Response of soil-microbe-extracellular enzyme stoichiometric characteristics to nitrogen deposition in a Pinus yunnanensis forest in central Yunnan Province, Southwest China.

To understand the effects of nitrogen deposition on element cycling and nutrient limitation status in forest ecosystems, we examined the effects of nitrogen deposition on the stoichiometric characteristics of forest soil-microbial-extracellular enzymes in Pinus yunnanensis forest. We conducted a field experiment with control (CK, 0 g N·m-2·a-1), low nitrogen (LN, 10 g N·m-2·a-1), medium nitrogen (MN, 20 g N·m-2·a-1) and high nitrogen (HN, 25 g N·m-2·a-1) since 2019. We collected soil samples (0-5 cm, 5-10 cm and 10-20 cm) at September 2022, and measured the contents of soil organic, total nitrogen, total phosphorus, microbial biomass carbon, nitrogen and phosphorus (MBC, MBN, MBP) and the activities of C, N, and P acquisition enzymes. The results showed that nitrogen deposition significantly reduced soil organic content, C:N and C:P by 6.9%-29.8%, 7.6%-45.2% and 6.5%-28.6%, and increased soil total N content and N:P by 10.0%-45.0% and 19.0%-46.0%, respectively. Nitrogen addition did not affect soil total P content. Except for soil C:N and C:P, soil nutrient content and stoichiometric ratio were highest in 0-5 cm soil layer. MN and HN treatments significantly decreased MBN by 11.0%-12.7%. MBC, MBP, and their stoichiometry did not change significantly under nitrogen deposition. Soil microbial nutrient content in 0-5 cm soil layer was significantly higher than that in other soil layers. Nitrogen deposition significantly decreased the activities of cellobiose hydrolase and leucine aminopeptidase (decreased by 14.5%-16.2% and 48.7%-66.3%). HN treatment promoted ß-1,4-glucosidase activity (increased by 68.0%), but inhibited soil enzyme stoichiometric carbon to nitrogen ratio and nitrogen to phosphorus ratio (decreased by 95.4% and 88.4%). LN and MN treatment promoted ß-1,4-N-acetylglucosaminidase activity (increased by 68.3%-116.6%), but inhibited enzyme stoichiometric carbon to phosphorus ratio (decreased by 14.9%-29.4%). Alkaline phosphatase activity had no significant change. Soil enzyme activities were significantly decreased with increasing soil depth. Soil total N and total P and microbial nutrients were negatively correlated with vector angle (representing microbial nitrogen or phosphorus limitation), while vector length (representing microbial carbon limitation) was consistently significantly positively correlated with vector angle, suggesting the synergistic promotion between microbial carbon limitation and phosphorus limitation. Nitrogen deposition gradually shifted to phosphorus limitation while alleviating microbial nitrogen limitation in P. yunnanensis forest. In addition, microbial activities in this region was limited by C availability, and the relationship between microbial C and P limitation was proportional.

Antibody Levels and Infection Status of Pertussis in the Population under Pertussis Resurgence in Guangxi in 2018: A Cross-Sectional Survey.

Objective: Pertussis cases have increased markedly since 2018 in Guangxi. The aim of this study was to evaluate antibody levels and the infection status of pertussis in the resident population. Method: A total of 10,215 serum samples from residents were collected from August-November 2018 and tested for anti-pertussis IgG and toxin IgG using the enzyme-linked immunosorbent assay (ELISA). Results: Of the collected samples, 1,833 (17.94%) tested positive for anti-pertussis IgG, with the median concentration of 16.06 IU/mL. Antibody level < 10 IU/mL accounted for more than 60% in children under 4 years of age, but declined with age, whereas the percentages of the other three levels (10-40, 40-50, and ≥ 50 IU/mL) increased almost with age ( P < 0.001). Moreover, 7,924 samples were selected for anti-pertussis toxin IgG, of which 653 (8.24%) tested positive (≥ 40 IU/mL) with the median concentration of 5.89 IU/mL, and 204 participants (2.56%) had recent pertussis infection (≥ 100 IU/mL). Among the different age groups, the highest rates of positivity and recent infection were observed at 11-20 years of age, the lowest positivity rate at 5 years of age, and the lowest recent infection rate at 4 years of age ( P < 0.001, P = 0.005, respectively). Conclusion: The survey results showed that all age groups in Guangxi lacked immunity against pertussis, which was one of the main factors contributing to the resurgence of pertussis in 2018. In addition, the prevalence of pertussis is relatively high in Guangxi, and its incidence is seriously underestimated, especially in adolescents and adults.

Association of cardiometabolic multimorbidity with all-cause and cardiovascular disease mortality among Chinese hypertensive patients.

