Search

Rationale and Objective To investigate age-related brain morphological changes of boys with high functioning autism (HFA). Materials and Methods Forty-six medication-naive boys with HFA and 48 age-matched typically developing boys (4–12 years old) were included in this study. Structural brain images were processed with FreeSurfer to calculate the brain morphometric features including regional volume, surface area, average cortical thickness, and Gaussian curvature. General linear model was used to identify significant effects of diagnosis and age-by-diagnosis interaction. Correlations between age and the brain morphometric variables of significant clusters were explored. Results Primarily, most of the regions with statistically significant intergroup differences were located in the temporal lobe gyri. Importantly, the volume of bilateral superior temporal gyrus (STG) and the average cortical thickness of the right STG demonstrated significantly age-related intergroup differences. Further age-stratified analysis also revealed morphological alterations of STG among subgroups of preschool and school-aged children with or without HFA. Conclusion The findings demonstrated abnormal age-related volume and cortical thickness atrophy of the STG in HFA children, which reflect brain development trajectories of ASD may initiate to diverge from early overgrowth in childhood period. The anatomical localization of specific brain regions would help us better understand the neurobiology alterations of HFA patients and indicate the effect of age should be carefully delineated and examined in future studies about HFA.

Background A recent epigenome-wide association study of genes associated with type 2 diabetics (T2D), used integrative cross-omics analysis to identify 22 abnormally methylated CpG sites associated with insulin and glucose metabolism. Here, in this epigenetic analysis we preliminarily determine whether the same CpG sites identified in T2D also apply to type 1 diabetes (T1D). We then determine whether BCG vaccination could correct the abnormal methylation patterns, considering that the two diseases share metabolic derangements. Methods T1D (n = 13) and control (n = 8) subjects were studied at baseline and then T1D subjects studied yearly for 3 years after receiving BCG vaccinations in a clinical trial. In this biomarker analysis, methylation patterns were evaluated on CD4+ T-lymphocytes from baseline and yearly blood samples using the human Illumina Methylation EPIC Bead Chip. Methylation analysis combined with mRNA analysis using RNAseq. Results Broad but not complete overlap was observed between T1D and T2D in CpG sites with abnormal methylation. And in the three-year observation period after BCG vaccinations, the majority of the abnormal methylation sites were corrected in vivo. Genes of particular interest were related to oxidative phosphorylation (CPT1A, LETM1, ABCG1), to the histone lysine demethylase gene (KDM2B), and mTOR signaling through the DDIT4 gene. The highlighted CpG sites for both KDM2B and DDIT4 genes were hypomethylated at baseline compared to controls; BCG vaccination corrected the defect by hypermethylation. Conclusions Glycolysis is regulated by methylation of genes. This study unexpectedly identified both KDM2B and DDIT4 as genes controlling BCG-driven re-methylation of histones, and the activation of the mTOR pathway for facilitated glucose transport respectively. The BCG effect at the gene level was confirmed by reciprocal mRNA changes. The DDIT4 gene with known inhibitory role of mTOR was re-methylated after BCG, a step likely to allow improved glucose transport. BCGs driven methylation of KDM2B’s site should halt augmented histone activity, a step known to allow cytokine activation and increased glycolysis.

PURPOSE This study was designed to assess the ability of perioperative circulating tumor DNA (ctDNA) to predict surgical outcome and recurrence following neoadjuvant chemoradiation for locally advanced rectal cancer (LARC). MATERIALS AND METHODS Twenty-nine patients with newly diagnosed LARC treated between January 2014 and February 2018 were enrolled. Patients received long-course neoadjuvant chemoradiation prior to surgery. Plasma ctDNA was collected at baseline, preoperatively, and postoperatively. Next-generation sequencing was used to identify mutations in the primary tumor, and mutation-specific droplet digital polymerase chain reaction was used to assess mutation fraction in ctDNA. RESULTS The median age was 54 years. The overall margin-negative, node-negative resection rate was 73% and was significantly higher among patients with undetectable preoperative ctDNA (n = 17, 88%) versus patients with detectable preoperative ctDNA (n = 9, 44%; P = .028). Undetectable ctDNA was also associated with more favorable neoadjuvant rectal scores (univariate linear regression, P = .029). Recurrence-free survival (RFS) was calculated for the subset (n = 19) who both underwent surgery and had postoperative ctDNA available. At a median follow-up of 20 months, patients with detectable postoperative ctDNA experienced poorer RFS (hazard ratio, 11.56; P = .007). All patients (4 of 4) with detectable postoperative ctDNA recurred (positive predictive value = 100%), whereas only 2 of 15 patients with undetectable ctDNA recurred (negative predictive value = 87%). CONCLUSION Among patients treated with neoadjuvant chemoradiation for LARC, patients with undetectable preoperative ctDNA were more likely to have a favorable surgical outcome as measured by the rate of margin-negative, node-negative resections and neoadjuvant rectal score. Furthermore, we have confirmed prior reports indicating that detectable postoperative ctDNA is associated with worse RFS. Future prospective study is needed to assess the potential for ctDNA to assist with personalizing treatment for LARC.

Background Poor physical function is strongly associated with mortality and poor clinical outcomes in adults with chronic kidney disease (CKD). Handgrip strength (HGS) is an important index for physical function in the general population, and the association between HGS and CKD is worth investigating. Methods From September to November 2015, we conducted a cross-sectional study consisting of 10,407 participants in Jurong City, China. Age-related and sex-specific HGS percentile curves were constructed using the GAMLSS method. In addition, logistic regression was applied to estimate the association between HGS and the presence of CKD with odds ratios (ORs) and 95 % confidence intervals (CIs). Results Participants with low HGS tended to be older and were more likely to have CKD (8.73 %). Smoothed centile curves of HGS showed a similar shape in both sexes: participants peaked at approximately 20–35 years old and gradually decreased after the age of 50. In addition, independent of age and other factors, the decreased presence of CKD was significantly identified in individuals with moderate (OR: 0.64, 95 % CI: 0.49–0.83) and high HGS (OR: 0.37, 95 % CI: 0.23–0.58). Conclusions We concluded that HGS was significantly negatively associated with CKD in Chinese community-dwelling persons.

To explore the role of plasma miRNAs in exosomes in early postmenopausal women. Small RNA sequencing was implemented to clarify the expression of miRNA in plasma exosomes obtained from 15 postmenopausal women, divided into groups of osteoporosis, osteopenia, and normal bone mass based on bone mineral density. Differentially expressed miRNAs (DEMs) were identified by comparing miRNA expression profiles. Five putative miRNAs, miR-224-3p, miR-25-5p, miR-302a-3p, miR-642a-3p, and miR-766-5p were confirmed by real-time PCR; miRNA target genes were obtained from 4 databases: miRWalk, miRDB, RNA22, and TargetScan. The miRNA-mRNA- Kyoto Encyclopedia of Genes and Genomes (KEGG) networks were analyzed, and the DEMs' potential role was investigated by gene ontology terms and KEGG pathway annotation. The results suggest that characterizing plasma exosomal miRNA profiles of early postmenopausal women by small RNA sequencing could identify novel exo-miRNAs involved in bone remodeling, and miR-642a-3p maybe contribute to the prediction and diagnosis of early postmenopausal osteoporosis.

Our study aimed to validate the clinicopathological characteristics and prognosis of lung adenocarcinoma (ADC) with a filigree pattern and to further investigate the relationship between the filigree pattern and the classical micropapillary (MP) pattern. We retrospectively reviewed the clinical and pathologic characteristics of 461 Chinese patients with completely resected ADC (stage I, 310; stage II, 44; stage III, 107). The filigree pattern was more likely to be observed in ADC with a higher stage (p = 0.003) and the classical MP pattern (p < 0.001). Patients with filigree-predominant ADC showed poor survival, similar to those with classical MP-predominant ADC. Multivariate analysis confirmed that the presence of the filigree pattern was an independent prognostic factor for recurrence-free survival (hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.50-2.68; p < 0.001) and overall survival (OS; HR, 1.83; 95% CI, 1.34-2.50; p < 0.001). Patients with both classical MP-positive and filigree-positive ADC had the worst survival compared with those with the filigree pattern or classical MP pattern alone. In stage I, ADC with both the filigree and classical MP patterns had a higher incidence of micrometastasis than ADC with the filigree pattern or classical MP pattern alone. Lymph node micrometastasis indicated poor survival in patients with ADC with the filigree pattern or classical MP pattern. Similar clinicopathologic features between patients with the filigree pattern and the classical MP pattern support the inclusion of the filigree pattern in the MP category. Recognition of the filigree pattern could provide helpful prognostic information, especially for stage I ADC.

