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Summary Background We sought to evaluate the safety and feasibility of single-stage treatment with left iliac vein stenting and saphenous stripping in patients with left iliac vein compression (LIVC) and left great saphenous vein (GSV) incompetence. Method s: We conducted a prospective cohort study of 72 patients diagnosed with LIVC and left GSV incompetence between June 2012 to Oct 2018. We evaluated the periprocedural, 30-day, and 1-year outcomes of venous clinical severity score (VCSS), Chronic Venous Insufficiency Questionnaire 2 (CIVIQ2), the success rate of stent placement, duration of intervention, length of hospital stay, duplex recurrence, and clinically visible recurrence. Results There were 43 patients in the two-staged group and 29 patients in the single-staged group. The clinical characteristics of the two groups were similar. There were no differences between the two groups in the technical success rate, perioperative mortality, and surgical morbidity. There was no significant difference in the duplex and clinically visible recurrence. The length of hospital stay was significantly lower in the single-staged group. The single-staged group was associated with a higher complication rate of ecchymosis. There was no death, pulmonary embolism, or contrast-induced nephropathy among the patients. The 1-year primary patency rate was similar. Conclusions Both treatment approaches were equally effective and had a high technical success rate. The single-staged group had a higher complication rate of ecchymosis due to heparin applying during the procedure.

Nasopharyngeal carcinoma (NPC) is a typical type of malignant tumor. This research paper aims to study the function and mechanism of long non-coding RNA lung adenocarcinoma-related transcript 1 (lncRNA-LUADT1) in the progression of NPC. In this study, the expressions of lncRNA-LUADT1, miR-1207-5p, and TEAD1 in NPC tissues and cell lines were detected by RT-qPCR. Initially, the expression of lncRNA-LUADT1 and TEAD1 were significantly up-regulated in NPC tissues and cells, while miR-1207-5p was significantly down-regulated. Next, miR-1207-5p was confirmed to bind to lncRNA-LUADT1 or TEAD1 by bioinformatics and luciferase reporter assay. In addition, after interfering with lncRNA-LUADT1 expression, experiments of CCK8, EDU staining, and Transwell invasion were used to detect proliferation, invasion, and migration of NPC cells. The results showed that interfering with lncRNA-LUADT1 expression could inhibit the proliferation, invasion, and migration of NPC cells. Western blot showed that lncRNA-LUADT1 knockdown significantly decreased the expression of Hippo/YAP pathway protein (YAP1 and TAZ). However, interfering with the expression of miR-1207-5p reversed these results. In addition, the nude mouse tumor formation experiment suggested that low-expressed lncRNA-LUADT1 reduced the volume and weight of tumor tissues. In summary, lncRNA-LUADT1 down-regulation could inhibit NPC cell proliferation and invasion, which may be achieved through regulating miR-1207-5p expression and affecting TEAD1 expression, thus inhibiting the activation of Hippo/YAP signaling pathway.

Background : American Institute of Medicine (IOM) recommends different ranges of gestational weight gain (GWG) based on pre-pregnancy body mass index (BMI). In Taiwan, IOM guidelines are implemented concurrently with the local recommendation for GWG (10–14 kg). This study compared between the two sets of guidelines in relation to adverse perinatal outcomes.Methods : We analyzed 31653 primiparas with singletons from 2011-2016 annual National Breastfeeding Surveys. Logistic regressions for preterm birth, small for gestational age (SGA), large for gestational age (LGA), cesarean section and excessive postpartum weight retention (PWR) were fitted separately for GWG categorized according to IOM and Taiwan ranges. Areas under the receiver-operator curves (AUC) and the predicted probabilities for each outcome were compared in each BMI group.Results : AUC for both guidelines ranged within 0.51 – 0.73. Compared to Taiwan recommendation, IOM ranges showed lower probabilities of SGA for underweight (0.11–0.15 versus 0.14–0.18), of LGA for obese (0.12–0.15 versus 0.15–0.18), of excessive PWR for overweight (0.19–0.30 versus 0.27–0.39), and obese (0.15–0.22 versus 0.25-0.36); and higher probabilities of excessive PWR for underweight (0.17-0.33 versus 0.14-0.22).Conclusions : Discriminative performance of IOM and Taiwan recommendations was poor for the five adverse birth outcomes, and no preference for either set of recommendations could be inferred from our results. In the absence of specific GWG guidelines, health care workers may provide inconsistent information to their patients. Future research is needed to explore optimal GWG ranges that can reliably predict locally relevant perinatal outcomes for mother and child.

Cancer metastasis is the main cause of mortality associated with non-small-cell lung cancer (NSCLC), accounting for up to 70% of deaths among patients. The mechanisms underlying distal metastasis remain largely unknown. Golgi phosphoprotein 3 (GOLPH3) correlates negatively with overall survival in multiple tumors. In this study, we evaluated the function of GOLPH3 in NSCLC distal metastasis. GOLPH3 was expressed at high levels in samples from patients with NSCLC and was positively associated with clinicopathologic characteristics including clinical stage (P P = 0.001), N (P = 0.007), and M (P = 0.001) classification. Functionally, Transwell and wound-healing assays suggested that GOLPH3 overexpression enhances NSCLC cell migration and invasion abilities. Tumor-sphere formation and flow cytometry assays demonstrated that GOLPH3 overexpression enhances a stem cell-like phenotype of NSCLC cells. Metastasis models established by tail vein and intracardiac injection confirmed the pro-metastatic function of GOLPH3 in vivo. A subcutaneous tumor formation model confirmed that GOLPH3 overexpression increased the tumorigenicity of NSCLC cells. Mechanistically, gene set enrichment analysis revealed a positive association of GOLPH3 mRNA expression with WNT-activated gene signatures. Luciferase-reporter and nuclear extract assays showed that GOLPH3 overexpression enhances metastasis and tumorigenicity through activation of the WNT/β-catenin pathway. Immunoprecipitation-mass spectrometry and gene ontology analysis demonstrated that GOLPH3 interacts with cytoskeleton-associated protein 4 (CKAP4) in exosome-mediated distal metastasis. We found that GOLPH3 decreased the amount of plasma membrane-localized CKAP4 and increased the amount of exosome-localized CKAP4 to promote the formation of CKAP4-containing exosomes. Furthermore, we demonstrated that CKAP4 binds exosomal WNT3A to enhance its secretion. Therefore, the GOLPH3/CKAP4 axis plays a crucial role in promoting exosomal-WNT3A secretion to enhance and maintain the stem-like phenotype and metastasis in NSCLC, thus indicating the therapeutic potential of GOLPH3 in patients with NSCLC metastasis.

PURPOSE: To explore the application value of SMI scoring assignment method combined with 2017 American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TI-RADS) in differentiating benign and malignant thyroid nodules. METHODS: According to the 2017 ACR TI-RADS classification, the enrolled nodules were divided into 3 points group, 4 points group, 5 points group, 6 points group and≥7 points group. The nodules were assigned scores according to the echocity of the nodules and the microvessels detected by SMI and their distribution patterns based on ACR TI-RADS. Accompany with the scores increased or decreased after assignment, the thyroid nodules were re-grouped. RESULTS: The AUC after the scores assignment is better than before (Z = 3.881, P

Objective: To explore the effect of ureteroscopy with double J tube placement and drainage on ureteral stones during pregnancy, to compare the clinical effect of ureteroscope with double J tube placement on pregnancy complicated with ureteral stones, and using medical imaging to diagnose the patient’s condition and design a treatment plan. Methods: Eighty pregnant patients with ureteral calculi treated in our hospital were selected as the research object, and were divided into a test group and a control group according to the random number table method, 40 cases in each group. The test group underwent ureteroscope double J tube placement, and the control group underwent ureteroscope lithotripsy. Combined with the ultrasound scan results of the patients before and after the operation, the operation time, time to get out of bed and hospitalization time of the two groups of patients were compared. The operation success rate and the incidence of complications within 1 month after surgery were counted in the two groups of patients. Results: The total effective rate of the observation group was 100.0%, which is higher than that of the control group of 90.0%. The difference between the two groups was statistically significant (P < 0.05). The adverse reaction rate in the observation group was 5.0%, which was lower than 17.5% in the control group. The difference between the two groups was statistically significant (P < 0.05). The comparison results are then prepared. Conclusions: Double J tube placement under ureteroscopy has a significant effect on the treatment of ureteral stones during pregnancy, and it has good safety and is worthy of widespread application.

Introduction: We designed 5 convolutional neural network (CNN) models and ensemble models to differentiate malignant and benign thyroid nodules on CT, and compared the diagnostic performance of CNN models with that of radiologists. Material and methods: We retrospectively included CT images of 880 patients with 986 thyroid nodules confirmed by surgical pathology between July 2017 and December 2019. Two radiologists retrospectively diagnosed benign and malignant thyroid nodules on CT images in a test set. Five CNNs (ResNet50, DenseNet121, DenseNet169, SE-ResNeXt50, and Xception) were trained-validated and tested using 788 and 198 thyroid nodule CT images, respectively. Then, we selected the 3 models with the best diagnostic performance on the test set for the model ensemble. We then compared the diagnostic performance of 2 radiologists with 5 CNN models and the integrated model. Results: Of the 986 thyroid nodules, 541 were malignant, and 445 were benign. The area under the curves (AUCs) for diagnosing thyroid malignancy was 0.587–0.754 for 2 radiologists. The AUCs for diagnosing thyroid malignancy for the 5 CNN models and ensemble model was 0.901–0.947. There were significant differences in AUC between the radiologists’ models and the CNN models (p < 0.05). The ensemble model had the highest AUC value. Conclusions: Five CNN models and an ensemble model performed better than radiologists in distinguishing malignant thyroid nodules from benign nodules on CT. The diagnostic performance of the ensemble model improved and showed good potential.

