The Long Noncoding RNA Cardiac Mesoderm Enhancer-Associated Noncoding RNA (Carmn) Is a Critical Regulator of Gastrointestinal Smooth Muscle Contractile Function and Motility.

BACKGROUND & AIMS: Visceral smooth muscle cells (SMCs) are an integral component of the gastrointestinal (GI) tract that regulate GI motility. SMC contraction is regulated by posttranslational signaling and the state of differentiation. Impaired SMC contraction is associated with significant morbidity and mortality, but the mechanisms regulating SMC-specific contractile gene expression, including the role of long noncoding RNAs (lncRNAs), remain largely unexplored. Herein, we reveal a critical role of Carmn (cardiac mesoderm enhancer-associated noncoding RNA), an SMC-specific lncRNA, in regulating visceral SMC phenotype and contractility of the GI tract. METHODS: Genotype-Tissue Expression and publicly available single-cell RNA sequencing (scRNA-seq) data sets from embryonic, adult human, and mouse GI tissues were interrogated to identify SMC-specific lncRNAs. The functional role of Carmn was investigated using novel green fluorescent protein (GFP) knock-in (KI) reporter/knock-out (KO) mice. Bulk RNA-seq and single nucleus RNA sequencing (snRNA-seq) of colonic muscularis were used to investigate underlying mechanisms. RESULTS: Unbiased in silico analyses and GFP expression patterns in Carmn GFP KI mice revealed that Carmn is highly expressed in GI SMCs in humans and mice. Premature lethality was observed in global Carmn KO and inducible SMC-specific KO mice due to GI pseudo-obstruction and severe distension of the GI tract, with dysmotility in cecum and colon segments. Histology, GI transit, and muscle myography analysis revealed severe dilation, significantly delayed GI transit, and impaired GI contractility in Carmn KO vs control mice. Bulk RNA-seq of GI muscularis revealed that loss of Carmn promotes SMC phenotypic switching, as evidenced by up-regulation of extracellular matrix genes and down-regulation of SMC contractile genes, including Mylk, a key regulator of SMC contraction. snRNA-seq further revealed SMC Carmn KO not only compromised myogenic motility by reducing contractile gene expression but also impaired neurogenic motility by disrupting cell-cell connectivity in the colonic muscularis. These findings may have translational significance, because silencing CARMN in human colonic SMCs significantly attenuated contractile gene expression, including MYLK, and decreased SMC contractility. Luciferase reporter assays showed that CARMN enhances the transactivation activity of the master regulator of SMC contractile phenotype, myocardin, thereby maintaining the GI SMC myogenic program. CONCLUSIONS: Our data suggest that Carmn is indispensable for maintaining GI SMC contractile function in mice and that loss of function of CARMN may contribute to human visceral myopathy. To our knowledge this is the first study showing an essential role of lncRNA in the regulation of visceral SMC phenotype.

Generation of Multiple Concentration Gradients Using a Two-Dimensional Pyramid Array.

Concentration heterogeneity of diffusible reactants is a prevalent phenomenon in biochemical processes, requiring the generation of concentration gradients for the relevant experiments. In this study, we present a high-density pyramid array microfluidic network for the effective and precise generation of multiple concentration gradients. The complex gradient distribution in the 2D array can be adaptively adjusted by modulating the reactant velocities and concentrations at the inlets. In addition, the unique design of each reaction chamber and mixing block in the array ensures uniform concentrations within each chamber during dynamic changes, enabling large-scale reactions with low reactant volumes. Through detailed numerical simulation of mass transport within the complex microchannel networks, the proposed method allows researchers to determine the desired number of reaction chambers within a given concentration range based on experimental requirements and to quickly obtain the operating conditions with the help of machine learning-based prediction. The effectiveness in generating a multiple concentration gradient environment was further demonstrated by concentration-dependent calcium carbonate crystallization experiments. This device provides a highly efficient mixing and adaptable concentration platform that is well suited for high-throughput and multiplexed reactions.

Determination of anthracnose (Colletotrichum fructicola) resistance mechanism using transcriptome analysis of resistant and susceptible pear (Pyrus pyrifolia).