The systemic inflammatory response caused by host-tumor interactions is currently recognized as a hallmark feature of cancer. No study has confirmed which systemic inflammatory factors can accurately predict the progression and long-term prognosis of gastric cancer (GC). Through the analysis of receiver operating characteristic curve (ROC), in the discovery cohort, a variety of indicators composed of usual inflammatory factors were compared. Fibrinogen-albumin ratio (FAR), which can accurately predict the long-term survival of GC patients was selected and was further verified in the test cohort and the external validation cohort. The ROC curve analysis showed that the area under curve (AUC) value of FAR on the overall survival (OS) of GC patients was higher than that of other combined markers (P < 0.01). Patients in the high FAR group showed more advanced pathological stages, larger tumor diameters, and more poorly differentiated pathological type than those in the low FAR group (P < 0.05). Logistic regression analysis elucidated that, FAR was an independent risk factor for LN metastasis and tumor invasion of GC. High FAR was an independent risk factor for poor prognosis of GC patients. The relationship between FAR and pathological stage of GC and long-term prognosis of patients was verified in the test cohort and the external validation cohort with the same FAR cutoff value. The results are consistent with those of the discovery cohort. As a new developed inflammation-related marker, FAR can independently and effectively predict the tumor burden and long-term prognosis of patients with advanced GC.

PURPOSE To investigate the effect of dynamic changes in systemic inflammatory markers (SIM) on long-term prognosis of patients with gastric cancer (GC). METHODS A retrospective analysis was performed on the data of 2180 patients with GC who underwent radical gastrectomy in the Fujian medical university Union Hospital from January 2009 to December 2014. Changes in SIM between preoperatively and 1-6 months and 12 months postoperatively were reported. RESULTS In multivariate analysis, higher preoperative systemic inflammation score (pre-SIS) was independent predictor of poor prognosis (p

Establish patient-derived tumor xenograft (PDTX) from advanced GICs and assess the clinical value and applicability of PDTX for the treatment of advanced gastrointestinal cancers. Patients with advanced GICs were enrolled in a registered multi-center clinical study (ChiCTR-OOC-17012731). The performance of PDTX was evaluated by analyzing factors that affect the engraftment rate, comparing the histological consistency between primary tumors and tumorgrafts, examining the concordance between the drug effectiveness in PDTXs and clinical responses, and identifying genetic variants and other factors associated with prognosis. Thirty-three patients were enrolled in the study with the engraftment rate of 75.8% (25/33). The success of engraftment was independent of age, cancer types, pathological stages of tumors, and particularly sampling methods. Tumorgrafts retained the same histopathological characteristics as primary tumors. Forty-nine regimens involving 28 drugs were tested in seventeen tumorgrafts. The median time for drug testing was 134.5 days. Follow-up information was obtained about 10 regimens from 9 patients. The concordance of drug effectiveness between PDTXs and clinical responses was 100%. The tumor mutation burden (TMB) was correlated with the effectiveness of single drug regimens, while the outgrowth time of tumorgrafts was associated with the effectiveness of combined regimens. The engraftment rate in advanced GICs was higher than that of other cancers and meets the acceptable standard for applying personalized therapeutic strategies. Tumorgrafts from PDTX kept attributes of the primary tumor. Predictions from PDTX modeling closely agreed with clinical drug responses. PDTX may already be clinically applicable for personalized medication in advanced GICs.

CARD9 is an essential adaptor protein in antifungal innate immunity mediated by C-type lectin receptors. The activity of CARD9 is critically regulated by ubiquitination; however, the deubiquitinases involved in CARD9 regulation remain incompletely understood. In this study, we identified ovarian tumor deubiquitinase 1 (OTUD1) as an essential regulator of CARD9. OTUD1 directly interacted with CARD9 and cleaved polyubiquitin chains from CARD9, leading to the activation of the canonical NF-κB and MAPK pathway. OTUD1 deficiency impaired CARD9-mediated signaling and inhibited the proinflammatory cytokine production following fungal stimulation. Importantly, Otud1–/– mice were more susceptible to fungal infection than wild-type mice in vivo. Collectively, our results identify OTUD1 as an essential regulatory component for the CARD9 signaling pathway and antifungal innate immunity through deubiquitinating CARD9.

Objectives The Bio-Rad SARS-CoV-2 ddPCR Kit (Bio-Rad Laboratories) was the first droplet digital polymerase chain reaction (ddPCR) assay to receive Food and Drug Administration (FDA) Emergency Use Authorization approval, but it has not been evaluated clinically. We describe the performance of ddPCR—in particular, its ability to confirm weak-positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results. Methods We clinically validated the Bio-Rad Triplex Probe ddPCR Assay. The limit of detection was determined by using serial dilutions of SARS-CoV-2 RNA in an artificial viral envelope. The ddPCR assay was performed according to the manufacturer’s specifications on specimens confirmed to be positive (n = 48) or negative (n = 30) by an FDA-validated reverse transcription–polymerase chain reaction assay on the m2000 RealTime system (Abbott). Ten borderline positive cases were also evaluated. Results The limit of detection was 50 copies/mL (19 of 20 positive). Forty-seven specimens spanning a range of quantification cycles (2.9-25.9 cycle numbers) were positive by this assay (47 of 48; 97.9% positive precent agreement), and 30 negative samples were confirmed as negative (30 of 30; 100% negative percent agreement). Nine of 10 borderline cases were positive when tested in triplicate. Conclusions The ddPCR of SARS-CoV-2 is an accurate method, with superior sensitivity for viral RNA detection. It could provide definitive evaluation of borderline positive cases or suspected false-negative cases.

BACKGROUND: Our study aimed to comprehensively investigate the age of onset, magnetic resonance imaging (MRI) features, and prognosis of children with trilateral retinoblastoma (TRB). METHODS: We included 14 patients with TRB diagnosed or followed up in our hospital. The age of onset and MRI features of the intraocular tumor and intracranial lesions were evaluated. A follow-up study was also conducted. RESULTS: A total of 11 participants were diagnosed with concurrent TRB at the age of 11.1±7.4 months, and 3 participants had late-onset TRB at age 37±19.1 months. The incidence of TRB with unilateral eye involvement was 7.1% (1/14). The intraocular tumors showed intense enhancement in contrast-enhanced T1-weighted images (WI) and significant diffusion restriction in diffusion WI (DWI) with an apparent diffusion coefficient (ADC) of (0.619±0.22)×10(−3) mm(2)/s. The intracranial lesions showed similar DWI aspects with an ADC value of (0.680±0.206)×10(−3) mm(2)/s. Therapeutically, 8 participants had a period of intraocular tumor stabilization and significant intracranial lesion volume reduction after chemotherapy, and 6 participants had given up treatment. Only 2 participants who simultaneously received high-dose chemotherapy and autologous hematopoietic stem cell rescue were still alive with no recurrence at 24 and 54 months of follow-up. The 1-, 2-, and 3-year overall survival (OS) rates were 80%, 18.75%, and 12.5%, respectively. CONCLUSIONS: Patients with unilateral or bilateral RB can develop TRB. The intraocular and intracranial tumors showed slightly different ADC values. High-dose chemotherapy, combined with stem cell rescue can significantly improve survival. A long term and scheduled follow-up before 60 months of age is necessary for screening later-onset TRB patients.

