Search

We aimed to compare the analgesic effect and incidence of lower limb weakness of transmuscular quadratus lumborum (TQL) block via subfascial approach with that via extrafascial after laparoscopic cholecystectomy (LC).Eighty patients undergoing LC were randomized to receive ultrasound-guided bilateral TQL block via subfascial (subfascial group) or extrafascial (extrafascial group) using 30 mL of 0.33% ropivacaine unilaterally. Pain scores of port sites while rest and coughing at 1, 6, 12, 24, 36, and 48 hours postoperatively as primary outcome were compared. Modified Lovett Rating Scale, ambulatory dependency, and rescue analgesia requirement was also compared.The pain score of the subxiphoid and of the right subcostal port site for up to the postoperative 36 hours (2 [1 to 2]) and 24 hours (2 [2 to 3]) in the subfascial group was significantly lower than that in extrafascial group (2 [2 to 2] and 3 [2.25 to 4]). Up to postoperative 24 hours, the rescue analgesia requirement in subfascial group was significantly lower than that in extrafascial group, namely less fentanyl consumption and parecoxib (1.3 [±5.5] μg vs. 5.6 [±10.6] μg; 17.5% vs. 37.5%). The ratio of patients with LRS score of 6 at postoperative 1 hour (65.0%), and with dependent ambulation at postoperative 1 and 6 hours in subfascial group (15.0% and 0.0%) was significantly lower than that in extrafascial group (10.0%, 80.0%, and 17.5%).TQL block via subfascial had the advantages of better analgesic effect and less lower limbs weakness after LC over that via extrafascial.

With the spread of coronavirus disease 2019 (COVID-19) worldwide, extrapulmonary lesions, including liver dysfunction, have attracted growing attention. The mechanisms underlying liver dysfunction in COVID-19 remain unclear. The reported prevalence of liver dysfunction varies widely across studies. In addition, its impact on clinical outcomes and its recovery after discharge are still controversial. In this review, pathological and laboratory findings were analyzed to reveal the potential mechanisms of COVID-19-induced liver injury from onset to recovery. Four patterns of liver damage were summarized according to the pathological findings, including hypoxemia and shock changes, vascular thrombosis and vascular damage, bile duct damage, and other histological changes. With a strict definition, the prevalence of liver dysfunction was not as high as reported. Meanwhile, liver dysfunction improved during the process of recovery. Nevertheless, the definite liver dysfunction was significantly associated with severe clinical course, which should not be ignored.

The objective of this study is to determine the accuracy of the G.LAB MD41A0 upper-arm oscillometric blood pressure (BP) monitor for self/home BP measurement in patients with diabetes according to the Association for the Advancement of Medical Instrumentation /European Society of Hypertension /International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018).Patients with diabetes were recruited according to AAMI/ESH/ISO Universal Standard using the same arm sequential BP measurement method. The standard cuff of the test device was used for arm circumference 22-44 cm.A total of 92 patients with diabetes were recruited and 85 were analyzed with an average age of 55.1 ± 17.7 years, 48 men, and arm circumference of 32.0 ± 6.0 cm. For the validation Criterion 1, the mean ± SD of the differences between the test device and reference BP readings was 0.89 ± 6.04/-0.84 ± 5.11 mmHg (systolic/diastolic). For Criterion 2, the SD of the averaged BP differences between the test device and reference BP per subject was 4.23/4.19 mmHg (systolic/diastolic).The G.LAB MD41A0 upper arm BP monitor fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) in patients with diabetes and can be recommended for self/home use.

To introduce a novel technique of using incisional vacuum-assisted closure (VAC) after 1-stage incision suture combined with closed suction irrigation system (CSIS) for treating early deep surgical site infection (SSI) after posterior lumbar fusion with instrumentation and to compare it with traditional CSIS.This was a retrospective study. Patients with early deep SSI after posterior lumbar fusion with instrumentation from January 2013 to May 2020 who were treated by meticulous debridement followed by either CSIS or incisional VAC after 1-stage incision suture combined with CSIS were identified. The demographic characteristics, treatment features, and outcomes were analyzed and compared between the 2 treatment methods.A total of 48 patients (48/5016, 0.96%) developed early deep SSI, 46 of whom were enrolled in this study. This included 24 patients in the CSIS group (group 1) and 22 patients in the incisional VAC after 1-stage incision suture combined with CSIS group (group 2). All patients received follow-up, with an average of 19.7 months (range, 13-30 months). There were no significant differences in demographic characteristics in both groups (P0.05). The number of VAC foam dressing or ordinary dressing changes (P0.001), number of debridements (P = 0.028), intravenous antibiotic duration (P = 0.042), oral antibiotic duration (P = 0.019), and hospital stay (P = 0.029) in group 1 were significantly higher than those in group 2. The irrigation duration in group 1 was significantly shorter than that in group 2 (P = 0.007). All patients were eventually cured with satisfactory outcomes.Compared with CSIS, incisional VAC after 1-stage incision suture combined with CSIS may be recommended considering that it has fewer dressing changes, fewer debridements, longer irrigation duration, shorter duration of antibiotic use, shorter hospital stay, and more convenient nursing care.

In this study, a catalytic polydopamine-remodeling gold nanoparticle sensitized with an antinucleolin AS1411 probe (pAu nanoprobe) is synthesized, where the surface of the gold nanoparticles (AuNPs) is modified with a spontaneous self-polymerization of a polydopamine coating that imparts the probe functionalization ability and antispecific protein binding while the intrinsic catalytic property of the AuNPs is preserved. The functionalized AS1411 probe exerts specific recognition with nucleolin protein that is found to be overexpressed on the surface of breast cancer cells (MDA-MB-231). Scanning electron microscopy (SEM) confirms that the specific binding of the pAu nanoprobe occurs at the cancer cell surface. Taking advantage of the catalytic ability of the pAu nanoprobe in reducing blue-colored methylene blue (MB) to colorless leuco-MB, a colorimetric biosensing platform is established based on the accessible catalytic active sites on the pAu nanoprobe toward MB. The specific binding inhibits the pAu nanoprobe from efficiently catalyzing the reduction of MB, resulting in a "

Estrogen mainly binds to estrogen receptors (ERs) to regulate menstrual cycles and reproduction. The expression of ERalpha (ERα), ERbeta (ERβ), and G-protein-coupled estrogen receptor (GPER) mRNA could be detected in ovary, suggesting that they play an important role in estrogen signal transduction in ovary. And many studies have revealed that abnormal expression of estrogen and its receptors is closely related to ovarian disease or malignant tumors. With the continuous development and research of animal models, tissue-specific roles of both ERα and ERβ have been demonstrated in animals, which enable people to have a deeper understanding of the potential role of ER in regulating female reproductive diseases. Nevertheless, our current understanding of ERs expression and function in ovarian disease is, however, incomplete. To elucidate the biological mechanism behind ERs in the ovary, this review will focus on the role of ERα and ERβ in polycystic ovary syndrome (PCOS), ovarian cancer and premature ovarian failure (POF) and discuss the major challenges of existing therapies to provide a reference for the treatment of estrogen target tissue ovarian diseases.

Overuse or misuse of antibiotics and their residues in the environment results in the emergence and prevalence of drug-resistant bacteria and leads to serious health problems. Notable progress in liposome research has been made in drug delivery and several liposomal drugs have been approved for clinical use owing to its biocompatibility and improved efficacy. Recently, liposomes have been engineered further to release encapsulated drugs on the target of interest in a dose-controlled fashion in response to external stimuli such as light, pH, and heat. Among those, light-activated liposomal drug delivery gained a lot of attention because drug release at the targeted sites can be precisely controlled by varying laser/light duration, energy and beam area. We envision potential applications of the light-activated liposomal delivery systems for effective drug-resistant antimicrobial therapies. The use of light-activated liposomes will be widely spread in antimicrobial therapies if the amount of drug is precisely controlled for a prolonged time at a target location. In this review, we discussed the breadth and depth of various light-activated liposomal drug delivery technology. Emphasis was given to repetitive release mechanism and applications of light-activated liposomes because the repeatability provides stability and precise control of the drug delivery system to prevent overdose of antimicrobials and treat with minimal doses. We described limitations on translation from pre-clinical to clinical settings and strategies to overcome the limitations. Careful consideration of light-responsive materials, lipid composition, laser parameters and laser safety is important when selecting and designing the drug delivery system for successful applications.

