and LAI, respectively (P = 0.005). Lower general anesthesia conversion rate, less cumulative rescuing sufentanil consumption, and higher satisfaction rates by nephrologists and patients were recorded in group TAP, compared with groups TPVB and LAI., Conclusions: Single-injection US-TPVB provided a better pain relief at catheter exit site. The quality and reliability of anesthesia after a single-injection US-TPVB was comparable to that of LAI, but not better than that of an oblique subcostal TAP block for PDC implantation., Trial Registration: TCTR20160911002 . Registered on 8 September 2016.

Background: We assessed whether a postoperative bilateral, ultrasound-guided, posterior transversus abdominis plane (TAP) block could reduce 24 h rescue tramadol requirement compared with placebo in patients undergoing elective laparoscopic colorectal cancer surgery., Methods: Patients scheduled to undergo elective laparoscopic surgery following the diagnosis of colorectal cancer were included in this study and randomized into Group and Group Control. The patients received a postoperative bilateral, ultrasound-guided, posterior TAP block in either 20 mL of 0.5% ropivacaine (Group TAP) per side or an equivalent volume of normal saline (Group Control). The primary outcome was the cumulative consumption of rescue tramadol within 24 h after the surgery. Secondary endpoints included (1) resting and movement numerical rating scale (NRS) pain scores at 2, 4, 6, 12, 24, 48, and 72 h; (2) incidences of related side effects; (3) time to the first request for rescue tramadol; (4) patient satisfaction regarding postoperative analgesia; (5) time to restoration of intestinal function; (6) time to mobilization; and (7) the length of hospital stay., Results: In total, 92 patients were randomized, and 82 patients completed the analysis. The total rescue tramadol requirement (median [interquartile range]) within the first 24 h was lower in Group TAP (0 [0, 87.5] mg) than in Group Control (100 [100, 200] mg), P < 0.001. The posterior TAP block reduced resting and movement NRS pain scores at 2, 4, 6, 12, and 24 h after surgery (all P < 0.001) but showed similar scores at 48 h or 72 h. A higher level of satisfaction with postoperative analgesia was observed in Group TAP on day 1 (P = 0.002), which was similar on days 2 (P = 0.702) and 3 (P = 0.551), compared with the Group Control. A few incidences of opioid-related side effects (P < 0.001) and a lower percentage of patients requiring rescue tramadol analgesia within 24 h (P < 0.001) were observed in Group TAP. The time to the first request for rescue analgesia was prolonged, and the time to mobilization and flatus was reduced with a shorter hospital stay in Group TAP as compared with Group Control., Conclusions: A postoperative bilateral, ultrasound-guided, posterior TAP block resulted in better pain management and a faster recovery in patients undergoing laparoscopic colorectal cancer surgery, without adverse effects., Trial Registration: The study was registered at http://www.chictr.org.cn ( ChiCTR-IPR-17012650 ; Sep 12, 2017).

Background: Anterior gradient-2 (AGR2) is a proto-oncogene involved in tumorigenesis and cancer progression. AGR2, predominantly localized in the endoplasmic reticulum (ER), is also a secreted protein detected in the extracellular compartment in multiple cancers. However, the biological functions of intracellular and extracellular AGR2 remain to be elucidated., Methods: Based on the biochemical structure of AGR2 protein, PANC-1 pancreatic cancer cells stably expressing ER-resident or secreted AGR2 were generated by a lentivirus-mediated stable overexpression system. The capacities of cell proliferation, migration, invasion and survival were assessed in PANC-1 stable cells. Moreover, EGFR expression and activation were determined to explore the possible mechanism of AGR2 roles in pancreatic cancer tumorigenesis., Results: It was discovered that secreted AGR2, but not ER-resident AGR2, promotes cell proliferation, migration and invasion of PANC-1 cells. Moreover, the data indicated that both the ER-resident and the secreted AGR2 enhance the survival capacity of PANC-1 cells after tunicamycin-induced ER stress and gemcitabine treatment. However, EGFR expression and activation were not found to be involved in AGR2-dependent oncogenic phenotypes in PANC-1 cells., Conclusions: Secreted AGR2 is predominantly involved in cell proliferation, migration and invasion in PANC-1 pancreatic cancer cells. Both secreted and ER-resident AGR2 contribute to the survival of PANC-1 cells under the challenging conditions. These findings provide insight into how different localizations of AGR2 have contributed to pancreatic cancer growth, metastasis, and drug sensitivity.