BACKGROUND: Anthracnose, mainly caused by Colletotrichum fructicola, leads to severe losses in pear production. However, there is limited information available regarding the molecular response to anthracnose in pears. RESULTS: In this study, the anthracnose-resistant variety 'Seli' and susceptible pear cultivar 'Cuiguan' were subjected to transcriptome analysis following C. fructicola inoculation at 6 and 24 h using RNA sequencing. A total of 3186 differentially expressed genes were detected in 'Seli' and 'Cuiguan' using Illumina sequencing technology. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that the transcriptional response of pears to C. fructicola infection included responses to reactive oxygen species, phytohormone signaling, phenylpropanoid biosynthesis, and secondary metabolite biosynthetic processes. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway and phenylpropanoid biosynthesis were involved in the defense of 'Seli'. Furthermore, the gene coexpression network data showed that genes related to plant-pathogen interactions were associated with C. fructicola resistance in 'Seli' at the early stage. CONCLUSION: Our results showed that the activation of specific genes in MAPK, calcium signaling pathways and phenylpropanoid biosynthesis was highly related to C. fructicola resistance in 'Seli' and providing several potential candidate genes for breeding anthracnose-resistant pear varieties.

Validity across four common street-crossing distraction indicators to predict pedestrian safety.

BACKGROUND: Multiple distraction indicators have been applied to measure street-crossing distraction but their validities in predicting pedestrian safety are poorly understood. METHODS: Based on a video-based observational study, we compared the validity of four commonly used distraction indicators (total duration of distraction while crossing a street, proportion of distracted time over total street-crossing time, duration of the longest distraction time, and total number of distractions) in predicting three pedestrian safety outcomes (near-crash incidence, frequency of looking left and right, and speed crossing the street) across three types of distraction (mobile phone use, talking to other pedestrians, eating/drinking/smoking). Change in Harrell's C statistic was calculated to assess the validity of each distraction indicator based on multivariable regression models including only covariates and including both covariates and the distraction indicator. RESULTS: Heterogeneous capacities in predicting the three safety outcomes across the four distraction indicators were observed: 1) duration of the longest distraction time was most predictive for the occurrence of near-crashes and looks left and right among pedestrians with all three types of distraction combined and talking with other pedestrians (Harrell's C statistic changes ranged from 0.0310 to 0.0335, P < 0.05), and for the occurrence of near-crashes for pedestrians involving mobile phone use (Harrell's C statistic change: 0.0053); 2) total duration of distraction was most predictive for speed crossing the street among pedestrians with the combination and each of the three types of distraction (Harrell's C statistic changes ranged from 0.0037 to 0.0111, P < 0.05), frequency of looking left and right among pedestrians distracted by mobile phone use (Harrell's C statistic change: 0.0115), and the occurrence of near-crash among pedestrians eating, drinking, or smoking (Harrell's C statistic change: 0.0119); and 3) the total number of distractions was the most predictive indicator of frequency of looking left and right among pedestrians eating, drinking, or smoking (Harrell's C statistic change: 0.0013). Sensitivity analyses showed the results were robust to change in grouping criteria of the four distraction indicators. CONCLUSIONS: Future research should consider the pedestrian safety outcomes and type of distractions to select the best distraction indicator.

Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice.

Sepsis is a major cause of mortality in intensive care units, which results from a severely dysregulated inflammatory response that ultimately leads to organ failure. While antibiotics can help in the early stages, effective strategies to curtail inflammation remain limited. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. While HMGB1 has been shown to play a role in sepsis, the role of other family members including HMGXB4 remains unknown. We found that expression of HMGXB4 is strongly induced in response to lipopolysaccharide (LPS)-elicited inflammation in murine peritoneal macrophages. Genetic deletion of Hmgxb4 protected against LPS-induced lung injury and lethality and cecal ligation and puncture (CLP)-induced lethality in mice, and attenuated LPS-induced proinflammatory gene expression in cultured macrophages. By integrating genome-wide transcriptome profiling and a publicly available ChIP-seq dataset, we identified HMGXB4 as a transcriptional activator that regulates the expression of the proinflammatory gene, Nos2 (inducible nitric oxide synthase 2) by binding to its promoter region, leading to NOS2 induction and excessive NO production and tissue damage. Similar to Hmgxb4 ablation in mice, administration of a pharmacological inhibitor of NOS2 robustly decreased LPS-induced pulmonary vascular permeability and lethality in mice. Additionally, we identified the cell adhesion molecule, ICAM1, as a target of HMGXB4 in endothelial cells that facilitates inflammation by promoting monocyte attachment. In summary, our study reveals a critical role of HMGXB4 in exacerbating endotoxemia via transcriptional induction of Nos2 and Icam1 gene expression and thus targeting HMGXB4 may be an effective therapeutic strategy for the treatment of sepsis.