Site-specific variation in colorectal cancer (CRC) incidence, biology and prognosis are poorly understood. We sought to determine whether common genetic variants influencing CRC risk might exhibit topographical differences on CRC risk through regional differences in effects on gene expression in the large bowel mucosa. We conducted a site-specific genetic association study (10,630 cases, 31,331 controls) to identify whether established risk variants exert differential effects on risk of proximal, compared to distal CRC. We collected normal colorectal mucosa and blood from 481 subjects and assessed mucosal gene expression using Illumina HumanHT-12v4 arrays in relation to germline genotype. Expression quantitative trait loci (eQTLs) were explored by anatomical location of sampling. The rs3087967 genotype (chr11q23.1 risk variant) exhibited significant site-specific effects - risk of distal CRC (OR=1.20, P=8.20x10-20 ) with negligible effects on proximal CRC risk (OR=1.05, P=0.10). Expression of 1261 genes differed between proximal and distal colonic mucosa (top hit PRAC gene, fold-difference=10, P=3.48x10-57 ). In eQTL studies, rs3087967 genotype was associated with expression of 8 cis- and 21 trans-genes. Four of these (AKAP14, ADH5P4, ASGR2, RP11-342M1.7) showed differential effects by site, with strongest trans-eQTL signals in proximal colonic mucosa (e.g. AKAP14, beta=0.61, P=5.02x10-5 ) and opposite signals in distal mucosa (AKAP14, beta=-0.17, P=0.04). In summary, genetic variation at the chr11q23.1 risk locus imparts greater risk of distal rather than proximal CRC and exhibits site-specific differences in eQTL effects in normal mucosa. Topographical differences in genomic control over gene expression relevant to CRC risk may underlie site-specific variation in CRC. Results may inform individualised CRC screening programmes. This article is protected by copyright. All rights reserved. Site-specific variation in colorectal cancer (CRC) incidence, biology and prognosis are poorly understood. We sought to determine whether common genetic variants influencing CRC risk might exhibit topographical differences on CRC risk through regional differences in effects on gene expression in the large bowel mucosa. We conducted a site-specific genetic association study (10,630 cases, 31,331 controls) to identify whether established risk variants exert differential effects on risk of proximal, compared to distal CRC. We collected normal colorectal mucosa and blood from 481 subjects and assessed mucosal gene expression using Illumina HumanHT-12v4 arrays in relation to germline genotype. Expression quantitative trait loci (eQTLs) were explored by anatomical location of sampling. The rs3087967 genotype (chr11q23.1 risk variant) exhibited significant site-specific effects - risk of distal CRC (OR=1.20, P=8.20x10-20 ) with negligible effects on proximal CRC risk (OR=1.05, P=0.10). Expression of 1261 genes differed between proximal and distal colonic mucosa (top hit PRAC gene, fold-difference=10, P=3.48x10-57 ). In eQTL studies, rs3087967 genotype was associated with expression of 8 cis- and 21 trans-genes. Four of these (AKAP14, ADH5P4, ASGR2, RP11-342M1.7) showed differential effects by site, with strongest trans-eQTL signals in proximal colonic mucosa (e.g. AKAP14, beta=0.61, P=5.02x10-5 ) and opposite signals in distal mucosa (AKAP14, beta=-0.17, P=0.04). In summary, genetic variation at the chr11q23.1 risk locus imparts greater risk of distal rather than proximal CRC and exhibits site-specific differences in eQTL effects in normal mucosa. Topographical differences in genomic control over gene expression relevant to CRC risk may underlie site-specific variation in CRC. Results may inform individualised CRC screening programmes. This article is protected by copyright. All rights reserved.

Background During pregnancy, nutritional requirements increase and if not met, pregnancy-related complications may manifest. To prevent these undesirable outcomes, the World Health Organization recommends daily oral iron and folic acid (IFA) supplementation as part of antenatal care. Despite this recommendation, the use of IFA supplements is still very low in several developing countries. Additionally, no prior information exists regarding the level of consumption of IFA in Eswatini. Thus, this study aimed to determine the prevalence of consumption of IFA supplements and to identify factors associated with the consumption of IFA supplements among pregnant women in Eswatini. Methods A cross-sectional questionnaire survey was conducted among 330 pregnant women aged ≥ 18 years in their third trimester in Eswatini. Participants were recruited from eight purposively selected healthcare facilities from July 2019 to October 2019. Good consumption was defined as consuming all or almost all IFA supplements throughout pregnancy. Results During the first trimester, 10.3 % of the participants consumed all or almost all IFA supplements. In the second and third trimesters, those who consumed all or almost all supplements were 37 and 39.7 %, respectively, for iron and 37.6 and 40.9 %, respectively, for folic acid. Barriers, including side effects, forgetfulness, safe previous pregnancies without IFA, others’ advice against consumption, IFA stock-outs, inability to meet transport costs, and inadequate supply of IFA tablets, contribute to low consumption of IFA. Multivariate logistic regression models showed that the barriers were inversely associated with good consumption of IFA supplements. Better knowledge and attitude toward IFA and older maternal age were positively associated with good consumption of IFA supplements. Conclusions Low consumption of IFA supplements in overall pregnancy is mainly owing to the late antenatal care attendance. Strategies such as establishing a preconception care unit and school-based provision of IFA may be helpful. It is evident that most women still lack knowledge, and some have negative attitudes about IFA supplements. Health education to raise awareness and emphasize the importance of starting antenatal care early as well as consuming supplements on time should be revisited and intensified. Multiple strategies such as including community health care workers for distributing IFA supplements, discussing with clients about the measures to reduce forgetfulness, advising ways to prevent and manage the side effects, providing subsidies to cover transport costs, and ensuring adequate supply of IFA supplements in facilities may need to be employed to reduce the identified barriers.

BackgroundPrimary hyperparathyroidism (PHPT) results from an excess of parathyroid hormone (PTH) produced from an overactive parathyroid gland. The study aimed to explore the sonographic features of parathyroid adenomas and assess the diagnostic performance of ultrasonography (US) and Tc-99m MIBI SPECT/CT for preoperative localization of parathyroid adenomas.MethodsA total of 107 patients were enrolled in this retrospective study who had PHPT and underwent parathyroidectomy. Of the 107 patients, 97 performed US and Tc-99m MIBI SPECT/CT examinations for preoperative localization of parathyroid nodules. The sensitivity and accuracy of each modality were calculated.ResultsIn this study, residual parathyroid sign and polar vascular sign were identified as characteristic US features of parathyroid adenomas. These manifestations were closely related to the size of the abnormal parathyroid lesions. Among the 108 parathyroid nodules from 97 patients with PHPT, the sensitivity and accuracy of US for locating the parathyroid nodules were significantly higher than those of Tc-99m MIBI SPECT/CT (93.0% vs. 63.0% and 88.0% vs. 63.0% respectively; χ2 = 26.224, 18.227 respectively, P 2 = 33.410, 21.587 respectively, P 2 = 0.866, 0.187 respectively, P = 0.352 and 0.665).ConclusionsUS shows significantly better sensitivity and accuracy for localization of parathyroid adenomas than Tc-99m MIBI SPECT/CT. However, US combined with Tc-99m MIBI SPECT/CT is of great clinical value in the preoperative localization of parathyroid nodules in patients with PHPT.

Nasopharyngeal carcinoma (NPC) is known for its potential to progress to the lymph nodes and distant metastases at an early stage. As an important regulator in tumorigenesis biological processes, the functions of lncRNA in NPC tumor development remain largely unclear. In this research, the expression of EPB41L4A-AS2 in NPC tissues and cells was analyzed via real-time quantitative polymerase chain reaction (qRT-PCR). CCK8, colony formation, and EDU experiments were used to determine the viability of NPC cells. Transwell and wound healing assays were performed to test NPC cell migration and invasion. RNA pull-down and mass spectrometry analysis were used to identify potential binding proteins. Then, a popliteal lymph node metastasis model was established to test NPC metastasis. EPB41L4A-AS2 is repressed by transforming growth factor-beta, which is downregulated in NPC cells and tissue. It is associated with the presence of distant metastasis and adverse outcomes. The univariate and multivariate survival assays confirmed that EPB41L4A-AS2 expression was an independent predictor of progression-free survival (PFS) in patients with NPC. Biological analyses showed that overexpression of EPB41L4A-AS2 reduced the metastasis and invasion of NPC in vitro and in vivo, but had no significant effect on cell proliferation. Mechanistically, in the nucleus we identified that EPB41L4A-AS2 relies on binding to YBX1 to reduce the stability of Snail mRNA to enhance the expression of E-cadherin and reverse the progression of epithelial-to-mesenchymal transition (EMT). In the cytoplasm, we found that EPB41L4A-AS2 blocked the invasion and migration of NPC cells by promoting LATS2 expression via sponging miR-107. In a whole, the findings of this study help to further understand the metastasis mechanism of NPC and could help in the prevention and treatment of NPC metastasis.