Background: Enteral nutrition (EN) therapy is widely used in clinical practice to provide artificial nutrition to patients, while the incidence of adverse events are relatively highly. In the clinical setting, the occurrence of adverse events is associated with the nurse's risk perception. Thus, using tool to evaluate nurse's risk perception of enteral nutrition is necessary., Methods: The draft questionnaire with 37-items was formed by comprehensive literature reviews and semi-structured in-depth interviews with 11 nurses. Two iterations of expert consultations were used to evaluate the content validity, and 4 items were deleted in this phrase. A 33-items questionnaire was used to survey 352 nurses from five tertiary hospitals in China from May to July 2019 with convenience sampling. Content validity, construct validity and known-groups validity were evaluated by content validity index (CVI), exploratory factor analysis, and the comparisons of the different EN risk perception levels of nurses at different working departments and different educational backgrounds, respectively. Reliability was tested by internal consistency, test-retest reliability, and split-half reliability., Results: After the exploratory factor analysis, four items were excluded. Finally, the newly developed questionnaire included 29 items explaining 71.356% of the total variance. It consisted of three factors: Risks of operation (15 items); Risks of EN-related adverse events (11 items), and Risks of EN solution selection (3 items). The CVI of the questionnaire was 0.95 and the CVI of items ranged from 0.875-1.0. The results of known-groups validity showed that the nurses with different educational backgrounds had a statistically significant difference of EN risk perception (z = - 3.024, p = 0.002), whereas there was not significantly different between EN risk perception of nurses working in different departments (z = - 1.644, p = 0.100). The Cronbach's α, test-retest reliability, and split-half reliability of the questionnaire were 0.967, 0.818, and 0.815, respectively., Conclusions: The newly developed questionnaire for assessing nurse's EN risk perception showed good reliability and validity. It can be used as a tool for nursing managers to assess Chinese nurses' EN risk perception ability, so as to help to reduce the occurrence of adverse events during EN implementation.

Background: High temperatures, particularly at night, decrease rice yield and quality. As high nighttime temperatures (HNTs) become increasingly frequent due to climate change, it is imperative to develop rice crops that tolerate HNTs. DNA methylation may represent a potential avenue for HNT-tolerant rice strain development, as this mechanism regulates gene activity and cellular phenotype in response to adverse environmental conditions without changing the nucleotide sequence., Results: After HNT exposure, the methylation patterns of cytosines in the CHH context differed noticeably between two coisogenic rice strains with significantly different levels in heat tolerance. Methylation differences between strains were primarily observed on successive cytosines in the promoter or downstream regions of transcription factors and transposon elements. In contrast to the heat-sensitive rice strain, the regions 358-359 bp and 2-60 bp downstream of two basal transcriptional factors (TFIID subunit 11 and mediator of RNA polymerase II transcription subunit 31, respectively) were fully demethylated in the heat-tolerant strain after HNT exposure. In the heat-tolerant strain, HNTs reversed the methylation patterns of successive cytosines in the promoter regions of various genes involved in abscisic acid (ABA)-related reactive oxygen species (ROS) equilibrium pathways, including the pentatricopeptide repeat domain gene PPR (LOC&#95;Os07g28900) and the homeobox domain gene homeobox (LOC&#95;Os01g19694). Indeed, PRR expression was inhibited in heat-sensitive rice strains, and the methylation rates of the cytosines in the promoter region of PRR were greater in heat-sensitive strains as compared to heat-tolerant strains., Conclusions: After HNT exposure, cytosines in the CHH context were more likely than cytosines in other contexts to be methylated differently between the heat-sensitive and heat-tolerant rice strains. Methylation in the promoter regions of the genes associated with ABA-related oxidation and ROS scavenging improved heat tolerance in rice. Our results help to clarify the molecular mechanisms underlying rice heat tolerance.