Introduction: An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan, Hubei Province, China. This study aimed to analyze the clinical and epidemiologic characteristics of patients with COVID-19 to better differentiate the suspected patients in Beijing, China. Methodology: This was a retrospective, single-center study. Clinical and epidemiologic data were collected from suspected patients with COVID-19 admitted to Beijing Ditan Hospital from January 29 to February 21, 2020. Results: One hundred and six patients (60 males and 46 females, median age 36 years) were enrolled. Thirty-six patients were ultimately laboratory confirmed. Fifty-three were excluded from the diagnosis of COVID-19. The remaining 17 patients were highly suspected, although their nucleic acid tests were repeatedly negative. The confirmed patients and highly suspected patients had a significantly higher proportion of epidemiologic history than the excluded patients (P < 0.001). There was no significant difference in clinical symptoms or the underlying diseases among the three groups. The confirmed patients had a higher frequency of lymphopenia and eosinopenia than the highly suspected and excluded patients. Chest computed tomography scans showed bilateral lung involvement, and ground-glass opacity was more likely observed in the confirmed patients. Conclusion: The clinical features of the confirmed patients with COVID-19 were insufficient for early diagnosis of COVID-19. The epidemiologic history was of great significance in the early diagnosis of COVID-19. More sensitive diagnostic methods are needed to aid the differential diagnosis of suspected patients with COVID-19.

Breast cancer is a malignant tumor with the highest incidence in women of the world. CXCR4 and Skp2 are highly expressed in breast cancer cells and CXCR4 was positively correlated with Skp2 by interference or overexpression. The microRNA array was used to detect the differentially expressed spectrum of micro RNAs in breast cancer cells the changes of miR-7-5p after CXCR4 inhibitor (NT21MP) treatment to block the CXCR4/SDF-1 pathway was founded. MiR-7-5p has been found to be correlated with Skp2 in various tumors in the literature, and Skp2 expression can be regulated by transfection with miR-7-5p mimics or inhibitors. The expression level of miR-7-5p was upregulated or downregulated after CXCR4 interference or overexpression. Combined with the correlation between CXCR4 and miR-7-5p in the chip results, CXCR4 may regulate Skp2 through miR-7-5p. Epithelial cells have the morphological characteristics of mesenchymal cells for some reason called epithelial-mesenchymal transformation (EMT). Transfection of miR-7-5p mimics into drug-resistant cells reduced Skp2 levels, decreased the expression of Vimentin, Snail, and slug, and increased the expression of E-cadherin. CXCR4 inhibitor (NT21MP) can reverse the EMT changes caused by miR-7-5p inhibitor. Similarly, in vivo results suggesting that CXCR4 inhibitors can reverse the EMT phenotype of drug-resistant breast cancer cells through the CXCR4/miR-7-5p/Skp2 pathway. In summary, the CXCR4/miR-7-5p/Skp2 signaling pathway plays an important role in the progression of breast cancer. This study provides a theoretical basis for the treatment of breast cancer by targeting the CXCR4 pathway.

Objectives: We aimed to observe the relationship between serum 25-hydroxyvitamin D (25-[OH] D) and different cognitive domains, and to evaluate the predictive value of 25-(OH) D level for cognitive impairment in patients with white matter lesions (WML). Methods: The differences in clinical data including 25-(OH) D were analyzed between cognitive normality (n = 87) and impairment (n = 139) groups, and variant cognitive domains were analyzed between groups of different levels of serum 25-(OH) D. Risk factors for cognitive impairments were evaluated with multivariate logistic regression analysis; a receiver operating characteristic (ROC) curve of 25-(OH) D levels was used to examine the association between 25-(OH) D and WML with cognitive dysfunction. Results: As the severity of WML increased, the proportion of patients with a low level of serum 25-(OH) D increased (p < 0.05). The total MoCA (Montreal Cognitive Assessment) scores and all domain scores except naming were significantly lower in patients with low levels of serum 25-(OH) D than in patients with high levels of serum 25-(OH) D (p < 0.05). Multivariate logistic regression analyses showed that serum 25-(OH) D levels were independently correlated with cognitive impairment. In the ROC analysis, the optimal cut-off value for 25-(OH) D was 17.53 with 76% sensitivity and 70% specificity (AUC =0.751, 95% CI: 0.674–0.819, p < 0.05). Conclusion: We observed that vitamin D deficiency is associated with multiple areas of cognitive impairment and that it is an independent risk factor for cognitive impairment in WML.

The short-term effects of long-acting somatostatin analogues (SSAs) on lipid profiles in patients with acromegaly are not well studied. We retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After SSAs treatment, both GH and IGF-1 significantly decreased (p0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, our current study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly.

Abnormal myocardial NaUsing recombinant adeno-associated virus subtype 9 (AAV9), rat cardiac PIASy was silenced using intraventricular injection of PIASy short hairpin RNA (shRNA). After two weeks, rat hearts were subjected to I/R and electrocardiography was performed to assess malignant arrhythmias. Tissues from peri-infarct areas of the left ventricle were collected for molecular biological measurements.PIASy was upregulated by I/R (P 0.01), with increased SUMO2/3 modification of Cav-3 and reduced membrane NaI/R-induced cardiac PIASy activation increased Cav-3 SUMOylation by SUMO2/3 and dysregulated Na

BackgroundColorectal cancer is a lethal cancer worldwide. Due to the low tumor mutation burden and low proportion of tumor-infiltrating lymphocytes in the microenvironment of most patients, innovative immunotherapeutic approaches need to be identified.MethodsUsing the TCGA-COAD dataset (n = 514), we identified TNFRSF11B as a prognostic factor of colon cancer. An immunohistochemistry (IHC) dataset (n = 86), 290 single colorectal cancer cells (GSE81861), and 31 paired colon cancer transcriptional datasets were further applied to validate the function of TNFRSF11B, which was confirmed via fluorescence-activated cell sorting (FACS) analysis.ResultsA risk score system consisting of eight immune-related genes (IRGs) (FGFR2, ZC3HAV1L, TNFRSF11B, CD79A, IGHV3-11, IGHV3-21, IGKV2D-30, and IGKV6D-21) was constructed to predict the prognosis of colon cancer patients. Only TNFRSF11B was closely correlated with late-stage lymph node metastasis and worse survival outcomes (p = 0.010, p = 0.014, and p = 0.0061). In our IHC dataset, 72.09% (62/86) of the colon cancer patients had TNFRSF11B overexpression with significantly shorter overall survival times (p = 0.072). High TNFRSF11B expression typically had a later TNM stage (p = 0.067), a higher frequency of lymph node (p = 0.029) and lymphovascular (p = 0.007) invasion, and a higher incidence of pneumonia (p = 0.056) than their counterparts. The expression of six genes (KRT18, ARPC5L, ACTG1, ARPC2, EZR, and YWHAZ) related to pathogenic E. coli infection was simultaneously increased with TNFRSF11B overexpression via gene set enrichment analysis (GSEA). These genes are involved in the regulation of the actin cytoskeleton, shigellosis, bacterial invasion of epithelial cells, and Salmonella infection. Finally, only activated memory CD4+ T cells (p = 0.017) were significantly decreased in the high TNFRSF11B expression group via CIBERSORT comparison, which was confirmed by TIMER2.0 analysis of the TCGA-COAD dataset. We also performed FACS analysis to show that TNFRSF11B decreased the infiltration of central memory CD4+ T cells and effector memory CD4+ T cells in the colorectal cancer microenvironment (all p <0.001).ConclusionTNFRSF11B acts as a prognostic factor for colon cancer patients and could affect the colon cancer immune response. TNFRSF11B was closely related to lymph node invasion and pathogenic E. coli. infection, which may negatively affect memory-activated CD4+ T cell infiltration in colon cancer.