Increasing the Accessibility of Internal Catalytic Sites in Covalent Organic Frameworks by Introducing a Bicontinuous Mesostructure.

Introducing continuous mesochannels into covalent organic frameworks (COFs) to increase the accessibility of their inner active sites has remained a major challenge. Here, we report the synthesis of COFs with an ordered bicontinuous mesostructure, via a block copolymer self-assembly-guided nanocasting strategy. Three different mesostructured COFs are synthesized, including two covalent triazine frameworks and one vinylene-linked COF. The new materials are endowed with a hierarchical meso/microporous architecture, in which the mesochannels exhibit an ordered shifted double diamond (SDD) topology. The hierarchically porous structure can enable efficient hole-electron separation and smooth mass transport to the deep internal of the COFs and consequently high accessibility of their active catalytic sites. Benefiting from this hierarchical structure, these COFs exhibit excellent performance in visible-light-driven catalytic NO removal with a high conversion percentage of up to 51.4 %, placing them one of the top reported NO-elimination photocatalysts. This study represents the first case of introducing a bicontinuous structure into COFs, which opens a new avenue for the synthesis of hierarchically porous COFs and for increasing the utilization degree of their internal active sites.

Road traffic death coding quality in the WHO Mortality Database.

Objective: To evaluate the precision and dependability of road traffic mortality data recorded in the World Health Organization Mortality Database and investigate how uncorrected data influence vital mortality statistics used in traffic safety programmes worldwide. Methods: We assessed country and territory-specific data quality from 2015 to 2020 by calculating the proportions of five types of nonspecific cause of death codes related to road traffic mortality. We compared age-adjusted road traffic mortality and changes in the average annual mortality rate before and after correcting the deaths with nonspecific codes. We generated road traffic mortality projections with both corrected and uncorrected codes, and redistributed the data using the proportionate method. Findings: We analysed data from 124 countries and territories with at least one year of mortality data from 2015 to 2020. The number of countries and territories reporting more than 20% of deaths with ill-defined or unknown cause was 2; countries reporting injury deaths with undetermined intent was 3; countries reporting unspecified unintentional injury deaths was 21; countries reporting unspecified transport crash deaths was 3; and countries reporting unspecified unintentional road traffic deaths was 30. After redistributing deaths with nonspecific codes, road traffic mortality changed by greater than 50% in 7% (5/73) to 18% (9/51) of countries and territories. Conclusion: Nonspecific codes led to inaccurate mortality estimates in many countries. We recommend that injury researchers and policy-makers acknowledge the potential pitfalls of relying on raw or uncorrected road traffic mortality data and instead use corrected data to ensure more accurate estimates when improving road traffic safety programmes.

Value of the short physical performance battery (SPPB) in predicting fall and fall-induced injury among old Chinese adults.