Background: Astrocytes are crucial regulators in the central nervous system. Abnormal activation of astrocytes contributes to some behavior deficits. However, mechanisms underlying the effects remain unclear. Here, we studied the activation of A1 astrocytes and their contribution to murine behavior deficits., Methods: A1 astrocytes were induced by treatment with lipopolysaccharide (LPS) in vitro. The functional phenotype of astrocytes was determined by quantitative RT-PCR, ELISA, and immunohistochemistry. To assess the role of A1 astrocytes in vivo, mice were injected intraperitoneally with LPS. Then, murine behaviors were tested, and the hippocampus and cortex were analyzed by quantitative RT-PCR, ELISA, and immunohistochemistry. The function of IL-10 and fluorocitrate on A1 astrocyte activation was also examined., Results: Our results show that astrocytes isolated from B6.129S6-Il10 tm1Flv /J homozygotes (IL-10 tm1/tm1 ) were prone to characteristics of A1 reactive astrocytes. Compared with their wild-type counterparts, IL-10 tm1/tm1 astrocytes exhibited higher expression of glial fibrillary acidic protein (GFAP). Whether or not they were stimulated with LPS, IL-10 tm1/tm1 astrocytes exhibited enhanced expression of A1-specific transcripts and proinflammatory factors IL-1β, IL-6, and TNFα. In addition, IL-10 tm1/tm1 astrocytes demonstrated hyperphosphorylation of STAT3. Moreover, astrocytes from IL-10 tm1/tm1 mice showed attenuated phagocytic ability and were neurotoxic. IL-10 tm1/tm1 mice demonstrated increased immobility time in the forced swim test and defective learning and memory behavior in the Morris water maze test. Moreover, enhanced neuroinflammation was found in the hippocampus and cortex of IL-10 tm1/tm1 mice, accompanying with more GFAP-positive astrocytes and severe neuron loss in the hippocampus. Pretreatment IL-10 tm1/tm1 mice with IL-10 or fluorocitrate decreased the expression of proinflammatory factors and A1-specific transcripts in the hippocampus and cortex, and then alleviated LPS-induced depressive-like behavior., Conclusion: These results demonstrate that astrocytes isolated from B6.129S6-Il10 tm1Flv /J homozygotes are prone to A1 phenotype and contribute to the depression-like behavior and memory deficits. Inhibiting A1 astrocyte activation may be an attractive therapeutic strategy in some neurodegenerative diseases.

Background: Many disease causing genes have been identified through different methods, but there have been no uniform annotations of biomedical named entity (bio-NE) of the disease phenotypes of these genes yet. Furthermore, semantic similarity comparison between two bio-NE annotations has become important for data integration or system genetics analysis., Results: The package pyMeSHSim recognizes bio-NEs by using MetaMap which produces Unified Medical Language System (UMLS) concepts in natural language process. To map the UMLS concepts to Medical Subject Headings (MeSH), pyMeSHSim is embedded with a house-made dataset containing the main headings (MHs), supplementary concept records (SCRs), and their relations in MeSH. Based on the dataset, pyMeSHSim implemented four information content (IC)-based algorithms and one graph-based algorithm to measure the semantic similarity between two MeSH terms. To evaluate its performance, we used pyMeSHSim to parse OMIM and GWAS phenotypes. The pyMeSHSim introduced SCRs and the curation strategy of non-MeSH-synonymous UMLS concepts, which improved the performance of pyMeSHSim in the recognition of OMIM phenotypes. In the curation of 461 GWAS phenotypes, pyMeSHSim showed recall > 0.94, precision > 0.56, and F1 > 0.70, demonstrating better performance than the state-of-the-art tools DNorm and TaggerOne in recognizing MeSH terms from short biomedical phrases. The semantic similarity in MeSH terms recognized by pyMeSHSim and the previous manual work was calculated by pyMeSHSim and another semantic analysis tool meshes, respectively. The result indicated that the correlation of semantic similarity analysed by two tools reached as high as 0.89-0.99., Conclusions: The integrative MeSH tool pyMeSHSim embedded with the MeSH MHs and SCRs realized the bio-NE recognition, normalization, and comparison in biomedical text-mining.

