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Abstract Background Off-label intranasal administration of injectable dexmedetomidine has been widely applied in the pediatric sedation setting. However, the development of an improved drug delivery system that is easy to use is needed. We developed a novel dexmedetomidine nasal spray that can be administered directly without dilution or configuration for pediatric pre-anesthetic sedation. This nasal spray has a fixed dose and is stable during storage. To the best of our knowledge, this is the first licensed nasal spray preparation of dexmedetomidine worldwide. Objective To evaluate the pre-anesthetic sedation efficacy and safety of the novel dexmedetomidine nasal spray in children. Methods The study was conducted at 11 sites in China between 24 November 2021 and 20 May 2022 and was registered in ClinicalTrials.gov (NCT05111431, first registration date: 20/10/2021). Subjects (n = 159) between 2 and 6 years old who were to undergo elective surgery were randomized to the dexmedetomidine group (n = 107) or the placebo group (n = 52) in a 2:1 ratio. The dosage was 30 µg or 50 µg based on the stratified body weight. The primary outcome measure was the proportion of subjects who achieved the desired child-parent separation and Ramsay scale ≥ 3 within 45 min of administration. Safety was monitored via the assessments of adverse events, blood pressure, heart rate, respiratory rate and blood oxygen saturation. Results The proportion of subjects achieving desired parental separation and Ramsay scale ≥ 3 within 45 min was significantly higher in the dexmedetomidine group (94.4%) vs the placebo group (32.0%) (P

Abstract Background Both body mass index (BMI) and genetic factors independently contribute to cardiovascular disease (CVD). However, it is unclear whether genetic risk modifies the association between BMI and the risk of incident CVD. This study aimed to investigate whether BMI categories and genetic risk jointly and interactively contribute to incident CVD events, including hypertension (HTN), atrial fibrillation (AF), coronary heart disease (CHD), stroke, and heart failure (HF). Methods A total of 496,851 participants from the UK Biobank with one or more new-onset CVD events were included in the analyses. BMI was categorized as normal weight (

Abstract Background Both ambient air pollution and lifestyle factors contribute to the incidence of non-alcoholic fatty liver disease (NAFLD), but previous studies usually focused on single-factor associations. We aimed to assess the joint associations of ambient air pollution and lifestyle with the NAFLD risk and investigate whether lifestyle modifies the association of air pollution with NAFLD risk. Methods A total of 417,025 participants from the UK Biobank were included in this study. Annual average concentrations of NO2, NOx, PM2.5, PM10, and PM2.5−10 were estimated. A composite lifestyle score was determined based on physical activity, alcohol intake, smoking status, dietary patterns, sedentary time, and sleep duration. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs), as well as the population attributable fraction (PAF). Potential additive interactions of air pollution with lifestyle were also examined by the relative excess risk due to the interaction (RERI) and the attributable proportion due to the interaction (AP). Results 4752 (1.14%) incident NAFLD events were recorded. Long-term exposure to air pollutants and an unhealthy lifestyle were significantly associated with the increased risk of incident NAFLD. Lifestyle was the primary factor of incident NAFLD, with a PAF of 37.18% (95% CI: 29.67%, 44.69%). In addition, a significant additive interaction between air pollution and lifestyle for NAFLD risk was observed (RERI: 0.36, 95% CI: 0.09–0.63). Conclusions Long-term exposure to ambient air pollutants and poor lifestyle were jointly associated with a higher risk of NAFLD.

Spinal cord injury (SCI) is a severe disease of the nervous system that causes irreparable damage and loss of function, for which no effective treatments are available to date. Engineered extracellular vesicles (EVs) carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy. In this study, we demonstrated the design of a drug delivery system of peptide CAQK-modified, siRNA-loaded EVs (C-EVs-siRNA) for SCI-targeted therapy. The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells (iNSCs). CCL2-siRNA was then loaded into the EVs through electroporation. The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo. C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells. C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA, thus enhancing the therapeutic effect against SCI. The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI, promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI. Thus, engineered EVs are a potentially feasible and efficacious treatment for SCI, and may also be used to develop targeted treatments for other diseases.

Background: Which noninvasive brain stimulation (NIBS) treatment – transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) – is more beneficial for stroke patients’ cognitive rehabilitation is still up for debate. Objectives: Our goal is to provide an overview of the research on the effectiveness and safety of various NIBS protocols. Design: Systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs). Methods: This NMA compared any active NIBS versus sham stimulation in adult stroke survivors to enhance cognitive function, with a focus on global cognitive function (GCF), attention, memory, and executive function (EF) using the databases MEDLINE, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov. The NMA statistical approach was built on a frequency framework. The effect size was estimated by the standardized mean difference (SMD) and a 95% confidence interval (CI). We compiled a relative ranking of the competing interventions based on their surface under the cumulative ranking curve (SUCRA). Results: NMA showed that high-frequency repeated TMS (HF-rTMS) improved GCF compared with sham stimulation (SMD = 1.95; 95% CI: 0.47–3.43), while dual-tDCS improved memory performance versus sham stimulation significantly (SMD = 6.38; 95% CI: 3.51–9.25). However, various NIBS stimulation protocols revealed no significant impact on enhancing attention, executive function, or activities of daily living. There was no significant difference between the active stimulation protocols for TMS and tDCS and sham stimulation in terms of safety. Subgroup analysis demonstrated an effect favoring activation site of the left dorsolateral prefrontal cortex (DLPFC) (SUCRA = 89.1) for enhancing GCF and bilateral DLPFC (SUCRA = 99.9) stimulation for enhancing memory performance. Conclusion: The HF-rTMS over the left DLPFC appears to be the most promising NIBS therapeutic option for improving global cognitive performance after stroke, according to a comparison of numerous NIBS protocols. Furthermore, for patients with post-stroke memory impairment, dual-tDCS over bilateral DLPFC may be more advantageous than other NIBS protocols. Both tDCS and TMS are reasonably safe. Registration: PROSPERO ID: CRD42022304865

Abstract Background Long non-coding RNAs (lncRNA) have been implicated in a hand of studies that supported an involvement and co-operation in Uterine Corpus Endometrial Carcinoma (UCEC). Enhancer RNAs (eRNA), a functional subtype of lncRNA, have a key role throughout the genome to guide protein production, thus potentially associated with diseases. Methods In this study, we mainly applied the Cancer Genome Atlas (TCGA) dataset to systematically discover crucial eRNAs involving UCEC. For the key eRNAs in UCEC, we employed RT-qPCR to compare eRNA expression levels in tumor tissues and paired normal adjacent tissues from UCEC patients for validation. Furthermore, the relationships between the key eRNAs and immune activities were measured from several aspects, including the analysis for tumor microenvironment, immune infiltration cells, immune check point genes, tumor mutation burden, and microsatellite instability, as well as m6A related genes. Finally, the key eRNAs were verified by a comprehensive pan-cancer analysis. Results IGFBP7 Antisense RNA 1 (IGFBP7-AS1) was identified as the key eRNA for its expression patterns of low levels in tumor tissues and favorable prognostic value in UCEC correlated with its target gene IGFBP7. In RT-qPCR analysis, IGFBP7-AS1 and IGFBP7 had down-regulated expression in tumor tissues, which was consistent with previous analysis. Moreover, IGFBP7-AS1 was found closely related with immune response in relevant immune analyses. Besides, IGFBP7-AS1 and its target gene IGFBP7 correlated with a multi-omics pan-cancer analysis. Conclusions Finally, we suggested that IGFBP7-AS1 played a key role in impacting on clinical outcomes of UCEC patients for its possible influence on immune activity.