Background Major depressive disorder (MDD) is associated with high risk of suicide, but the biological underpinnings of suicidality in MDD patients are far from conclusive. Previous neuroimaging studies using voxel-based morphometry (VBM) demonstrated that depressed individuals with suicidal thoughts or behaviors exhibit specific cortical structure alterations. To complement VBM findings, surface-based morphometry (SBM) can provide more details into gray matter structure, including the cortical complexity, cortical thickness and sulcal depth for brain images. Objective This study aims to use SBM to investigate cortical morphology alterations to obtain evidence for neuroanatomical alterations in depressed patients with suicidality. Methods Here, 3D T1-weighted MR images of brain from 39 healthy controls, 40 depressed patients without suicidality (patient controls), and 39 with suicidality (suicidal groups) were analyzed based on SBM to estimate the fractal dimension, gyrification index, sulcal depth, and cortical thickness using the Computational Anatomy Toolbox. Correlation analyses were performed between clinical data and cortical surface measurements from patients. Results Surface-based morphometry showed decreased sulcal depth in the parietal, frontal, limbic, occipital and temporal regions and decreased fractal dimension in the frontal regions in depressed patients with suicidality compared to both healthy and patient controls. Additionally, in patients with depression, the sulcal depth of the left caudal anterior cingulate cortex was negatively correlated with Hamilton Depression Rating Scale scores. Conclusions Depressed patients with suicidality had abnormal cortical morphology in some brain regions within the default mode network, frontolimbic circuitry and temporal regions. These structural deficits may be associated with the dysfunction of emotional processing and impulsivity control. This study provides insights into the underlying neurobiology of the suicidal brain.

BACKGROUND This study describes the use of a moisture chamber to treat corneal ulceration due to temporary lagophthalmos in a critically ill patient. CASE SUMMARY A 46-year-old woman was admitted to the intensive care unit after a car accident. She suffered multiple injuries that included brain injury and presented with moderately decreased consciousness and lagophthalmos in her right eye. Within 6 d, her consciousness improved considerably; at which time, exposure keratopathy occurred and worsened to corneal ulceration. Lubricating gel, antibiotic ointment, and bandage contact lens were all ineffective in preventing or treating the exposure keratopathy. Instead of tarsorrhaphy, a moisture chamber was applied which successfully controlled the corneal ulceration. The moisture chamber was discontinued when complete eyelid closure recovered a week later. CONCLUSION A moisture chamber may be an effective, noninvasive alternative to tarsorrhaphy for treating severe exposure keratopathy due to temporary lagophthalmos.

IL-33 is an IL-1 family cytokine that signals through its cognate receptor, ST2, to regulate inflammation. Whether IL-33 serves a pathogenic or protective role during inflammatory bowel disease is controversial. Herein, two different strains of cell-specific conditionally deficient mice were used to compare the role of myeloid- versus intestinal epithelial cell–derived IL-33 during dextran sodium sulfate–induced colitis. Data show that loss of CD11c-restricted IL-33 exacerbated tissue pathology, coinciding with increased tissue Il6 levels and loss of intestinal forkhead box p3(+) regulatory T cells. Surprisingly, the lack of intestinal epithelial cell–derived IL-33 had no impact on disease severity or tissue recovery. Thus, we show that myeloid-derived IL-33 functionally restrains colitic disease, whereas intestinal epithelial cell–derived IL-33 is dispensable.

The interaction between gut microbiota and the host has gained widespread concern. Gut microbiota not only provides nutrients from the ingested food but also generates bioactive metabolites and signalling molecules to impact host physiology, especially in chronic kidney disease (CKD). The development of CKD, accompanied by changed diet and medication, alters the gut flora and causes the effect in distant organs, leading to clinical complications. Vascular calcification (VC) is an actively regulated process and a high prevalence of VC in CKD has also been linked to an imbalance in gut microbiota and altered metabolites. In this review, we focused on gut microbiota‐derived metabolites involved in VC in CKD and explained how these metabolites influence the calcification process. Correcting the imbalance of gut microbiota and regulating microbiota‐derived metabolites by dietary modification and probiotics are new targets for the improvement of the gut‐kidney axis, which indicate innovative treatment options of VC in CKD.

Down-regulated lncRNA AC061961.2 in dilated cardiomyopathy (DCM) patients was previous reported. Whether AC061961.2 has regulatory effect on DCM still need exploration. Here, we tried to investigate the effect of AC061961.2 on DCM. After DCM model rat was established through injecting Adriamycin, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were measured by echocardiography. Histopathological changes and apoptosis were detected by hematoxylin-eosin, Masson staining, and TUNEL. After cardiomyocytes were isolated and identified by immunofluorescence, DCM cell model was established by injecting adriamycin. After transfected with overexpressed-AC061961.2 plasmids, cell apoptosis was detected by flow cytometry. The expressions of AC061961.2, β-catenin, Axin2, c-Myc, CRP78, CHOP, Caspase-3, Bcl-2, and Bax in cardiomyocytes and heart tissues were detected by RT-qPCR or western blot. LVEDD and LVESD were increased while LVEF and LVFS were decreased in DCM rats. The histopathological of heart tissues showed a typical sign of DCM. Apoptosis were increased in heart tissues of DCM rats. In DCM rats, the expressions of AC061961.2, β-catenin, Axin2, c-Myc, and Bcl-2 were decreased, the expressions of CRP78, CHOP, Caspase-3, and Bax were increased. After the overexpression of AC061961.2, levels of β-catenin, Axin2, c-Myc, and Bcl-2 were increased, while levels of CRP78, CHOP, Caspase-3, and Bax were decreased, compared with that in DCM cardiomyocytes. LncRNA AC061961.2 overexpression inhibited endoplasmic reticulum stress induced apoptosis in DCM rats and cardiomyocytes via activating Wnt/β-catenin pathway.

The Bethesda System for Reporting Thyroid Cytopathology has paved the way for comparisons of the practice of thyroid cytology in many different regions. However, there have been comparatively few studies documenting differences between Asian and non-Asian practice. Here, we aim to compare a few key parameters between the two regions, focusing on the indeterminate category of atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS). We compared its incidence, resection rates (RRs), risk of malignancy (ROM), rate of repeat fine needle aspiration (rFNA), ROMs of cytomorphologic subcategories of nuclear atypia (AUS-N) vs. architectural atypia (AUS-A), and, finally, the incidence of papillary thyroid carcinoma (PTC) vs. follicular neoplasms (FNs) in resected AUS/FLUS cases in Asian and non-Asian regions. Where possible, these metrics were compared with the Singapore experience from a tertiary referral institution. While the incidence of AUS/FLUS was similar in both regions, we found geographical differences in the RRs and ROMs, which may reflect a higher collective threshold for surgery in Asian countries. However, both cohorts showed higher ROMs in the AUS-N subcategory as compared to the AUS-A subcategory, supporting the subclassification of the AUS/FLUS based on the presence of nuclear atypia. We also observed a higher incidence of AUS-N coupled with a higher incidence of PTC in resected AUS/FLUS nodules in Asian cohorts, while AUS-A and follicular-patterned neoplasms featured more prominently in the non-Asian cohorts. These incidences may account for the starkly different molecular approaches that we noted-in Asian (chiefly Korean and Chinese) centers, BRAF mutational analysis was favored, while gene panels and gene expression classifiers were more frequently applied in non-Asian centers (chiefly in the United States of America). Overall, the data from Singapore appears more closely aligned to non-Asian trends, despite its geographical location in Southeast Asia and its predominantly Asian population. We conclude that there is significant heterogeneity in the outcomes of the AUS/FLUS categories between and within regions, which is only partially explained by regional variations, and may also reflect different regional diagnostic and management practices. This highlights the importance of understanding the local context in the interpretation of indeterminate Bethesda categories, rather than adopting a "one-size fits all" approach.

Background To utilise Multiphoton Microscopy as a novel imaging technique to characterize and quantify collagen at the Renal Cell Carcinoma Pseudocapsule, to assess for both intra-tumoral and inter-tumoral variation of collagen characteristics. MPM combines Second Harmonic Generation and Two Photon Excitation Fluorescence to image extracellular matrix architecture. Methods 20 partial nephrectomy specimen tissues were retrieved, cut into 5‎-micron sections, mounted on slides and deparaffinized. The pseudocapsules were imaged with 2X and 20X objective at selected Regions of Interest. Corresponding clinical information was retrieved. Pseudocapsule thickness was determined. Collagen parameters measured included quantification by the Collagen Area Ratio, and qualitative measurements by the Collagen Fiber Density and Collagen Reticulation Index. Results The boundaries between tumor, PC and normal renal parenchyma were distinguished by Multiphoton Microscopy without the need for staining. In the thickest areas of the pseudocapsule, collagen content and density were quantitatively higher compared to the thinnest areas. Median Collagen Area Ratio was higher in the thickest compared to the thinnest areas of the PC (p=0.01). Clear Cell RCC specimens had a consistently higher Collagen Fiber Density in both the thickest and thinnest areas compared to non-Clear Cell RCC specimens (p=0.02). Conclusions In this study, we demonstrated the ability of Multiphoton Microscopy to quantify collagen characteristics of pseudocapsules without fluorescent labelling. Tumor enucleation for Renal Cell Carcinoma along its Pseudocapsule remains debatable with regards to oncological safety. Even with a complete and intact pseudocapsule, the pseudocapsule is not a homogenous structure, and varies in its thickness and its collagen characteristics within, and between, tumours.