BACKGROUND: The short physical performance battery (SPPB) is an easy-to-use tool for fall risk prediction, but its predictive value for falls and fall-induced injuries among community dwellers has not been examined through a large-sample longitudinal study. METHODS: We analyzed five-round follow-up data (2, 3, 4, 5, 7 years) of the China Health and Retirement Longitudinal Study (CHARLS) (2011-2018). Data concerning falls and fall-induced injuries during multi-round follow-ups were collected through participant self-report. The Cochran-Armitage trend test examined trends in fall incidence rate across SPPB performance levels. Multivariable logistic regression and negative binomial regression models examined associations between SPPB performance and subsequent fall and fall-induced injury. The goodness-of-fit and area under the receiver operating curve (AUC) were used together to quantify the value of the SPPB in predicting fall and fall-induced injury among community-dwelling older adults. RESULTS: The CHARLS study included 9279, 6153, 4142, 4148, and 3583 eligible adults aged 60 years and older in the five included follow-up time periods. SPPB performance was associated with fall and fall-induced injury in two and three of the five follow-up time periods, respectively (P < 0.05). The goodness-of-fit for all predictive models was poor, with both Cox-Snell R2 and Nagelkerke R2 under 0.10 and AUCs of 0.53-0.57 when using only SPPB as a predictor and with both Cox-Snell R2 and Nagelkerke R2 lower than 0.12 and AUCs of 0.61-0.67 when using SPPB, demographic variables, and self-reported health conditions as predictors together. Sex and age-specific analyses displayed highly similar results. CONCLUSIONS: Neither use of SPPB alone nor SPPB together with demographic variables and self-reported health conditions appears to offer good predictive performance for falls or fall-induced injuries among community-dwelling older Chinese adults.

Evaluating the effectiveness of the safety experience room, an affordable interactive education intervention to prevent unintentional injury among rural preschoolers in China: protocol for a cluster randomized controlled trial.

BACKGROUND: Interactive and experiential learning programs have proven effective to teach children safety and prevent child unintentional injury. However, previously-published programs were designed primarily to address safety concerns of children living in urban, well-resourced areas, and therefore might be less effective or economically infeasible to distribute to children in resource-limited areas, such as those living in rural areas or underdeveloped regions. This proposed study will evaluate the effectiveness of teaching children safety lessons to rural preschoolers in China through the preschool-based Safety Experience Room intervention that was developed based on relevant theories, the lessons of previous intervention research, the characteristics of child injuries in underdeveloped rural areas, and the needs and circumstances of rural families and preschools in China. The study will also evaluate the cost-effectiveness of delivering the program. METHODS AND ANALYSIS: A single-blinded, 12-month follow-up, parallel-group cluster randomized controlled trial with a 1:1 allocation ratio will be implemented in two selected counties. In total, at least 2378 rural preschoolers aged 3-6 years old will be recruited from 12 preschools, 6 in Yang County and 6 in Shicheng County. Clusters will be randomized at the preschool level and allocated to the control group (routine school-based education) or the intervention group (routine school-based education plus the Safety Experience Room education). External support strategies will be implemented by local partners to minimize attrition. Data collection will be conducted at baseline and then every 3 months during a 12-month follow-up time period. Intention-to-treat (ITT) data analysis will be used. Generalized estimation equations (GEE) will evaluate the effectiveness of the program and generalized cost-effectiveness analysis (GCEA) will evaluate the cost-effectiveness of it. A per-protocol (PP) sensitivity analysis will assess the robustness of ITT results. Subgroup analyses will be performed to evaluate the impact of socio-demographic factors on the intervention effect, following the same strategies as the primary analyses. DISCUSSION: The newly-designed Safety Experience Room program is expected to be feasible, effective, and financially beneficial. If these hypotheses prove true, we will take steps to disseminate the program to rural preschools across China. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ), CHiCTR2000038025, registered on 8 September 2020.

Content Quality of Web-Based Short-Form Videos for Fire and Burn Prevention in China: Content Analysis.