Abstract Background Spinal cord ischemia reperfusion injury (SCIRI) is a complication of aortic aneurysm repair or spinal cord surgery that is associated with permanent neurological deficits. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been shown to be potential therapeutic options for improving motor functions after SCIRI. Due to their easy access and multi-directional differentiation potential, adipose‐derived stem cells (ADSCs) are preferable for this application. However, the effects of ADSC-derived sEVs (ADSC-sEVs) on SCIRI have not been reported. Results We found that ADSC-sEVs inhibited SCIRI-induced neuronal apoptosis, degradation of tight junction proteins and suppressed endoplasmic reticulum (ER) stress. However, in the presence of the ER stress inducer, tunicamycin, its anti-apoptotic and blood–spinal cord barrier (BSCB) protective effects were significantly reversed. We found that ADSC-sEVs contain tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) whose overexpression inhibited ER stress in vivo by modulating the PI3K/AKT pathway. Conclusions ADSC-sEVs inhibit neuronal apoptosis and BSCB disruption in SCIRI by transmitting TSG-6, which suppresses ER stress by modulating the PI3K/AKT pathway.

Uterine corpus endometrial carcinoma (UCEC) is a malignant disease globally, and there is no unified prognostic signature at present. In our study, two clusters were identified. Cluster 1 showed better prognosis and higher infiltration level, such as tumor microenvironment (TME), tumor mutation burden (TMB), and immune checkpoint genes expression. Gene set enrichment analysis (GSEA) indicated that some tumor-related pathways and immune-associated pathways were exposed. What is more, six pyroptosis-related long noncoding RNAs (lncRNAs) (PRLs) were applied to establish a prognostic signature through multiple Cox regression analysis. In both training and testing sets, patients with higher risk score had poorer survival than patients with low risk. The area under the curve (AUC) of receiver operating characteristic (ROC) curves performed that the survival probability was better in people with lower risk score. Mechanism analysis revealed that high risk score was correlated with reduced immune infiltration and T cells exhaustion, matching the definition of an “immune-desert” phenotype. Patients with lower risk score were characterized by higher immune checkpoint gene expression and TMB and have a sensitive response to immunotherapy and chemotherapy compared with patients with high risk score. The signature has accurate prediction ability of UCEC and is a promising therapeutic target to improve the effect of immunotherapy.

Abstract Background Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small‐scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first‐line treatment in locally advanced or metastatic LSCC. Methods Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression‐free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45‐Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses. Results The median duration of follow‐up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF‐α, IFN‐γ, IL‐6, and IL‐8, demonstrating an overlapping trend. Conclusion The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.

Pyroptosis, a form of inflammatory programmed cell death, is accompanied by inflammation and participate in the body's immune response. The expression of pyroptosis-related genes (PRGs) is associated with tumor prognosis in ovarian cancer (OC), but it is still unknown whether pyroptosis can affect tumor immune microenvironment (TME) of OC. Based on 30 PRGs, we comprehensively assessed the pyroptosis patterns by using PRGscore and correlated them with TME features in 474 OC patients. Finally, we identified three pyroptosis modification patterns and TME immune characteristics of these patterns were in response to three immune phenotypes (immune-desert, immune-inflamed, and immune-excluded phenotypes). PRGscore can predict patient survival, staging, grading, and immunotherapy efficacy. Low PRGscore was associated with better survival advantage and increased mutation burden. Low PRGscore patients showed significantly better therapeutic effects and clinical results in chemotherapy and immunotherapy. Besides, the capability of PRGscore in predicting prognosis and immunotherapy sensitivity was further verified in other three tumor cohorts. In conclusion, the comprehensive assessment of OC pyroptosis modifications can help enhancing our understanding of TME immune infiltration and provide better personalized treatment tactics for OC patients.

Background. The exosome is of vital importance throughout the entire progression of cancer. Because of the lack of effective biomarkers in ovarian cancer (OV), we intend to investigate the connection between exosomes and tumor immune microenvironment to verify that exosome-related genes (ERGs) can precisely forecast the prognosis of OV patients. Methods. First, 117 ERGs in The Cancer Genome Atlas (TCGA) dataset were recognized. Afterwards, the risk signature consisting of four ERGs with prognostic significance was built by univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis. We also validated the risk signature by Kaplan-Meier analysis, receiver operating characteristic curve analysis and principal component analysis. Furthermore, gene set enrichment analysis was performed to compare the enrichment patterns between the two risk subgroups. The connections between the exosome-related gene risk score (ERGRS) and clinical features, immune infiltration, immune checkpoint-related genes, copy number variation, and drug sensitivity were explored. We also assessed the function of the ERGRS to forecast immunotherapeutic efficacy by immunophenoscore (IPS). Results. The high-risk group had a worse prognosis than the group with low risk. We verified that the established model possessed a relatively good prognostic value. Pathway enrichment analysis indicated that the genome-wide group with low risk was enriched in immune-related pathways. We discovered that resting dendritic cells and stromal scores were upregulated in patients with high risk in the TCGA and Gene Expression Omnibus (GEO) cohorts. Moreover, the expression of six common immune checkpoint inhibitor targets was assessed, which revealed that the expression levels of CD274 (PD-L1), PDCD1 (PD-1), and IDO1 in patients with high risk were lower than those in patients with low risk. Afterwards, the low-risk group had higher IPS across the four immunotherapies, implying that it had better effects of immunotherapies. Conclusion. Our study demonstrates that the exosome-related gene risk model is closely associated with immune infiltration. It can well forecast the prognosis of OV patients and guide the selection of immunotherapeutic strategies.

Osteosarcoma (OS) is a malignant bone tumor that mainly occurs in adolescents. It is accompanied by a high rate of lung metastasis, and high mortality. Recent studies have suggested the important roles of tripartite motif-containing (TRIM) family proteins in regulating various substrates and signaling pathways in different tumors. However, the detailed functional role of TRIM family proteins in the progression of OS is still unknown and requires further investigations. In this study, we found that tripartite motif-containing 22 (TRIM22) was downregulated in OS tissues and was hence associated with better prognosis. In vitro and in vivo functional analysis demonstrated that TRIM22 inhibits proliferation and metastasis of OS cells. Nuclear factor erythroid 2-related factor 2 (NRF2), a redox regulator, was identified as a novel target for TRIM22. TRIM22 interacts with and accelerates the degradation of NRF2 by inducing its ubiquitination dependent on its E3 ligase activity but independent of Kelch-like ECH-associated protein 1 (KEAP1). Further, a series of gain- and loss-of-function experiments showed that knockdown or overexpression of NRF2 reversed the functions of knockdown or overexpression of TRIM22 in OS. Mechanistically, TRIM22 inhibited OS progression through NRF2-mediated intracellular reactive oxygen species (ROS) imbalance. ROS production was significantly promoted and mitochondrial potential was remarkably inhibited when overexpressing TRIM22, thus activating AMPK/mTOR signaling. Moreover, TRIM22 was also found to inhibit Warburg effect in OS cells. Autophagy activation was found in OS cells which were overexpressed TRIM22, thus leading to autophagic cell death. Treatment with N-Acetylcysteine (NAC), a ROS scavenger or the autophagy inhibitor 3-Methyladenine (3-MA) abolished the decreased malignant phenotypes in TRIM22 overexpressing OS cells. In conclusion, our study indicated that TRIM22 inhibits OS progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating ROS/AMPK/mTOR/Autophagy signaling that leads to autophagic cell death in OS. Therefore, our findings indicated that targeting TRIM22/NRF2 could be a promising therapeutic target for treating OS.

