Sarcopenic obesity is part of obesity paradox in dementia development: evidence from a population-based cohort study.

BACKGROUND: Sarcopenic obesity, a clinical and functional condition characterized by the coexistence of obesity and sarcopenia, has not been investigated in relation to dementia risk and its onset. METHODS: We included 208,867 participants from UK biobank, who aged 60 to 69 years at baseline. Dementia diagnoses were identified using hospital records and death register data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models to evaluate the associations of obesity, sarcopenia, and sarcopenic obesity with dementia risk, stratified by sex. Stratified analyses were performed across dementia-related polygenic risk score (PRS). Restricted mean survival time models were established to estimate the difference and 95%CIs of dementia onset across different status. Additionally, linear regression models were employed to estimate associations of different status with brain imaging parameters. The mediation effects of chronic diseases were also examined. RESULTS: Obese women with high PRS had a decreased risk (HR = 0.855 [0.761-0.961]), but obese men with low PRS had an increased risk (HR = 1.223 [1.045-1.431]). Additionally, sarcopenia was associated with elevated dementia risk (HRwomen = 1.323 [1.064-1.644]; HRmen = 2.144 [1.753-2.621]) in those with low PRS. Among those with high PRS, however, the association was only significant in early-life (HRwomen = 1.679 [1.355-2.081]; HRmen = 2.069 [1.656-2.585]). Of note, sarcopenic obesity was associated with higher dementia risk (HRwomen = 1.424 [1.227-1.653]; HRmen = 1.989 [1.702-2.323]), and results remained similar stratified by PRS. Considering dementia onset, obesity was associated with dementia by 1.114 years delayed in women, however, 0.170 years advanced in men. Sarcopenia (women: 0.080 years; men: 0.192 years) and sarcopenic obesity (women: 0.109 years; men: 0.511 years) respectively advanced dementia onset. Obesity, sarcopenia, and sarcopenic obesity were respectively related to alterations in different brain regions. Association between sarcopenic obesity and dementia was mediated by chronic diseases. CONCLUSIONS: Sarcopenic obesity and sarcopenia were respectively associated with increased dementia risk and advanced dementia onset to vary degree. The role of obesity in dementia may differ by sex and genetic background.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Macrolide resistance of Mycoplasma pneumoniae in several regions of China from 2013 to 2019.

This paper retrospectively analysed the prevalence of macrolide-resistant Mycoplasma pneumoniae (MRMP) in some parts of China. Between January 2013 and December 2019, we collected 4,145 respiratory samples, including pharyngeal swabs and alveolar lavage fluid. The highest PCR-positive rate of M. pneumoniae was 74.5% in Beijing, the highest resistance rate was 100% in Shanghai, and Gansu was the lowest with 20%. The highest PCR-positive rate of M. pneumoniae was 74.5% in 2013, and the highest MRMP was 97.4% in 2019; the PCR-positive rate of M. pneumoniae for adults in Beijing was 17.9% and the MRMP was 10.48%. Among the children diagnosed with community-acquired pneumonia (CAP), the PCR-positive and macrolide-resistant rates of M. pneumoniae were both higher in the severe ones. A2063G in domain V of 23S rRNA was the major macrolide-resistant mutation, accounting for more than 90%. The MIC values of all MRMP to erythromycin and azithromycin were ≥ 64 µg/ml, and the MICs of tetracycline and levofloxacin were ≤ 0.5 µg/ml and ≤ 1 µg/ml, respectively. The macrolide resistance varied in different regions and years. Among inpatients, the macrolide-resistant rate was higher in severe pneumonia. A2063G was the common mutation, and we found no resistance to tetracycline and levofloxacin.

Evidence Supporting That C-to-U RNA Editing Is the Major Force That Drives SARS-CoV-2 Evolution.