Bai-Rong Wang,1,2 Jun-Teng Yao,2 Hui Zheng,1 Quan-Min Li1 1Department of Endocrinology, Medical College of Soochow University, Suzhou 215123, Jiangsu, People’s Republic of China; PLA Rocket Force Characteristic Medical Center, Beijing, 100088, People’s Republic of China; 2Department of Endocrinology, Jinjiang Municipal Hospital, Jinjiang, 362200, People’s Republic of ChinaCorrespondence: Quan-Min LiPLA Rocket Force Characteristic Medical Center, Beijing, 100088, People’s Republic of ChinaTel +86 10 66927601Email liquanming369@163.comObjective: This study aimed to investigate the association of the glycated albumin (GA)/glycosylated hemoglobin (HbA1c) ratio with the mean amplitude of glycemic excursion (MAGE) in type 2 diabetes mellitus (T2DM).Methods: A total of 102 patients with T2DM who were first treated in Jinjiang Hospital of Fujian Province were enrolled in this study. The patients’ general clinical data, including HbA1c, GA, fasting blood glucose, and fasting and peak C-peptide values upon diagnosis and after one year of follow-up, were collected, and their MAGE was calculated.Results: With the increase of the GA/HbA1c ratio at baseline, the patients’ fasting and peak C-peptide values decreased gradually from baseline to follow-up, while their MAGE, HbA1c, and fasting blood glucose increased gradually. A regression analysis demonstrated that the baseline MAGE was independently positively correlated with the GA/HbA1c ratio. A Cox regression analysis demonstrated that a baseline GA/HbA1c ratio of > 2.78 was an independent risk factor for poor fasting blood glucose and HbA1c.Conclusion: The GA/HbA1c ratio is closely related to the MAGE and islet function in patients with T2DM.Keywords: type 2 diabetes mellitus, glycated albumin, glycosylated hemoglobin, blood glucose control, blood glucose fluctuation

Background Medulloblastoma (MB) is the most common pediatric embryonal tumor. Accurate identification of cerebral spinal fluid (CSF) dissemination is important in prognosis prediction. Both MRI of the central nervous system (CNS) and CSF cytology will appear false positive and negative. Our objective was to investigate the added value of preoperative-enhanced T1-weighted image-based radiomic features to clinical characteristics in predicting preoperative CSF dissemination for children with MB. Materials and methods This retrospective study included 84 children with histopathologically confirmed MB between November 2006 and November 2018 (training cohort, n=60; internal validation cohort, n=24). A set of cases between December 2018 and February 2020 were used for external validation (n=40). The children with normal head and spine magnetic resonance images (MRI) and no subsequent dissemination in 1 year were diagnosed as non-CSF dissemination. The CSF dissemination was manifested as intracranial or intraspinal nodular-enhanced lesions. Clinical features were collected, and conventional MRI features of preoperative head MRI examinations were evaluated. A total of 385 radiomic features were extracted from preoperative-enhanced T1-weighted images. Minimum redundancy, maximum correlation, and least absolute shrinkage and selection operator were performed to select the features with the best performance in predicting preoperative CSF dissemination. A combined clinical-MRI radiomic prediction model was developed using multivariable logistic regression. Receiver operating curve analysis (ROC) was used to validate the predictive performance. Nomogram and decision curve analysis (DCA) were developed to evaluate the clinical utility of the combined model. Results One clinical and nine radiomic features were selected for predicting preoperative CSF dissemination. The combined model incorporating clinical and radiomic features had the best predictive performance in the training cohort with an AUC of 0.89. This was validated in the internal and external cohorts with AUCs of 0.87 and 0.73. The clinical utility of the model was confirmed by a clinical-MRI radiomic nomogram and DCA. Conclusions The combined model incorporating clinical, conventional MRI, and radiomic features could be applied to predict preoperative CSF dissemination for children with MB as a noninvasive biomarker, which could aid in risk evaluation.

The application of splenic hilar lymph node (no. 10 LN) dissection (no. 10 LND) for proximal gastric cancer (PGC) remains controversial. This study aimed to investigate the clinical relevance of no. 10 LND from the perspective of long-term survival. The main study population included 995 previously untreated patients who underwent laparoscopic radical total gastrectomy between January 2008 and December 2014. Of these 995 patients, 564 underwent no. 10 LND (no. 10D+ group) and the remaining 431 patients did not (no. 10D– group). Propensity score-matching was applied to reduce the effects of confounding factors. The study end points were overall survival (OS) and disease-free survival (DFS). Additionally, 39 patients who received neoadjuvant chemotherapy during the same period also were included as a separate population for analysis. The metastasis rate for no. 10 LN was 10.5 % (59/564). No significant differences were observed in intra- and postoperative complications nor in mortality between the no. 10D+ and no. 10D– groups (all P > 0.05). After 1:1 matching, the two groups were comparable in clinicopathologic characteristics. The no. 10D+ group had significantly better survival than the no. 10D– group (5-year OS: 63.3 % vs 52.2 %, P = 0.003; 5-year DFS: 60.4 % vs 48.1 %, P = 0.013). For the patients who received neoadjuvant chemotherapy, the 5-year OS rates in the no. 10D+ and no. 10D– groups were respectively 50.6 % and 31.3 % (P = 0.150) and the 5-year DFS rates were respectively 51.5 % and 31.3 % (P = 0.123). Patients with untreated PGC may achieve the benefit of long-term survival from no. 10 LND. For patients with PGC who undergo neoadjuvant chemotherapy, no. 10 LND may not bring survival benefits. However, further validation with a large-sample study is needed.

Background: Mixed medullary and follicular thyroid carcinoma (MMFC) displays heterogeneous morphological components and immunophenotypical features intermingled within the same lesion, which is rare and most described in the sporadic form. We report herein a Chinese patient with multiple endocrine neoplasia type 2B (MEN2B) harboring germline RET M918T and associated MMFC. Methods: A case of a 39-year-old male patient with MEN2B presented palpable neck masses in both thyroid lobes (maximum sizes: left, 3.9 cm; right, 5.4 cm) and a definitive phenotype. Serum levels of calcitonin (Ctn; >2000pg/mL), carcinoembryonic antigen (CEA; 719.27ng/mL), and thyroglobulin (Tg; 98.54ng/mL) were high. Fine-needle aspiration cytology showed features positive for malignancy, suggesting the possibility of medullary thyroid carcinoma (MTC). Total thyroidectomy, along with extending bilateral neck lymph nodes dissection, and subsequently, genetics family screening were performed. Results: The histopathological examination yielded a diagnosis of MMFC that showed immunohistochemical characteristic patterns of the component of MTC positive for Ctn and CEA, chromogranin A, and the follicular carcinoma components were positive for Tg. Lymph node metastasis was observed showing medullary tumoral cells positive for Ctn and follicular-like structures lacking tumor cells positive for Tg staining (T4bN1bM0). Genetics screening confirmed RET M918T (c.2753T>C) mutation manifested in the patient but was not detected in other family members. Follow up showed that the serum Ctn, CEA and Tg levels respectively dropped to 54.38pg/ml, 4.16ng/mL and 0.04ng/mL 16 months after the surgery. Conclusion: Particular and diverse patterns of MMFC should be recognized with immunostaining features. MMFC occurring in a patient with MEN2B harboring RET M918T may be unique biological behavior and the treatment is mostly radical surgery.

p18 is a key negative regulator of cell cycle progression and mediates cell cycle arrest at the G1/S phase. Ubiquitination is the prime mechanism in regulating p18 protein abundance. However, so far no post- translational regulator, especially DUBs, has been identified to regulate the protein stability of p18. In this paper, we identified CYLD as a deubiquitinase of p18, which binds to and removes the K48-linked polyubiquitylation chains conjugated onto p18, thus stabilizing the p18 protein. Loss of CYLD causes the degradation of p18 and induces the G1/S transition. Epstein–Barr virus (EBV), is the human oncovirus etiologically linked to nasopharyngeal carcinoma (NPC). Here we found that EBV drives a replication passive environment by deregulating the CYLD-p18 axis. Functionally, CYLD inhibits cell proliferation and tumorigenesis through p18 in vivo. Restoring CYLD prevents EBV induced viral replication and tumor growth. Collectively, our results identify CYLD directly stabilizes p18 to regulate the cellular G1/S transition. The reconstitution of CYLD-p18 axis could be a promising approach for EBV-positive cancer therapy.

Background Distant metastasis is the leading cause of death for esophageal squamous cell carcinoma (ESCC) with limited treatment options and unsatisfactory effectiveness. Bromodomain (BRD) containing proteins are emerging targets for cancer therapy with promising effects. As a unique member of BRD family, the function and molecular mechanism of ATAD2 in cancer development is seldomly investigated. Methods The clinical impact of ATAD2 was assessed both at RNA and protein level in 75 and 112 ESCC patients separately. The biological function of ATAD2 was investigated in vitro and in vivo. Signaling pathway and downstream effectors of ATAD2 were identified by RNA sequencing, luciferase reporter, co-immunoprecipitation, chromatin immunoprecipitation, immunofluorescence and western blot assay. Results We found that elevated ATAD2 expression was significantly associated with lymph node metastasis, advanced clinical stage as well as poor survival of ESCC patients. Silencing ATAD2 significantly suppressed ESCC cell migration and invasion in vitro, and inhibited tumor growth and lung metastasis in vivo. Mechanically, we identified a new cofactor, C/EBPβ. ATAD2 directly interacted with C/EBPβ and promoted its nuclear translocation, which directly bound to the promoter region of TGF-β1 and activated its expression. Further, we demonstrated that TGF-β1 activated its downstream effectors in a Smad3 dependent manner. In addition, we further found that ATAD2 promoted ESCC metastasis through TGF-β signaling induced Snail expression and the subsequent epithelial-mesenchymal transition. Conclusion Our findings demonstrated the pro-metastatic function of ATAD2 and uncovered the new molecular mechanism by regulating C/EBPβ/TGF-β1/Smad3/Snail signaling pathway, thus providing a potential target for the treatment of ESCC metastasis.