Abstract Background Obesity is a globally increasing health epidemic requiring early lifestyle intervention. Our main objective was to examine the effectiveness of companion-intensive multi-aspect weight management (CIMWM) in Chinese adults with obesity. Methods In this 6-month, prospective, open-label, multicenter, randomized controlled clinical trial, we recruited 272 obese adults aged 18–50 years with a body mass index (BMI) ≥ 28.0 kg/m2 and capable of using smartphones. CIMWM (n = 136) offered both daily online instructions and monthly face-to-face guidance by physicians, dietitians, and health managers along with the provision of meal replacements in the first 3 months. Traditional multi-aspect weight management (TMWM, n = 136) provided monthly face-to-face guidance by the same panel of professionals and the same meal replacements as CIMWM group, but required subjects to complete daily self-monitoring instead of offering daily online instructions. Body composition and metabolic parameters were assessed at baseline, 1, 2, 3, and 6 months by physicians. The primary outcomes were clinically-significant weight loss and changes in BMI and body composition. Results Participants in both groups showed significantly reduced BMI, body fat mass (BFM), visceral fat area (VFA), and HOMA-IR (p

Objective: Cardiovascular disease (CVD) is one of the leading causes of death worldwide, and answers are urgently needed regarding many aspects, particularly risk identification and prognosis prediction. Real-world studies with large numbers of observations provide an important basis for CVD research but are constrained by high dimensionality, and missing or unstructured data. Machine learning (ML) methods, including a variety of supervised and unsupervised algorithms, are useful for data governance, and are effective for high dimensional data analysis and imputation in real-world studies. This article reviews the theory, strengths and limitations, and applications of several commonly used ML methods in the CVD field, to provide a reference for further application. Methods: This article introduces the origin, purpose, theory, advantages and limitations, and applications of multiple commonly used ML algorithms, including hierarchical and k-means clustering, principal component analysis, random forest, support vector machine, and neural networks. An example uses a random forest on the Systolic Blood Pressure Intervention Trial (SPRINT) data to demonstrate the process and main results of ML application in CVD. Conclusion: ML methods are effective tools for producing real-world evidence to support clinical decisions and meet clinical needs. This review explains the principles of multiple ML methods in plain language, to provide a reference for further application. Future research is warranted to develop accurate ensemble learning methods for wide application in the medical field.

Background: Emerging evidence shows that genome instability-related long non-coding RNAs (lncRNAs) contribute to tumor–cell proliferation, differentiation, and metastasis. However, the biological functions and molecular mechanisms of genome instability-related lncRNAs in endometrial cancer (EC) are underexplored.Methods: EC RNA sequencing and corresponding clinical data obtained from The Cancer Genome Atlas (TCGA) database were used to screen prognostic lncRNAs associated with genomic instability via univariate and multivariate Cox regression analysis. The genomic instability-related lncRNA signature (GILncSig) was developed to assess the prognostic risk of high- and low-risk groups. The prediction performance was analyzed using receiver operating characteristic (ROC) curves. The immune status and mutational loading of different risk groups were compared. The Genomics of Drug Sensitivity in Cancer (GDSC) and the CellMiner database were used to elucidate the relationship between the correlation of prognostic lncRNAs and drug sensitivity. Finally, we used quantitative real-time PCR (qRT-PCR) to detect the expression levels of genomic instability-related lncRNAs in clinical samples.Results: GILncSig was built using five lncRNAs (AC007389.3, PIK3CD-AS2, LINC01224, AC129507.4, and GLIS3-AS1) associated with genomic instability, and their expression levels were verified using qRT-PCR. Further analysis revealed that risk score was negatively correlated with prognosis, and the ROC curve demonstrated the higher accuracy of GILncSig. Patients with a lower risk score had higher immune cell infiltration, a higher immune score, lower tumor purity, higher immunophenoscores (IPSs), lower mismatch repair protein expression, higher microsatellite instability (MSI), and a higher tumor mutation burden (TMB). Furthermore, the level of expression of prognostic lncRNAs was significantly related to the sensitivity of cancer cells to anti-tumor drugs.Conclusion: A novel signature composed of five prognostic lncRNAs associated with genome instability can be used to predict prognosis, influence immune status, and chemotherapeutic drug sensitivity in EC.

BackgroundFew studies have answered the guiding significance of individual components of the Framingham risk score (FRS) to the risk of cardiovascular disease (CVD) after antihypertensive treatment. This study on the systolic blood pressure intervention trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD-BP) aimed to reveal previously undetected association patterns between individual components of the FRS and heterogeneity of treatment effects (HTEs) of intensive blood pressure control.MethodsA self-organizing map (SOM) methodology was applied to identify CVD-risk-specific subgroups in the SPRINT (n = 8,773), and the trained SOM was utilized directly in 4,495 patients from the ACCORD. The primary endpoints were myocardial infarction (MI), non-myocardial infarction acute coronary syndrome (non-MI ACS), stroke, heart failure (HF), death from CVD causes, and a primary composite cardiovascular outcome. Cox proportional hazards models were then used to explore the potential heterogeneous response to intensive SBP control.ResultsWe identified four SOM-based subgroups with distinct individual components of FRS profiles and the CVD risk. For individuals with type 2 diabetes mellitus (T2DM) in the ACCORD or without diabetes in the SPRINT, subgroup I characterized by male with the lowest concentrations for total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol measures, experienced the highest risk for major CVD. Conversely, subgroup III characterized by a female with the highest values for these measures represented as the lowest CVD risk. Furthermore, subgroup II, with the highest systolic blood pressure (SBP) and no antihypertensive agent use at baseline, had a significantly greater frequency of non-MI ACS under intensive BP control, the number needed to harm (NNH) was 84.24 to cause 1 non-MI ACS [absolute risk reduction (ARR) = −1.19%; 95% CI: −2.08, −0.29%] in the SPRINT [hazard ratio (HR) = 3.62; 95% CI: 1.33, 9.81; P = 0.012], and the NNH of was 43.19 to cause 1 non-MI ACS (ARR = −2.32%; 95% CI: −4.63, 0.00%) in the ACCORD (HR = 1.81; 95% CI: 1.01–3.25; P = 0.046). Finally, subgroup IV characterized by mostly younger patients with antihypertensive medication use and smoking history represented the lowest risk for stroke, HF, and relatively low risk for death from CVD causes and primary composite CVD outcome in SPRINT, however, except stroke, a low risk for others were not observed in ACCORD.ConclusionSimilar findings in patients with hypertensive with T2DM or without diabetes by multivariate subgrouping suggested that the individual components of the FRS could enrich or improve CVD risk assessment. Further research was required to clarify the potential mechanism.