Mutations of DNA organisms are introduced by replication errors. However, SARS-CoV-2, as an RNA virus, is additionally subjected to rampant RNA editing by hosts. Both resources contributed to SARS-CoV-2 mutation and evolution, but the relative prevalence of the two origins is unknown. We performed comparative genomic analyses at intra-species (world-wide SARS-CoV-2 strains) and inter-species (SARS-CoV-2 and RaTG13 divergence) levels. We made prior predictions of the proportion of each mutation type (nucleotide substitution) under different scenarios and compared the observed versus the expected. C-to-T alteration, representing C-to-U editing, is far more abundant that all other mutation types. Derived allele frequency (DAF) as well as novel mutation rate of C-to-T are the highest in SARS-CoV-2 population, and C-T substitution dominates the divergence sites between SARS-CoV-2 and RaTG13. This is compelling evidence suggesting that C-to-U RNA editing is the major source of SARS-CoV-2 mutation. While replication errors serve as a baseline of novel mutation rate, the C-to-U editing has elevated the mutation rate for orders of magnitudes and accelerates the evolution of the virus.

Impact of intracardiac echocardiography usage on the safety of cryoballoon atrial fibrillation ablation: Subanalysis of the prospective FREEZE cluster cohort study.

INTRODUCTION: Cryoballoon ablation (CBA) aiming at pulmonary vein isolation (PVI) became a standardized atrial fibrillation (AF) ablation procedure. Life-threatening complications like cardiac tamponade exist. Intracardiac echocardiography (ICE) usage is associated with superior safety in radiofrequency ablation. It is unclear if ICE has an impact on safety of CBA. METHODS: The FREEZE Cohort (NCT01360008) subanalysis included patients undergoing "PVI only" CBA. Patients with intraprocedural transesophageal echocardiography were excluded. Group A comprises conventional, group B ICE-guided CBA. Periprocedural results were compared. RESULTS: From 2011 to 2016, a total of 4189 patients were enrolled, and 1906 (45.5%) were included in this subanalysis, split up in two groups (A: 1066 [55.9%], B: 840 [44.1%]). Group A was younger (60.6 ± 10.8 vs. 62.4 ± 10.5 years, p < .001), with smaller left atria (41 vs. 43 mm, p < .001), and less persistent AF (23.1 vs. 38.1%, p < .001). Procedure, left atrial, and fluoroscopy times were shorter in group A as compared to group B. Dose area product was significantly higher in group A (2911 vs. 2072 cGyxcm2 , p < .001). In-hospital major adverse cerebrovascular and cardiac event rates including two deaths in group A were not different between groups (0.5% vs. 0.1%, p = .18). The rate of total procedural (10.4% vs. 5.1%, p < .001) and major complications (3.2% vs. 1.3%, p < .001) was significantly higher in group A. Cardiac tamponade occurred significantly more frequently in group A (8 [0.8%] vs. 1 [0.1%], p = .046). Independent predictors for major complications were female sex (odds ratio [OR] 2.03, p = .03) and non-ICE usage (OR 2.38, p = .02). No differences were observed for persistent phrenic nerve palsy, nor for groin complications. CONCLUSION: CBA was significantly safer and required less radiation if ICE was used, although the procedures were more complex. The risk of groin complications was not increased with ICE usage. Non-ICE usage was the only modifiable independent predictor of major complications.

Real-world systemic sequential therapy with regorafenib for recurrent hepatocellular carcinoma: analysis of 93 cases from a single center.