Summary Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy. Methods We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879. Findings Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI –2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [–1·6 to 3·6], –0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related. Interpretation A similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy. Funding AbbVie Inc.

Due to lacking evidence for confirming the efficacy of performing laparoscopic surgery for locally advanced gastric cancer (LAGC). Therefore, this study aimed to compare the static and dynamic failure patterns after laparoscopic gastrectomy (LG) and open gastrectomy (OG) in LAGC. A total of 1792 LAGC patients who underwent radical resection between January 2010 and January 2017 were divided into the LG group (n = 1557) and the OG group (n = 235). Propensity score matching was performed to balance the two groups. Dynamic hazard rates of failure were calculated using the hazard function. Early and late failure were defined as failure occurring before and after 2 years since surgery, respectively. A total of 1175 patients with LAGC were included after matching (LG group, n = 940; OG, n = 235). The failure rate of the whole cohort was 43.2% (508/1175), accounting for 41.4% (389/940) and 50.6% (119/235) in the LG and OG groups, respectively. Although the two groups showed no significant differences in failure rate for any failure type, landmark analysis showed a lower early distant recurrence rate in the stage IIa–IIIb subgroup of the LG group (OG versus LG: 30.3% versus 21.1%, P = 0.004). The dynamic hazard rate peaked at 9.4 months (peak rate = 0.0186) before gradually declining. In stage IIa–IIIb patients, the hazard rate of the OG group remained significantly higher than that of the LG group within the first 2 years in terms of distant recurrence (peak rate: OG versus LG, 0.0091 versus 0.0055). Given the differences in early failure between LG and OG, more intensive surveillance for distant recurrence within the first 2 years should be considered for patients with stage IIa–IIIb after OG.

Objectives Furosemide is usually administered before the Coronary artery bypass grafting (CABG) to improve water–sodium retention. However, no final conclusions are available on the postoperative renal outcome of furosemide. We evaluated the effect of preoperative furosemide on acute kidney injury (AKI) after CABG. Methods We recorded the use of furosemide 14 days before surgery in all patients who underwent CABG from 2016 to 2017. Patients were divided into furosemide (F) group and non-furosemide (NF) group according to preoperative use of furosemide. A 1:1 propensity score matching was performed. Multivariate analyses were conducted to determine risk factors for AKI after CABG. Results Overall, 974 patients were included in the study, of which 82 cases were complicated with postoperative AKI. The incidence of AKI was significantly increased in F group than NF group (28.9% vs. 7.4%, p = 0.000). After adjusting for risk factors, the incidence of AKI in the F group was 5.34 times more than the NF group (95% confidence interval [CI] 2.45–11.64; p = 0.000). The incidence of AKI increased significantly when the cumulative dosage of furosemide exceeded 110 mg (odds ratio [OR] 6.23; 95% CI 2.07–18.74, p = 0.001) and 250 mg (OR 8.31; 95% CI 2.87–24.02, p = 0.000). After the propensity-matching group analysis, same results were obtained. Conclusions The incidence of AKI after CABG was related to the use of preoperative furosemide, and it increased exponentially with the increase of cumulative dose of furosemide. This provides guidance for the dose of preoperative furosemide.

Classic innate immune signaling pathways provide most of the immune response in the brain. This response activates many of the canonical signaling mechanisms identified in peripheral immune cells, despite their relative absence in this immune-privileged tissue. Studies over the past decade have strongly linked complement protein production and activation to age-related functional changes and neurodegeneration. The reactivation of the complement signaling pathway in aging and disease has opened new avenues for understanding brain aging and neurological disease pathogenesis and has implicated cell types such as astrocytes, microglia, endothelial cells, oligodendrocytes, neurons, and even peripheral immune cells in these processes. In this review, we aim to unravel the past decade of research related to complement activation and its numerous consequences in aging and neurological disease.

BACKGROUND Fat embolism syndrome (FES) is a rare disease characterized by pulmonary distress, neurologic symptoms, and petechial rash and seriously threatens human life and health. It is still neglected clinically because of the lack of verifiable diagnostic criteria and atypical clinical symptoms. No studies on FES with pulmonary embolism (PE) and tympanic membrane perforation have been reported to date. Here, we report a rare case of concomitant FES, PE and tympanic membrane perforation after surgery in a patient with a tibiofibular fracture. CASE SUMMARY A 39-year-old man presented with right lower extremity pain due to a car accident while driving a motorbike on the road. X-ray and computed tomography scans revealed a fracture of the right mid-shaft tibia and proximal fibula categorized as a type A2 fracture according to the AO classification. A successful minimally invasive operation was performed 3 d after the injury. Postoperatively, the patient developed sudden symptoms of respiratory distress and hearing loss. Early diagnosis was made, and supportive treatments were used at the early stage of FES. Seven days after surgery, he presented a clear recovery from respiratory symptoms. The outcome of fracture healing was excellent, and his hearing of the left ear was mildly impaired at the last follow-up of 4 mo. CONCLUSION Concomitant FES, PE and tympanic membrane perforation are very rare but represent potentially fatal complications of trauma or orthopedic surgery and present with predominantly pulmonary symptoms. Early diagnosis and treatment can reduce the mortality of FES, and prevention is better than a cure.

Background Botulinum neurotoxin A (BoNT-A) was the primary choice for preventive treatment of chronic migraine. Topiramate and acupuncture showed promising effect for chronic migraine, but their effectiveness relative to BoNT-A was rarely studied. We aimed to perform a network meta-analysis to compare the effectiveness and acceptability between topiramate, acupuncture, and BoNT-A. Methods We searched OVID Medline, Embase, the Cochrane register of controlled trials (CENTRAL), the Chinese Clinical Trial Register, and clinicaltrials.gov for randomized controlled trials (RCTs) that compared topiramate, acupuncture, and BoNT-A with any of them or placebo in the preventive treatment of chronic migraine. A network meta-analysis was performed by using a frequentist approach and a random-effects model. The primary outcomes were reduction in monthly headache days and monthly migraine days at week 12. Acceptability was defined as the number of dropouts owing to adverse events. Results We included 15 RCTs (n = 2545). Eleven RCTs were at low risk of bias. The network meta-analyses (n = 2061) showed that acupuncture (2061 participants; standardized mean difference [SMD] -1.61, 95% CI: -2.35 to -0.87) and topiramate (582 participants; SMD -0.4, 95% CI: -0.75 to -0.04) ranked the most effective in the reduction of monthly headache days and migraine days, respectively; but they were not significantly superior over BoNT-A. Topiramate caused the most treatment-related adverse events and the highest rate of dropouts owing to adverse events. Conclusions Topiramate and acupuncture were not superior over BoNT-A; BoNT-A was still the primary preventive treatment of chronic migraine. Large-scale RCTs with direct comparison of these three treatments are warranted to verified the findings.

A key uncertainty in the obesity-mortality association continues to be how this association changes over the life course. Prior studies tend to rely on cross-sectional design with static weight status taken at the time of the survey. This study tracks a cohort of individuals and employs lifelong body mass index information from the Framingham Heart Study original cohort (1948 to 2010). We focus on respondents who were younger than age 45 at time of their first survey (n=2,176) and evaluate how the mortality risk associated with obesity changes over three age groups (below 45, 45–59, and 60 and above) and how population compositions may contribute to this pattern. We find the hazard ratio associated with obesity compared to normal weight decreases over three age groups, but this pattern is influenced by different ages of onset of obesity, inconsistency in the reference group (normal weight) over ages, and mortality selection effects. These factors explain away the decreasing effect of obesity (with onset before age 45) on mortality up to age 60; after age 60, the detrimental effect still declines, but to a much less degree. Later onset of obesity, however, is not significantly associated with excess mortality risks after age 60.