Increasing evidence indicates that lymphocyte cytosolic protein 1 (LCP1) overexpression contributes to tumor progression; however, its role in osteosarcoma (OS) remains unclear. We aimed to investigate the potential effect of LCP1 in OS and the underlying mechanisms. We first demonstrated that LCP1 is upregulated in OS cell lines and tissues. Then, we found that aberrant expression of LCP1 could induce the proliferation and metastasis of OS cells in vitro and in vivo by destabilizing neuregulin receptor degradation protein-1 (Nrdp1) and subsequently activating the JAK2/STAT3 signaling pathway. When coculturing OS cells with bone marrow-derived mesenchymal stem cells (BMSCs) in vitro, we validated that oncogenic LCP1 in OS was transferred from BMSCs via exosomes. Moreover, microRNA (miR)-135a-5p, a tumor suppressor, was found to interact upstream of LCP1 to counteract the pro-tumorigenesis effects of LCP1 in OS. In conclusion, BMSC-derived exosomal LCP1 promotes OS proliferation and metastasis via the JAK2/STAT3 pathway. Targeting the miR-135a-5p/LCP1 axis may have potential in treating OS.

Background: During the current COVID-19 pandemic, a link between acute cardiac injury and COVID-19 infection has been observed. There is currently no consensus on the incidence of cardiac injury, its relationship to prognosis, or its possible cause. In this article we provide a comprehensive review and meta-analysis of the incidence, comorbidities, outcomes, and possible mechanisms of acute cardiac injury in COVID-19 patients. Methods: We searched PubMed and Embase for studies that evaluated cardiac injury in hospitalized COVID-19 patients. Data on demographic information, comorbidities, and relevant laboratory values were extracted and a meta-analysis was performed. Results: Sixteen studies from China, Italy, and the United States with 2224 patients were included in this meta-analysis. The incidence of cardiac injury was 24.4% (542/2224 patients) in hospitalized COVID-19 patients. The all-cause mortality in patients with cardiac injury was 72.6% (odds ratio, 17.32; 95% confidence interval, 9.21-32.57) compared with those without cardiac injury (14.5%). In subgroup analyses, factors associated with increased risk of developing cardiac injury were older age and history of hypertension, and chronic obstructive respiratory disease. Conclusions: Cardiac injury is common in hospitalized COVID-19 patients and is significantly associated with mortality. Patients who were older with hypertension and chronic obstructive respiratory disease were prone to develop cardiac injury. Early screening, triage, and cardiac monitoring are recommended for these patients. Résumé: Contexte: Durant la pandémie de COVID-19 qui sévit actuellement, un lien a été observé entre l’infection par le virus de la COVID-19 et l’apparition de lésions cardiaques aiguës. À l’heure actuelle, il n’y a pas de consensus quant à l’incidence de telles lésions cardiaques, à leur lien avec le pronostic ou à leur cause possible. Nous présentons ici une revue exhaustive et une méta-analyse de l’incidence des lésions cardiaques aiguës chez les patients atteints de COVID-19 ainsi que des affections concomitantes, des issues et des mécanismes qui pourraient y être associés. Méthodologie: Nous avons effectué une recherche dans les bases de données PubMed et Embase afin de recenser les études évaluant les lésions cardiaques chez les patients atteints de COVID-19 admis à l’hôpital. Les caractéristiques démographiques des patients ainsi que les données sur les affections concomitantes et d’autres paramètres de laboratoire pertinents ont été extraites des études recensées, puis soumises à une méta-analyse. Résultats: La méta-analyse portait sur les données de 16 études réalisées en Chine, en Italie et aux États-Unis qui regroupaient 2 224 patients au total. L’incidence des lésions cardiaques chez les patients atteints de COVID-19 hospitalisés s’établissait à 24,4 % (542 patients sur 2 224). La mortalité toutes causes confondues chez les patients présentant des lésions cardiaques était de 72,6 % (rapport de cotes : 17,32; intervalle de confiance à 95 % : 9,21 à 32,57) comparativement à 14,5 % chez les patients sans lésions cardiaques. Dans les analyses par sous-groupe, les facteurs associés à un risque accru d’apparition de lésions cardiaques étaient l’âge plus avancé et des antécédents d’hypertension, ainsi que la présence d’une maladie respiratoire obstructive chronique. Conclusions: Les lésions cardiaques sont fréquentes chez les patients atteints de COVID-19 hospitalisés et sont associées de manière significative à la mortalité. Les patients plus âgés ayant des antécédents d’hypertension et atteints d’une maladie respiratoire obstructive chronique étaient plus susceptibles de présenter des lésions cardiaques. Un dépistage précoce, un triage approprié et une surveillance cardiaque sont recommandés chez ces patients.

Abstract Background The article aims to compare the efficiency of minimax, optimal and admissible criteria in Simon’s and Fleming’s two-stage design. Methods Three parameter settings (p 1-p 0 = 0.25–0.05, 0.30–0.10, 0.50–0.30) are designed to compare the maximum sample size, the critical values and the expected sample size for minimax, optimal and admissible designs. Type I & II error constraints (α, β) vary across (0.10, 0.10), (0.05, 0.20) and (0.05, 0.10), respectively. Results In both Simon’s and Fleming’s two-stage designs, the maximum sample size of admissible design is smaller than optimal design but larger than minimax design. Meanwhile, the expected samples size of admissible design is smaller than minimax design but larger than optimal design. Mostly, the maximum sample size and expected sample size in Fleming’s designs are considerably smaller than that of Simon’s designs. Conclusions Whenever (p 0, p 1) is pre-specified, it is better to explore in the range of probability q, based on relative importance between maximum sample size and expected sample size, and determine which design to choose. When q is unknown, optimal design may be more favorable for drugs with limited efficacy. Contrarily, minimax design is recommended if treatment demonstrates impressive efficacy.

BackgroundThis meta-analysis was designed to explore the relationship between the level of serum potassium and the treatment effect of epidermal growth factor receptor (EGFR) antagonist in advanced non-small cell lung cancer (aNSCLC).MethodsWe searched phase II/III prospective clinical trials on treatment with EGFR antagonists for aNSCLC patients. The objective response rate (ORR) and/or the disease control rate (DCR) and the incidence of hypokalemia of high grade (equal to or greater than grade 3) were summarized from all eligible trials. Heterogeneity, which was evaluated by Cochran’s Q-test and the I2 statistics, was used to determine whether a random effects model or a fixed effects model will be used to calculate pooled proportions. Subgroup analysis was performed on different interventions, line types, phases, and drug numbers.ResultsFrom 666 potentially relevant articles, 36 clinical trials with a total of 9,761 participants were included in this meta-analysis. The pooled ORR was 16.25% (95%CI = 12.45–21.19) when the incidence of hypokalemia was 0%–5%, and it increased to 34.58% (95%CI = 24.09–45.07) when the incidence of hypokalemia was greater than 5%. The pooled DCR were 56.03% (95%CI = 45.03–67.03) and 64.38% (95%CI = 48.60–80.17) when the incidence rates of hypokalemia were 0%–5% and greater than 5%, respectively. The results of the subgroup analysis were consistent with the results of the whole population, except for not first-line treatment, which may have been confounded by malnutrition or poor quality of life in long-term survival.ConclusionThe efficacy of anti-EGFR targeted therapy was positively associated with the hypokalemia incidence rate. Treatment effects on the different serum potassium strata need to be considered in future clinical trials with targeted therapy.