BACKGROUND: Regorafenib is an oral multikinase inhibitor and became the first second-line systemic treatment for hepatocellular carcinoma (HCC) following the phase III RESORCE trial. This single-center study retrospectively analyzed the clinical data and follow-up results of patients with recurrent HCC treated with regorafenib and discussed the prognostic factors to provide guidance for clinical treatment. METHODS: Ninety-three recurrent HCC patients were enrolled in the research and follow up from December 2017 to December 2020. Clinical and pathological data were collected. SPSS software v26.0 was used (Chicago, IL, USA) for statistical analysis. A two-sided P < 0.05 was considered statistically significant. RESULTS: The patients included 81 males and 12 females with a median age of 57 years. Eighty-seven patients had hepatitis B virus (HBV) infection. The objective response rate (ORR) was 14.0%, and the disease control rate (DCR) was 62.4%. The median overall survival (mOS) and median time to progression (mTTP) were 15.9 and 5.0 months. Multivariate analysis showed that Child-Pugh classification, the Eastern Cooperative Oncology Group performance status (ECOG PS), the neutrophil-to-lymphocyte ratio (NLR), combined treatment, and the time from first diagnosis of HCC to second-line treatment were independent factors affecting the prognosis of recurrent HCC patients. CONCLUSIONS: This real-world study demonstrated similar findings to those of the RESORCE trial. Regorafenib could effectively improve the prognosis of patients after first-line treatment failure. Combination therapy under multidisciplinary treatment (MDT) team guidance could be effective in impeding tumor progression and improving the prognosis of recurrent HCC patients.

Migration experiences and reported commercial and non-commercial sexual behaviors among newly diagnosed HIV infections in China: a cross-sectional study.

BACKGROUND: Migration is known to influence human health. China has a high migration rate and a significant number of people who are HIV-positive, but little is known about how these factors intersect in sexual risk behaviors. OBJECTIVE: This study aimed to explore sexual risk behaviors between migrants and non-migrants among newly diagnosed HIV infections, and assess the changes of sexual risk behaviors with length of stay in the current city of migrants. METHODS: A cross-sectional questionnaire was conducted among people newly diagnosed with HIV from July 2018 to December 2020 who lived in Zhejiang Province. In the study, sexual risk behaviors included having multiple sexual partners and unprotected sexual behaviors (in commercial sexual behaviors, non-commercial sexual behaviors, heterosexual behaviors, and homosexual behaviors). Binary logistic regression models were employed to explore the influencing factors of sexual risk behaviors, measured by multiple sexual partners and unprotected sexual partners. RESULTS: A total of 836 people newly diagnosed with HIV/AIDS were incorporated in the study and 65.31% (546) were migrants. The percentages of non-commercial sexual behaviors among migrants were statistically higher than those of non-migrants. Commercial heterosexual behavior was higher among non-migrants compared with migrants. The proportion of study participants having unprotected sexual behaviors and multiple sexual partners with commercial/non-commercial partners was both higher among migrants compared with non-migrants. Among migrants, the likelihood of sexual risk behaviors in both commercial and non-commercial sex increased in the first 3 years and reduced after 10 years. Compared with non-migrants, migrants were statistically associated with multiple sexual partners [P = .007, odds ratio (OR) = 1.942]. However, migrants did not exhibit a significant difference in unprotected sexual behaviors compared with non-migrants. In addition, migrants aged between 18 and 45 years who relocated to the current city in the past 2-3 years tended to have multiple sexual partners (P < .05). CONCLUSIONS: People newly diagnosed with HIV engaged in different sexual risk behaviors among migrants and non-migrants and more attention should be paid to migrants. For non-migrants, it is urgent to promote the prevention of commercial sexual behaviors. For migrants, prevention of non-commercial sexual behaviors and universal access to health care especially for new arrivals who migrated to the current city for 2-3 years are needed. Moreover, sexual health education and early HIV diagnosis are necessary for the entire population.

Robotic magnetic navigation-guided pulmonary vein isolation in an atrial fibrillation patient with dextrocardia situs inversus: techniques and potential advantages.