The physiological role of estrogen in the female endometrium is well established. On the basis of responses to steroid hormones (progesterone, androgen, and estrogen), the endometrium is considered to have proliferative and secretory phases. Estrogen can act in the endometrium by interacting with estrogen receptors (ERs) to induce mucosal proliferation during the proliferative phase and progesterone receptor (PR) synthesis, which prepare the endometrium for the secretory phase. Mouse knockout studies have shown that ER expression, including ERα, ERβ, and G-protein-coupled estrogen receptor (GPER) in the endometrium is critical for normal menstrual cycles and subsequent pregnancy. Incorrect expression of ERs can produce many diseases that can cause endometriosis, endometrial hyperplasia (EH), and endometrial cancer (EC), which affect numerous women of reproductive age. ERα promotes uterine cell proliferation and is strongly associated with an increased risk of EC, while ERβ has the opposite effects on ERα function. GPER is highly expressed in abnormal EH, but its expression in EC patients is paradoxical. Effective treatments for endometrium-related diseases depend on understanding the physiological function of ERs; however, much less is known about the signaling pathways through which ERs functions in the normal endometrium or in endometrial diseases. Given the important roles of ERs in the endometrium, we reviewed the published literature to elaborate the regulatory role of estrogen and its nuclear and membrane-associated receptors in maintaining the function of endometrium and to provide references for protecting female reproduction. Additionally, the role of drugs such as tamoxifen, raloxifene, fulvestrant and G-15 in the endometrium are also described. Future studies should focus on evaluating new therapeutic strategies that precisely target specific ERs and their related growth factor signaling pathways.

Introduction: Curriculum learning through the wisdom tree massive open online course platform not only gets rid of the limitations of specialty, school and region, eliminates the limitations of time and space in traditional teaching, but also effectively solves the problem of educational equity. Objectives: This paper proposes an intelligent algorithm combining decision tree, support vector machine, and simulated annealing to obtain the best classification accuracy and decision rules for university students' satisfaction with the wisdom tree massive open online course platform. Methods: This study takes the university students in Fuzhou city information management department as the survey object, and adopts the electronic questionnaire survey method. A total of 1136 formal questionnaires were responded, and 1028 valid questionnaires were obtained after data cleaning and deleting invalid questionnaires (the effective rate was 90.49%). In this paper, the reliability and validity of the questionnaire were tested by IBM SPSS-20.0 software, and six explanatory variables including function, achievement, exercise, quality, richness, and interaction were obtained by principal component analysis. Then, the questionnaire data is converted to CSV (comma separated values) format for analysis. This paper proposes an intelligent algorithm combining decision tree, support vector machine, and simulated annealing to obtain the best classification accuracy and decision rules for university students' satisfaction with the wisdom tree massive open online course platform. In this paper, the proposed algorithm is compared with decision tree, random forest, k-nearest neighbor, and support vector machine to verify its performance. Results: The experimental results show that training set classification accuracy of decision tree, random forest, k-nearest neighbor, only support vector machine and the proposed algorithm (simulated annealing + support vector machine) are 92.21%, 96.10%, 95.67%, 97.29%, and 99.58%, respectively. Conclusion: The proposed algorithm simulated annealing + support vector machine does increase the classification accuracy. At the same time, the 11 decision rules generated by simulated annealing + decision tree can provide useful information for decision makers.

The literature is full of claims regarding the consumption of polyphenol or polyamine-rich foods that offer some protection from developing cardiovascular disease (CVD). This is achieved by preventing cardiac hypertrophy and protecting blood vessels through improving the function of endothelium. However, do these interventions work in the aged human hearts? Cardiac aging is accompanied by an increase in left ventricular hypertrophy, along with diastolic and systolic dysfunction. It also confers significant cardiovascular risks for both sexes. The incidence and prevalence of CVD increase sharply at an earlier age in men than women. Furthermore, the patterns of heart failure differ between sexes, as do the lifetime risk factors. Do caloric restriction (CR)-mimetics, rich in polyphenol or polyamine, delay or reverse cardiac aging equally in both men and women? This review will discuss three areas: (1) mechanisms underlying age-related cardiac remodeling; (2) gender-related differences and potential mechanisms underlying diminished cardiac response in older men and women; (3) we select a few polyphenol or polyamine rich compounds as the CR-mimetics, such as resveratrol, quercetin, curcumin, epigallocatechin gallate and spermidine, due to their capability to extend health-span and induce autophagy. We outline their abilities and issues on retarding aging in animal hearts and preventing CVD in humans. We discuss the confounding factors that should be considered for developing therapeutic strategies against cardiac aging in humans.

Microplastics (MPs) are ubiquitous in drinking water and pose potential threats to human health. Despite increasingly attentions on the toxicity of MPs, the deleterious effects of MPs after chlorine disinfection, which might be a more accessible form of MPs, has rarely been considered. Here, we first treated pristine polystyrene microplastics (PS-MPs) with chlorine to simulate the reactions that occur during drinking water treatment, and investigated and compared the cytotoxicity of chlorinated PS-MPs to those of pristine PS-MPs. Chlorine disinfection did not change the size of pristine PS-MPs, but increased the surface roughness. In addition, abundant carbon-chlorine bonds and persistent free radicals were generated on the surface of chlorinated PS-MPs. Compared with pristine PS-MPs, chlorinated PS-MPs markedly inhibited the cell proliferation, changed cellular morphology, destroyed cell membrane integrity, induced cell inflammatory response and apoptosis. Proteomics confirmed the difference in interactions with intracellular proteins between these particles. Furthermore, we found that the regulation of PI3K/AKT and Bcl-2/Bax pathways, oxidative stress-triggered mitochondrial depolarization, and the activation of caspase cascade were identified as the underlying mechanisms for the enhanced apoptosis ratio in GES-1 cells when exposed to chlorinated PS-MPs. This exacerbated cytotoxicity could be explained by the enhanced surface roughness and changed surface chemistry of these PS-MPs after chlorine disinfection. This work discloses the impacts of chlorine disinfection on the cytotoxicity of PS-MPs, which provides new insights for a more systematic risk assessment of MPs.

Inflammatory responses change several aspects of malignancies such as proliferation, survival, angiogenesis, and metastasis and lead to tumor progression. Lung cancer is the leading type of cancer worldwide and cancer-related inflammatory mediators challenge the successful treatments. Lentinan, a polysaccharide derived from Lentinula edodes, has shown anti-inflammatory characteristics in colitis and has been approved as an adjuvant therapy for cancer treatment. In the present study, we explored the mechanism underlying anti-inflammatory function of Lentinan in lung cancer cells. We showed that Lentinan reduced the inflammatory cytokines IL-6 and IL-1β in LPS-stimulated A549 cells at the concentrations much lower than the IC50. Lentinan failed to alter the NLRP3 expression profile at transcriptional and translational levels. However, it showed a huge inhibition of caspase-1 activity. Lentinan downregulated the expression of IL-6 and IL-1β at the mRNA level. We also showed that Lentinan altered the oxidative status of the cells by increasing the intracellular ROS content and attenuating the activity of GPx4, the key player in the anti-oxidative defense system. Lentinan-induced ROS generation was associated with caspase-3 activation and induction of DNA breaks. This alteration was also associated with mitochondrial membrane depolarization shown by TMRE staining. Using recombinant caspase-1, we showed that Lentinan did not directly target caspase-1 but it led to caspase-1 inhibition. In conclusion, cytotoxicity and anti-inflammatory functions are separated by the dose of Lentinan. Lentinan increased the ROS and mitochondrial dysfunction in a level that is insufficient to induce cell death, but is sufficient to regulate the NLRP3 activation.

BackgroundDynamic prediction of patient mortality risk in the ICU with time series data is limited due to high dimensionality, uncertainty in sampling intervals, and other issues. A new deep learning method, temporal convolution network (TCN), makes it possible to deal with complex clinical time series data in ICU. We aimed to develop and validate it to predict mortality risk using time series data from MIMIC III dataset.MethodsA total of 21,139 records of ICU stays were analysed and 17 physiological variables from the MIMIC III dataset were used to predict mortality risk. Then we compared the model performance of the attention-based TCN with that of traditional artificial intelligence (AI) methods.ResultsThe area under receiver operating characteristic (AUCROC) and area under precision-recall curve (AUC-PR) of attention-based TCN for predicting the mortality risk 48 h after ICU admission were 0.837 (0.824 -0.850) and 0.454, respectively. The sensitivity and specificity of attention-based TCN were 67.1% and 82.6%, respectively, compared to the traditional AI method, which had a low sensitivity (ConclusionsThe attention-based TCN model achieved better performance in the prediction of mortality risk with time series data than traditional AI methods and conventional score-based models. The attention-based TCN mortality risk model has the potential for helping decision-making for critical patients.Trial registrationData used for the prediction of mortality risk were extracted from the freely accessible MIMIC III dataset. The project was approved by the Institutional Review Boards of Beth Israel Deaconess Medical Center (Boston, MA) and the Massachusetts Institute of Technology (Cambridge, MA). Requirement for individual patient consent was waived because the project did not impact clinical care and all protected health information was deidentified. The data were accessed via a data use agreement between PhysioNet, a National Institutes of Health–supported data repository (https://www.physionet.org/), and one of us (Yu-wen Chen, Certification Number: 28341490). All methods were carried out in accordance with the institutional guidelines and regulations.