BackgroundAlthough COVID-19 vaccines hold the potential to dramatically alter the COVID-19 pandemic, vaccine hesitancy remains a serious threat to the management and control of COVID-19 infections. Vaccination of young adults plays a crucial role in achieving herd immunity. However, the determinants of COVID-19 vaccine acceptance among the youth in China have not been fully explored. Our study aims to investigate the direct and indirect effects of perceived health literacy on COVID-19 vaccine acceptance.MethodsThis survey was conducted among Chinese college students during September and October, 2020. COVID-19 vaccine acceptance was defined as the likelihood that participants would get a COVID-19 vaccine. A mediation analysis was employed to explore the direct and indirect effects of perceived health literacy on COVID-19 vaccine acceptance.ResultsA total of 2,587 college students were included in our study. The results of the survey revealed that the majority (80.40%) of the participants expressed high COVID-19 vaccine acceptance. After controlling for demographic characteristics, the relationship between perceived health literacy and COVID-19 vaccine acceptance was mediated by positive attitudes toward general vaccination (std.β = 0.004, p = 0.037) and self-efficacy of COVID-19 vaccine (std.β = 0.053, p < 0.001).ConclusionsThe findings suggest that interventions targeting health literacy to promote COVID-19 vaccination coverage might consider placing greater emphasis on enhancing the positive attitude towards and self-efficacy of vaccines among youth.

Endometrial cancer has the highest incidence of uterine corpus cancer, the sixth most typical cancer in women until 2020. High recurrence rate and frequent adverse events were reported in either standard chemotherapy or combined therapy. Hence, developing precise diagnostic and prognostic approaches for endometrial cancer was on demand. Four hypoxia-related genes were screened for the EC prognostic model by the univariate, LASSO, and multivariate Cox regression analysis from the TCGA dataset. QT-PCR and functional annotation analysis were performed. Associations between predicted risk and immunotherapy and chemotherapy responses were investigated by evaluating expressions of immune checkpoint inhibitors, infiltrated immune cells, m6a regulators, and drug sensitivity. The ROC curve and calibration plot indicated a fair predictability of our prognostic nomogram model. NR3C1 amplification, along with IL-6 and SRPX suppressions, were detected in tumor. High stromal score and enriched infiltrated aDCs and B cells in the high-risk group supported the hypothesis of immune-deserted tumor. Hypoxia-related molecular subtypes of EC were then identified via the gene signature. Cluster 2 patients showed a significant sensitivity to Vinblastine. In summary, our hypoxia signature model accurately predicted the survival outcome of EC patients and assessed translational and transcriptional dysregulations to explore targets for precise medical treatment.

BackgroundUterine corpus endometrial carcinoma (UCEC) is a gynecological malignant tumor with low survival rate and poor prognosis. The traditional clinicopathological staging is insufficient to estimate the prognosis of UCEC. It is necessary to select a more effective prognostic signature of UCEC to predict the prognosis and immunotherapy effect of UCEC.MethodsCIBERSORT and weighted correlation network analysis (WGCNA) algorithms were combined to screen modules related to regulatory T (Treg) cells. Subsequently, univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses were used to identify the genes in key modules. The difference in overall survival (OS) between high- and low-risk patients was analyzed by Kaplan–Meier analysis. The Tregs-related risk signature (TRRS) was screened by uni- and multivariate Cox analyses. Afterward, we analyzed the expression difference of TRRS and verified its ability to predict the prognosis of UCEC and the effect of immunotherapy.ResultsRed module has the highest correlation with Tregs among all clustered modules. Pathways enrichment indicated that the related processes of UCEC were primarily associated to the immune system. Eight genes (ZSWIM1, NPRL3, GOLGA7, ST6GALNAC4, CDC16, ITPK1, PCSK4, and CORO1B) were selected to construct TRRS. We found that this TRRS is a significantly independent prognostic factor of UCEC. Low-risk patients have higher overall survival than high-risk patients. The immune status of different groups was different, and tumor-related pathways were enriched in patients with higher risk score. Low-risk patients are more likely take higher tumor mutation burden (TMB). Meanwhile, they are more sensitive to chemotherapy than patients with high-risk score, which indicated a superior prognosis. Immune checkpoints such as PD-1, CTLA4, PD-L1, and PD-L2 all had a higher expression level in low-risk group. TRRS expression really has a relevance with the sensitivity of UCEC patients to chemotherapeutic drugs.ConclusionWe developed and validated a TRRS to estimate the prognosis and reflect the immune status of UCEC, which could accurately assess the prognosis of patients with UCEC and supply personalized treatments for them.

Background: As the fourth most common malignant tumors in women, uterine corpus endometrial carcinoma (UCEC) requires novel and reliable biomarkers for prognosis prediction to improve the overall survival. Oxidative phosphorylation (OXPHOS) is found to be strongly correlated with the progression of tumor. Here, we aimed to construct an OXPHOS-related and immune microenvironment prognostic signature to stratify UCEC patients for optimization of treatment strategies.Method: Prognosis-associated OXPHOS-related differentially expressed genes were identified by multivariable Cox regression from TCGA–UCEC cohort. Based on the candidate genes, an OXPHOS-related prognostic signature was constructed by the train set data and verified by the entire set. When integrated with relevant clinical characteristics, a nomogram was also created for clinical application. Through comparison of tumor microenvironment between different risk groups, the underlying mechanism of the model and the inner correlation between immune microenvironment and energy metabolism were further investigated.Results: An OXPHOS-related signature containing ATP5IF1, COX6B1, FOXP3, and NDUFB11 was constructed and had better predictive ability compared with other recently published signatures in UCEC. Patients with lower risk score showed higher immune cell infiltration, higher ESTIMATE score (p = 2.808E−18), lower tumor purity (p = 2.808E−18), higher immunophenoscores (IPSs) (p < 0.05), lower expression of mismatch repair (MMR) proteins (p < 0.05), higher microsatellite instability (MSI), lower expression of markers of N6-methyladenosine (m6A) mRNA methylation regulators, higher tumor mutation burden (TMB) (p = 1.278E−9), and more sensitivity to immune checkpoint blockade (ICB) (p < 0.001) and chemotherapy drugs, thus, possessing improved prognosis.Conclusion: An OXPHOS-related and immune microenvironment prognostic signature classifying EC patients into different risk subsets was constructed in our study, which could be used to predict the prognosis of patients and help to select a specific subset of patients who might benefit from immunotherapy and chemotherapy, thus, improving the overall survival rate of UCEC. These findings may contribute to the discovery of novel and robust biomarkers or target therapy in UCEC and give new insights into the molecular mechanism of tumorigenesis and progression of UCEC.