BACKGROUND: Dextrocardia with situs inversus (DSI) is a very rare congenital anomaly. Catheter manipulation and ablation of atrial fibrillation (AF) in patients with this anatomical variant is challenging for the operators. This case report presents a safe and effective AF ablation guided by the robotic magnetic navigation (RMN) system in combination with intracardiac echocardiograhy (ICE) in a patient with DSI. CASE PRESENTATION: A 64-year-old male with DSI was referred for catheter ablation of symptomatic, drug-refractory paroxysmal AF. One transseptal access was achieved via the left femoral vein under the guidance of ICE. The three-dimensional reconstruction of the left atrium and the pulmonary veins (PVs) were performed by the magnetic catheter using the CARTO and the RMN system. Then, the electroanatomic map and pre-acquired CT images were merged. Finally, bilateral circumferential ablation lines were delivered around the ipsilateral PV ostia to achieve complete PV isolation (PVI). CONCLUSIONS: This case demonstrates that AF catheter ablation under the guidance of the RMN system using ICE is feasible and safe in a patient with DSI. Moreover, the combination of these technologies broadly facilitates treatment of patients with complex anatomy, while reducing the risk of complications.

Pathophysiological Insight into Fatty Acid-Binding Protein-4: Multifaced Roles in Reproduction, Pregnancy, and Offspring Health.

Fatty acid-binding protein-4 (FABP4), commonly known as adipocyte-fatty acid-binding protein (A-FABP), is a pleiotropic adipokine that broadly affects immunity and metabolism. It has been increasingly recognized that FABP4 dysfunction is associated with various metabolic syndromes, including obesity, diabetes, cardiovascular diseases, and metabolic inflammation. However, its explicit roles within the context of women's reproduction and pregnancy remain to be investigated. In this review, we collate recent studies probing the influence of FABP4 on female reproduction, pregnancy, and even fetal health. Elevated circulating FABP4 levels have been found to correlate with impaired reproductive function in women, such as polycystic ovary syndrome and endometriosis. Throughout pregnancy, FABP4 affects maternal-fetal interface homeostasis by affecting both glycolipid metabolism and immune tolerance, leading to adverse pregnancy outcomes, including miscarriage, gestational obesity, gestational diabetes, and preeclampsia. Moreover, maternal FABP4 levels exhibit a substantial linkage with the metabolic health of offspring. Herein, we discuss the emerging significance and potential application of FABP4 in reproduction and pregnancy health and delve into its underlying mechanism at molecular levels.

A novel mutation in human EMD gene and mitochondrial dysfunction in emerin knockdown cardiomyocytes.

Emerin is an inner nuclear envelope protein encoded by the EMD gene, mutations in which cause Emery-Dreifuss muscular dystrophy type 1 (EDMD1). Cardiac involvement has become a major threat to patients with EDMD1; however, the cardiovascular phenotype spectrums of emerinopathy and the mechanisms by which emerin regulates cardiac pathophysiology remain unclear. Here, we identified a novel nonsense mutation (c.C57G, p.Y19X) in the EMD gene in a Han Chinese family through high-throughput sequencing. Two family members were found to have EDMD1 with muscle weakness and cardiac arrhythmia. Mechanistically, we first discovered that knockdown of emerin in HL-1 or H9C2 cardiomyocytes lead to impaired mitochondrial oxidative phosphorylation capacity with downregulation of electron transport chain complex I and IV and upregulation of complex III and V. Moreover, loss of emerin in HL-1 cells resulted in collapsed mitochondrial membrane potential, altered mitochondrial networks and downregulated multiple factors in RNA and protein level, such as PGC1α, DRP1, MFF, MFN2, which are involved in regulation of mitochondrial biogenesis, fission and fusion. Our findings suggest that targeting mitochondrial bioenergetics might be an effective strategy against cardiac disorders caused by EMD mutations.

The Sponge Interaction Between Circular RNA and microRNA Serves as a Fast-Evolving Mechanism That Suppresses Non-small Cell Lung Cancer (NSCLC) in Humans.