Background: China is the second highest pulmonary tuberculosis (PTB) burden country worldwide. However, retreatment of PTB has often developed resistance to at least one of the four first-line anti-TB drugs. The cure rate (approximately 50.0-73.3%) and management of retreatment of PTB in China needs to be improved. Qinbudan decoction has been widely used to treat PTB in China since the 1960s. Previously clinical studies have shown that the Qinbudan tablet (QBDT) promoted sputum-culture negative conversion and lesion absorption. However, powerful evidence from a randomized controlled clinical trial is lacking. Therefore, the aim of this study was to compare the efficacy and safety of QBDT as an adjunct therapy for retreatment of PTB., Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial in China. People diagnosed with PTB were enrolled who received previous anti-TB treatment from April 2011 to March 2013. The treatment group received an anti-TB regimen and QBDT, and the control group was administered an anti-TB regimen plus placebo. Anti-TB treatment options included isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin for 2 months (2HRZES), followed by isoniazid, rifampicin, ethambutol for 6 months (6HRE), daily for 8 months. Primary outcome was sputum-culture conversion using the MGIT 960 liquid medium method. Secondary outcomes included lung lesion absorption and cavity closure. Adverse events and reactions were observed after treatment. A structured questionnaire was used to record demographic information and clinical symptoms of all subjects. Data analysis was performed by SPSS 25.0 software in the full analysis set (FAS) population., Results: One hundred eighty-one cases of retreatment PTB were randomly divided into two groups: the placebo group (88 cases) and the QBDT group (93 cases). A total of 166 patients completed the trial and 15 patients lost to follow-up. The culture conversion rate of the QBDT group and placebo group did not show a noticeable improvement by using the covariate sites to correct the rate differences (79.6% vs 69.3%; rate difference = 0.10, 95% confidence interval (CI): - 0.02-0.23; F = 2.48, P = 0.12) after treatment. A significant 16.6% increase in lesion absorption was observed in the QBDT group when compared with the placebo group (67.7% vs 51.1%; rate difference = 0.17, 95% CI: 0.02-0.31; χ 2  = 5.56, P = 0.02). The intervention and placebo group did not differ in terms of cavity closure (25.5% vs 21.1%; rate difference = 0.04, 95% CI: - 0.21-0.12; χ 2  = 0.27, P = 0.60). Two patients who received chemotherapy and combined QBDT reported pruritus/nausea and vomiting., Conclusions: No significant improvement in culture conversion was observed for retreatment PTB with traditional Chinese medicine plus standard anti-TB regimen. However, QBDT as an adjunct therapy significantly promoted lesion absorption, thereby reducing lung injury due to Mycobacterium tuberculosis infection., Trial Registration: This trial is registered at ClinicalTrials.gov, NCT02313610.

Backgrounds: There is a discrepancy between west and east on the relationship between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). This study aimed to find out the possible reason for this and to clarify the association between NAFLD and CKD by analyzing two population-based datasets from the US and China., Methods: Two health examination datasets from China and the US were used. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m 2 or and/or abnormal albuminuria and/or overt proteinuria. Binary logistic regression was used to examine the association between NAFLD and CKD., Results: A total of 60,965 participants were analyzed, including 11,844 from the US and 51,229 from China. The prevalence of NAFLD was 27.12% in the Chinese population and 36.08% in the US population (p < 0.001). The proportions of CKD and late stage CKD (stages 3-5) were higher in the US population than the Chinese one. NAFLD was independently associated with an increased risk of CKD in Chinese population, whereas in the US population, the NAFLD was not an independent risk factor of CKD. In subgroup analyses which excluded late stages CKD (stages 3-5), the risks of mild renal function decline became consistent: NAFLD was associated with early stages of CKD but not the late stages of CKD in both populations., Conclusion: NAFLD increased the risk of early stages of CKD in both Chinese and the US population. The conflicting results reported by previous studies might result from the different proportion of late stages of CKD.