Background Balloon dilatation with stent implantation has been proved to be an effective option for left iliac vein compression syndrome (LIVCS), but thrombosis may still occur after the operation. Currently, warfarin is used for anticoagulant therapy, but long-term monitoring is required, while rivaroxaban does not need laboratory monitoring, which can simplify treatment. Therefore, this study aimed to compare the efficacy and safety of rivaroxaban and warfarin in anticoagulation. Methods This study is a multicenter, randomized controlled trial. We will recruit 224 patients with thrombotic LIVCS from 9 hospitals. Moreover, these patients will be randomized to either the experimental group (rivaroxaban) or the control group (warfarin plus nadroparin). The primary outcome is stent occlusion rate. Secondary outcomes are quality of life scale survey results, all-cause mortality, anticoagulation-related mortality, and the proportion of participants with stent displacement/fracture, thrombosis, hemorrhage, and other vascular events. Discussion This study will provide reliable, evidence-based clinical evidence for the efficacy and safety of rivaroxaban antithrombotic therapy after stent implantation. Trial registration ClinicalTrials.gov NCT04067505. Registered on August 26, 2019.

Background This study aimed to compare the efficacy and toxicity of raltitrexed (Saiweijian®) plus cisplatin (SP regimen) and 5‐fluorouracil plus cisplatin (FP regimen) as concurrent chemoradiotherapy (CCRT) in patients with locally advanced nasopharyngeal carcinoma (LA‐NPC). Methods Eligible patients (N = 135) were allocated randomly in a ratio of 1:1 to receive CCRT with either SP or FP. At least 2 cycles of chemotherapy was administrated during radiotherapy. Progression free survival (PFS) was primary endpoint. Secondary endpoints included overall survival (OS), loco‐regional relapse free survival (LRRFS), distant metastasis free survival (DMFS) and toxicity. Results In this study, 68 patients received SP as CCRT, and 67 received FP. Objective responses were noted in 97.1% of the patients in the SP group and in 97.0% of the patients in the FP group (P = 1.00). At the end of a median 36 months follow‐up period, the estimated 3‐year PFS rates were 70.1% for SP and 66.6% for FP, respectively. The 3‐year LRRFS, DMFS and OS rates were 88.9%, 74.7% and 84.0%, respectively, for the SP group, and 92.3%, 71.0% and 73.7%, respectively, for the FP group. Overall, there was no difference between treatment groups with regard to response or survival. The most frequent acute toxicities monitored in both groups were bone marrow suppression, gastrointestinal side effects and oral mucositis (OM). The overall incidence of grade 3‐4 OM in the FP group (47.8%) was higher than in the SP group (11.8%). However, the incidence of other adverse effects observed in both groups was similar (P > .05). Conclusions These data indicate that SP and FP therapies have similar efficacy in treating LA‐NPC. The SP regimen showed a tolerable safety profile along with a lower frequency of severe OM and therefore, an improved life quality. In conclusion, SP was a well tolerated, effective, regimen for LA‐NPC treatment., The incidence of other adverse effects seen in both groups was similar (P > .05).The efficacy of both regimens i.e. SP and FP are found similar. The SP regimen has tolerable safety profile, with a lower incidence of severe OM and consequently, an improved quality of life.

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and prognosis after potentially curative gastrectomy remains poor. Administration of GC-targeting molecules in combination with adjuvant chemo- or radiotherapy following surgical resection has been proposed as a potentially effective treatment option. Here, we have identified DOCK6, a guanine nucleotide exchange factor (GEF) for Rac1 and CDC42, as an independent biomarker for GC prognosis. Clinical findings indicate the positive correlation of higher DOCK6 expression with tumor size, depth of invasion, lymph node metastasis, vascular invasion, and pathological stage. Furthermore, elevated DOCK6 expression was significantly associated with shorter cumulative survival in both univariate and multivariate analyses. Gene ontology analysis of three independent clinical GC cohorts revealed significant involvement of DOCK6-correlated genes in the WNT/β-catenin signaling pathway. Ectopic expression of DOCK6 promoted GC cancer stem cell (CSC) characteristics and chemo- or radioresistance concomitantly through Rac1 activation. Conversely, depletion of DOCK6 suppressed CSC phenotypes and progression of GC, further demonstrating the pivotal role of DOCK6 in GC progression. Our results demonstrate a novel mechanistic link between DOCK6, Rac1, and β-catenin in GCCSC for the first time, supporting the utility of DOCK6 as an independent marker of GC.

Autophagy of cardiomyocytes after myocardial infarction (MI) is an important factor affecting the prognosis of MI. Excessive autophagy can lead to massive death of cardiomyocytes, which will seriously affect cardiac function. IKKε plays a crucial role in the occurrence of autophagy, but the functional role in MI remains largely unknown. To evaluate the impact of IKKε on the autophagy of cardiomyocytes after MI, MI was induced by surgical left anterior descending coronary artery ligation in IKKε knockout (KO) mice and wild-type (WT) mice. Starvation of H9c2 cells with IKKε siRNA and rescued with IKKε overexpressed afterwards to test the mechanism of IKKε in autophagy in vitro. Our results demonstrated that the expression of IKKε was upregulated in mice myocardial tissues which were consistent with cardiomyocyte autophagy after MI. Significantly, the IKKε KO mice showed increased infarct size, decreased viable cardiomyocytes, and exacerbated cardiac dysfunction when compared with the wild-type mice. Western blot and electron micrography analysis also revealed that loss of IKKε induces excessive cardiomyocyte autophagy and reduced the expression of p-Akt and p-mTOR. Similar results were observed in IKKε siRNA H9c2 cells in vitro which were under starvation injury. Notably, the levels of p-Akt and p-mTOR can restore in IKKε rescued cells. In conclusion, our results indicated that IKKε protects cardiomyocyte survival by reduced autophagy following MI via regulation of the Akt/mTOR signaling pathway. Thus, our study suggests that IKKε might represent a potential therapeutic target for the treatment of MI.

Accumulating evidences indicate that circular RNAs (circRNAs), a subclass of noncoding RNAs, play important role in regulating gene expression in eukaryotes. Hsa_circ_0046263 (circ-0046263) was found aberrantly expressed in nasopharyngeal carcinoma (NPC), but its role in tumor growth and metastasis remains largely unclear. Sanger sequencing, RNase R assay, and nucleic acid electrophoresis were conducted to verify the identification of circ-0046263. Nuclear separation and fluorescence in situ hybridization (FISH) assays were used to determine the localization of circ-004263. Dual luciferase reporter and RNA immunoprecipitation (RIP) were employed to confirm the binding of circ-0046263 with miR-133a-5p. Colony formation, proliferation, wound healing, transwell, western blot, and in vivo tumor growth and metastasis assays were performed to assess the roles of circ-0046263, miR-133a-5p, IGFBP3 and their interactions in NPC cells. Circ-0046263 was upregulated in both NPC cell lines and tissues. The in vitro functional studies revealed that knockdown of circ-0046263 inhibited the proliferation, invasion, and migration of NPC cells, whereas its overexpression produced the opposite result. In vivo experiments indicated that knockdown or overexpression of circ-0046263 attenuated or promoted tumor growth and metastasis, respectively. Mechanistically, circ-0046263 could act as a miRNA sponge to absorb miR-133a-5p and upregulate the expression of miRNA downstream target IGFBP3. In addition, miR-133a-5p inhibition or IGFBP3 overexpression could rescue the malignant behavior induced by circ-0046263 silencing. Finally, circ-0046263 plays a tumor-promoting role in NPC to enhance malignant behavior through the miR-133a-5p/IGFBP3 axis, which could be a potential target for NPC therapy.