Non-small cell lung cancer (NSCLC) is one of the most lethal cancer types in the world. Currently, the molecular mechanisms and pathways underlying NSCLC oncogenesis are poorly understood. Using multiple Omics data, we systematically explored the differentially expressed circular RNAs (circRNAs) in NSCLC. We also investigated potential microRNA sponges (that absorb circRNAs) in NSCLC and downstream target genes with experimental verifications. hsa_circ_0003497 was down-regulated in NSCLC and played an inhibitory role in tumorigenesis. In contrast, miR-197-3p was up-regulated in NSCLC. hsa_circ_0003497 directly interacts with miR-197-3p and releases a target gene of miR-197-3p termed CTNND1 (a known tumor suppressor gene). Evolutionary analysis reveals fast evolution of this hsa_circ_0003497-miR-197-3p-CTNND1-NSCLC axis in mammals. This work clarified the biological functions and molecular mechanisms of how hsa_circ_0003497 suppresses NSCLC through miR-197-3p and CTNND1. We discovered molecular markers for the prognosis of NSCLC and provided potential intervention targets for its treatment.

Identification of immune infiltration-related genes as prognostic indicators for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high degree of malignancy and a poor prognosis. Immune infiltration-related genes have shown good predictive value in the prognosis of many solid tumours. In this study, we established and verified prognostic biomarkers consisting of immune infiltration-related genes in HCC. Gene expression data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Differential gene expression analysis, univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression algorithm were used to screen prognostic immune infiltration-related genes and to construct a risk scoring model. Kaplan-Meier (KM) survival plots and receiver operating characteristic (ROC) curve analysis were used to evaluate the prognostic performance of the risk scoring model in the TCGA-HCC cohort. In addition, a nomogram model with a risk score was established, and its predictive performance was verified by ROC analysis and calibration plot analysis in the TCGA-HCC cohort. Gene set enrichment analysis (GSEA) identified pathways and biological processes that may be enriched in the high-risk group. Finally, immune infiltration analysis was used to explore the characteristics of the tumour microenvironment related to the risk score. We identified 17 immune infiltration-related genes with prognostic value and constructed a risk scoring model. ROC analysis showed that the risk scoring model can accurately predict the 1-year, 3-year, and 5-year overall survival (OS) of HCC patients in the TCGA-HCC cohort. KM analysis showed that the OS of the high-risk group was significantly lower than that of the low-risk group (P < 0.001). The nomogram model effectively predicted the OS of HCC patients in the TCGA-HCC cohort. GSEA indicated that the immune infiltration-related genes may be involved in biological processes such as amino acid and lipid metabolism, matrisome and small molecule transportation, immune system regulation, and hepatitis virus infection. Immune infiltration analysis showed that the level of immune cell infiltration in the high-risk group was low, and the risk score was negatively correlated with infiltrating immune cells. Our prognostic model based on immune infiltration-related genes in HCC could help the prognostic assessment of HCC patients and provide potential targets for HCC inhibition.

Methodology and experiences of rapid advice guideline development for children with COVID-19: responding to the COVID-19 outbreak quickly and efficiently.

BACKGROUND: Rapid Advice Guidelines (RAG) provide decision makers with guidance to respond to public health emergencies by developing evidence-based recommendations in a short period of time with a scientific and standardized approach. However, the experience from the development process of a RAG has so far not been systematically summarized. Therefore, our working group will take the experience of the development of the RAG for children with COVID-19 as an example to systematically explore the methodology, advantages, and challenges in the development of the RAG. We shall propose suggestions and reflections for future research, in order to provide a more detailed reference for future development of RAGs. RESULT: The development of the RAG by a group of 67 researchers from 11 countries took 50 days from the official commencement of the work (January 28, 2020) to submission (March 17, 2020). A total of 21 meetings were held with a total duration of 48 h (average 2.3 h per meeting) and an average of 16.5 participants attending. Only two of the ten recommendations were fully supported by direct evidence for COVID-19, three recommendations were supported by indirect evidence only, and the proportion of COVID-19 studies among the body of evidence in the remaining five recommendations ranged between 10 and 83%. Six of the ten recommendations used COVID-19 preprints as evidence support, and up to 50% of the studies with direct evidence on COVID-19 were preprints. CONCLUSIONS: In order to respond to public health emergencies, the development of RAG also requires a clear and transparent formulation process, usually using a large amount of indirect and non-peer-reviewed evidence to support the formation of recommendations. Strict following of the WHO RAG handbook does not only enhance the transparency and clarity of the guideline, but also can speed up the guideline development process, thereby saving time and labor costs.