BACKGROUND The incidence of hepatocellular carcinoma (HCC) is high in China, and approximately 15%-20% of HCC cases occur in the absence of cirrhosis. Compared with patients with cirrhotic HCC, those with non-cirrhotic HCC have longer postoperative tumor-free survival. However, the overall survival time is not significantly increased, and the risk of postoperative recurrence remains. Strategies to improve the postoperative survival rate in these patients are currently required. CASE SUMMARY A 47-year-old man with a family history of HCC was found to have hepatitis B virus (HBV) infection 25 years ago. In 2000, he was administered lamivudine for 2 years, and entecavir (ETV 0.5 mg) was administered in 2006. In October 2016, magnetic resonance imaging revealed a tumor in the liver (5.3 cm × 5 cm × 5 cm); no intraoperative hepatic and portal vein and bile duct tumor thrombi were found; and postoperative pathological examination confirmed a grade II HCC with no nodular cirrhosis (G1S3). ETV was continued, and no significant changes were observed on imaging. After receiving pegylated interferon alfa-2b (PEG IFNα-2b) (180 μg) + ETV in February 2019, the HBsAg titer decreased significantly within 12 wk. After receiving hepatitis B vaccine (60 μg) in 12 wk, HBsAg serological conversion was realized at 48 wk. During the treatment, no obvious adverse reactions were observed, except for early alanine aminotransferase flares. The reexamination results of liver pathology were G2S1, and reversal of liver fibrosis was achieved. CONCLUSION The therapeutic regimen of ETV+ PEG IFNα-2b + hepatitis B vaccine for patients with HBV-associated non-cirrhotic HCC following hepatectomy can achieve an HBV clinical cure and prolong the recurrence-free survival.

Background: Compared with other histologic types, signet ring cell gastric carcinoma (SRC) has unique oncological characteristics, and its implication on the prognosis of gastric cancer patients remains unclear. The purpose of this study was to evaluate the prognostic impact of body mass index (BMI) on SRC patients. Methods: A retrospective analysis was performed using the clinical records of 3342 patients with SRC or tubular adenocarcinoma who underwent radical gastrectomy between 2000 and 2014. Patients were divided into three groups according to histologic subtype: SRC, well-to-moderately differentiated adenocarcinoma (WMD), and poorly differentiated adenocarcinoma (PD). We compared the survival of SRC patients with that of tubular adenocarcinoma patients according to BMI. Results: The 5-year survival of SRC was significantly worse than that of WMD (P 0.05) and better than that of PD (P

Background: Carcinoembryonic antigen (CEA) is one of the important indexes for the diagnosis and prognosis of gastrointestinal cancer. Systemic inflammatory response (SIR) is closely related to the occurrence and development of gastrointestinal cancer. Methods: A total of 803 patients who underwent radical gastrectomy in Qinghai University Affiliated Hospital from January 2012 to December 2016 were included as training set. Multivariable Cox proportional hazard regression was used to identify associations with outcome of gastric cancer (GC). CNLR was established by combining CEA and the neutrophils to lymphocytes ratio (NLR, a typical parameter in SIR) to generate a novel prognostic score system and its prognostic value was externally validated. Results: Multivariate analysis showed that CEA and NLR were independent prognostic factors for GC patients (both p < 0.05). A higher CNLR was significantly associated with older age, male sex, larger tumor size, vascular invasion and advanced stages (all p < 0.05). Patients with higher CNLR had poor prognosis than those with lower CNLR (p < 0.05). Multivariate analysis showed that CNLR was an independent prognostic factor (p < 0.05). Incorporation of the CNLR into a prognostic model including age and TNM stage generated a nomogram, which predicted accurately 3- and 5-year survival for GC patients. And similar results were obtained in the external validation set. Conclusions: The CNLR prognostic scoring system established by combining CEA and NLR is an independent prognostic factor for GC, which can be incorporated into the traditional TNM staging to improve the prediction of long-term survival outcomes.

Japanese encephalitis (JE) is a vector-borne vaccine preventable infectious disease for which vaccine provides direct protection. China introduced nationwide JE vaccination of young children in 2007, rapidly achieving high coverage. In 2018, 1,800 JE cases were reported in China, with morbidity and mortality rates of 0.13/100,000 and 0.0097/100,000. Nationally, 64% of cases were among adults aged 40 years or older, and in northern China, 82% were among adults, mainly in outbreaks. Severity varied little by age grouping. Compared with the previous 10 years, the proportion and absolute number of cases among adults increased, indicating possible emergence of adult JE in China as childhood JE decreased. We describe JE epidemiology and clinical features nationally and in areas with low endemicity after more than 10 years of routine childhood JE vaccination. Determining population JE seroprevalence should be a priority; vaccination campaigns among adults in high risk areas should be considered.

AIM: To obtain the baseline data on presenting visual acuity (PVA) and evaluate the prevalence and associated factors for visual impairment based on PVA in 9070 Chinese college students. METHODS: The freshmen at a university in southern China, including 6527 undergraduate students and 2543 graduate students, were investigated for some socio-demographic characteristics and underwent routine medical examination, including measuring PVA, height, and weight. Visual impairment was defined according to the new World Health Organization criteria for blindness and visual impairment. RESULTS: In 9070 college students, the mean PVA in the better eye was 0.094±0.163 logMAR. The prevalence of visual impairment based on PVA was 2.7%. Only 38.3% college students had normal visual acuity [PVA equal to 0 logMAR (20/20) in both eyes]. There were 69.8% of students wearing spectacles. Logistic regression showed that home region (non-Guangdong provinces, P

The poor prognosis of gastric cancer (GC) results largely from metastasis and chemotherapy resistance. Toward novel therapeutic strategies that target or evade these phenomena, we evaluated the function of the transcriptional regulator transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in GC cells, including stem-like cells. In this study, the correlation of expression of TBL1XR1 and clinical features and GC patients' outcomes was evaluated. Knockdown or exogenous expression of TBL1XR1 was combined with in vitro (2D and 3D cultures) and in vivo (mouse lung and lymphatic metastasis models) assays to evaluate the function of TBL1XR1. TBL1XR1's downstream signaling was delineated by phospho-kinase array and knockdown of candidate mediators. Analysis of clinical data showed that TBL1XR1 overexpression was correlated with worse prognosis. Functional assays showed that TBL1XR1 promoted stemness, epithelial-mesenchymal transition (EMT), and lung and lymphatic metastasis in GC cells. TBL1XR1 activated ERK1/2-Sox2 signaling and was dependent on signaling via PI3K/AKT, in GC stem-like cells distinguished by CD44 expression. Moreover, inhibition of these signaling proteins reversed chemoresistance in in vitro and in vivo models. Taken together, our results indicate that TBL1XR1 promotes stemness and metastasis in GC, making it a potential prognostic indicator. The PI3K/AKT-TBL1XR1-ERK1/2-Sox2 axis may represent a target for the treatment of GC.

Introduction Angiosarcoma is a malignant tumor with low incidence. Especially in the advanced tumors, there is still a lack of knowledge of evidence-based medicine. Case presentation We report a case of a 55-year-old woman with abdominal pain of 2 months of duration, which had increased in severity for 2 weeks prior to the presentation. The diagnosis is primary gastric angiosarcoma. We performed multiple disciplinary team (MDT), and doxorubicin-based neoadjuvant chemotherapy (NAC) was proposed. After two cycles of NAC, a computed tomography (CT) scan showed complete regression compared with the previous scan. An open surgery was done, and surgical specimens were confirmed as a pathological complete response (PCR) by pathological and immunohistochemical examination, but unfortunately, the patient suffered a relapse after the surgery in 3 months. Conclusion Repeated endoscopic biopsy and biopsy specimen examinations can improve accuracy in diagnosis. It seems that NAC could be a candidate for advanced primary gastric angiosarcomas. But after the rapid relapse, we are wondering whether pathologic complete response is the surrogate in primary gastric angiosarcoma undergoing NAC.