Aims and objectives To examine how changes in physical activity, sitting time and sleep duration through pre‐, mid‐ and late pregnancy are in association with Caesarean section, medically indicated Caesarean section and small for gestational age. Background While circadian activities could change throughout pregnancy, studies exploring the effect of change in those activities on pregnancy outcomes remain limited. Design This study applied a prospective panel design. Methods A self‐reported questionnaire was used to assess the three activities before and during pregnancy and was administered three times from August 2015–July 2017. Multiple logistic regression models were used. The analysis included 488, 477 and 455 participants in the models for Caesarean section, medically indicated Caesarean section and small for gestational age, respectively. This study followed the STROBE guidelines. Results The mean age of participants was 32.18 years, and more than half (54.90%) were primiparous. Sleep duration of >8 hr/day before pregnancy and experiencing a decrease in mid‐pregnancy was a risk factor for Caesarean section and medically indicated Caesarean section. Sitting ≥8 hr/weekday in pre‐, mid‐ and late pregnancy had a protective effect for Caesarean section and medically indicated Caesarean section. Sitting

To investigate the effect of spleen tyrosine kinase (Syk) inhibitor R406 on diabetic retinopathy (DR) in diabetic mellitus (DM) rats. Rats were randomized into Normal, DM, DM + 5 mg/kg R406 and DM + 10 mg/kg R406 groups. DM rats were established via injection of streptozotocin (STZ). One week after model establishment, rats in treatment groups received 5 mg/kg or 10 mg/kg R406 by gavage administration for 12 weeks consecutively, followed by the detection with hematoxylin-eosin (HE) staining, Evans blue angiography, retinal trypsin digestion assay, Western blotting, immunohistochemistry, TUNEL assay, immunofluorescence assay and quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). The retina of DM rats presented different degree of edema, disordered and loose structure, swollen cells with enlarged intercellular space, and dilated and congested capillaries. Besides, the retinal vessels of DM rats showed high fluorescence leakage. However, R406 alleviated the above-mentioned conditions, which was much better with high concentration of R406 (10 mg/kg). R406 also reversed the down-regulations of occludin, claudin-5, ZO-1 and the up-regulation of and VEGF in retinal tissues of DM rats; inhibited retinal cell apoptosis; strengthened retinal cell proliferation; and reduced expressions of IL-1β, IL-6, TNF-α and nuclear p65 NF-κB in retinal tissues. The improvement in all these indexes was much more significant in rats of DM + 10 mg/kg R406 group than in rats of DM + 5 mg/kg R406 group. Syk inhibitor R406 could attenuate retinal inflammation in DR rats via the repression of NF-κB activation.

Background Long noncoding RNAs (lncRNAs) are known as key regulators in many cancer types, but their biological functions in nasopharyngeal carcinoma (NPC) remain largely unknown. In the present study, we aim to explore the role of the lncRNA ZNRD1-AS1 in NPC tumor development. Methods The role of ZNRD1-AS1 in NPC tissues and cells was explored by using quantitative real-time PCR assay. Cellular behavioral experiments were used in testing NPC cell proliferation, invasion, and migration. Luciferase reporter assay, RNA-binding protein immunoprecipitation, and Western blot analysis were used in estimating the associations among ZNRD1-AS1, miR-335, and ROCK1. Results ZNRD1-AS1 expression was elevated in the NPC tissues and cells, and ZNRD1-AS1 overexpression was positively correlated with advanced TNM stage and the presence of lymph node metastasis. Our biological experiments indicated that ZNRD1-AS1 knockdown reduces NPC cell invasion and metastasis. Further analyses revealed that ZNRD1-AS1 as a ceRNA promotes the migration and invasion of NPC cells by sponging miR-335. We provided evidence that ZNRD1-AS1 facilitates the invasion and metastasis of NPC cells via the miR-335-ROCK1 axis. Conclusion Our data shed light on the oncogenic role of ZNRD1-AS1 in NPC tumor development, and a promising therapeutic target for NPC was identified.

Inherited antithrombin deficiency (OMIM 107300) is a rare autosomal dominant disorder that could increase the risk of venous thromboembolism and is usually caused by mutations of SERPINC1. Herein, we present a case of a novel mutation in the SERPINC1 gene in a Chinese patient. The patient was a 54-year-old man who presented with recurrent venous thromboembolism and was without a recent history of any precipitating factors. Whole exome sequencing and Sanger sequencing identified a novel heterozygous variant on exon 2 of SERPINC1 gene (c.142G>A, p.P48S).

Background Mounting evidence has reported that microRNA-154-5p (miR-154-5p) is involved in the development of multiple cancers, but its function in nasopharyngeal carcinoma (NPC) remains not well investigated. Methods Real-time quantitative PCR (qRT-PCR) was used to detect miR-154-5p expression in NPC tissues and cells. CCK8, colony formation, wound healing and transwell assays were performed to assess cell proliferation, migration and invasion. Dual-luciferase reporter assays and Western blots were performed to confirm the target gene of miR-154-5p. Rescue experiments were conducted to explore the influence of target gene KIF14 on the functions of miR-154-5p. Xenograft tumor model was conducted to detect the effect of miR-154-5p in vivo. Results qRT-PCR results revealed that the expression of miR-154-5p was down-regulated in NPC tissues and cell lines compared to normal nasopharyngeal tissues and cell line. Overexpression of miR-154-5p inhibited cell migration and invasion. However, miR-154-5p had no influence on the proliferation of NPC cells. MiR-154-5p overexpression suppressed xenograft tumor metastasis in vivo. Dual-luciferase reporter analysis identified KIF14 as a target gene of miR-154-5p. Rescue experiments showed that knockdown of KIF14 reversed the effect of inhibiting miR-154-5p expression on NPC cell migration and invasion. Conclusion Taken together, miR-154-5p suppresses tumor migration and invasion by targeting KIF14 in NPC. The newly identified miR-154-5p/KIF14 interaction offers further insights into the progression of NPC, which may represent a novel target for NPC diagnosis and treatment.

Bone is reported to be one of the most common sites of metastasis. Acrometastasis is an extremely rare situation and accounts for approximately 0.1% of all metastatic lesions to the skeleton. Here, we present a case of acrometastasis in a 55-year-old woman who presented with a 3-month history of atraumatic right ring fingertip pain and swelling and was subsequently diagnosed with metastatic renal cell carcinoma. This report highlights the importance of clinical suspicion of malignancy at unusual sites in the setting of non-resolving symptoms.

Previous genome-wide association study showing a novel variant near LSP1P3 was associated with knee osteoarthritis (KOA) in Caucasians. Replication study in different populations was essential to validate the association of novel susceptible genes with KOA. To our knowledge, there is a lack of study concerning the role of the LSP1P3 gene in Chinese KOA patients. We aimed to determine the association between the novel variant near LSP1P3 gene and the susceptibility of KOA in the Chinese population and to further investigate its relationship with the severity of KOA.A total of 532 primary KOA patients who received treatment in our clinic center were included in the current study. Nine hundred twenty-seven age- and gender-matched healthy subjects were recruited as controls. The severity of KOA was graded according to the Kellgren-Lawrence (KL) grading system, with KL grade of 1 or 2 classified as mild KOA and KL grade of 3 or 4 classified as severe KOA. Three variants were genotyped using TaqMan SNP genotyping assay, including rs4867568 of LSP1P3 gene, rs143383 of GDF5, and rs1558902 of FTO. The differences in terms of genotype and allele distributions between the cases and the controls were analyzed by the chi-square test.There were 215 male and 317 female patients with a mean age of 58.1 ± 7.2 years. According to the KL score, 172 (32.3%) patients had mild KOA and 360 (67.7%) had severe KOA. There were remarkably lower frequencies of allele T of rs4867568 and allele C of rs143383 in the patients than in the controls (31.5% vs. 36.0%, p = 0.01 for rs4867568; 24.6% vs. 28.7%, p = 0.02 for rs143383), with an OR of 0.82 and 0.81, respectively. As for rs1558902, no significant difference regarding the frequency of allele and genotype was found between the patients and the controls. Patients with severe KOA had remarkably lower incidence of genotype TT of rs4867568 than patients with mild KOA (6.7% vs. 12.2%, p = 0.04). There was significantly higher frequency of allele T in patients with mild KOA than in those with severe KOA (36.3% vs. 29.2%, p = 0.02, OR = 0.72).The association of rs4867568 and rs143383 with KOA was successfully replicated in the Chinese Han population. Moreover, rs4867568 was found significantly associated with the severity of KOA. More studies are warranted to explore the functional role of rs4867568 in the development of KOA. Key Points • A novel variant near Lsp1p3 is associated with knee osteoarthritis. • Baseline characteristics of the subjects. • Comparison of the genotype and allele frequency of the Lsp1p3, GDF5, and FTO. • Association of the Lsp1p3, GDF5, and FTO with KOA severity.