Background As an oncogene, long noncoding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) can promote tumor metastasis. Hyperexpression of MALAT1 has been observed in many malignant tumors, including hepatocellular carcinoma (HCC). However, the role and mechanism of MALAT1 in HCC remain unclear. Methods Thirty human HCC and paracancerous tissue specimens were collected, and the human hepatoma cell lines Huh7 and HepG2 were cultured according to standard methods. MALAT1 and Snail family zinc finger (Slug) expression were measured by real‐time PCR, immunohistochemistry, and western blotting. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay verified the direct interaction between miR‐124‐3p and Slug(SNAI2) or MALAT1. Wound healing and transwell assays were performed to examine invasion and migration, and a subcutaneous tumor model was established to measure tumor progression in vivo. Results MALAT1 expression was upregulated in HCC tissues and positively correlated with Slug expression. MALAT1 and miR‐124‐3p bind directly and reversibly to each other. MALAT1 silencing inhibited cell migration and invasion. miR‐124‐3p inhibited HCC metastasis by targeting Slug. Conclusions MALAT1 regulates Slug through miR‐124‐3p, affecting HCC cell metastasis. Thus, the MALAT1/miR‐124‐3p/Slug axis plays an important role in HCC., Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) regulates Slug through miR‐124‐3p, affecting cell migration and cell invasion. Thus, the MALAT1/miR‐124‐3p/Slug axis plays an important role in hepatocellular carcinoma.

Activation of hepatic stellate cells (HSCs) is a prominent driver of liver fibrogenesis, including alcoholic liver fibrosis (ALF). Furthermore, autophagy contributes to HSCs activation. This study aims to investigate the role and the mechanisms of long noncoding RNA XIST in regulating HSCs autophagy and activation. Human HSC cells (LX-2) were treated with 100 mmol/L ethanol to mimic HSCs activation. The HSCs activation was evaluated by determining cell viability and protein levels of fibrosis markers α-smooth muscle actin (α-SMA) and collagen type 1 α1 (CoL1A1). The autophagy was evaluated by measuring autophagy markers Beclin-1 and LC3-II. The interaction among XIST, miR-29b, and high-mobility group box-1 (HMGB1) were analyzed using luciferase reporter assay, qRT-PCR, and western blot. Lentiviruses targeting sh-XIST (LV-sh-XIST) were injected into ALF model mice via tail vein to elucidate the in vivo role of XIST in ALF injury. XIST was upregulated in ethanol-activated LX-2 cells. Furthermore, XIST served as a competitive endogenous RNA of miR-29b to facilitate HMGB1 expression, and thus enhanced ethanol-induced HSCs autophagy and activation. Further in vivo assay showed that downregulation of XIST by LV-sh-XIST alleviated ALF injury in ALF model mice. Collectively, XIST enhances ethanol-induced HSCs autophagy and activation via miR-29b/HMGB1 axis.

The natriuretic peptide system plays an important role in regulation of blood pressure. The purpose of this study was to comprehensively examine the associations among NPPA gene SNPs, serum atrial natriuretic peptide (ANP) levels, and hypertension. In 736 new-onset hypertensive cases and 736 age- and sex-matched controls, we measured concentrations of serum NT-proANP and genotyped 3 tag-SNPs in NPPA. Serum ANP levels were significantly lower in hypertensive patients than in controls (Wilcoxon two sample test P = 0.011). The difference was also significant in male (P = 0.0161) and female subgroups (P = 0.0011). Compared with the reference group, participants with the highest quartile of ANP levels had a significant decreased risk of hypertension (odds ratio = 0.56, P = 0.0006). The nonsynonymous SNP rs5063 (p.Val32Met) seemed to be associated with ANP levels (P = 0.0209). eQTL analysis found that rs198358 was associated with NPPA gene expression in testis (1.66 × 10−9) and whole blood (4.58 × 10−52). The findings suggested that a common NPPA SNPs rs5063 was associated with serum ANP levels and ANP was prospectively associated with hypertension in the Chinese Han population.

Genome-wide association studies have identified a large number of genetic loci for blood pressure in European populations. The associations in other populations are needed to determine. The purpose of this study was to examine the associations between the single nucleotide polymorphisms (SNPs) identified in European populations and hypertension in the Chinese Han population, and highlight the potential roles. Seven tag-SNPs were genotyped in 857 hypertension cases and 927 controls to test the associations. The intronic SNP rs10224002 (PRKAG2) which could affect DNase and regulatory motif was associated with hypertension (P = 0.024). This SNP was also found to be associated with coronary artery disease and stroke. We searched for potential functional variants by bioinformatics analysis and found various kinds of variants such as missense mutations, phosphorylation-related SNPs and SNPs that have regulatory potentials in the blood pressure loci. We performed expression quantitative trait locus (eQTL) and differential expression analyses for the identified variants and genes. eQTL analysis found that rs10224002 was associated with PRKAG2 gene expression in peripheral blood (P = 0.0016). PRKAG2 was differentially expressed between hypertension cases and controls (P = 0.0133), coronary artery disease cases and controls (P = 0.02112) and stroke cases and controls (P = 0.0059). Our study demonstrated that SNPs rs10224002 may be associated with hypertension in the Chinese Han population and PRKAG2 may play a role in the etiology of hypertension and cardiovascular diseases.

Excessive consumption of analgesic drug acetaminophen (APAP) can cause severe oxidative stress-mediated liver injury. Here, we investigated the protective effect and mechanism of aged citrus peel (Chenpi, CP), a Chinese herb usually used in foods in Asia, against APAP-induced hepatotoxicity. CP water (CP-WE), ethanolic (CP-EE), and water extraction residue ethanolic (CP-WREE) extracts were prepared. We found that CP-WREE contained higher content of bioactive flavonoids, including narirutin, nobiletin, and tangeretin, and more effectively enhanced the Nrf2 pathway in ARE-luciferase reporter gene transfected human HepG2-C8 cells. In mouse AML-12 hepatocytes, CP-WREE minimized APAP-induced damage and lipid peroxidation and increased mRNA and protein expressions of Nrf2 and its downstream defense enzymes (HO-1, NQO1, and UGT1A). CP-WREE also downregulated HDACs and DNMTs, upregulated KDMs, and increased the unmethylated Nrf2 promoter level. Additionally, CP-WREE blocked in vitro DNA methyltransferase activity. Taken together, CP-WREE might attenuate oxidative stress-induced hepatotoxicity through epigenetically regulating Nrf2-mediated cellular defense system.

We have performed a gene-based association study and detected several important blood pressure (BP)-associated genes. In this study, we explored functional variants in these genes by bioinformatics analysis and validated the associations between the functional single nucleotide polymorphisms (SNPs) and hypertension with public data and our in-house data of 857 cases and 927 controls. We found various functional variants in the BP-associated genes, including missense mutations and phosphorylation-related SNPs. Most of these SNPs were associated with expressions of the local genes. Some of these SNPs were associated with coronary artery disease or ischemic stroke. The associations between 12 functional SNPs in 7 genes and BP were validated (P < 5 × 10). The intronic SNP rs176185, which may influence promoter histone, enhancer histone, DNase and regulatory motifs and showed cis-eQTL effect on WBP1L, was associated with hypertension in the Chinese Han population (P = 0.0119). Our study detected plenty of potential functional SNPs in the BP-associated genes and demonstrated that rs176185 may be associated with hypertension in the Chinese Han population.

To investigate the risk factors for increased surgical drain output after transforaminal lumbar interbody fusion (TLIF).Patients who underwent TLIF in a single center from June 2017 to January 2020 were included in this study. They were divided into the increased surgical drain output group and no increased surgical drain output group according to the boundary of the median drain output. Patients' demographic and clinical parameters were compared between the 2 groups. Risk factors for increased surgical drain output were identified by univariate and multivariate logistic regression analysis.This study enrolled 368 patients who underwent TLIF. Among them, 187 patients had increased surgical drain output (drain output ≥50th percentile or 480 mL). Univariate analysis showed that age (P0.001), smoking status (P = 0.002), number of fused levels (P0.001), intraoperative blood loss (P0.001), intraoperative end plate injury (P0.001), administration of tranexamic acid (TXA) (P = 0.002), and surgical duration (P0.001) were significantly associated with increased surgical drain output. Multiple logistic regression analysis revealed that older age (P = 0.001), smoking (P = 0.005), more fused levels (P0.001), and intraoperative end plate injury (P = 0.017) were the independent risk factors, while administration of TXA (P = 0.012) was a protective factor.This study showed that older age, smoking, more fused levels, and intraoperative end plate injury were the independent risk factors, while administration of TXA was a protective factor for increased surgical drain output after TLIF.