BackgroundOvarian cancer (OC) is an immunogenetic disease that contains tumor-infiltrating lymphocytes (TILs), and immunotherapy has become a novel treatment for OC. With the development of next-generation sequencing (NGS), profiles of gene expression and comprehensive landscape of immune cells can be applied to predict clinical outcome and response to immunotherapy.MethodsWe obtained data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and applied two computational algorithms (CIBERSORT and ESTIMATE) for consensus clustering of immune cells. Patients were divided into two subtypes using immune cell infiltration (ICI) levels. Then, differentially expressed genes (DEGs) associated with immune cell infiltration (ICI) level were identified. We also constructed ICI score after principle-component analysis (PCA) for dimension reduction.ResultsPatients in ICI cluster B had better survival than those in ICI cluster A. After construction of ICI score, we found that high ICI score had better clinical OS and significantly higher tumor mutation burden (TMB). According to the expression of immune checkpoints, the results showed that patients in high ICI group showed high expression of CTLA4, PD1, PD-L1, and PD-L2, which implies that they might benefit from immunotherapy. Besides, patients in high ICI group showed higher sensitivity to two first-line chemotherapy drugs (Paclitaxel and Cisplatin).ConclusionICI score is an effective prognosis-related biomarker for OC and can provide valuable information on the potential response to immunotherapy.

Backgroundrecently, many researches have concentrated on the relevance between N1-methyladenosine (m1A) methylation modifications and tumor progression and prognosis. However, it remains unknown whether m1A modification has an effect in the prognosis of ovarian cancer (OC) and its immune infiltration.MethodsBased on 10 m1A modulators, we comprehensively assessed m1A modification patterns in 474 OC patients and linked them to TME immune infiltration characteristics. m1Ascore computed with principal component analysis algorithm was applied to quantify m1A modification pattern in OC patients. m1A regulators protein and mRNA expression were respectively obtained by HPA website and RT-PCR in clinical OC and normal samples.ResultsWe finally identified three different m1A modification patterns. The immune infiltration features of these m1A modification patterns correspond to three tumor immune phenotypes, including immune-desert, immune-inflamed and immune-excluded phenotypes. The results demonstrate individual tumor m1A modification patterns can predict patient survival, stage and grade. The m1Ascore was calculated to quantify individual OC patient’s m1A modification pattern. A high m1Ascore is usually accompanied by a better survival advantage and a lower mutational load. Research on m1Ascore in the treatment of OC patients showed that patients with high m1Ascore showed marked therapeutic benefits and clinical outcomes in terms of chemotherapy and immunotherapy. Lastly, we obtained four small molecule drugs that may potentially ameliorate prognosis.ConclusionThis research demonstrates that m1A methylation modification makes an essential function in the prognosis of OC and in shaping the immune microenvironment. Comprehensive evaluation of m1A modifications improves our knowledge of immune infiltration profile and provides a more efficient individualized immunotherapy strategy for OC patients.

Up to 30 May 2021, the cumulative number of patients diagnosed with corona virus disease-19 (COVID-19) globally has exceeded 170 million, with more than 152 million patients recovered from COVID-19. However, the long-term effect of the virus infection on the human body’s function is unknown for convalescent patients. It was reported that about 63% of COVID-19 patients had observable lung damage on CT scans after being released from the hospital. Bufei Huoxue (BFHX) capsules, including three active ingredients of traditional Chinese herbal medicine, has been used clinically to prevent and treat pulmonary heart diseases with Qi deficiency and blood stasis syndrome. Some small-scale clinical trials have found that BFHX can improve lung ventilation function, reduce blood viscosity, and improve cardiopulmonary function. However, the efficacy and safety of BFHX in the treatment of the recovery phase of COVID-19 are unknown. This study is a multicenter, double-blinded, randomized, controlled trial. Subjects with convalescent COVID-19 were randomized (1:1) into either a BFHX or control group and observed for three months concomitant with receiving routine treatment. The primary efficacy indicators are the evaluation results and changes of the St. George’s Respiratory Questionnaire score, Fatigue Assessment Inventory, and 6-min walk distance. Based on the intention-to-treat principle, all randomly assigned participants will be included in the statistical analysis. The last visit’s outcomes will be used as the final outcomes for participants who prematurely withdraw from the trial. Per protocol set will pick up from the full analysis set for analysis. Efficacy analysis will be performed on the intention-to-treat datasets and per-protocol datasets. This study and its protocol were approved by the Ethics Committee of our University. Prior to participation, all subjects provided written informed consent. Results will be disseminated at medical conferences and in journal publications. We aimed to determine the efficacy and safety of BFHX for the treatment of the convalescent COVID-19 patients. Trial registration number: ChiCTR2000032573

Background: OV is the most lethal gynecological malignancy. M6A and lncRNAs have a great impact on OV development and patient immunotherapy response. In this paper, we decided to establish a reliable signature of mRLs. Method: The lncRNAs associated with m6A in OV were analyzed and obtained by co-expression analysis of the TCGA-OV database. Univariate, LASSO and multivariate Cox regression analyses were employed to establish the model of mRLs. K-M analysis, PCA, GSEA and nomogram based on the TCGA-OV and GEO database were conducted to prove the predictive value and independence of the model. The underlying relationship between the model and TME and cancer stemness properties were further investigated through immune feature comparison, consensus clustering analysis and pan-cancer analysis. Results: A prognostic signature comprising four mRLs, WAC-AS1, LINC00997, DNM3OS and FOXN3-AS1, was constructed and verified for OV according to the TCGA and GEO database. The expressions of the four mRLs were confirmed by qRT-PCR in clinical samples. Applying this signature, one can identify patients more effectively. The samples were divided into two clusters, and the clusters had different overall survival rates, clinical features and tumor microenvironments. Finally, pan-cancer analysis further demonstrated that the four mRLs were significantly related to immune infiltration, TME and cancer stemness properties in various cancer types. Conclusions: This study provided an accurate prognostic signature for patients with OV and elucidated the potential mechanism of the mRLs in immune modulation and treatment response, giving new insights into identifying new therapeutic targets.

Background: How to handle patients with anti-tumor necrosis factor (anti-TNF) failure was a common challenge to clinicians in Crohn’s disease (CD). The present study is dedicated to clarifying whether fecal microbiota transplantation (FMT) could be a switch therapy for patients with prior failure of infiiximab (IFX) in CD in a long-term observation.Methods: Thirty-six patients with CD who had prior failure of IFX were recruited from January 2013 to December 2019. The “one-hour FMT protocol” was followed in all patients. All patients received the first course of FMT through gastroscopy or mid-gut transendoscopic enteral tubing. After April 2014, the methodology of FMT was coined as washed microbiota transplantation (WMT), substituting for the manual methods, which is dependent on the automatic microbiota purification system and the washing process. The primary endpoint of this study was the clinical remission at one month and one year after FMT. The secondary endpoint was the safety of FMT in the short and long term, and clinical factors as predictors for long-term efficacy of FMT. Clinical factors as independent predictors of efficacy from FMT were isolated using univariable and multivariable logistic regression analysis.Results: There was no significant difference in the rates of clinical response and remission between IFX treatment stage and FMT treatment stage (at one month, three months and six months after administration) (p > 0.05). Compared with those of 19 patients who achieved clinical remission at one month after FMT, the rates of clinical relapse were significantly higher in 18 patients who achieved clinical remission at one month after IFX [log-rank test p = 0.0009 HR = 3.081 (95% CI 1.43–6.639)]. Multivariate analysis revealed that the gender of donor (95% CI: 0.001–0.72; p = 0.031) was an independent predictor of efficacy at one year after FMT. No serious adverse events (AEs) associated with FMT were observed during and after FMT. The rate of AEs was significantly lower in group FMT than that in group IFX (p = 0.002).Conclusion: The present findings first time provided the evidence for clinicians to consider FMT into practice as an alternative switch therapy for patients with prior loss of response or intolerance to IFX in CD.Clinical Trial Registration:https://clinicaltrials.gov, identifier NCT01793831