Transcriptomic analysis using dual RNA sequencing revealed a Pathogen-Host interaction after Edwardsiella anguillarum infection in European eel (Anguilla anguilla).

Many studies have explored differentially expressed genes (DEGs) between some pathogens and hosts, but no study has focused on the interaction of DEGs between Edwardsiella anguillarum (Ea) and Anguilla anguilla (Aa). In this study, we examined the interactions of DEGs during Ea infection and Aa anti-infection processes by dual RNA sequencing. Total RNA from in vitro and in vivo (Aa liver) Ea culture was extracted. Using high-throughput transcriptomics, significant DEGs that were expressed between Ea cultured in vitro versus in vivo and those in the liver of the infected group versus control group were identified. Protein-protein interactions between the pathogen and host were explored using Cytoscape according to the HPIDB 3.0 interaction transcription database. The results showed that the liver in the infection group presented with severe bleeding and a large number of thrombi in the hepatic vessels. We found 490 upregulated and 398 downregulated DEGs of Ea in vivo versus Ea cultured in vitro, and 2177 upregulated and 970 downregulated genes in the liver of the infected eels. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the pathogen DEGs revealed that the upregulated genes were mainly enriched in migration, colonization, biofilm formation, and significantly enriched in ABC transport and quorum sensing; the downregulated genes were mainly involved in metabolism, information transduction, organelle formation, enzyme catalysis, molecular transport, and binding. GO of the host DEGs showed that metabolic process, catalytic activity, single organism metabolic process, small molecule binding, nucleotide binding, nucleotide phosphate binding, and anion binding were markedly enriched. Finally, we found that 79 Ea and 148 Aa proteins encoded by these DEGs were involved in an interaction network, and some pathogen (DegP, gcvP, infC, carB, rpoC, trpD, sthA, and FhuB) and host proteins (MANBA, STAT1, ETS2, ZEP1, TKT1, NMI and RBPMS) appear to play crucial roles in infection. Thus, determining the interaction networks revealed crucial molecular mechanisms underlying the process of pathogenic infection and host anti-infection.

Early recurrence after cryoballoon versus radiofrequency ablation for paroxysmal atrial fibrillation: mechanism and implication in long-term outcome.

BACKGROUND: Early recurrence (ER) after catheter ablation for atrial fibrillation (AF) has been considered as a common phenomenon but its mechanism and implication in long-term outcome has not been fully elucidated. We aimed to clarify the relation between post-ablation inflammation and ER after cryoballoon ablation (CBA) or radio-frequency ablation (RFA) and evaluate the clinical significance of ER. METHODS: A total of 154 patients with paroxysmal AF undergoing ablation were consecutively recruited, including 90 patients undergoing RFA (RF group) and 64 patients undergoing CBA (CB group). Myocardial injury and inflammation biomarkers were analyzed before and 6 h, 24 h and 48 h after ablation. Acute early recurrence (AER), non-acute early recurrence (NAER) and late recurrence (LR) was defined as recurrence of atrial tachyarrhythmia during 0-3, 4-90 days and beyond a 90-day blanking period after ablation. RESULTS: Cardiac troponin I was significantly higher in CB group while C reactive protein (CRP) and Ratio Neutrophil/Lymphocyte were more elevated in RF group. Higher CRP level after RFA was significantly associated with AER in RF group and lower CRP level after CBA was predictive of AER in CB group. In addition, average cryoablation duration was positively correlated with CRP level after CB group. Cox regression revealed that NAER and left atrial diameter were associated with LR in RF group, while AER and NAER were predictive of LR after CBA. CONCLUSIONS: Post-ablation inflammation was greater in RFA than in CBA. Excessive inflammatory response may be an important factor of AER after RFA. AER after CBA was related with lower inflammation and predictive of LR. Further investigations are still warranted to address on these findings.