Background This study attempted to investigate the impact of hepatopulmonary syndrome (HPS) on postoperative outcomes in hepatitis B virus-induced hepatocellular carcinoma (HBV-HCC) patients. Methods HBV-HCC patients undergoing primary curative hepatectomy for HCC in our hospital were diagnosed with HPS by contrast-enhanced echocardiography (CEE) and arterial blood gas analysis. Patients were divided into HPS, intrapulmonary vascular dilation (IPVD) (patients with positive CEE results and normal oxygenation) and control (patients with negative CEE results) groups. Baseline information, perioperative clinical data and postoperative pulmonary complications (PPCs) were compared among all groups. Cytokines in patient serums from each group (n = 8) were also assessed. Results Eighty-seven patients undergoing hepatectomy from October 2019 to January 2020 were analyzed. The average time in the postanaesthesia care unit (112.10 ± 38.57 min) and oxygen absorption after extubation [34.0 (14.5-54.5) min] in the HPS group was longer than in IPVD [81.81 ± 26.18 min and 16.0 (12.3-24.0) min] and control [93.70 ± 34.06 min and 20.5 (13.8-37.0) min] groups. There were no significant differences in oxygen absorption time after extubation between HPS and control groups. The incidence of PPCs, especially bi-lateral pleural effusions in the HPS group (61.9%), was higher than in IPVD (12.5%) and control (30.0%) groups. Increased serum levels of the growth-regulated oncogene, monocyte chemoattractant protein, soluble CD40 ligand and interleukin 8 might be related to delayed recovery in HPS patients. Conclusions HPS patients with HBV-HCC suffer delayed postoperative recovery and are at higher risk for PPCs, especially bi-lateral pleural effusions, which might be associated with changes in certain cytokines.

OBJECTIVES: To investigate whether the baseline apparent diffusion coefficient (ADC) can predict survival in the hepatocellular carcinoma (HCC) patients receiving chemoembolization. MATERIALS AND METHODS: Diffusion-weighted MR imaging of HCC patients is performed within 2 weeks before chemoembolization. The ADC of the largest index lesion is recorded. Responses are assessed by mRECIST after the start of the second course of chemoembolization. Receiver operating characteristic (ROC) curve analysis is performed to evaluate the diagnostic performance and determine optimal cut-off values. Cox regression and Kaplan–Meier survival analyses are used to explore the differences in overall survival (OS) between the responders and non-responders. RESULTS: The difference is statistically significant in the baseline ADC between the responders and non-responders (P < 0.001). ROC analyses indicate that the baseline ADC value is a good predictor of response to treatment with an area under the ROC curve (AUC) of 0.744 and the optimal cut-off value of 1.22×10–3 mm2/s. The Cox regression model shows that the baseline ADC is an independent predictor of OS, with a 57.2% reduction in risk. CONCLUSION: An optimal baseline ADC value is a functional imaging response biomarker that has higher discriminatory power to predict tumor response and prolonged survival following chemoembolization in HCC patients.

Cigarette smoke (CS)-induced macrophage activation and airway epithelial injury are both critical for the development of chronic obstructive pulmonary disease (COPD), while the eventual functions of autophagy in these processes remain controversial. We have recently developed a novel COPD mouse model which is based on the autoimmune response sensitized by CS and facilitated by elastin. In the current study, we therefore utilized this model to investigate the roles of autophagy in different stages of the development of bronchitis-like airway inflammation. Autophagic markers were increased in airway epithelium and lung tissues, and Becn+/- or Lc3b-/- mice exhibited reduced neutrophilic airway inflammation and mucus hyperproduction in this COPD mouse model. Moreover, treatment of an autophagic inhibitor 3-methyladenine (3-MA) either during CS-initiated sensitization or during elastin provocation significantly inhibited the bronchitis-like phenotypes in mice. Short CS exposure rapidly induced expression of matrix metallopeptidase 12 (MMP12) in alveolar macrophages, and treatment of doxycycline, a pan metalloproteinase inhibitor, during CS exposure effectively attenuated the ensuing elastin-induced airway inflammation in mice. CS extract triggered MMP12 expression in cultured macrophages, which was attenuated by autophagy impairment (Becn+/- or Lc3b-/-) or inhibition (3-MA or Spautin-1). These data, taken together, demonstrate that autophagy mediates both the CS-initiated MMP12 activation in macrophages and subsequent airway epithelial injury, eventually contributing to development COPD-like airway inflammation. This study reemphasizes that inhibition of autophagy as a novel therapeutic strategy for CS-induced COPD.

BACKGROUND: The new coronavirus pneumonia (NCP, COVID-19) outbreak began in Wuhan in December 2019. The new coronavirus (2019 novel coronavirus (2019-nCoV)) can cause multiple organ damage, mainly to lung tissue, and induce inflammation in the body. OBJECTIVES: To investigate the changes of high-density lipoprotein (HDL) level in patients with COVID-19 and assess its value in the evaluation and prognosis of this disease. MATERIAL AND METHODS: This paper is a cross-sectional retrospective study. Eighty-six severe COVID-19 patients, 132 non-severe COVID-19 patients and 76 healthy individuals (control group) were recruited to measure triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) using enzyme-coupled colorimetry. RESULTS: The serum HDL-C level in COVID-19 group was 1.02 ±0.28 mmol/L which was significantly lower than in control group (1.52 ±0.55 mmol/L) (p < 0.05). In addition, the serum HDL-C level in severe COVID-19 group was 0.83 ±1.67 mmol/L, which was significantly lower than that in non-severe COVID-19 group (1.15 ±0.27 mmol/L) (p < 0.05). CONCLUSIONS: Changes in HDL levels in patients with COVID-19 can reflect the severity of the disease and have a clinical significance in establishing the prognosis.

Diabetic cardiomyopathy (DCM) is a specific myocardial alteration in patients with diabetics. LncRNA KCNQ1OT1 has been previously demonstrated to be involved in various diabetic complications. Our aims are to further investigate the underlying regulatory mechanisms/pathways of KCNQ1OT1 in DCM.In vitro and in vivo models of DCM were established in high glucose (HG)-treated human cardiomyocytes and in streptozotocin (STZ)-induced diabetic mice, respectively. Gene and protein expressions were examined by qPCR, western blotting and ELISA. Cell proliferation and apoptosis were determined by CCK8 assay, flow cytometry and TUNEL staining. The association between KCNQ1OT1 and miR-181a-5p, miR-181a-5p and PDCD4 was predicted using bioinformatics methods and subsequently confirmed by dual luciferase reporter and RNA immunoprecipitation assays. Mouse cardiac tissues were collected and analysed using HE staining, Masson's staining and immunohistochemical analysis.KCNQ1OT1 and PDCD4 were upregulated in HG-treated human cardiomyocytes, while miR-181a-5p was downregulated. In addition, KCNQ1OT1 could negatively regulate miR-181a-5p expression; meanwhile, miR-181a-5p also negatively regulated PDCD4 expression. KCNQ1OT1 silencing suppressed the expression of inflammatory cytokines and cell apoptosis in vitro, whereas inhibition of miR-181a-5p abrogated those effects of KCNQ1OT1 knockdown. Moreover, overexpressed PDCD4 abolished the inhibition on inflammation and apoptosis caused by miR-181a-5p overexpression. Finally, KCNQ1OT1 knockdown reduced the expression of PDCD4 via regulating miR-181a-5p and inhibited myocardial inflammation and cardiomyocyte apoptosis in the in vivo DCM model.Our findings suggest that KCNQ1OT1 and its target gene miR-181a-5p regulate myocardial inflammation and cardiomyocyte apoptosis by modulating PDCD4 in DCM.