Purpose Capecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some side effects caused by capecitabine. The aim of our study is to identify the possible genetic predictors of capecitabine-induced HFS (CAP-HFS) in Chinese colorectal cancer patients.Materials and Methods Whole exons of TYMS were sequenced for 288 extreme phenotype HFS patients, including 144 severe or early-onset (first 2 cycles) moderate HFS extreme cases and 144 extreme controls with no reported HFS. The associations between polymorphisms and CAP-HFS were analyzed using logistic regression under an additive model.Results We identified a novel risk mutation (c.1A>G, chr18:657743), was associated with severe HFS in an extreme case who was affected during the first cycle of treatment. Moreover, we identified three new variants, rs3786362, rs699517, rs2790, and two previously reported variants, 5’VNTR 2R/3R and 3′-untranslated region 6-bp ins-del, which were significantly associated with CAP-HFS (p < 0.05). In silico analysis revealed that the effect of these polymorphisms in the TYMS region on the development of HFS might not be restricted solely to the regulation of TYMS expression, but also the TYMS catalytic activity through the indirect effect on ENOSF1 expression.Conclusion This study identified new polymorphisms in TYMS gene significantly associated with CAP-HFS, which may serve as useful genetic predictors for CAP-HFS and help to elucidate the underlying mechanism of HFS.

Objective: To determine the effectiveness of proprioceptive training on knee function and proprioception following anterior cruciate ligament reconstruction. Data sources: PubMed, EMBASE, The Cochrane Library, Ovid, EBMSCO- host, ScienceDirect, CNKI, VIP, WanFang Data and CBM were searched until 2nd October 2020. Review methods: Trials with proprioceptive training for patients with anterior cruciate ligament reconstruction were included. Study screening, data extraction, risk of bias and quality assessments were performed independently by two researchers. We performed a stratified analysis based on the quality of the study. Sensitivity analyses were performed if the heterogeneity was high. Results: Seventeen trials with 878 participants were included, and 12/17 with low quality. After stratified analysis, the pooled effect of high-quality studies showed significant improvement for proprioceptive training group in range of motion ( P 2 = 0%), but no differences in Cincinnati knee rating system score ( P > 0.05, I2 = 83%), hop test ( P>0.05, I2 = 0%) and proprioception ( P = 0.17, I2 = 77%) compared to conventional training group; while the pooled effect of low-quality studies showed significant differences in knee functional improvement ( P 2 = 69%), but no difference in proprioception ( P > 0.05, I2 = 84%) between two groups. The pooled effect of all studies showed a significant benefit in both function and proprioception. Conclusion: The effects of proprioceptive training on knee functional and proprioceptive improvement after anterior cruciate ligament reconstruction is mixed. It is more likely that proprioceptive training in high-quality studies has few detectable effects and that low-quality studies show an effect because of an unconscious bias. A large well designed high-quality study needs to be undertaken in the future.

China has conducted surveillance for hepatitis A since 1990, and hepatitis A was highly-to-intermediately endemic in 1992 when a Chinese hepatitis A vaccine (HepA) was licensed and introduced as a family-pay vaccine. In 2008, HepA was introduced into the Expanded Program on Immunization as a free childhood vaccine.Three nationally representative surveys conducted in 1992, 2006, and 2014 assessed hepatitis B serology. The 1992 survey included hepatitis A virus (HAV) serology, and we tested sera from the 2006 and 2014 surveys for HAV antibodies. We used surveillance, seroprevalence, and vaccination status data to describe the changing epidemiology of hepatitis A in China from 1990 through 2014. Before HepA licensure, anti-HAV seroprevalence was 60% at 4 years of age, 70% at 10 years, and 90% at 59 years; incidence was 52/100,000 and peaked at 4 years. In 2006, after10 years of private sector vaccination, HepA coverage was30% among children5 years, and incidence was 5.4/100,000 with a peak at 10 years. In 2014, coverage was90% among children under 5 years; incidence was 1.9/100,000. Individuals born before the national introduction of HepA (1988-2004) had lower anti-HAV seroprevalence than earlier and later birth cohorts.The incidence of hepatitis A declined markedly following HepA introduction and improvement of sanitation and hygiene. The emerging epidemiology is consistent with disease-induced immunity having been replaced by vaccine-induced immunity, resulting in a low incidence of hepatitis A. Catch-up HepA campaigns to close the immunity gap among the 1998-2004 birth cohorts should be considered.

Objectives Pulmonary hypertension (PH) patients represent a complex subset of patients in the emergency department (ED), yet little is known about their presentations and outcomes. The objective of this study is to analyze the demographics, dispositions and the rates of return visits for PH patients visiting the ED, focusing on PH patients identified as having high frequency visits. Methods We performed a retrospective cohort analysis of all patients with ICD-9-CM and ICD-10-CM codes corresponding to PH presenting to an academic medical center emergency department during a 21-month period. The primary outcome was patients with high frequency ED visits, defined as 4 or more visits in a 12-month period. Secondary outcomes included ED dispositions, return ED visits, hospital length of stay, and in-hospital mortality. Results Six hundred and eighty four unique patients with a coded diagnosis of PH visited the emergency department a total of 1447 times. Eighty-four patients (12.28%) were identified as having high frequency visits. Factors associated with high frequency ED visits included male sex, liver disease, rheumatologic disease, and having Group 1 PH. PH patients’ admission rate was substantial at 56.60%, and their inpatient mortality was increased (6.7% vs 3.7% for all admissions from ED, P Conclusion PH patients in this study had frequent return ED visits, as well as elevated admission and readmission rates. Factors associated with high frequency ED visits included male sex, liver disease, rheumatologic disease, and Group 1 PH. PH patients also had increased mortality rates compared to the general ED population.

To construct a CT-based radiomics signature and assess its performance in predicting MYCN amplification (MNA) in pediatric patients with neuroblastoma. Seventy-eight pediatric patients with neuroblastoma were recruited (55 in training cohort and 23 in test cohort). Radiomics features were extracted automatically from the region of interest (ROI) manually delineated on the three-phase computed tomography (CT) images. Selected radiomics features were retained to construct radiomics signature and a radiomics score (rad-score) was calculated by using the radiomics signature–based formula. A clinical model was established with clinical factors, including clinicopathological data, and CT image features. A combined nomogram was developed with the incorporation of a radiomics signature and clinical factors. The predictive performance was assessed by receiver operating characteristics curve (ROC) analysis and decision curve analysis (DCA). The radiomics signature was constructed using 7 selected radiomics features. The clinical radiomics nomogram, which was based on the radiomics signature and two clinical factors, showed superior predictive performance compared with the clinical model alone (area under the curve (AUC) in the training cohort: 0.95 vs. 0.82, the test cohort: 0.91 vs. 0.70). The clinical utility of clinical radiomics nomogram was confirmed by DCA. This proposed CT-based radiomics signature was able to predict MNA. Combining the radiomics signature with clinical factors outperformed using clinical model alone for MNA prediction. • A CT-based radiomics signature has the ability to predict MYCN amplification (MNA) in neuroblastoma. • Both pre- and post-contrast CT images are valuable in predicting MNA. • Associating the radiomics signature with clinical factors improved the predictive performance of MNA, compared with clinical model alone.

Aims Right ventricular (RV) failure causes death from acute pulmonary embolism (PE), due to a mismatch between RV systolic function and increased RV afterload. We hypothesized that an echocardiographic ratio of this mismatch [RV systolic function by tricuspid annular plane systolic excursion (TAPSE) divided by pulmonary arterial systolic pressure (PASP)] would predict adverse outcomes better than each measurement individually, and would be useful for risk stratification in intermediate-risk PE. Methods and results This was a retrospective analysis of a single academic centre Pulmonary Embolism Response Team registry from 2012 to 2019. All patients with confirmed PE and a formal transthoracic echocardiogram performed within 2 days were included. All echocardiograms were analysed by an observer blinded to the outcome. The primary endpoint was a 7-day composite outcome of death or haemodynamic deterioration. Secondary outcomes were 7- and 30-day all-cause mortality. A total of 627 patients were included; 135 met the primary composite outcome. In univariate analysis, the TAPSE/PASP was associated with our primary outcome [odds ratio = 0.028, 95% confidence interval (CI) 0.010–0.087; P Conclusion A combined echocardiographic ratio of RV function to afterload is superior in prediction of adverse outcome in acute intermediate-risk PE. This ratio may improve risk stratification and identification of the patients that will suffer short-term deterioration after intermediate-risk PE.

Based on the current domestic and foreign research reports on COVID-19, this paper makes a prospective summary. While focusing on the health of the public, it analyzes the common psychological stress response of the public in response to sudden infectious diseases, including three stages of typical stress response, emotional, mental, physical and behavioral changes in response to psychological stress. And put forward the appropriate psychological adjustment suggestions, which is conducive to the adjustment of people’s mentality, to face the changes of the epidemic situation with a positive attitude.