Long-term outcomes of a time to isolation - based strategy for cryoballoon ablation compared to radiofrequency ablation in patients with symptomatic paroxysmal atrial fibrillation.

BACKGROUND: Cryoballoon ablation (CBA) is one of the most commonly used technologies designed for pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF), although the dosing of CBA remains controversial. We evaluated the long-term efficacy and safety of a novel individualized strategy of CBA compared to radiofrequency ablation (RFA) for patients with PAF. METHODS: In this observational study, symptomatic patients with drug-refractory paroxysmal AF were prospectively consented and enrolled in four centers, being assigned either to the CBA or RFA arm for ablation. In the CBA group, we used a time to isolation (TTI) - based dosing protocol. The primary endpoint was the recurrence of atrial arrhythmia >30 s following a 90-day blanking period. The secondary endpoint was procedure-related complications and procedure parameters. RESULTS: A total of 500 patients were recruited in either the CBA group (n = 247) or the RFA group (n = 253) between January 2017 and July 2018. After a median follow-up of 778 days, the atrial tachyarrhythmia-free survival was 71.7% in the CBA group and 67.0% in the RFA group. CBA and RFA displayed similar major or minor complication occurrence, while the former had a significantly shorter procedure duration (82.5 min vs. 141.1 min, p < .001) and left atrial dwell time (60.1 min vs. 109.9 min, p < .001) but longer fluoroscopy exposure (13.8 min vs. 8.1 min, p < .001). CONCLUSION: Compared to RFA, our TTI-based CBA dosing protocol showed comparable efficacy and safety, with a significantly reduced procedure duration in patients with PAF.

Guidelines for the prevention and management of children and adolescents with COVID-19.

Children are the future of the world, but their health and future are facing great uncertainty because of the coronavirus disease 2019 (COVID-19) pandemic. In order to improve the management of children with COVID-19, an international, multidisciplinary panel of experts developed a rapid advice guideline at the beginning of the outbreak of COVID-19 in 2020. After publishing the first version of the rapid advice guideline, the panel has updated the guideline by including additional stakeholders in the panel and a comprehensive search of the latest evidence. All recommendations were supported by systematic reviews and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Expert judgment was used to develop good practice statements supplementary to the graded evidence-based recommendations. The updated guideline comprises nine recommendations and one good practice statement. It focuses on the key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin (IVIG) for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health. CONCLUSION: This updated evidence-based guideline intends to provide clinicians, pediatricians, patients and other stakeholders with evidence-based recommendations for the prevention and management of COVID-19 in children and adolescents. Larger studies with longer follow-up to determine the effectiveness and safety of systemic glucocorticoids, IVIG, noninvasive ventilation, and the vaccines for COVID-19 in children and adolescents are encouraged. WHAT IS KNOWN: • Several clinical practice guidelines for children with COVID-19 have been developed, but only few of them have been recently updated. • We developed an evidence-based guideline at the beginning of the COVID-19 outbreak and have now updated it based on the results of a comprehensive search of the latest evidence. WHAT IS NEW: • The updated guideline provides key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.

Integrated analysis of 1804 samples of six centers to construct and validate a robust immune-related prognostic signature associated with stromal cell abundance in tumor microenvironment for gastric cancer.