Abstract Background Ready-to-eat (RTE) vegetables have become increasingly popular along with the trend of moving towards a healthy lifestyle. However, RTE vegetables are at a higher risk of containing pathogens, maybe owing to lack of rigorous sanitization procedures. To understand the prevalence and potential risk of Listeria monocytogenes in RTE vegetables, we investigated the contamination level and characteristics of L. monocytogenes isolated from fresh vegetables. Results Twenty-three (5.49%) of the 419 vegetables samples were positive for L. monocytogenes. Phylogenetic group I.1 (1/2a-3a) and II.2 (1/2b-3b-7) strains were predominant in 30 isolates, which accounted for 33.3 and 50.0%, respectively. Multilocus sequence typing of the 30 isolates grouped them into nine sequence types (STs). The most common STs were ST87 (36.7%) and ST8 (26.7%). Virulence analysis showed that all 30 isolates harbored eight classical virulence genes, 10.0% isolates harbored the llsX gene (ST3 and ST1 strains), and 36.7% carried the ptsA gene and belonged to ST87. Approximately 83.3% isolates carried full-length inlA, whereas five isolates had premature stop codons in inlA, three of which belonged to ST9 and two to ST8. Antibiotic susceptibility showed the isolates were varyingly resistant to 13 antibiotics, 26.7% of the isolates were multi-drug resistant. Conclusions The fresh vegetables contain some potential hypervirulent L. monocytogenes (ST1 and ST87) in the Chinese markets. In addition, the high rate of L. monocytogenes isolates was multi-drug resistant. Fresh raw vegetables may be a possible transmission route for L. monocytogenes infection in consumers. Therefore, sanitization of raw fresh vegetables should be strengthened to ensure their microbiological safety when used as RTE vegetables.

Abstract Background Adequate bowel preparation is required for magnetic resonance enterography (MRE), which can be achieved by administering contrast solution after mid-gut tubing or taking contrast solution orally. We present the design of randomized controlled trial (RCT) to compare the efficacy and compliance of bowel preparation between mid-gut tubing and oral administering for MRE in patients with Crohn’s disease (CD). Methods/design This is an open-label, multicenter RCT. Ninety-six patients with CD in need of MRE examination and mid-gut tubing (prepared for fecal microbiota transplantation and/or enteral nutrition), aged ≥ 14 years, will be included. Patients will be randomized 1:1 into either bowel preparation by oral administering (oral group) or bowel preparation through mid-gut transendoscopic enteral tubing (TET) (tubing group). The primary outcome measures are: (1) degree of discomfort before/during/after bowel preparation for MRE using a visual 5-grade scale (1 = few, 5 = very severe); and (2) grade of bowel distention evaluated by a 5-grade scale (1 = 0–20% segmental distention, 2 = 20–40% distention, 3 = 40–60% distention, 4 = 60–80% distention, 5 = 80–100% distention). The secondary outcome measure is the accuracy of lesion detection through MRE confirmed by colonoscopy which is evaluated by a 5-point scale. Discussion The outcome of this study is expected to provide a novel effective clinical protocol of bowel preparation for MRE in patients with CD. We hope to highlight the concept of physician–patient satisfaction based on different methods of bowel preparation for MRE. Trial registration ClinicalTrials.gov, NCT03541733. Registered on 30 May 2018.

Redox plays a central part in the pathogeneses and development of tumors. We comprehensively determined the expression patterns of redox-related genes (RRGs) in endometrial carcinoma (EC) cohorts from public databases and identified four different RRG-related clusters. The prognosis and the characteristics of TME cell infiltration of RRGcluster C patients were worse than those of other RRG clusters. When it comes to the gene cluster, there were great differences in clinicopathology traits and immunocyte infiltration. The RRG score was calculated by Cox analyses, and an RRG-based signature was developed. The risk score performed well in the EC cohort. Samples were separated into two risk subgroups with the standard of the value of the median risk score. Low-risk patients had a better prognosis and higher immunogenicity. In addition, RRG score was closely associated with immunophenoscore, microsatellite instability, tumor mutation burden, tumor stem cell index, copy number variation and chemotherapy sensitivity. The nomogram accurately predicted the prognosis of patients, and our model showed better performance than other published models. In conclusion, we built a prognostic model of RRGs which can help to evaluate clinical outcomes and guide more effective treatment.

Background: Cap-assisted endoscopic sclerotherapy is a new interventional therapy for internal hemorrhoids and rectal prolapse under colonoscopy. The proper length of the endoscopic injection needle is the core for performing cap-assisted endoscopic sclerotherapy well with more benefits and less complications. However, no data are currently available to guide endoscopists to consider the length of injection needle before cap-assisted endoscopic sclerotherapy. This study is designed to evaluate the efficacy and safety of cap-assisted endoscopic sclerotherapy with long or short injection needle in the treatment of internal hemorrhoids. Methods: This is a nationwide multi-center, prospective, single-blind and randomized controlled trial. Patients with grade I-II internal hemorrhoids who have failed to conservative treatments and grade III internal hemorrhoids who are not suitable for surgery or refuse surgery will be included. Participants will be randomized 1:1 into either long or short injection needle group. The primary outcome is the recurrence rate of internal hemorrhoids 24 weeks after cap-assisted endoscopic sclerotherapy. The secondary outcomes are as follows: (1) symptom severity score, (2) three-level EuroQoL five dimensions health scale scores, (3) occurrence of adverse events and severe adverse events, and (4) patients’ attitudes toward cap-assisted endoscopic sclerotherapy. Data collection will be conducted before and during operation, the 1st day, 1st week, 2nd week, and 24th week after cap-assisted endoscopic sclerotherapy. Discussion: The outcome of this study is expected to provide a practical clinical protocol of cap-assisted endoscopic sclerotherapy for patients with internal hemorrhoids and promote the use of this new endoscopic technique. Trial registration: ClinicalTrials.gov, NCT03917056. Registered on 12 April 2019.

The aim of this study was to develop a potential microbial preservative to prevent the growth of fungi in food. The isolate ZC-G-5 showed strong antifungal activity against food spoilage fungi and Streptomyces albulus was identified on the basis of morphologic, culture, and 16S rDNA sequence analyses. The active metabolite was elucidated as tetramycin A (TMA) through spectroscopic techniques, including HR-ESI-MS, 1D-NMR, and 2D-NMR. An antifungal activity assay revealed that the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of TMA were 1.50–2.50 and 3.00–5.00 μg/ml, respectively. In situ antifungal activity analyses demonstrated that 90.0 μg/ml of TMA could inhibit the growth of fungi for over 14 days. In order to enhance TMA production, the high-yield mutant strain YB101 was screened, based on the isolate ZC-G-5, using a high-throughput screening method. The best metabolic precursor was selected during fermentation, when the concentration of glycerol was 8% (v/v) in Gauze’s broth medium to cultivate the mutant strain YB101; the concentration of TMA could be increased to 960.0 μg/ml, compared with the original isolate ZC-G-5, where the concentration of the TMA was only 225.0 μg/ml. Our study may contribute to the application of S. albulus and its active metabolite as a potential bio-preservative in the food industry.