Hao Long,1 Hui Zheng,2 Long Ai,1 Kamil Osman,1 Zhigang Liu3 1Department of Pain Management, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 2Orthopedics Department, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 3Department of Pain Management, The Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of ChinaCorrespondence: Zhigang Liu Department of Pain ManagementThe Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, Jilin 130041, People’s Republic of ChinaEmail liuzhigang_82@163.comIntroduction: Cancer-induced bone pain (CIBP) is very common in patients with advanced cancer. Recent studies have shown that reactive oxygen species (ROS) can sense and regulate pain response process through spinal cord mechanism, and play a role in CIBP. NADPH oxidase (NOX) is a group of protease complexes that produce ROS. In the current study, we investigated the expression of NOX4 in the spinal dorsal horn of rats with CIBP and its related role and molecular mechanism.Materials and Methods: A rat CIBP model was established by injecting Walker-256 cells into the tibia medullary cavity, and the expression of NOX4 in spinal dorsal horn was down-regulated by injecting lentivirus into spinal cord. RT-PCR, Western blot and immunofluorescence staining were used to detect the expression of NOX4 in CIBP rats, cell localization and its effect on CIBP rats, and the effect of down-regulating the expression of NOX4 on the expression of H2O2, nitric oxide synthase nNO, antioxidant enzyme SOD, and the activity of neuro-receptor in spinal dorsal horn of rats.Results: In rats with CIBP, the expression of NOX4 was significantly increased, and immunofluorescence showed that NOX4 was mainly expressed in microglia in the dorsal horn of spinal cord. Down-regulating the expression of NOX4 in rats can reduce the level of H2O2 and nNO in dorsal horn tissue, and increase the expression of SOD to reduce the oxidative stress response. At the same time, down-regulating NOX4 can reduce the sensitivity of spinal cord and relieve the pain of bone cancer by inhibiting the expression of NMDAR and GABAA-γ 2 in dorsal horn tissue.Conclusion: NOX4 is a promising therapeutic target in CIBP, and down-regulation of NOX4 expression can alleviate CIBP in rats by reducing oxidative stress and weakening spinal cord sensitization.Keywords: cancer-induced bone pain, NOX4, reactive oxygen species, spinal cord sensitization

Background The COVID-19 has spread to more than 200 countries and territories. But less is known about the knowledge, protection behavior and anxiety regarding the outbreak among the general population. Methods A cross-sectional, population-based online survey was conducted in China and abroad from January 28 to February 1, 2020. Socio-demographic information was collected and knowledge scores, practice scores, anxiety scores and perceived risk were calculated. General linear model and binary logistic regression were used to identify possible associations. Results We included 9,764 individuals in this study, and 156 (1.6%) were from Hubei Province. The average knowledge score was 4.7 (standard deviation, 1.0) (scored on a 6-point scale); 96.1% maintained hand hygiene, and 90.3% of participants had varying levels of anxiety. People in Hubei Province were the most anxious, followed by those in Beijing and Shanghai. People who had experienced risk behaviors did not pay more attention to wearing masks and hand hygiene. Conclusions The public had high awareness on knowledge of COVID-19 outbreak, and a high proportion of people practiced good hand hygiene behavior. Many people claimed anxiety, especially in heavily affected areas during pandemic, suggesting the importance of closing the gap between risk awareness and good practice and conduct psychological counseling to public and patients.

Background Postoperative pain after breast cancer surgery remains a major challenge in patient care. Local infiltration analgesia is a standard analgesic technique used for pain relief after surgery. Its application in patients who underwent mastectomy requires more clear elucidation. This study aimed to investigate the effect of ropivacaine infiltration of drainage exit site in ameliorating the postoperative pain after mastectomy. Methods A prospective randomized controlled study was conducted in 74 patients who were scheduled for unilateral mastectomy by standardized general anesthesia. Both intervention group and control group were given infiltration of the two entry points of drainage catheters with 10 ml 0.5% ropivacaine (Group A) (n = 37) or 10 ml normal saline (Group B) (n = 37). Pain scores were recorded in post-anesthesia care unit (PACU), at 6 h, 12 h, 24 h and 36 h after operation by using a visual analogue scale (VAS). Postoperative nausea and vomiting (PONV) incidence, postoperative analgesic and antiemetic requirements, the incidence of chronic pain, as well as the quality of recovery were recorded. Results The patients in Group A showed a significant reduction in postoperative pain in PACU (p p p p p p Conclusions Ropivacaine infiltration of the two drainage exit sites decreased the degree of postoperative acute pain after mastectomy, and this approach improved patients’ quality of recovery. Trial registration retrospectively registered in Chictr.org.cn registry system on 24 February 2020 (ChiCTR2000030139).

Background The relationship between sarcopenia and the prognoses of patients with gastric neuroendocrine neoplasms (g-NENs) is unclear. This study was designed to explore the effects of sarcopenia on short-term and long-term outcomes of patients with g-NENs after radical gastrectomy. Methods This study retrospectively collected data from 138 patients with g-NENs after radical gastrectomy. The skeletal muscle index (SMI) diagnostic threshold for sarcopenia was determined using X-tile software. Cox regression analyses were performed to determine the independent risk factors for 3-year overall survival (OS) and 3-year recurrence-free survival (RFS). Results In this study, 59 patients (42.8%) were diagnosed with sarcopenia. Among patients in the sarcopenia group and nonsarcopenia group, the incidences of total postoperative complications were 33.9 and 30.4%, incidences of serious postoperative complications were 0 and 3.7%, incidences of postoperative surgical complications were 13.6 and 15.2%, and incidences of postoperative systemic complications were 20.3 and 15.2%, respectively (all p > 0.05). The 3-year OS and RFS rates were significantly worse in the sarcopenia group than in the nonsarcopenia group (OS: 42.37% vs 65.82%, p = 0.004; RFS: 52.54% vs 68.35%, p = 0.036). The multivariate analysis revealed a relation between sarcopenia and the long-term prognoses of patients with g-NENs. A stratified analysis based on the pathological type revealed that the Kaplan-Meier curve was only significantly different in patients with gastric mixed adenoneuroendocrine carcinoma (gMANEC) (OS: 40.00% vs 71.79%, p = 0.007; RFS: 51.43% vs 74.36%, p = 0.026); furthermore, the multivariate analysis identified sarcopenia as an independent risk factor for patients with gMANEC (p Conclusions Sarcopenia is not related to the short-term prognoses of patients with g-NENs. Sarcopenia is an independent risk factor for patients with gMANEC after radical surgery.

Opioids, like morphine and naloxone, regulate the proliferation and neuronal differentiation of neural stem cells (NSCs) in a receptor-independent and ten-eleven translocation methylcytosine dioxygenase (TET1)-dependent manner in vitro. Whether naloxone regulates hippocampal NSCs and contextual learning in vivo in a similar manner was determined. Naloxone infusion increased the Ki67 and Doublecortin positive cells in subgranular zone of wild type mice, which suggested the increased proliferation and differentiation of hippocampal NSCs in vivo and was consistent with the in vitro functions of naloxone. In addition, naloxone infusion also facilitated the contextual learning and memory of wild type mice. To determine the contribution of μ-opioid receptor (OPRM1) and TET1 to these functions of naloxone, several types of knockout mice were used. Since Tet1-/- mice have high deficiency in contextual learning and memory, Tet1+/- mice were used instead. The abilities of naloxone to regulate NSCs and to facilitate contextual learning were significantly impaired in Tet1+/- mice. In addition, these abilities of naloxone were not affected in Oprm1-/- mice. Therefore, naloxone facilitates contextual learning and memory in a receptor-independent and Tet1-dependent manner, which provides new understanding on the receptor-independent functions of opioids.