BackgroundImmune response changes have been reported in amyotrophic lateral sclerosis (ALS), but their clinical relevance remains undetermined. Therefore, we aim to evaluate the relationships between blood leukocyte subpopulations and prognosis of ALS.MethodsA longitudinal cohort of 288 ALS patients with up to 5 years of follow-up during 2015-2020 were recruited at the only tertiary referral center for ALS in Stockholm, Sweden. Routine differential leukocyte counts, and determination of lymphocyte subpopulations including an extended T cell panel with flow cytometry, collected at diagnosis and at regular intervals thereafter. The primary outcome was risk of death (alternatively use of invasive ventilation) after diagnosis of ALS. The secondary outcomes included repeatedly measured functional status - through Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) score and disease progression rate. Cox model was used to evaluate the associations between leukocytes and risk of death. Generalized estimating equation model (GEE) was used to assess the correlation between leukocytes and ALSFRS-R score and disease progression rate.ResultsThe counts of leukocytes, neutrophils and monocytes increased gradually over time since diagnosis and were negatively correlated with ALSFRS-R score, but not associated with risk of death or disease progression rate. Focusing on lymphocyte subpopulations, increasing counts of natural killer (NK) cells (HR=0.61, 95% CI= [0.42-0.88] per SD increase) and proportions of Th2-diffrentiated CD4+ central memory (CM) T cells (HR=0.64, 95% CI= [0.48-0.85] per SD increase) were correlated with a lower risk of death. Increasing proportions of CD4+ effector memory cells re-expressing CD45RA (EMRA) T cells (HR=1.39, 95% CI= [1.01-1.92] per SD increase) and CD8+ T cells (HR=1.38, 95% CI= [1.03-1.86] per SD increase) were associated with a higher risk of death. None of the lymphocyte subpopulations was correlated with ALSFRS-R score or disease progression rate.ConclusionOur findings suggest a dual role of immune responses in ALS prognosis, where neutrophils and monocytes primarily reflect functional status whereas NK cells and different T lymphocyte populations act as prognostic markers for survival. The findings also provide insights for cell-specific treatment for ALS.FundingThis work was supported by the European Research Council (ERC) Starting Grant (MegaALS, No. 802091), the Swedish Research Council (No. 2019-01088), Karolinska Institutet (Strategic Research Area in Epidemiology and Senior Researcher Award), and China Scholarship Council.

Objective. To explore the image enhancement model based on deep learning on the effect of ureteroscopy with double J tube placement and drainage on ureteral stones during pregnancy. We compare the clinical effect of ureteroscopy with double J tube placement on pregnancy complicated with ureteral stones and use medical imaging to diagnose the patient’s condition and design a treatment plan. Methods. The image enhancement model is constructed using deep learning and implemented for quality improvement in terms of image clarity. In the way, the relationship of the media transmittance and the image with blurring artifacts was established, and the model can estimate the ureteral stone predicted map of each region. Firstly, we proposed the evolution-based detail enhancement method. Then, the feature extraction network is used to capture blurring artifact-related features. Finally, the regression subnetwork is used to predict the media transmittance in the local area. Eighty pregnant patients with ureteral calculi treated in our hospital were selected as the research object and were divided into a test group and a control group according to the random number table method, 40 cases in each group. The test group underwent ureteroscopy double J tube placement, and the control group underwent ureteroscopy lithotripsy. Combined with the ultrasound scan results of the patients before and after the operation, the operation time, time to get out of bed, and hospitalization time of the two groups of patients were compared. The operation success rate and the incidence of complications within 1 month after surgery were counted in the two groups of patients. Results. We are able to improve the quality of the images prior to medical diagnosis. The total effective rate of the observation group was 100.0%, which is higher than that of the control group (90.0%). The difference between the two groups was statistically significant ( P < 0.05 ). The adverse reaction rate in the observation group was 5.0%, which was lower than 17.5% in the control group. The difference between the two groups was statistically significant ( P < 0.05 ). The comparison results are then prepared. Conclusions. The image enhancement model based on deep learning is able to improve medical diagnosis which can assist radiologists to better locate the ureteral stones. Based on our method, double J tube placement under ureteroscopy has a significant effect on the treatment of ureteral stones during pregnancy, and it has good safety and is worthy of widespread application.

The coronavirus disease-19 (COVID-19) elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastating health, economic and social impact worldwide. Its clinical spectrum ranges from asymptomatic to respiratory failure and multi-organ failure or death. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response. It involves activation of multiple inflammatory pathways leading to hyperinflammation and cytokine storm, resulting in tissue damage, acute respiratory distress syndrome (ARDS) and multi-organ failure. Accumulating evidence has raised concern over the long-term health effects of COVID-19. Importantly, the neuroinvasive potential of SARS-CoV-2 may have devastating consequences in the brain. This review provides a conceptual framework on how the virus tricks the host immune system to induce infection and cause severe disease. We also explore the key differences between mild and severe COVID-19 and its short- and long-term effects, particularly on the human brain.

Mother-to-child transmission (MTCT) through breastfeeding remains a major source of pediatric HIV-1 infection worldwide. To characterize plasma HIV-1 subtype C populations from infected mothers during pregnancy that related to subsequent breast milk transmission, an exploratory study was designed to apply next generation sequencing and a custom bioinformatics pipeline for HIV-1 gp41 extending from heptad repeat region 2 (HR2) through the membrane proximal external region (MPER) and the membrane spanning domain (MSD). MPER harbors linear and highly conserved epitopes that repeatedly elicits HIV-1 neutralizing antibodies with exceptional breadth. Viral populations during pregnancy from women who transmitted by breastfeeding, compared to those who did not, displayed greater biodiversity, more frequent amino acid polymorphisms, lower hydropathy index and greater positive charge. Viral characteristics were restricted to MPER, failed to extend into flanking HR2 or MSD regions, and were unrelated to predicted neutralization resistance. Findings provide novel parameters to evaluate an association between maternal MPER variants present during gestation and lactogenesis with subsequent transmission outcomes by breastfeeding. Importance HIV-1 transmission through breastfeeding accounts for 39% of MTCT and continues as a major route of pediatric infection in developing countries where access to interventions for interrupting transmission is limited. Identifying women who are likely to transmit HIV-1 during breastfeeding would focus therapies, such as broad neutralizing HIV monoclonal antibodies (bn-HIV-Abs), during the breastfeeding period to reduce MTCT. Findings from our pilot study identify novel characteristics of gestational viral MPER quasispecies related to transmission outcomes and raise the possibility for predicting MTCT by breastfeeding based on identifying mothers with high-risk viral populations.

Background We explored the associations between chronic stress and dynamic working patterns of the whole brain using resting state MRI data in drug-naive, first-episode adolescents with major depressive disorder (MDD). Methods We compared dynamic functional connectivity (dyn-FC) and screen out networks with difference in whole brain between 45 healthy controls (HC) and 60 adolescent MDD patients using dynamic independent components analysis. In each of these networks with difference between groups, hub brain regions were selected as functionally connected to more than 30 brain regions at the same time. Then we extracted the dyn-FC coefficients of each hub brain region with other brain regions in each component at different time points and calculated the average value of the entire scan time. Finally, we explored correlations between these average values of the entire scan time and scores on the Childhood Chronic Stress Questionnaire (CCSQ). Results We found three networks as well as some hub brain regions with different dyn-FC patterns between adolescent MDD and HC. Scores on the CCSQ were found to correlate with dynamic FC between hub brain areas and certain other brain areas in MDD patients. Limitations our cross-sectional study design does not allow us to speculate about causality between chronic stress and depression. Prospective cohort studies should explore in detail how the changes in dynamic FC appear and evolve during MDD. Conclusions Chronic stress is related with the brain dynamic working patterns in adolescent MDD.

Background: Thyroid cancer is the most common malignant tumor of the head and neck. In recent years, the incidence of thyroid cancer (THCA) worldwide has rapidly increased and shows a trend in the younger generation. This study attempted to screen key genes and potential prognostic biomarkers for thyroid cancer using bioinformatics analysis.Methods: This study attempted to screen key genes and potential prognostic biomarkers for thyroid cancer using bioinformatics analysis. 101 cases of thyroid cancer and 78 cases of normal thyroid tissue were collected from three Gene Expression Omnibus (GEO) databases, then we identified the differentially expressed genes (DEGs) and conducted downstream analyses. Moreover, we screened hub genes by constructing a protein‐protein interaction (PPI) network. Finally, we assessed the expression level of hub genes in thyroid cancer tissue and its normal tissue using GEPIA and qRT-PCR respectively. Results: 159 upregulated and 251 downregulated genes were determined after gene integration of these three GEO data sets. Through PPI analysis, we consider the top 20 DEGs with high connectivity as the hub genes of THCA. After that, this study verified 20 central genes through the GEPIA database and found that only four hub genes (TOP2A, FN1, TIMP1, and MMP9) had significantly higher expression levels in thyroid cancer tissues than in normal thyroid tissues. We further analyzed the correlation between these four hub genes and the prognosis of patients with thyroid cancer, which suggests that FN1, MMP9, TIMP1 help assess the prognosis of patients with thyroid cancer. We performed GSEA analysis on these 4 hub genes simultaneously, found that the high expression of these 4 hub genes enriched the "cell cycle." Subsequently, we collected thyroid cancer tissue specimens, verified these four hub gene expression levels by RT-PCR, and found that only FN1 and TIMP1 genes in thyroid cancer tissues had significantly higher mRNA levels than normal tissues. Conclusions: Our research has identified 20 hub genes that may be related to the occurrence and development of thyroid cancer through multiple gene expression profile data sets and a series of comprehensive bioinformatics analyses. Further database and tissue validation analysis revealed that only 2 hub genes may be considered as potential prognostic biomarkers, including FN1 and TIMP1. In addition, these two hub genes are involved in the cell cycle, suggesting that they may play a role in the occurrence and development of thyroid cancer.