BACKGROUND: Web-based short-form videos are increasingly popular for disseminating fire and burn prevention information, but their content quality is unknown. OBJECTIVE: We aimed to systematically assess the characteristics, content quality, and public impact of web-based short-form videos offering primary and secondary (first aid) prevention recommendations for fires and burns in China between 2018 and 2021. METHODS: We retrieved short-form videos offering both primary and secondary (first aid) information to prevent fire and burn injuries published on the 3 most popular web-based short-form video platforms in China: TikTok, Kwai, and Bilibili. To assess video content quality, we calculated the proportion of short-form videos that included information on each of the 15 recommendations for burn prevention education from the World Health Organization (WHO; P1) and that correctly disseminated each recommendation (P2). High P1 and P2 indicated better content quality. To assess their public impact, we calculated the median (IQR) of 3 indicators: the number of comments, likes, and saves as a favorite by viewers. Chi-square test, trend chi-square test, and Kruskal-Wallis H test examined differences in indicators across the 3 platforms, years, content, and time duration of videos and between videos disseminating correct versus incorrect information. RESULTS: Overall, 1459 eligible short-form videos were included. The number of short-form videos increased by 16 times between 2018 and 2021. Of them, 93.97% (n=1371) were about secondary prevention (first aid) and 86.02% (n=1255) lasted <2 minutes. The proportion of short-form videos including each of the 15 WHO recommendations ranged from 0% to 77.86% (n=1136). Recommendations 8, 13, and 11 had the highest proportions (n=1136, 77.86%; n=827, 56.68%; and n=801, 54.9%, respectively), whereas recommendations 3 and 5 were never mentioned. Among the short-form videos that included the WHO recommendations, recommendations 1, 2, 4, 6, 9, and 12 were always disseminated correctly, but the other 9 recommendations were correctly disseminated in 59.11% (120/203) to 98.68% (1121/1136) of videos. The proportion of short-form videos including and correctly disseminating the WHO recommendations varied across platforms and years. The public impact of short videos varied greatly across videos, with a median (IQR) of 5 (0-34) comments, 62 (7-841) likes, and 4 (0-27) saves as a favorite. Short-form videos disseminating correct recommendations had larger public impact than those disseminating either partially correct or incorrect knowledge (median 5 vs 4 comments, 68 vs 51 likes, and 5 vs 3 saves as a favorite, respectively; all P<.05). CONCLUSIONS: Despite the rapid increase in the number of web-based short-form videos about fire and burn prevention available in China, their content quality and public impact were generally low. Systematic efforts are recommended to improve the content quality and public impact of short-form videos on injury prevention topics such as fire and burn prevention.

CARMN Is an Evolutionarily Conserved Smooth Muscle Cell-Specific LncRNA That Maintains Contractile Phenotype by Binding Myocardin.

BACKGROUND: Vascular homeostasis is maintained by the differentiated phenotype of vascular smooth muscle cells (VSMCs). The landscape of protein coding genes comprising the transcriptome of differentiated VSMCs has been intensively investigated but many gaps remain including the emerging roles of noncoding genes. METHODS: We reanalyzed large-scale, publicly available bulk and single-cell RNA sequencing datasets from multiple tissues and cell types to identify VSMC-enriched long noncoding RNAs. The in vivo expression pattern of a novel smooth muscle cell (SMC)-expressed long noncoding RNA, Carmn (cardiac mesoderm enhancer-associated noncoding RNA), was investigated using a novel Carmn green fluorescent protein knock-in reporter mouse model. Bioinformatics and quantitative real-time polymerase chain reaction analysis were used to assess CARMN expression changes during VSMC phenotypic modulation in human and murine vascular disease models. In vitro, functional assays were performed by knocking down CARMN with antisense oligonucleotides and overexpressing Carmn by adenovirus in human coronary artery SMCs. Carotid artery injury was performed in SMC-specific Carmn knockout mice to assess neointima formation and the therapeutic potential of reversing CARMN loss was tested in a rat carotid artery balloon injury model. The molecular mechanisms underlying CARMN function were investigated using RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. RESULTS: We identified CARMN, which was initially annotated as the host gene of the MIR143/145 cluster and recently reported to play a role in cardiac differentiation, as a highly abundant and conserved, SMC-specific long noncoding RNA. Analysis of the Carmn GFP knock-in mouse model confirmed that Carmn is transiently expressed in embryonic cardiomyocytes and thereafter becomes restricted to SMCs. We also found that Carmn is transcribed independently of Mir143/145. CARMN expression is dramatically decreased by vascular disease in humans and murine models and regulates the contractile phenotype of VSMCs in vitro. In vivo, SMC-specific deletion of Carmn significantly exacerbated, whereas overexpression of Carmn markedly attenuated, injury-induced neointima formation in mouse and rat, respectively. Mechanistically, we found that Carmn physically binds to the key transcriptional cofactor myocardin, facilitating its activity and thereby maintaining the contractile phenotype of VSMCs. CONCLUSIONS: CARMN is an evolutionarily conserved SMC-specific long noncoding RNA with a previously unappreciated role in maintaining the contractile phenotype of VSMCs and is the first noncoding RNA discovered to interact with myocardin.

Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma.

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

FERMT1 contributes to the migration and invasion of nasopharyngeal carcinoma through epithelial-mesenchymal transition and cell cycle arrest.

BACKGROUND: Fermitin family member 1 (FERMT1) is significantly overexpressed in human cancers and associated with poor prognosis, but its contributions to tumorigenesis and nasopharyngeal carcinoma (NPC) progression remain unclear. METHODS: The public GEO database was examined to investigate the role of FERMT1. Immunohistochemistry (IHC) staining of FERMT1 was performed in NPC tissues to corroborate the results. Western blotting and qRT-PCR were performed to test the expression of related proteins and mRNAs. Cell counting kit-8 assay (CCK8 assay) and colony formation assays were carried out to investigate the association of FERMT1 expression with NPC cell proliferation. The wound healing assay and Transwell assay were used to detect the migration and invasion of NPC cells. Flow cytometric analysis was conducted to detect the cell cycle transition of NPC cells. Co-immunoprecipitation (Co-IP) was employed to identify the correlation of FEMRT1 and Nod-like receptor family protein 3 (NLRP3). Xenograft tumors were generated to investigate the effect of FERMT1 on the growth of NPC cells in vivo. RESULTS: Here, we found that FERMT1 was upregulated in NPC tissues and correlated with the clinicopathological characteristics of NPC patients. Moreover, knockdown of FERMT1 significantly decreased cell proliferation, migration and invasion by mediating epithelial-mesenchymal transition (EMT) and cell cycle arrest of NPC cells both in vitro and in vivo. Knockdown FERMT1 inhibited EMT through directly binding to the NLRP3 and inhibited NF-kB signaling pathway. CONCLUSION: These data indicated that FERMT1 could be a good potential therapeutic target for NPC treatment.

Effectiveness of a helmet promotion campaign, China.

Objective: To evaluate the effectiveness of a 2020 nationwide helmet promotion campaign, in terms of helmet wearing and correct helmet wearing, aimed at electric bike riders and motorcyclists in China. Methods: We obtained 192 hours of film of traffic before (2019) and after (2021) implementation of the campaign at eight road intersections in Changsha, recording cyclist (traditional and electric) and motorcyclist helmet-wearing behaviour during both weekdays and the weekend, and peak and off-peak traffic. We extracted data on rider characteristics and helmet-wearing behaviour. We applied a logistic regression to obtain estimates of helmet wearing and correct helmet wearing, and calculated odds ratios adjusted for rider variables. Findings: We filmed 11 525 cyclists and motorcyclists, 5256 (45.6%) before and 6269 (54.4%) after the campaign. We estimated a substantial increase in the overall percentage of helmet wearing from 8.8% (95% confidence interval, CI: 8.0-9.6) to 62.0% (95% CI: 60.8-63.2). After controlling for covariates, we noted that helmet wearing increased in all groups. However, we observed a decrease in the overall percentage of correct helmet wearing from 91.9% (95% CI: 89.4-94.3) to 83.5% (95% CI: 82.3-84.7). Post-campaign, we estimated the highest percentage of helmet wearing for delivery riders (88.8%) and lowest for traditional cyclists (3.8%); we estimated the lowest percentage of correct helmet wearing for three-wheeled motorcyclists (58.8%). Conclusion: To increase helmet wearing and correct helmet wearing, we recommend amending the campaign to include traditional cyclists as well as education and legislation on the correct fastening of helmet chinstraps.

Predicting coronary artery calcified plaques using perivascular fat CT radiomics features and clinical risk factors.