Previous functional magnetic resonance imaging (fMRI) analyses have shown that the dorsal attention network (DAN) is involved in the pathophysiological changes of tinnitus, but few relevant studies have been conducted, and the conclusions to date are not uniform. The purpose of this research was to test whether there is a change in intrinsic functional connectivity (FC) patterns between the DAN and other brain regions in tinnitus patients. Thirty-one patients with persistent tinnitus and thirty-three healthy controls were enrolled in this study. A group independent component analysis (ICA), degree centrality (DC) analysis, and seed-based FC analysis were conducted. In the group ICA, the tinnitus patients showed increased connectivity in the left superior parietal gyrus in the DAN compared to the healthy controls. Compared with the healthy controls, the tinnitus patients showed increased DC in the left inferior parietal gyrus and decreased DC in the left precuneus within the DAN. The clusters within the DAN with significant differences in the ICA or DC analysis between the tinnitus patients and the healthy controls were selected as regions of interest (ROIs) for seeds. The tinnitus patients exhibited significantly increased FC from the left superior parietal gyrus to several brain regions, including the left inferior parietal gyrus, the left superior marginal gyrus, and the right superior frontal gyrus, and decreased FC to the right anterior cingulate cortex. The tinnitus patients exhibited decreased FC from the left precuneus to the left inferior occipital gyrus, left calcarine cortex, and left superior frontal gyrus compared with the healthy controls. The findings of this study show that compared with healthy controls, tinnitus patients have altered functional connections not only within the DAN but also between the DAN and other brain regions. These results suggest that it may be possible to improve the disturbance and influence of tinnitus by regulating the DAN.

MicroRNAs (miRNAs/miRs) are small, non-coding RNAs that are reported to serve numerous important regulatory functions; however, the role of miRNAs in regulating breast cancer cell biology remains poorly understood. Accumulating evidence has demonstrated that miRNAs orchestrate multiple cellular functions and serve crucial roles in cell differentiation and cancer development, either by acting as tumor suppressors or oncogenes. In particular, miR-155-5p expression levels have been found to be upregulated and serve as a prognostic marker in numerous types of solid cancer, including human breast cancer. More than half of patients with breast cancer benefit from treatment with adjuvant paclitaxel chemotherapy following the early postoperative period. Despite the initial response to intensive combination chemotherapy, the majority of most patients will eventually acquire resistance to the drug and succumb to their disease. Therefore, further investigations into the association between miRNAs and the mechanism of paclitaxel resistance are required. The results of the present study revealed a strong positive association between miR-155-5p expression levels and the paclitaxel resistance, as the expression levels of miR-155-5p were upregulated in resistant cells. MiR-155-5p was further validated to regulate paclitaxel resistance using gain- and loss-of-function experiments. TP53INP1 was identified as a direct target gene of miR-155-5p by combining the results from the prediction algorithm based on free energy minimization and reverse transcription-quantitative PCR (qRT-PCR) analysis. Also, miR-155-5p was suggested to be a key regulator of paclitaxel resistance in tumor cells, as it increased cell viability and motility, and promoted resistance to paclitaxel-induced apoptosis. The transfection with miR-155-5p inhibitors re-sensitized the paclitaxel-resistant breast cancer cells, while the overexpression of miR-155-5p led to an increase in the resistance to paclitaxel. Furthermore, the overexpression of the target gene, TP53INP1, contributed to the re-sensitivity of drug-resistant cells to paclitaxel. The subsequent combination of the knockdown of miR-155-5p and the overexpression of TP53INP1 conferred paclitaxel sensitivity in resistant cells. These results may enhance the understanding of the molecular mechanisms underlying breast cancer progression and resistance to chemotherapy, and suggested that miR-155-5p or TP53INP1 may serve as novel therapeutic approaches to combat resistance to therapy, as well as the proliferation and evasion of apoptosis in breast cancer.

The novel coronavirus disease (COVID-19) has affected hundreds of millions of people worldwide. Data collection in the ascending phase is crucial to address a rapidly evolving crisis by helping us understand the uncertain relationship between risk communication and psychological responses. Data were collected from 26 January 26, 2020, until February 17, 2020, with a mean test–retest interval of 16 days. A total of 846 adults from four residential communities in high-risk areas (Wuhan city) and low-risk areas (Zhengzhou city) were invited to complete a set of Internet-based questionnaires measuring the adoption of preventive behaviors, appraisal of risk communication, anxiety level, and susceptibility to emotional contagion. At the baseline assessment (Wave 1), 58 withdrew from the study, and 788 (433 females) completed the questionnaires. At the Wave 2 survey, 318 (185 females) adults from Wave 1 were retained. The results from cross-lagged models demonstrated reciprocal negative associations between anxiety and risk communication and between the appraisal of risk communication and the adoption of preventive behaviors. In addition, a higher appraisal of risk communication in the initial period of the outbreak mitigated the respondents' susceptibility to emotional contagion later on. Susceptibility to emotional contagion was positively associated with preventive behaviors taken. Furthermore, multiple-group structural equation modeling suggested that risk communication was more likely to affect the susceptibility to emotional contagion of people on the frontline of the outbreak than people living in low-risk areas. This study demonstrated the importance of risk communication aimed at encouraging appropriate countermeasures against virus outbreaks.

To investigate the clinical characteristics, laboratorial and bone marrow pathological features of primary thrombocytopenia (ET) patients with different mutations of CALR, JAK2 and MPL genes.The chinical data of 120 cases of ET in Jiangsu provincial people's hospital/ The First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2017 were collected and analyzed, including 76 cases with JAK2 gene mutation, 40 cases with CALR gene mutation, 2 cases with MPL gene mutations, 2 cases without gene mutation.Among the ET patients, compared with the JAK2 gene mutation, CALR gene mutation showed statistically significant deareament of white blood cells and hemoglobin (P=0.001, P=0.01) and the male platelets in CALR group showed significant increament (P=0.04). Fourthermore, the average number of megakaryocytes and its cluster numbers in each hight power field of vision showed statistically significant decreament in CALR group as compared with JAK2 group (P=0.001, P=0.001), and thrombotic events in CALR group were signicantly lower than those in JAK2 group (7.5% vs 18.4%) (P=0.03).Mutations of CALR, JAK2 have different clinical characteristics and blood pathological changes of Chinese ET patients, and their clinical significance is worth to explore.不同基因突变的中国原发性血小板增多症患者临床特征 及骨髓病理学特点.探讨CALR、JAK2、MPL不同基因突变原发性血小板增多症（ET）患者的临床特征、实验室及骨髓病理学特点.2015年1月- 2017年12月于我院确诊的ET患者120例，其中JAK2基因突变76例，CALR基因突变40例，MPL基因突变2例，3基因突变阴性患者2例.比较JAK2基因突变ET与CALR基因突变ET临床及实验室特点，采用Nikon cclipsc显微镜进行病理切片观察，每个病理切片取10个不同高倍视野进行巨核计数，巨核细胞集簇数并测量每个高倍视野最大巨核细胞直径.ET患者中，CALR突变组与JAK2突变组相比较，白细胞数、血红蛋白水平均明显降低（P=0.001，P=0.001），男性血小板数明显升高（P=0.04）；每高倍镜视野中巨核细胞平均值明显降低（P=0.001），平均巨核细胞集簇数明显减少（P=0.001）。CALR突变组血栓事件显著低于JAK2突变组（7.5% vs 18.4%)（P=0.03）.中国ET患者中，CALR基因突变者较JAK2基因突变者临床特征和血液病理改变存在差异，临床意义值得探索.

BackgroundThe disease burden caused by pulmonary tuberculosis (TB) in Sichuan province still persisted at a high level, and large spatial variances were presented across regional distribution disparities. The socio-economic factors were suspected to affect the population of TB notification, we aimed to describe TB case notification rate (CNR) and identify which factors influence TB epidemic are necessary for the prevention and control of the disease in Sichuan province.MethodsA retrospective cross-sectional study and an ecological spatial analysis was conducted to quantify the presence and location of spatial clusters of TB by the Moran’sIindex and examined these patterns with socio-economic risk factors by hierarchical Bayesian spatio-temporal model.ResultsA total of 630,009 pulmonary TB cases were notified from 2006 to 2015 in 181 counties of Sichuan province. The CNR decreased year by year since 2007, from 88.70 to 61.37 per 100,000 persons. The spatial heterogeneities of CNR were observed during the study periods. Global Moran’sIindex varied from 0.23 to 0.44 with allP-value DIC)(19,379.01), and in which the quadratic form of time was taken. The proportion of age group and education year were all associated with CNR after adjusting the spatial effect, temporal effect and spatio-temporal interactions. TB CNR increased by 10.2% [95% credible interval (CI): 6.7–13.7%] for every 1-standard-deviation increase in proportion of age group and decreased by 23% (95%CI: 13.7–32.7%) for every 1-standard-deviation increase in education year.ConclusionsThere were spatial clusters of TB notification rate in Sichuan province from 2006 to 2015, and heavy TB burden was mainly attributed to aging and low socioeconomic status including poor education. Thus, it is more important to pay more attention to the elderly population and improve socioeconomic status including promoting education level in Sichuan province to reduce the TB burden.