BACKGROUND: Stromal cells in tumor microenvironment could promote immune escape through a variety of mechanisms, but there are lacking research in the field of gastric cancer (GC). METHODS: We identified differential expressed immune-related genes (DEIRGs) between the high- and low-stromal cell abundance GC samples in The Cancer Genome Atlas and GSE84437 datasets. A risk score was constructed basing on univariate cox regression analysis, LASSO regression analysis, and multivariate cox regression analysis in the training cohort (n=772). The median value of the risk score was used to classify patients into groups with high and low risk. We conducted external validation of the prognostic signature in four independent cohorts (GSE26253, n=432; GSE62254, n=300; GSE15459, n=191; GSE26901, n=109) from the Gene Expression Omnibus (GEO) database. The immune cell infiltration was quantified by the CIBERSORT method. RESULTS: The risk score contained 6 genes (AKT3, APOD, FAM19A5, LTBP3, NOV, and NOX4) showed good performance in predicting 5-year overall survival (OS) rate and 5-year recurrence-free survival (RFS) rate of GC patients. The risk death and recurrence of GC patients growing with the increasing risk score. The patients were clustered into three subtypes according to the infiltration of 22 kinds of immune cells quantified by the CIBERSORT method. The proportion of cluster A with the worst prognosis in the high-risk group was significantly higher than that in the low-risk group; the risk score of cluster C subtype with the best prognosis was significantly lower than that of the other two subtypes. CONCLUSION: This study established and validated a robust prognostic model for gastric cancer by integrated analysis 1804 samples of six centers, and its mechanism was explored in combination with immune cell infiltration characterization.

Development and validation of a CTNNB1-associated metabolic prognostic model for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy closely related to metabolic reprogramming. We investigated how CTNNB1 mutation regulates the HCC metabolic phenotype and thus affects the prognosis of HCC. We obtained the mRNA expression profiles and clinicopathological data from The Cancer Genome Atlas (TCGA), the International Cancer Genomics Consortium (ICGC) and the Gene Expression Omnibus database (GSE14520 and GSE116174). We conducted gene set enrichment analysis on HCC patients with and without mutant CTNNB1 through TCGA dataset. The Kaplan-Meier analysis and univariate Cox regression analysis assisted in screening metabolic genes related to prognosis, and the prognosis model was constructed using the Lasso and multivariate Cox regression analysis. The prognostic model showed good prediction performance in both the training cohort (TCGA) and the validation cohorts (ICGC, GSE14520, GSE116174), and the high-risk group presented obviously poorer overall survival compared with low-risk group. Cox regression analysis indicated that the risk score can be used as an independent predictor for the overall survival of HCC. The immune infiltration in different risk groups was also evaluated in this study to explore underlying mechanisms. This study is also the first to describe an metabolic prognostic model associated with CTNNB1 mutations and could be implemented for determining the prognoses of individual patients in clinical practice.

Eleven immune-gene pairs signature associated with TP53 predicting the overall survival of gastric cancer: a retrospective analysis of large sample and multicenter from public database.

BACKGROUND: Growing attention have been paid to the relationship between TP53 and tumor immunophenotype, but there are still lacking enough search on the field of gastric cancer (GC). MATERIALS AND METHODS: We identified differential expressed immune-related genes (DEIRGs) between the TP53-altered GC samples (n = 183) and without TP53-altered GC samples (n = 192) in The Cancer Genome Atlas and paired them. In the TCGA cohort (n = 350), a risk score was determined through univariate and multivariate cox regression and Lasso regression analysis. Patients were divided into two groups, high-risk and low-risk, based on the median risk score. Four independent cohorts (GSE84437,n = 431; GSE62254, n = 300; GSE15459, n = 191; GSE26901, n = 100) from the Gene Expression Omnibus (GEO) database were used to validate the reliability and universal applicability of the model. RESULTS: The signature contained 11 gene pairs showed good performance in predicting progression-free survival (PFS), disease-free survival (DFS), disease special survival (DSS), and the overall survival (OS) for GC patients in the TCGA cohort. The subgroup analysis showed that the signature was suitable for GC patients with different characteristics. The signature could capable of distinguish GC patients with good prognosis and poor prognosis in all four independent external validation cohorts. The high- and low-risk groups differed significantly in the proportion of several immune cell infiltration, especially for the T cells memory resting, T cells memory activated and follicular helper, and Macrophage M0, which was also related to the prognosis of GC patients. CONCLUSION: The present work proposed an innovative system for evaluating the prognosis of gastric cancer. Considering its stability and general applicability, which may become a widely used tool in clinical practice.