OBJECTIVE: The purpose of this study was to develop a combined radiomics model to predict coronary plaque texture using perivascular fat CT radiomics features combined with clinical risk factors. METHODS: The data of 200 patients with coronary plaques were retrospectively analyzed and randomly divided into a training group and a validation group at a ratio of 7:3. In the training group, The best feature set was selected by using the maximum correlation minimum redundancy method and the least absolute shrinkage and selection operator. Radiomics models were built based on different machine learning algorithms. The clinical risk factors were then screened using univariate logistic regression analysis. and finally a combined radiomics model was developed using multivariate logistic regression analysis to combine the best performing radiomics model with clinical risk factors and validated in the validation group. The efficacy of the model was assessed by a receiver operating characteristic curve, the consistency of the nomogram was assessed using calibration curves, and the clinical usefulness of the nomogram was assessed using decision curve analysis. RESULTS: Twelve radiomics features were used by different machine learning algorithms to construct the radiomics model. Finally, the random forest algorithm built the best radiomics model in terms of efficacy, and this was combined with age to construct a combined radiomics model. The area under curve for the training and validation group were 0.98 (95% confidence interval, 0.95-1.00) and 0.97 (95% confidence interval, 0.92-1.00) with sensitivities of 0.92 and 0.86 and specificities of 0.99 and 1, respectively. The calibration curve demonstrated that the nomogram had good consistency, and the decision curve analysis demonstrated that the nomogram had high clinical utility. CONCLUSIONS: The combined radiomics model established based on CT radiomics features and clinical risk factors has high value in predicting coronary artery calcified plaque and can provide a reference for clinical decision-making.

Coding quality of deaths and its impact on elderly unintentional fall mortality data from 1990 to 2019: a retrospective analysis of the WHO Mortality Database.

BACKGROUND: Several studies have assessed the reporting quality of all-cause mortality data from the WHO Mortality Database, but little is known about coding quality and its impact on elderly unintentional fall mortality data worldwide. We aimed to assess the coding quality of deaths and its impact on elderly unintentional fall mortality. METHODS: Using data from the WHO Mortality Database, 1990-2019, we calculated the number of countries/territories that had mortality data in the database, and the proportion of deaths with five types of problematic codes based on the 10th International Classification of Disease (unspecified deaths, injury deaths with undetermined intent, unspecified unintentional injury, unintentional falls with unspecified mechanism, unintentional falls with unknown occurrence place). We estimated age-adjusted unintentional fall mortality before and after correcting problematic codes. RESULTS: Only 64% (124/194) of WHO member states had at least 1 year of mortality data in the database during 1990-2019, and data unavailability was more common for underdeveloped countries/territories than for developed countries/territories. Coding quality was poor for many countries/territories. Among the study years when countries/territories possessed mortality data, 80, 53, 51, and 63% had a proportion of unintentional fall deaths with unspecified mechanism over 50% in low-income, lower middle-income, upper middle-income, and high-income countries/territories, respectively; comparable proportions for unintentional fall deaths with unknown occurrence place were 100, 42, 71, and 62%. Among the 94 countries/territories having mortality data, problematic codes caused a relative mortality difference ≥ 50% in 59 countries/territories (63%). After correcting problematic codes, 5 of 55 countries/territories with data witnessed a reverse in mortality changes between 2005 and 2015. Among the 82 countries/territories with mortality data for 5 or more years, 18 countries/territories (22%) experienced a directional reverse in linear regression coefficient. CONCLUSIONS: The availability and coding quality of global data related to elderly unintentional fall mortality was poor between 1990 and 2019. When data are available, varying coding quality across countries/territories and over time have a substantial impact on mortality estimates and mortality comparisons. Global agencies plus each individual government should be aware of the importance of collecting and sharing high-quality mortality data, and take action to improve data quality for inclusion in the WHO Mortality Database.

A survey on the public's discrimination rate of typical rumors during the coronavirus disease 2019 epidemic. / æ–°åž‹å† çŠ¶ç— æ¯’è‚ºç‚Žæµè¡ŒæœŸé—´å ¬ä¼—å¯¹å ¸åž‹è°£è¨€æ­£ç¡®ç”„åˆ«çŽ‡çš„è°ƒæŸ¥.