Aim Protein therapeutics have potential to elicit immune responses resulting in undesirable anti-drug antibodies (ADA) that might affect product efficacy and patient safety, and should be assessed in animals before applying the treatment to humans. In this paper, we aim to assess the immunogenicity and toxicokinetics of the mono-PEGylated recombinant human interleukin-11 (rhIL-11), a novel protein therapeutic for the treatment of chemotherapy-induced thrombocytopenia, in repeated administration to cynomolgus monkeys. Main methods Enzyme-linked immunosorbent assay (ELISA) methods were developed to measure ADA responses and plasma PEGylated IL-11 (PEG-IL11) concentration in monkeys. Assay parameters of immunogenicity and toxicokinetics methods were evaluated during validation in accordance with regulatory guidelines. We also employed cell-based assays to test the neutralizing activity of ADA provoked in monkeys. Key findings The results showed that weak immunogenicity occurred in some monkeys after receiving repeated dose of 0.1–0.3 mg/kg by subcutaneous administration and disappeared after the recovery period. More pronounced immunogenicity occurred at high dose of 0.9 mg/kg, with a higher positive rate and titer, and some ADAs had neutralizing activity, but it can be greatly reduced after recovery. Such ADAs generated in monkeys may be accounted for the plasma toxicokinetics changes of PEG-IL11 and a minor reduction in systemic exposure. Significance These methods have been successfully applied to immunogenicity and toxicokinetic studies of PEG-IL11 in repeated dose toxicity following subcutaneous administration to monkeys, and could be successfully used in clinical trials after some modifications.

Objective This study aims at realizing unsupervised term discovery in Chinese electronic health records (EHRs) by using the word segmentation technique. The existing supervised algorithms do not perform satisfactorily in the case of EHRs, as annotated medical data are scarce. We propose an unsupervised segmentation method (GTS) based on the graph partition principle, whose multi-granular segmentation capability can help realize efficient term discovery. Methods A sentence is converted to an undirected graph, with the edge weights based on n-gram statistics, and ratio cut is used to split the sentence into words. The graph partition is solved efficiently via dynamic programming, and multi-granularity is realized by setting different partition numbers. A BERT-based discriminator is trained using generated samples to verify the correctness of the word boundaries. The words that are not recorded in existing dictionaries are retained as potential medical terms. Results We compared the GTS approach with mature segmentation systems for both word segmentation and term discovery. MD students manually segmented Chinese EHRs at fine and coarse granularity levels and reviewed the term discovery results. The proposed unsupervised method outperformed all the competing algorithms in the word segmentation task. In term discovery, GTS outperformed the best baseline by 17 percentage points (a 47% relative percentage of increment) on F1-score. Conclusion In the absence of annotated training data, the graph partition technique can effectively use the corpus statistics and even expert knowledge to realize unsupervised word segmentation of EHRs. Multi-granular segmentation can be used to provide potential medical terms of various lengths with high accuracy.

A massively parallel array of monoclonal antibodies enables rapid antibody development and target discovery across species., Antibodies are essential for elucidating gene function. However, affordable technology for proteome-scale antibody generation does not exist. To address this, we developed Proteome Epitope Tag Antibody Library (PETAL) and its array. PETAL consists of 62,208 monoclonal antibodies (mAbs) against 15,199 peptides from diverse proteomes. PETAL harbors binders for a great multitude of proteins in nature due to antibody multispecificity, an intrinsic antibody feature. Distinctive combinations of 10,000 to 20,000 mAbs were found to target specific proteomes by array screening. Phenotype-specific mAb-protein pairs were found for maize and zebrafish samples. Immunofluorescence and flow cytometry mAbs for membrane proteins and chromatin immunoprecipitation–sequencing mAbs for transcription factors were identified from respective proteome-binding PETAL mAbs. Differential screening of cell surface proteomes of tumor and normal tissues identified internalizing tumor antigens for antibody-drug conjugates. By finding high-affinity mAbs at a fraction of current time and cost, PETAL enables proteome-scale antibody generation and target discovery.

Background In December 2019, the outbreak of 2019 novel coronavirus disease (COVID-19) began in Wuhan, Hubei Province, China. The disease has rapidly spread from Wuhan to other provinces and other countries. Clinical and epidemiological knowledge is limited. We aimed to describe the clinical and epidemiological characteristics of a family cluster of COVID-19 in Beijing.Methods We reported a family cluster of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases in Beijing, China. We obtained and analyzed clinical and epidemiologic data from these patients. Throat swab samples were tested for SARS-CoV-2 using real-time reverse transcriptase-polymerase chain reaction assays.Results This family comprised three laboratory confirmed cases with clinical symptoms. All three patients had close contact with a relative from Wuhan, Hubei Province. Chest computerized tomography revealed ground-glass opacities and consolidation. Patient 1 was finally intubated and mechanical ventilated. Patient 2 received high-flow oxygen therapy. The clinical condition of Patient 3 has resolved.Conclusion SARS-CoV-2 infections tend to clusters. Advanced age and comorbidities are associated with adverse outcomes. Physicians should be aware of contact history so that infected patients can be identified promptly and further spreading prevented.

Mesenchymal stem cells (MSCs) are considered a promising candidate for use in cell-based therapy for cartilage repair. To promote understanding of the molecular control of chondrogenesis differentiation in MSCs, we compared the changes in microRNAs during in vitro chondrogenesis process of human bone-marrow mesenchymal stem cells (hBMSCs). MiR-199b-5p was up-regulated significantly during this process. The aim of the study was to investigate the effects of miR-199b-5p on chondrogenic differentiation of C3H10T1/2 MSC cells and explore the underlying mechanisms. MiR-199b-5p mimics or inhibitor were transfected into C3H10T1/2 cells, respectively, and then, the effects of miR-199b-5p on chondrogenic differentiation of C3H10T1/2 cells were detected. The results indicated that miR-199b-5p overexpression inhibited the growth of C3H10T1/2 cells but promoted transforming growth factor-β3 (TGF-β3)-induced C3H10T1/2 cells of chondrogenic differentiation, as supported by enhancing the gene and protein expression of chondrocyte specific markers of SOX9, aggrecan, and collagen type II (Col2a1). In contrast, inhibiting miR-199b-5p notably promoted the proliferation of C3H10T1/2 cells but decreased chondrogenic differentiation. Furthermore, mechanism studies revealed that JAG1 was a direct target of miR-199b-5p by dual luciferase reporter assays. While silencing of JAG1 by isRNA resulted an increase of chondrogenic differentiation. Further, JAG1 knockdown was demonstrated to block the effect of miR-199b-5p inhibition. In conclusion, the present study revealed for the first time that miR-199b-5p was the positive regulators to modulate chondrogenic differentiation of C3H10T1/2 cells by targeting JAG1. These findings may provide a novel insight on miRNA-mediated MSC therapy for cartilage related disorders.

Breast cancer (BC) is the leading cause of cancer-related death in women worldwide and one of the most prevalent malignancy. In recent years, increasing evidence had illuminated that long noncoding RNAs (lncRNAs) serve as critical factors in multiple tumor progression, including BC. Emerging references had indicated that the lncRNA H19 acts as significant roles in tumor progression and epithelial-mesenchymal transition (EMT). However, the underlying molecular mechanisms and biological roles of H19 in BC invasion, metastasis and EMT are still unclear. In this study, it was detected that the expression level of H19 was increased in BC paclitaxel-resistant (PR) cells subline (MCF-7/PR) in comparison with MCF-7 parental cells. In vitro, there were demonstrated that H19 overexpression promoted BC cells proliferation, metastasis, invasion and EMT procedures, and suppressed cells apoptosis. Whereas, H19 suppression resulted in the contrary biological effects. Besides, bioinformatics tools and dual-luciferase reporters assays indicated that miR-340-3p could act as a potential target gene of H19, the underlying mechanism studies proved that H19 could act as a competing endogenous RNA (ceRNA) via competitively binding miR-340-3p to promote BC cell proliferation, metastasis and EMT by regulating tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) and potentiate the Wnt/β-catenin signaling in BC cells. In summary, our findings demonstrated that H19 could act as a ceRNA in BC progression, metastasis and EMT through modulating miR-340-3p/YWHAZ axis and activating the canonical Wnt/β-catenin signaling pathway, indicating that H19 might act as an underlying therapeutic target and prognostic biomarker for BC therapy.