Melioidosis is a serious infectious disease caused by the environmental Gram-negative bacillus Burkholderia pseudomallei. It has been shown that the host immune system, mainly comprising various types of immune cells, fights against the disease. The present study was to specify correlation between septicemic melioidosis and the levels of multiple immune cells. First, the genes with differential expression patterns between patients with septicemic melioidosis (B. pseudomallei) and health donors (control/healthy) were identified. These genes being related to cytokine binding, cell adhesion molecule binding, and MHC relevant proteins may influence immune response. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed 23 enriched immune response pathways. We further leveraged the microarray data to investigate the relationship between immune response and septicemic melioidosis, using the CIBERSORT analysis. Comparison of the percentages of 22 immune cell types in B. pseudomallei vs. control/healthy revealed that those of CD4 memory resting cells, CD8+ T cells, B memory cells, and CD4 memory activated cells were low, whereas those of M0 macrophages, neutrophils, and gamma delta T cells were high. The multivariate logistic regression analysis further revealed that CD8+ T cells, M0 macrophages, neutrophils, and naive CD4+ cells were strongly associated with the onset of septicemic melioidosis, and M2 macrophages and neutrophils were associated with the survival in septicemic melioidosis. Taken together, these data point to a complex role of immune cells on the development and progression of melioidosis.

BackgroundOsteoarthritis (OA) is one of the most common age-related degenerative diseases. In recent years, some studies have shown that pathological changes in the synovial membrane occur earlier than those in the cartilage in OA. However, the molecular mechanism of synovitis in the pathological process of OA has not been elucidated. This study aimed to identify novel biomarkers associated with OA and to emphasize the role of immune cells in the pathogenesis of OA.MethodsMicroarray datasets were obtained from the Gene Expression Omnibus (GEO) and ArrayExpress databases and were then analyzed using R software. To determine differential immune cell subtype infiltration, the CIBERSORT deconvolution algorithm was used. Quantitative reverse transcription PCR (qRT-PCR) was used to determine the relative expressions of selected genes. Besides, Western blotting was used to assess the protein expression levels in osteoarthritic chondrocytes.ResultsAfter analyzing the database profiles, two potential biomarkers, collagen type 3 alpha 1 chain (COL3A1), and matrix metalloproteinase 9 (MMP9), associated with OA were discovered, which were confirmed by qRT-PCR and Western blotting. Specifically, the results revealed that, as the concentration of IL-1β increased, so did the gene and protein expression levels of COL3A1 and MMP9.ConclusionThe findings provide valuable information and direction for future research into novel targets for OA immunotherapy and diagnosis and aids in the discovery of the underlying biological mechanisms of OA pathogenesis.

Background: COVID-19 is a global pandemic. The prevention of SARS-CoV-2 infection and the rehabilitation of survivors are currently the most urgent tasks. However, after patients with COVID-19 are discharged from the hospital, how long the antibodies persist, whether the lung lesions can be completely absorbed, and whether cardiopulmonary abnormalities exist remain unclear.Methods: A total of 56 COVID-19 survivors were followed up for 12 months, with examinations including serum virus-specific antibodies, chest CT, and cardiopulmonary exercise testing.Results: The IgG titer of the COVID-19 survivors decreased gradually, especially in the first 6 months after discharge. At 6 and 12 months after discharge, the IgG titer decreased by 68.9 and 86.0%, respectively. The IgG titer in patients with severe disease was higher than that in patients with non-severe disease at each time point, but the difference did not reach statistical significance. Among the patients, 11.8% were IgG negative up to 12 months after discharge. Chest CT scans showed that at 3 and 10 months after discharge, the lung opacity had decreased by 91.9 and 95.5%, respectively, as compared with that at admission. 10 months after discharge, 12.5% of the patients had an opacity percentage >1%, and 18.8% of patients had pulmonary fibrosis (38.5% in the severe group and 5.3% in the non-severe group, P < 0.001). Cardiopulmonary exercise testing showed that 22.9% of patients had FEV1/FVC%Pred 2 AT 2/kg/min, and 22.9% of patients had a VE/VCO2 slope >30%.Conclusions: IgG antibodies in most patients with COVID-19 can last for at least 12 months after discharge. The IgG titers decreased significantly in the first 6 months and remained stable in the following 6 months. The lung lesions of most patients with COVID-19 can be absorbed without sequelae, and a few patients in severe condition are more likely to develop pulmonary fibrosis. Approximately one-fifth of the patients had cardiopulmonary dysfunction 6 months after discharge.

An abdominal aortic aneurysm (AAA) is a localized dilatation of the aorta related to the regional weakening of the wall structure, resulting in substantial morbidity and mortality with the aortic ruptures as complications. Ruptured AAA is a dramatic catastrophe, and aortic emergencies constitute one of the leading causes of acute death in older adults. AAA management has been centered on surgical repair of larger aneurysms to mitigate the risks of rupture, and curative early diagnosis and effective pharmacological treatments for this condition are still lacking. Nanoscience provided a possibility of more targeted imaging and drug delivery system. Multifunctional nanoparticles (NPs) may be modified with ligands or biomembranes to target agents' delivery to the lesion site, thus reducing systemic toxicity. Furthermore, NPs can improve drug solubility, circulation time, bioavailability, and efficacy after systemic administration. The varied judiciously engineered nano-biomaterials can exist stably in the blood vessels for a long time without being taken up by cells. Here, in this review, we focused on the NP application in the imaging and treatment of AAA. We hope to make an overview of NP-assisted diagnoses and therapy in AAA and discussed the potential of NP-assisted treatment.

Background Nasopharyngeal carcinoma (NPC) is one of the most frequent head and neck malignant tumors. Long noncoding RNAs play critical roles in tumorigenesis. Methods Real‐time quantitative PCR arrays were used to evaluate the expression levels of cytoskeleton regulator RNA (CYTOR) in NPC tissues and cells. Cell counting kit‐8 and colony formation analyses were used to test the NPC cell viability, while wound healing and transwell assays were employed to detect cell invasion and migration ability. Luciferase reporter assay and Western blot analyses were employed to explore the relationships among CYTOR, miR‐613, and ANXA2. Results We found that CYTOR expression was elevated both in NPC tissues and cells. Functional assays revealed that CYTOR promoted the invasion and migration of NPC cells. The established spontaneous lymph node metastasis model also confirmed that CYTOR promoted NPC cell metastasis in vivo. Mechanically, we found that the subcellular localization of CYTOR mostly occurred in the cell cytoplasm. Luciferase reporter and RIP assays confirmed that CYTOR functioned as the molecular sponge of miR‐613. Subsequent experiments confirmed that ANXA2 was directly targeted by miR‐613. Gain‐ and loss‐of‐function studies further confirmed that CYTOR induced the upregulation of ANXA2 by competitively binding to miR‐613, thus leading to NPC metastasis. Conclusion Our results highlight the importance of CYTOR in NPC development and provide new insights into potential therapeutic targets for NPC., Cytoskeleton regulator RNA (CYTOR) is upregulated in nasopharyngeal carcinoma (NPC) tissues and cells and facilitates the invasion and metastasis of NPC cells. CYTOR induced the upregulation of ANXA2 by competitively binding to miR‐613, thus leading to NPC metastasis.

Background Mutations in the SPAST gene are the most frequent cause of hereditary spastic paraplegia (HSP). We aim to extend the mutation spectrum of spastic paraplegia 4 (SPG4) and carried out experiment in vitro to explore the influence of the SPAST gene mutation on the function of corresponding protein. Methods Whole-exome sequencing (WES) combined with multiplex ligation-dependent probe amplification (MLPA) were performed in a cohort of 150 patients clinically diagnosed with HSP. We focus on screening for mutations in SPAST gene and carrying out functional experiments to assess the effects of the novel variants. Results A total of 34 different mutations in the SPAST gene were identified, of which 10 were novel, including 1 missense (c.1479T > A), 1 nonsense (c.766G > T), 3 splicing (c.1413 + 1_1413+4delGTAA, c.1729-1G > A and c.1536+2T > G) and 5 frameshift mutations (c.1094delC, c.885dupA, c.517_518delAG, c.280delG and c.908dupC). For 7 novel non-splicing mutations, functional study showed that accumulated M1 spastin colcocalized with microtubules which was different from a uniformly diffused M87 spastin. While an impairment in severing activity was observed in both mutant M1 and mutant M87, except for c.280delG. All 3 novel splicing variants w ere predicted to affect splicing by using bioinformatic programs. However, only c.1536+2T > G had no influence on splice site in vitro, which conflicts with the in-silico analysis. Conclusion We genetically diagnosed 40 SPG4 patients. All the novel non-splicing mutations except for c.280delG were certified to exert an effect on the microtubule-severing and all the novel splicing mutations other than c.1536+2T > G would cause abnormal splicing of the spastin.

Background E2F transcription factor 3 (E2F3) is oncogenic and dysregulated in various malignancies. Complex networks involving microRNAs (miRNAs) and E2F3 regulate tumorigenesis and progression. However, the potential roles of E2F3 and its target miRNAs in nasopharyngeal carcinoma (NPC) are rarely reported. Methods E2F3 expression was detected in human NPC tissues and cell lines through quantitative real-time PCR. NPC cell proliferation, migration, and invasion were evaluated in vitro by colony forming, cell counting kit-8, wound healing, and Transwell invasion assays. Publicly available database software was used to explore the target miRNAs of E2F3. Dual-luciferase reporter assay was performed to identify the direct relationship. The function of miRNAs in vivo was investigated by using a tumor xenograft model. Results E2F3 was upregulated in NPC cell lines and tissues, and its exotic expression promoted NPC cell invasion and migration. E2F3 was identified as a target of miR-432, which restrained NPC cell invasion and migration in vitro and in vivo. Further experiments revealed that miR-432 repressed the invasion and migration potential of NPC cells by modulating E2F3 expression. Conclusion miRNA-432 suppressed the malignant biological behavior of NPC cells by targeting E2F3. This study provided further insights into NPC prognosis and treatment.