Background: Long noncoding RNAs (lncRNAs) play essential roles in tumor progression. However, the functions and targets of lncRNAs in neuroblastoma (NB) progression still remain to be determined. In this study, we aimed to investigate the effect of lncRNA DLX6 antisense RNA 1 (DLX6-AS1) on NB and the underlying mechanism involved., Methods: Through mining of public microarray datasets, we identify aberrantly expressed lncRNAs in NB. The gene expression levels were determined by quantitative real-time PCR, and protein expression levels were determined by western blot assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, wound-healing assay, transwell invasion assays and flow cytometry analysis were utilized to examine cell proliferation, migration, invasion and apoptosis. Luciferase reporter assay was performed to confirm the interaction between DLX6-AS1and its potential targets. Tumor xenograft assay was used to verify the role of DLX6-AS1 in NB in vivo., Results: We identified DLX6-AS1 was upregulated in NB by using a public microarray dataset. The expression of DLX6-AS1 was increased in NB tissues and derived cell lines, and high expression of DLX6-AS1 was positively correlated with advanced TNM stage and poor differentiation. Knockdown of DLX6-AS1 induced neuronal differentiation, apoptosis and inhibited the growth, invasion, and metastasis of NB cells in vitro and impaired tumor growth in vivo. MiR-107 was the downstream target of DLX6-AS1. MiR-107 was found to target brain-derived neurotrophic factor (BDNF) which is an oncogene in NB. Knockdown of miR-107 or overexpression of BDNF reversed the suppression of NB progression caused by DLX6-AS1 silence., Conclusion: Overall, our finding supports that DLX6-AS1 promotes NB progression by regulating miR-107/BDNF pathway, acting as a novel therapeutic target for NB., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Background: Nsa cytoplasmic male sterility (CMS) is a novel alloplasmic male sterility system derived from somatic hybridization between Brassica napus and Sinapis arvensis. Identification of the CMS-associated gene is a prerequisite for a better understanding of the origin and molecular mechanism of this CMS. With the development of genome sequencing technology, organelle genomes of Nsa CMS line and its maintainer line were sequenced by pyro-sequencing technology, and comparative analysis of the organelle genomes was carried out to characterize the organelle genome composition of Nsa CMS as well as to identify the candidate Nsa CMS-associated genes., Results: Nsa CMS mitochondrial genome showed a higher collinearity with that of S. arvensis than B. napus, indicating that Nsa CMS mitochondrial genome was mainly derived from S. arvensis. However, mitochondrial genome recombination of parental lines was clearly detected. In contrast, the chloroplast genome of Nsa CMS was highly collinear with its B. napus parent, without any evidence of recombination of the two parental chloroplast genomes or integration from S. arvensis. There were 16 open reading frames (ORFs) specifically existed in Nsa CMS mitochondrial genome, which could not be identified in the maintainer line. Among them, three ORFs (orf224, orf309, orf346) possessing chimeric and transmembrane structure are most likely to be the candidate CMS genes. Sequences of all three candidate CMS genes in Nsa CMS line were found to be 100% identical with those from S. arvensis mitochondrial genome. Phylogenetic and homologous analysis showed that all the mitochondrial genes were highly conserved during evolution., Conclusions: Nsa CMS contains a recombined mitochondrial genome of its two parental species with the majority form S. arvensis. Three candidate Nsa CMS genes were identified and proven to be derived from S. arvensis other than recombination of its two parental species. Further functional study of the candidate genes will help to identify the gene responsible for the CMS and the underlying molecular mechanism.

Background: Data on the pharmacological management of acute agitation in schizophrenia are scarce. The aim of this study is to investigate the prescription practices in the treatment of agitation in Chinese patients with schizophrenia., Methods: We conducted a large, multicenter, observational study in 14 psychiatry hospitals in China. Newly hospitalized schizophrenia patients with the PANSS-EC total score ≥ 14 and a value ≥4 on at least one of its five items were included in the study. Their drug treatments of the first 2 weeks in hospital were recorded by the researchers., Results: Eight hundred and 53 patients enrolled in and 847 (99.30%) completed the study. All participants were prescribed antipsychotics, 40 (4.72%) were prescribed benzodiazepine in conjunction with antipsychotics and 81 were treated with modified electric convulsive therapy (MECT). Four hundred and 12 (48.64%) patients were prescribed only one antipsychotic, in the order of olanzapine (120 patients, 29.13%), followed by risperidone (101 patients, 24.51%) and clozapine (41 patients, 9.95%). About 435 (51.36%) participants received antipsychotic polypharmacy, mostly haloperidol + risperidone (23.45%), haloperidol+ olanzapine (17.01%), olanzapine+ ziprasidone (5.30%), haloperidol + clozapine (4.37%) and haloperidol + quetiapine (3.90%). Binary logistic regression analysis suggests that a high BARS score (OR 2.091, 95%CI 1.140-3.124), severe agitation (OR 1.846, 95%CL 1.266-2.693), unemployment or retirement (OR 1.614, 95%CL 1.189-2.190) and aggressiveness on baseline (OR 1.469, 95%CL 1.032-2.091) were related to an increased antipsychotic polypharmacy odds. Male sex (OR 0.592, 95%CL 0.436-0.803) and schizophrenia in older persons (age ≥ 55 years, OR 0.466, 95%CL 0.240-0.902) were less likely to be associated with antipsychotic polypharmacy., Conclusion: The present study demonstrates that monotherapy and polypharmacy display equally common patterns of antipsychotic usage in managing agitation associated with schizophrenia in China. The extent and behavioral activities of agitation and several other factors were associated with polypharmacy.