Background The benefits of neoadjuvant therapy for patients with locally advanced gastric cancer (GC) are increasingly recognized. The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual first proposed ypTNM staging, but its accuracy is controversial. This study aims to develop a modified ypTNM staging. Patients and Methods Clinicopathological data of 1,791 patients who underwent curative-intent gastrectomy after neoadjuvant therapy in the Surveillance, Epidemiology, and End Results database, as the development cohort, were retrospectively analyzed. Modified ypTNM staging was established based on overall survival (OS). We compared the prognostic performance of the AJCC 8th edition ypTNM staging and the modified staging for patients after neoadjuvant therapy. Results In the development cohort, the 5-year OS for AJCC stages I, II, and III was 58.8%, 39.1%, and 21.6%, respectively, compared with 69.9%, 54.4%, 34.4%, 24.1%, and 13.6% for modified ypTNM stages IA, IB, II, IIIA, and IIIB. The modified staging had better discriminatory ability (C-index: 0.620 vs. 0.589, p < .001), predictive homogeneity (likelihood ratio chi-square: 140.71 vs. 218.66, p < .001), predictive accuracy (mean difference in Bayesian information criterion: 64.94; net reclassification index: 35.54%; integrated discrimination improvement index: 0.032; all p < .001), and model stability (time-dependent receiver operating characteristics curves) over AJCC. Decision curve analysis showed that the modified staging achieved a better net benefit than AJCC. In external validation (n = 266), the modified ypTNM staging had superior prognostic predictive power (all p < .05). Conclusion We have developed and validated a modified ypTNM staging through multicenter data that is superior to the AJCC 8th edition ypTNM staging, allowing more accurate assessment of the prognosis of patients with GC after neoadjuvant therapy. Implications for Practice The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual first proposed ypTNM staging, but its accuracy is controversial. Based on multi-institutional data, this study developed a modified ypTNM staging, which is superior to the AJCC 8th edition ypTNM staging, allowing more accurate assessment of the prognosis of patients with gastric cancer after neoadjuvant therapy.

OBJECTIVES To explore the feasibility of shear wave elastography (SWE) in the evaluation of arterial erectile dysfunction (ED). METHODS From November 2018 to November 2019, 26 patients with arterial ED and 30 patients with non-vascular ED were prospectively included. SWE values of corpus cavernosum penis (CCP) and the flow velocity of cavernous artery for all patients in both before intracavernous injection (ICI) (flaccid state) and after ICI (erectile state) were measured. Performance of SWE value in assessing arterial ED was studied. Correlation between SWE value of CCP and the age of patients was also investigated. RESULTS ICI significantly reduced SWE values in both arterial and non-vascular group (from 19.57 ± 6.33 KPa to 12.17 ± 3.64 KPa in the first, and from 19.91 ± 6.69 KPa to 8.04 ± 3.13 KPa in the former, both P

Rationale: Kawasaki disease (KD) is an acute vasculitis of early childhood that can result in permanent coronary artery structural damage. The cause for this arterial vulnerability in up to 15% of patients with KD is unknown. Vascular smooth muscle cell dedifferentiation play a key role in the pathophysiology of medial damage and aneurysm formation, recognized arterial pathology in KD. Platelet hyperreactivity is also a hallmark of KD. We recently demonstrated that uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype in vivo. Objective: We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD. Methods and Results: We prospectively recruited and studied 242 patients with KD, 75 of whom had documented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR demonstrated that patient with KD platelets have significant induction of miR-223 compared with healthy controls (HCs). Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, patients with KD with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from patients with KD are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of PDGFRβ (platelet-derived growth factor receptor β). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD ( Lactobacillus casei cell wall extract injection), miR-223 knockout mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmentation of medial elastic fibers compared with WT mice, which demonstrated significant miR-223 induction upon Lactobacillus casei cell wall extract challenge. The excessive arterial damage in the miR-223 knockout could be rescued by adoptive transfer of platelet, administration of miR-223 mimics, or the PDGFRβ inhibitor imatinib mesylate. Interestingly, miR-223 levels progressively increase with age, with the lowest levels found in Conclusions: Platelet-derived miR-223 (through PDGFRβ inhibition) promotes VSMC differentiation and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coronary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in patients with KD (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRβ represents potential therapeutic strategies to alleviate coronary pathology in KD. Graphic Abstract: A graphic abstract is available for this article.

Acupuncture is commonly used for migraine prophylaxis; however, evidence of its efficacy was equivocal. We aimed to evaluated the efficacy of acupuncture in migraine prophylaxis and calculated the required information size (RIS) to determine whether further clinical studies are required. We searched Cochrane library, EMBASE and PubMed from inception to April 23th, 2020. Randomized trials that compared acupuncture with conventional drug therapy or sham acupuncture were included. The primary outcome was migraine episodes. Secondary outcomes were responder rate and adverse event. Twenty studies (n = 3380) met the inclusion criteria. When it comes to migraine episodes, Acupuncture was superior over sham acupuncture [SMD = − 0.29, 95% CI (− 0.47 to − 0.11), P = 0.002] after treatment, while the difference between acupuncture and prophylactic drugs was not significant [SMD = − 0.21, 95% CI (− 0.42 to 0.00), P = 0.06].Both TSA graphs indicated that more RCTs are needed. As for responder rate, the results after treatment showed that acupuncture was statistically significantly better than sham acupuncture [RR 1.30, 95% CI (1.09–1.55), P = 0.003] as well as conventional drugs [RR 1.24, 95% CI (1.04–1.48), P = 0.01]. Both of their cumulative Z-curves intersected with the trial sequential monitoring boundaries favoring acupuncture. Compared to prophylactic medication, acupuncture can cause less adverse events [RR 0.34, 95% CI (0.14–0.81), P = 0.01]. Acupuncture can reduce migraine episodes compared to sham one and can be an alternative and safe prophylactic treatment for conventional drugs therapy, but it should be further verified through more RCTs. Available studies suggested acupuncture was superior to sham acupuncture and conventional drugs in terms of responder rate as verified by TSA.

BACKGROUND: Postoperative delirium is associated with adverse postoperative outcomes. However, whether intravenous and inhalation anesthetics are associated with different risks of postoperative delirium remains unknown. OBJECTIVE: We set up to determine the incidence and duration of postoperative delirium in older patients who had surgery under the intravenous anesthetic propofol or the inhalational anesthetic sevoflurane. METHODS: Participants were patients who had total hip/knee replacements and were randomized to propofol (N = 106) or sevoflurane (N = 103) anesthesia group. The Confusion Assessment Method was employed by investigators who were blinded to the anesthesia regimen to assess the incidence and duration (days of postoperative delirium per person) of postoperative delirium on postoperative days 1, 2 and 3. RESULTS: A total of 209 participants (71.2 ± 6.7 years old, 29.2% male) were included in the final data analysis. The incidence of postoperative delirium was 33.0% with propofol anesthesia and 23.3% with sevoflurane anesthesia (P = 0.119, Chi-square test), and we estimated that we would need 316 participants in each arm to detect a potential statistically significant difference. Days of postoperative delirium per person were higher in the propofol (0.5 ± 0.8) anesthesia group compared to the sevoflurane anesthesia group (0.3 ± 0.5, P = 0.049, Student’s t-test). CONCLUSION: This pilot study established a system to compare effects of different anesthetics and generated a hypothesis that propofol trended to have a higher incidence and had longer duration of postoperative delirium than sevoflurane. Additional studies with a larger sample size are needed to test this hypothesis.

Purpose To investigate the clinico-radiological findings and outcomes in pregnant women with COVID-19 pneumonia compared to age-matched non-pregnant women. Methods A retrospective case-controlled study was conducted to review clinical and CT data of 21 pregnant and 19 age-matched non-pregnant women with COVID-19 pneumonia. Four stages of CT images were analyzed and compared based on the time interval from symptom onset: stage 1 (0-6 days), stage 2 (7-9 days), stage 3 (10-16 days), and stage 4 (>16 days). The initial and follow-up data were analyzed and compared. Results Compared with age-matched non-pregnant women, initial absence of fever (13/21, 62%) and normal lymphocyte count (11/21, 52%) were more frequent in pregnant group. The predominant patterns of lung lesions were pure ground-glass opacity (GGO), GGO with consolidation or reticulation, and pure consolidation in both groups. Pure consolidation on chest CT was more common at presentation in pregnant cases. Pregnant women progressed with a higher consolidation frequency compared with non-pregnant group in stage 2 (95% vs 82%). Improvement was identified in stages 3 and 4 for both groups, but consolidation was still more frequent for pregnant women in stage 4. Most patients (38/40, 95%) were grouped as mild or common type. The length of hospitalization between the two groups was similar. Conclusion Pregnant women with COVID-19 pneumonia did not present typical clinical features, while developing a relatively more severe disease at imaging with a slower recovery course and experiencing similar outcomes compared with the non-pregnant women.