BackgroundCognitive deficits are common in patients with bipolar disorder (BD). Abnormal high density lipoprotein (HDL) levels have been implicated in cognitive deficits associated with ageing and neurodegenerative disorders. The present study aimed to investigate serum HDL levels, cognitive deficits and their association in patients with BD.MethodsThirty-seven patients with BD and 37 gender- and age-matched healthy controls (HCs) were recruited in a case–control study. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and serum HDL levels were measured using enzymatic colourimetry.ResultsThere was no difference in serum HDL levels between patients with BD and HCs after adjusting for gender, age, education and body mass index (BMI). Cognitive test scores in patients with BD were significantly lower than those in HCs except for the visuospatial/constructional index after adjusting for confounding variables. Serum HDL levels were positively correlated with RBANS total score and language score in patients with BD. Stepwise multiple regression analysis showed that serum HDL levels were significantly correlated with RBANS total score and subscale scores on immediate memory and language in patients with BD after adjusting for confounding factors.ConclusionsOur findings suggest that patients with BD had poorer cognitive performance than HCs except for the visuospatial/constructional domain, and decreased serum HDL levels were correlated with cognitive deficits, especially in immediate memory and language domains in patients with BD.

Targeting oncogenic proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer research. Bromodomain and extra-terminal (BET) family proteins are newly identified cancer-related epigenetic regulators, which have a role in the pathogenesis and progression of osteosarcoma. In this study, we investigated the in vitro and in vivo anti-osteosarcoma activity by targeting BET with a PROTAC molecule BETd-260. The results showed that BETd-260 completely depletes BET proteins and potently suppresses cell viability in MNNG/HOS, Saos-2, MG-63, and SJSA-1 osteosarcoma cell lines. Compared with BET inhibitors HJB-97 and JQ1, the activity of BETd-260 increased over 1000 times. Moreover, BETd-260 substantially inhibited the expression of anti-apoptotic Mcl-1, Bcl-xl while increased the expression of pro-apoptotic Noxa, which resulted in massive apoptosis in osteosarcoma cells within hours. In addition, pro-oncogenic protein c-Myc also was substantially inhibited by BETd-260 in the OS cells. Of note, BETd-260 induced degradation of BET proteins, triggered apoptosis in xenograft osteosarcoma tumor tissue, and profoundly inhibited the growth of cell-derived and patient-derived osteosarcoma xenografts in mice. Our findings indicate that BET PROTACs represent a promising therapeutic agent for human osteosarcoma.

An emerging body of evidence has promoted the understanding of the role of microRNAs (miRNAs) in tumorigenesis and progression, but the mediating function of miRNAs in nasopharyngeal carcinoma (NPC) development remains poorly elucidated. In this study, miR‐449b‐3p was downregulated in NPC specimens (P, We demonstrated that aberrantly down‐regulated miR‐449b‐3p targeted ADAM17 to promote NPC metastasis, and ADAM17‐activated NF‐κB could transcriptionally suppress miR‐449b‐3p gene expression in turn.

Background Isoniazid resistant tuberculosis is the most prevalent type of resistance in Swaziland and over two-thirds of the isoniazid resistant tuberculosis patients are tuberculosis and human immunodeficiency virus co-infected. The study aimed to determine risk factors associated with isoniazid resistant tuberculosis among human immunodeficiency virus positive patients in Swaziland. Methods This was a case-control study conducted in nine healthcare facilities across Swaziland. Cases were patients with isoniazid resistant tuberculosis (including 78 patients with isoniazid mono-resistant tuberculosis, 42 with polydrug-resistant tuberculosis, and 77 with multidrug-resistant tuberculosis). Controls were presumed drug-susceptible tuberculosis patients (n = 203). Multinomial logistic regression was used to determine related factors. Results The median time lag from diagnosis to tuberculosis treatment initiation was 50 days for isoniazid mono or poly drug-resistant tuberculosis, 17 days for multidrug-resistant tuberculosis compared to 1 day for drug-susceptible tuberculosis patients. History of previous tuberculosis treatment was positively associated with either isoniazid mono or poly drug-resistant tuberculosis (OR = 7.91, 95% CI: 4.14–15.11) and multidrug-resistant tuberculosis (OR = 12.20, 95% CI: 6.07–24.54). Isoniazid mono or poly resistant tuberculosis patients were more likely to be from rural areas (OR = 2.05, 95% CI: 1.23–3.32) and current heavy alcohol drinkers compared to the drug-susceptible tuberculosis group. Multi drug-resistant tuberculosis patients were more likely to be non-adherent to tuberculosis treatment compared to drug-susceptible tuberculosis group (OR = 3.01, 95% CI: 1.56–5.82). Conclusion To prevent and control isoniazid resistant tuberculosis among HIV-positive patients in Swaziland, the tuberculosis program should strengthen the use of rapid diagnostic tests, detect resistance early, promptly initiate supervised tuberculosis treatment and decentralize quality tuberculosis services to the rural areas. Adherence to tuberculosis treatment should be improved. Electronic supplementary material The online version of this article (10.1186/s12879-019-4384-6) contains supplementary material, which is available to authorized users.

Background and objective: Atrial electrical remodelling (AER) was significantly associated with atrial fibrillation (AF) development. Polymorphisms in hyperpolarization activated cyclic nuc...

There is a growing concern about the fertility preservation for adult cancer patients of reproductive age. Very little literature exists about fertility preservation of cancer survivors in Chinese text. This study is first to describe the knowledge level, attitude, and practice behaviors among physicians concerning fertility preservation in adult cancer patients in China. A cross-sectional survey with 30-item was conducted to assess Chinese oncology physicians’ knowledge, attitude, and behaviors regarding fertility issues. Of 360 oncology physicians, 206 (57.2%) submitted valid questionnaires. With possible overall scores for knowledge and attitude of 9 and 15, respectively, physicians’ responses to the questionnaires were 3.91 ± 1.67 and 12.29 ± 1.23. Only 49.5% of physicians routinely informed their cancer patients of childbearing age about the risk of infertility with cancer treatment. The knowledge score of the men physicians was 2-fold that of the women. Physicians aged 20–29 years were significantly more likely than other age groups to prioritize cancer treatment over fertility concerns. Men physicians were significantly more comfortable than the women discussing fertility preservation issues and cooperating with fertility specialists. The oncology physicians in China had limited knowledge of fertility preservation and rarely discussed these issues with their patients, although their attitude was positive. Results suggest that oncology physicians would welcome an in-house fertility-related training program. Key Messages This is the first study to address the topic of fertility preservation as it relates to the care that oncologists provide to cancer patients in China. These results revealed the importance of providing fertility-related training program to oncology physicians. Moreover, this study should provide useful information for other Asian countries, and highlight both the similarities and differences between China and Western countries concerning the reproductive rights of patients. This study should encourage international cooperation with institutions of scientific research and education. Electronic supplementary material The online version of this article (10.1007/s13187-019-01567-6) contains supplementary material, which is available to authorized users.

Background: The long-term predicted value of microvolt T-wave alternans (MTWA) for ventricular tachyarrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains unclear. Our study explored the characteristics of MTWA and its prognostic value when combined with an electrophysiologic study (EPS) in patients with ARVC. Methods: All patients underwent non-invasive MTWA examination with modified moving average (MMA) analysis and an EPS. A positive event was defined as the first occurrence of sudden cardiac death, documented sustained ventricular tachycardia (VT), ventricular fibrillation, or the administration of appropriate implantable cardioverter defibrillator therapy including shock or antitachycardia pacing. Results: Thirty-five patients with ARVC (age 38.6 ± 11.0 years; 28 males) with preserved left ventricular (LV) function were recruited. The maximal TWA value (MaxValt) was 17.0 (11.0–27.0) μV. Sustained VT was induced in 22 patients by the EPS. During a median follow-up of 99.9 ± 7.7 months, 15 patients had positive clinical events. When inducible VT was combined with the MaxValt, the area under the curve improved from 0.739 to 0.797. The receiver operating characteristic curve showed that a MaxValt of 23.5 μV was the optimal cutoff value to identify positive events. The multivariate Cox regression model for survival showed that MTWA (MaxValt, hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01–1.11; P = 0.01) and inducible VT (HR, 5.98; 95% CI, 1.33–26.8; P = 0.01) independently predicted positive events in patients with ARVC. Conclusions: MTWA assessment with MMA analysis complemented by an EPS might provide improved prognostic ability in patients with ARVC with preserved LV function during long-term follow-up. Key words: Modified moving average analysis; Microvolt T-wave alternans; Electrophysiologic study; Ventricular tachyarrhythmia; Arrhythmogenic right ventricular cardiomyopathy