Background: The Asia lotus (Nelumbo nucifera Gaertn.) is an ornamental aquatic plant with high economic value. Flower colour is an important ornamental trait, with much of N. nucifera breeding focusing on its yellow flowers. To explore the yellow flower colouration mechanism in N. nucifera, we analysed its pigment constituents and content, as well as gene expression in the flavonoid pathway, in two N. nucifera cultivars., Results: We performed metabolomic and gene expression analyses in two N. nucifera cultivars with yellow and white flowers, Molinqiuse (MLQS) and Yeguangbei (YGB), respectively, at five stages of flower colouration. Based on phenotypic observation and metabolite analyses, the later stages of flower colouration (S3-S5) were determined to be key periods for differences between MLQS and YGB, with dihydroflavonols and flavonols differing significantly between cultivars. Dihydroquercetin, dihydrokaempferol, and isorhamnetin were significantly higher in MLQS than in YGB, whereas kaempferol was significantly higher in YGB. Most of the key homologous structural genes in the flavonoid pathway were significantly more active in MLQS than in YGB at stages S1-S4., Conclusion: In this study, we performed the first analyses of primary and secondary N. nucifera metabolites during flower colouration, and found that isorhamnetin and kaempferol shunting resulted in petal colour differences between MLQS and YGB. Based on our data integration analyses of key enzyme expression in the putative flavonoid pathways of the two N. nucifera cultivars, NnFLS gene substrate specificity and differential expression of NnOMTs may be related to petal colour differences between MLQS and YGB. These results will contribute to determining the mechanism of yellow flower colouration in N. nucifera, and will improve yellow petal colour breeding in lotus species.

Background: Cysticercosis is an emerging and neglected tropical disease (NTD) that poses a serious public health concern worldwide. Disseminated cysticercosis (DCC) is an uncommon manifestation of cysticercosis, also found in China., Case Presentation: We report three cases of DCC in patients living in China, with different clinical and radiological presentations. All three patients had DCC with active ocular cysticercosis, including one patient with widespread DCC caused by direct ingestion of Taenia solium eggs. The intravitreal cysticercus cyst in this patient was completely extracted entirely by 23-gauge pars plana vitrectomy, and the cyst was oval in shape on the flat mount preparation., Conclusion: The clinical presentation of DCC is highly sophisticated. The diagnosis depended on the typical radiological presentations, biopsy and flat mount preparations of the cyst.