Background: Physicians and medical students in the world do not have high awareness of fecal microbiota transplantation (FMT). This study aimed to explore the recognition and attitude of postgraduate medical students towards FMT and to create awareness for it. Methods: A self-administered questionnaire was distributed to first-year Chinese postgraduate medical students across six medical universities. Basic descriptive statistical analyses were performed. Results: A total of 1828 eligible questionnaires were included into analysis. 47.76% of students did not know FMT prior to this survey. Respondents with a high-level recognition of FMT were more willing to donate feces or receive FMT therapy than those with a low-level recognition (80.26% vs. 69.62%, p = 0.000 and 56.80% vs. 41.45%, p = 0.000). The respondents from a leading institution of FMT in China showed better awareness compared with others, and 42.26% of them knew about FMT from medical lectures. The main reasons for respondents not supporting FMT were: limited reported clinical evidence (67.94%), raw technology (42.56%), and lack of analysis of patient willingness or cost-effectiveness (36.71%). However, the life-saving value (84.41%), the automatic purification system (38.68%), low expenses (36.00%), and convenient delivering ways (35.67%) were the major considerations for supporting FMT. Conclusions: This study revealed the low recognition level of postgraduate medical students about FMT. Therefore, medical education should not neglect the knowledge of FMT. Studies of FMT and standardized FMT should be carried out to promote its development.

An amendment to this paper has been published and can be accessed via the original article.

Listeria monocytogenes is an important Gram-positive foodborne pathogen. However, limited information is available on the comprehensive investigation and potential risk of L. monocytogenes in fresh aquatic products, which are popular to consumers in China. This study aimed to determine the occurrence, virulence profiles, and population diversity of L. monocytogenes isolated from aquatic products in China. In total, 846 aquatic product samples were collected between July 2011 and April 2016 from 43 cities in China. Approximately 7.92% (67/846) aquatic product samples were positive for L. monocytogenes, 86.57% positive samples ranged from 0.3 to 10 MPN/g, whereas 5.97% showed over 110 MPN/g by the Most Probable Number method, which included two samples of products intended to be eaten raw. Serogroups I.1 (serotype 1/2a), I.2 (serotype 1/2b), and III (serotype 4c) were the predominant serogroups isolated, whereas serogroup II.1 (serotype 4b) was detected at much lower frequencies. Examination of antibacterial resistance showed that nine antibacterial resistance profiles were exhibited in 72 isolates, a high level susceptibility of 16 tested antibiotics against L. monocytogenes were observed, indicating these common antibacterial agents are still effective for treating L. monocytogenes infection. Multilocus sequence typing revealed that ST299, ST87, and ST8 are predominant in aquatic products, indicating that the rare ST299 (serotype 4c) may have a special ecological niche in aquatic products and associated environments. Except llsX and ptsA, the 72 isolates harbor nine virulence genes (prfA, actA, hly, plcA, plcB, iap, mpl, inlA, and inlB), premature stop codons (PMSCs) in inlA were found in four isolates, three of which belonged to ST9. A novel PMSC was found in 2929-1LM with a nonsense mutation at position 1605 (TGG→TGA). All ST87 isolates harbored the ptsA gene, whereas 8 isolates (11.11%) carried the llsX gene, and mainly belonged to ST1, ST3, ST308, ST323, ST330, and ST619. Taken together, these results first reported potential virulent L. monocytogenes isolates (ST8 and ST87) were predominant in aquatic products which may have implications for public health in China. It is thus necessary to perform continuous surveillance for L. monocytogenes in aquatic products in China.

Genome-wide association studies (GWAS) have identified a number of genetic variants associated with lung cancer risk. However, these loci explain only a small fraction of lung cancer hereditability and other variants with weak effect may be lost in the GWAS approach due to the stringent significance level after multiple comparison correction. In this study, in order to identify important pathways involving the lung carcinogenesis, we performed a two-stage pathway analysis in GWAS of lung cancer in Han Chinese using gene set enrichment analysis (GSEA) method. Predefined pathways by BioCarta and KEGG databases were systematically evaluated on Nanjing study (Discovery stage: 1,473 cases and 1,962 controls) and the suggestive pathways were further to be validated in Beijing study (Replication stage: 858 cases and 1,115 controls). We found that four pathways (achPathway, metPathway, At1rPathway and rac1Pathway) were consistently significant in both studies and the P values for combined dataset were 0.012, 0.010, 0.022 and 0.005 respectively. These results were stable after sensitivity analysis based on gene definition and gene overlaps between pathways. These findings may provide new insights into the etiology of lung cancer.

Occupational exposure to endotoxin is associated with decrements in pulmonary function, but how much variation in this association is explained by genetic variants is not well understood.We aimed to identify single nucleotide polymorphisms (SNPs) that are associated with the rate of forced expiratory volume in one second (FEV1) decline by a large scale genetic association study in newly-hired healthy young female cotton textile workers.DNA samples were genotyped using the Illumina Human CVD BeadChip. Change rate in FEV1 was modeled as a function of each SNP genotype in linear regression model with covariate adjustment. We controlled the type 1 error in study-wide level by permutation method. The false discovery rate (FDR) and the family-wise error rate (FWER) were set to be 0.10 and 0.15 respectively.Two SNPs were found to be significant (P

BACKGROUND: It is uncertain whether adjunctive thrombolysis is beneficial for patients with ST-segment--elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) within 120 minutes of presentation. This study was to determine whether in patients presenting with ST-segment--elevation myocardial infarction a single bolus recombinant staphylokinase (r-SAK) before timely PCI leads to improved patency of the infarct-related artery and reduces the infarct size. METHODS: This is an open-label, prospective, multicenter, randomized study. We enrolled patients aged 18 to 75 years who were within 12 hours of symptom onset of ST-segment--elevation myocardial infarction and expected to undergo PCI within 120 minutes. Patients were administered loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive 5 mg bolus of r-SAK or normal saline intravenously before PCI. The primary end point was Thrombolysis in Myocardial Infarction flow grade 2 to 3 or grade 3 in the infarct-related artery 60 minutes after thrombolysis. The infarct size was detected by cardiac magnetic resonance 5 days after randomization. The safety end point was major bleeding (Bleeding Academic Research Consortium ≥3) during 30-day follow-up. RESULTS: A total of 283 patients were screened from 8 centers and 200 were randomized (median age, 58.5 years; 14% female). The median symptom to thrombolysis time was 252.5 (interquartile range, 142.8-423.8) minutes and thrombolysis to coronary arteriography was 50.0 (interquartile range, 37.0-66.0) minutes. Patients randomized to r-SAK compared with normal saline more often had Thrombolysis in Myocardial Infarction flow grade 2 to 3 (69.0% versus 29.0%; P<0.001) and Thrombolysis in Myocardial Infarction flow grade 3 (51.0% versus 18.0%; P<0.001) and had smaller infarct size (21.91±10.84% versus 26.85±12.37%; P=0.016). There was no increase in major bleeding (r-SAK, 1.0% versus control, 3.0%; P=0.616). CONCLUSIONS: A single bolus r-SAK before primary PCI for ST-segment--elevation myocardial infarction improves infarctrelated artery patency and reduces infarct size without increasing major bleeding. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05023681. [ABSTRACT FROM AUTHOR]