OBJECTIVES: During the epidemic of coronavirus disease-2019 (COVID-19), the wide spread of rumors caused significant public hazards. This study aims to understand the situation of discrimination for typical COVID-19 rumors by the public and related factors. METHODS: An anonymous online survey was carried out using Questionnaire Star. The contents included participants' gender, age, education level, the COVID-19 information sources, and the judgmental questions about 14 representative COVID-19 rumors. The discrimination rate and 95% confidence interval of 14 rumors were estimated, and the association of discrimination rate with gender, age, and education level was analyzed by binary logistic regression. RESULTS: A total of 2 087 valid questionnaires were collected. The participants were mainly female (62.7%) and below 35 years old (63.4%); the education level was predominantly college/bachelor's degree (47.3%) and master's degree or above (39.1%); the participants, who accessed to COVID-19 information included internet media, accounted for 91%. The participants with different gender, age, and education level had significant differences in the distribution of COVID-19 information sources (all P<0.01). The participants' discrimination rate for 14 rumors ranged from 67.4% to 98.6%, with 4 rumors less than 80%. Women's discrimination rate of 9 rumors was significantly higher than men's (all P<0.05). There was no significant difference in the discrimination rate of rumors among the different age groups (all P>0.05), but the differences in the discrimination rate of other rumors among the different age groups varied according to the rumor. Compared to those with high school or less education levels, the discrimination rates were also higher in the respondents with high education levels (P<0.05). CONCLUSIONS: A few publics are still unable to identify typical rumors during the COVID-19 epidemic. There are associations among genders, age, and the education levels with the discrimination of some rumors. The government authorities should strengthen the true information regarding COVID-19, and therefore enhance the public's ability to identify rumors.

Interfacial behavior of phospholipid monolayers revealed by mesoscopic simulation.

A mesoscopic model with molecular resolution is presented for dipalmitoyl phosphatidylcholine (DPPC) and palmitoyl oleoyl phosphatidylcholine (POPC) monolayer simulations at the air-water interface using many-body dissipative particle dynamics (MDPD). The parameterization scheme is rigorously based on reproducing the physical properties of water and alkane and the interfacial property of the phospholipid monolayer by comparison with experimental results. Using much less computing cost, these MDPD simulations yield a similar surface pressure-area isotherm as well as similar pressure-related morphologies as all-atom simulations and experiments. Moreover, the compressibility modulus, order parameter of lipid tails, and thickness of the phospholipid monolayer are quantitatively in line with the all-atom simulations and experiments. This model also captures the sensitive changes in the pressure-area isotherms of mixed DPPC/POPC monolayers with altered mixing ratios, indicating that the model is promising for applications with complex natural phospholipid monolayers. These results demonstrate a significant improvement of quantitative phospholipid monolayer simulations over previous coarse-grained models.

YAP1/TEAD1 upregulate platelet-derived growth factor receptor beta to promote vascular smooth muscle cell proliferation and neointima formation.

We have previously demonstrated that the transcription co-factor yes-associated protein 1 (YAP1) promotes vascular smooth muscle cell (VSMC) de-differentiation. Yet, the role and underlying mechanisms of YAP1 in neointima formation in vivo remain unclear. The goal of this study was to investigate the role of VSMC-expressed YAP1 in vascular injury-induced VSMC proliferation and delineate the mechanisms underlying its action. Experiments employing gain- or loss-of-function of YAP1 demonstrated that YAP1 promotes human VSMC proliferation. Mechanistically, we identified platelet-derived growth factor receptor beta (PDGFRB) as a novel YAP1 target gene that confers the YAP1-dependent hyper-proliferative effects in VSMCs. Furthermore, we identified TEA domain transcription factor 1 (TEAD1) as a key transcription factor that mediates YAP1-dependent PDGFRß expression. ChIP assays demonstrated that TEAD1 is enriched at a PDGFRB gene enhancer. Luciferase reporter assays further demonstrated that YAP1 and TEAD1 co-operatively activate the PDGFRB enhancer. Consistent with these observations, we found that YAP1 expression is upregulated after arterial injury and correlates with PDGFRß expression and VSMC proliferation in vivo. Using a novel inducible SM-specific Yap1 knockout mouse model, we found that the specific deletion of Yap1 in adult VSMCs is sufficient to attenuate arterial injury-induced neointima formation, largely due to inhibited PDGFRß expression and VSMC proliferation. Our study unravels a novel mechanism by which YAP1/TEAD1 promote VSMC proliferation via transcriptional induction of PDGFRß, thereby enhancing PDGF-BB downstream signaling and promoting neointima formation.