Background: First flower node (FFN) is an important trait for evaluating fruit earliness in pepper (Capsicum annuum L.). The trait is controlled by quantitative trait loci (QTL); however, studies have been limited on QTL mapping and genes contributing to the trait., Results: In this study, we developed a high density genetic map using specific-locus amplified fragment sequencing (SLAF-seq), a high-throughput strategy for de novo single nucleotide polymorphism discovery, based on 146 recombinant inbred lines (RILs) derived from an intraspecific cross between PM702 and FS871. The map contained 9328 SLAF markers on 12 linkage groups (LGs), and spanned a total genetic distance of 2009.69 centimorgan (cM) with an average distance of 0.22 cM. The sequencing depth for the map was 72.39-fold in the male parent, 57.04-fold in the female parent, and 15.65-fold in offspring. Using the genetic map, two major QTLs, named Ffn2.1 and Ffn2.2, identified on LG02 were strongly associated with FFN, with a phenotypic variance explanation of 28.62 and 19.56%, respectively. On the basis of the current annotation of C. annuum cv. Criollo de Morelos (CM334), 59 candidate genes were found within the Ffn2.1 and Ffn2.2 region, but only 3 of 59 genes were differentially expressed according to the RNA-seq results. Eventually we identified one gene associated with the FFN based on the function through GO, KEGG, and Swiss-prot analysis., Conclusions: Our research showed that the construction of high-density genetic map using SLAF-seq is a valuable tool for fine QTL mapping. The map we constructed is by far the most saturated complete genetic map of pepper, and using it we conducted fine QTL mapping for the important trait, FFN. QTLs and candidate genes obtained in this study lay a good foundation for the further research on FFN-related genes and other genetic applications in pepper.

Background: Neonatal hypoglycemia is tightly related to adverse neurodevelopmental and brain injury outcomes., Methods: A total of 195 infants who were born from diabetic mothers with a low blood glucose level (< 2.6 mM) within 0.5 h after birth were enrolled in this prospective cohort study. Of these, 157 infants who had neonatal hypoglycemia (group A) were followed up, and this group was further divided into A1 [blood glucose concentration (BGC) < 2.6 mM at < 2 h after birth], A2 (BGC < 2.6 mM at 2-24 h after birth), and A3 (BGC < 2.6 mM at > 24 h after birth). A total of 144 infants whose mothers had no high risk for gestational diabetes mellitus were followed up as the control group during the same period. The neurodevelopment of the infants was evaluated by the Gesell scoring method., Results: The adaptability in the A2 and A3 subgroups was significantly lower than that in the control group (73.9 ± 6.6 vs. 87.9 ± 11.2; 71.5 ± 8.9 vs. 87.9 ± 11.2, respectively). There were significantly more mothers who used insulin during the perinatal period in A3 than in A1 and A2 (31% vs. 2%; 31% vs. 7.9%, respectively). The mothers of babies in subgroups A2 and A3 gained more weight than those of the control group (15.3 ± 1.9 kg vs. 11.1 ± 2.2 kg; 14.8 ± 2.6 kg vs. 11.1 ± 2.2 kg, respectively)., Conclusions: Long and repeated neonatal hypoglycemia caused poor adaptability. The babies of mothers who used insulin or had a high weight gain during pregnancy were associated with severe or persistent neonatal hypoglycemia.

Background: Xenotropic and polytropic retrovirus receptor 1 (XPR1), a previously identified cellular receptor for several murine leukemia viruses, plays a role in many pathophysiological processes. However, the role of XPR1 in human cancers has not yet been characterized., Methods: Real-time PCR and western blotting assay were used to measure the expression of XPR1 in tongue squamous cell carcinoma (TSCC) tissues. Expression of XPR1 and p65 in clinical specimens was analyzed using immunohistochemical assay. The function of XPR1 on progression of TSCC was explored using in vitro and in vivo experiments. The molecular mechanism by which XPR1 helps to cancer progression was investigated by luciferase reporter activity, ELISA, PKA activity assay, immunofluorescence, western blotting and qPCR assay., Results: Herein, we find that XPR1 is markedly upregulated in TSCC tissues compared to normal tongue tissues. High expression of XPR1 significantly correlates with the malignant features and poor patient survival in TSCC. Ectopic expression of XPR1 increases, while silencing of XPR1 reduces the proliferation, invasion and anti-apoptosis capacities of TSCC cells. Importantly, silencing of XPR1 effectively inhibits the tumorigenecity of TSCC cells. Moreover, we identified that XPR1 increased the concentration of intracellular cAMP and activated PKA. Thus, XPR1 promoted phosphorylation and activation of NF-κB signaling, which is required for XPR1-mediated oncogenic roles and significantly correlates with XPR1 expression in clinical specimens., Conclusions: These findings uncover a critical role of XPR1 in TSCC progression via activation of NF-κB, and suggest that XPR1 might be a potential prognostic marker or therapeutic target.