Obesity is the third most risk factors of death in the middle-income and high-income countries. Whether DNA polymorphisms in CORIN and NPPA genes were associated with obesity, and if these associations could be modified by smoking in the Chinese Han population were unknown, hence a group of 1507 participants were recruited and genotyped for 12 tag single-nucleotide polymorphisms (SNPs) of CORIN and NPPA genes. Regression models were used to test the associations of SNPs with obesity. The potential SNP-smoking interactions were detected in regression models. NPPA SNPs rs5063 and rs198358 were associated with the body mass index (BMI) (P = 0.0053 and 0.0037, respectively). Rs198358 was associated with obesity in both univariate- and multivariable-adjusted analyses (P = 0.0138 and 0.0173, respectively). Rs5063 was associated with central obesity in both univariate- and multivariable-adjusted analyses (P = 0.0454 and 0.0361, respectively). Significant interactions between cigarette smoking and rs5063 and rs198358 were detected (P = 0.0019 and 0.0006, respectively). In subgroup analyses, rs5063 and rs198358 were associated with central obesity in smokers (P = 0.0081 and 0.0037, respectively). The results of our study demonstrated that the effect of NPPA SNPs rs5063 and rs198358 on central obesity might be modified by smoking in the Chinese Han population. Further studies are needed to confirm the associations and elucidate the underlying mechanisms.

Background Corin is an important convertase involved in the natriuretic peptide system and may indirectly regulate blood pressure. Genetic factors relate to corin remain unclear. The purpose of the current study was to comprehensively examine the associations among CORIN SNPs, methylations, serum corin levels and hypertension. Results We genotyped 9 tag-SNPs in the CORIN gene and measured serum corin levels in 731 new-onset hypertensive cases and 731 age- and sex-matched controls. DNA methylations were tested in 43 individuals. Mendelian randomization was used to investigate the causal associations. Under additive models, we observed associations of rs2289433 (p.Cys13Tyr), rs6823184, rs10517195, rs2271037 and rs12509275 with serum corin levels after adjustment for covariates (P = 0.0399, 0.0238, 0.0016, 0.0148 and 0.0038, respectively). The tag-SNP rs6823184 and SNPs that are in strong linkage disequilibrium with it, i.e., rs10049713, rs6823698 and rs1866689, were associated with CORIN gene expression (P = 2.38 × 10− 24, 5.94 × 10− 27, 6.31 × 10− 27 and 6.30 × 10− 27, respectively). Neither SNPs nor corin levels was found to be associated with hypertension. SNP rs6823184, which is located in a DNase hypersensitivity cluster, a CpG island and transcription factor binding sites, was significantly associated with cg02955940 methylation levels (P = 1.54 × 10− 7). A putative causal association between cg02955940 methylation and corin levels was detected (P = 0.0011). Conclusion This study identified potentially functional CORIN SNPs that were associated with serum corin level in the Chinese Han population. The effect of CORIN SNPs on corin level may be mediated by DNA methylation.

To investigate the short- and medium-term effect of vaginal antetheca submucosal-retropubic space with mesh repair through the implantation of organic patch (shortly as new-style vaginal mesh repair) in the treatment of patients with stress urinary incontinence (SUI).This was a clinical prospective single arm study in a tertiary grade hospital (General Hospital of Jinan Military Region, Jinan, China). From January 2009 to December 2014, 316 female patients were enrolled. 316 female patients with stress urinary incontinence (SUI) underwent the surgery. The treatment effect was evaluated using the urinary incontinence questionnaire (ICIQ-SF), urine pad test and coughing test. The perioperative and postoperative complications were also evaluated. The results were compared with 1-year cure rates of Burch retropubic urethropexy (Burch) and tension-free vaginal tape (TVT) procedure.The mean follow-up period was 25 ± 12 months. The success rate of the new surgical technique was 94.0% (297/316) at 1 month, and 91.5% (289/316) at 1-year postoperation. The ICIQ-SF score significantly decreased at the 1-year follow-up (P 0.01). There was no significant difference in the 1-year cure rate when compared with the Burch and TVT procedures (P 0.05). The rates of perioperative urinary tract irritation and mesh exposure were 9.5% (30/316) and 5.38% (17/316), respectively, and no serious complications were found.The surgery demonstrated favorable short-term and medium-term treatment effects. Given its advantages of being minimally invasive, cost efficient and requiring only local anesthesia, this new surgical technique has a potential for broader clinical application. CLINICALTRIALS.NCT02934490.

Objective To assess clinical value of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for differentiation of malignant from benign focal thyroid incidentaloma. Materials and Methods This retrospective study included 99 patients with focal thyroid incidentaloma of 5216 non-thyroid cancer patients that had undergone PET/CT. PET/CT semi-quantitative parameters, volume-based functional parameters, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of thyroid incidentaloma were assessed. Receiver-operating characteristic (ROC) analysis was conducted and areas under the curve (AUC) were compared by Hanley and McNeil test to evaluate usefulness of maximum standardized uptake value (SUVmax), MTV and TLG, as markers for differentiating malignant from benign thyroid incidentalomas. Results Of 99 thyroid incidentalomas, 64 (64.6%) were malignant and 35 (35.4%) were benign. Malignant thyroid incidentalomas were larger (1.8 cm vs. 1.3 cm, p = 0.006), and had higher SUVmax (11.3 vs. 4.8, p < 0.001), MTV (all p < 0.001) and TLG (all p < 0.001) than benign. TLG 4.0 had the highest performance for differentiation of malignant from benign thyroid incidentaloma in all semi-quantitative parameters with AUC 0.895 by ROC curve analysis. AUC (TLG 4.0) was significantly larger than AUC (SUVmean), AUC (MTV 2.5), AUC (MTV 3.0), AUC (MTV 3.5), AUC (TLG 2.5), and AUC (TLG 3.0), respectively (all, p < 0.05). There was no statistical difference between AUC (TLG 4.0) and AUC (SUVmax) (p > 0.05). A threshold TLG 4.0 of 2.475 had 81.3% sensitivity and 94.3% specificity for identifying malignant thyroid incidentalomas. Conclusion Volume-based PET/CT parameters could potentially have clinical value in differential diagnosis of thyroid incidentaloma along with SUVmax.

Maricultured organisms are chronically exposed to water containing antibiotics but the bioaccumulative behavior of antibiotics in exposed organisms at different growth stages has received little attention. Here, we investigated the concentrations and tissue-specific bioaccumulation characteristics of 19 antibiotics during three growth stages (youth stage, growth stage, and adult stage) of various organisms (Scophthalmus maximus, Penaeus vannamei, Penaeus japonicus, and Apostichopus japonicus) cultivated in typical marine aquaculture regions, and explored the factors that could affect the bioaccumulation of antibiotics. Tetracyclines (TCs) and fluoroquinolones (FQs) were the dominant antibiotics in all organisms, and the total concentrations of the target antibiotics in fish (S. maximus) were significantly higher than those in shrimp (P. vannamei and P. japonicus) and sea cucumber (A. japonicus) (p 0.01). The bioaccumulation capacity of a class of statistically significant antibiotics in most samples was strongest during the youth stage and weakest during the adult stage. The antibiotics exhibited higher bioaccumulation capacity in lipid-rich tissues (fish liver and shrimp head) or respiratory organs (fish gill) than muscle. Our results also reveal significant metabolic transformation of enrofloxacin in fish. Different from previous studies, the logarithm bioaccumulation factor (log BAF) was positively correlated with log D

Many hepatocellular carcinoma (HCC) patients do not qualify for curative surgical intervention and are instead treated with locoregional therapies (LRTs) including ablative and endovascular therapies. Assessment of imaging response is essential in the management of HCC for determining efficacy of therapy and as a surrogate marker for improved survival. The established morphological image biomarkers for tumor burden measurement continue to be applied, as size measurement can easily be used in clinical practice. However, in the setting of liver-directed LRTs for HCC, simple tumor morphological changes can be less informative and usually appear later than biologic changes. Functional imaging (such as perfusion and diffusion imaging, PET-CT/MR and MR spectroscopy) has the potential to be a promising technique for assessment of HCC response to LRTs. Although promising, none of these functional imaging biomarkers have gone through all the required steps of standardization and validation and established accepted criteria for clinical practice.