BACKGROUND: Hypertension usually clusters with multiple comorbidities. However, the association between cardiometabolic multimorbidity (CMM) and mortality in hypertensive patients is unclear. This study aimed to investigate the association between CMM and all-cause and cardiovascular disease (CVD) mortality in Chinese patients with hypertension. METHODS: The data used in this study were from the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors (CONSIDER), which comprised 5006 participants aged 19-91 years. CMM was defined as the presence of one or more of the following morbidities: diabetes mellitus, dyslipidemia, chronic kidney disease, coronary heart disease, and stroke. Cox proportional hazard models were used to calculate the hazard ratios (HR) with 95% CI to determine the association between the number of CMMs and both all-cause and CVD mortality. RESULTS: Among 5006 participants [mean age: 58.6 ± 10.4 years, 50% women (2509 participants)], 76.4% of participants had at least one comorbidity. The mortality rate was 4.57, 4.76, 8.48, and 16.04 deaths per 1000 person-years in hypertensive patients without any comorbidity and with one, two, and three or more morbidities, respectively. In the fully adjusted model, hypertensive participants with two cardiometabolic diseases (HR = 1.52, 95% CI: 1.09-2.13) and those with three or more cardiometabolic diseases (HR = 2.44, 95% CI: 1.71-3.48) had a significantly elevated risk of all-cause mortality. The findings were similar for CVD mortality but with a greater increase in risk magnitude. CONCLUSIONS: In this study, three-fourths of hypertensive patients had CMM. Clustering with two or more comorbidities was associated with a significant increase in the risk of all-cause and cardiovascular mortality among hypertensive patients, suggesting more intensive treatment and control in this high-risk patient group.

Health system barriers to timely routine measles vaccinations in rural southwest China: a qualitative study on the perspectives of township vaccination professionals and village doctors.

OBJECTIVES: A well-functioning health system ensures timely routine measles vaccinations for age-appropriate children, minimising measles risk. However, there is limited knowledge about the impact of the performance of immunisation programmes in health systems on the timeliness of measles vaccination. This study aimed to identify health system barriers to timely routine measles vaccination in rural southwest China, integrating the perspectives of township vaccination professionals and village doctors. DESIGN, SETTING AND PARTICIPANTS: Qualitative study among township vaccination professionals and village doctors in rural Guangxi, southwest China. METHODS: 20 focus group discussions (FGDs) at township level and 120 in-depth interviews (IDIs) at village level, based on a four-theme framework. We used convenience sampling to recruit 60 township vaccination professionals and 120 village doctors in 2015. Instruments used were a semistructured questionnaire and interview outlines. We collected township and village-level data focusing on themes of health resources allocation, pattern of vaccination services, management and supervision of vaccination services, and perceptions of vaccination policy. The FGDs and IDIs were audio-recorded and transcribed. Braun and Clarke's thematic analysis approach was adopted to synthesise findings into meaningful subthemes, narrative text and illustrative quotations. RESULTS: The health system barriers to timely routine vaccinations were explored across four themes. Barriers in the health resources allocation theme comprised (1) inadequacy of vaccination-related human resources (eg, lack of township vaccination professionals and lack of young village doctors), and (2) incompatible and non-identical information system of vaccination services across regions. Barriers in the pattern of vaccination services theme included inflexible vaccination services models, for example, routine vaccination services being offered monthly on fixed vaccination days, limited numbers of vaccination days per month, vaccination days being set on non-local market days, vaccination days being clustered into a specific period and absence of formal vaccination appointments. Ineffective economic incentive mechanism was identified as a barrier in the management and supervision of vaccination services theme. Low-degree participation of village doctors in routine vaccination services was identified as a barrier in the perceptions of vaccination policy theme. CONCLUSIONS: We encourage policymakers and stakeholders to apply these findings to improve the timeliness of routine vaccination. Barriers to timely routine vaccination include inadequate allocation of vaccination-related resources and inflexible vaccination service delivery models. Financial and non-financial incentives should be used to retain and recruit vaccination professionals and village doctors. Strengthening information systems with unified data standards enables cross-regional data exchange. Optimising immunisation services and rationalising vaccination days could eliminate health system barriers and improve vaccination timeliness in rural China.

Methylation of ESR1 promoter induced by SNAI2-DNMT3B complex promotes epithelial-mesenchymal transition and correlates with poor prognosis in ERα-positive breast cancers.

Estrogen receptor α (ERα) serves as an essential therapeutic predictor for breast cancer (BC) patients and is regulated by epigenetic modification. Abnormal methylation of cytosine phosphoric acid guanine islands in the estrogen receptor 1 (ESR1) gene promoter could silence or decrease ERα expression. In ERα-negative BC, we previously found snail family transcriptional repressor 2 (SNAI2), a zinc-finger transcriptional factor, recruited lysine-specific demethylase 1 to the promoter to transcriptionally suppress ERα expression by demethylating histone H3 lysine 4 dimethylation (H3K4me2). However, the role of SNAI2 in ERα-positive BC remains elusive. In this study, we observed a positive correlation between SNAI2 and ESR1 methylation, and SNAI2 promoted ESR1 methylation by recruiting DNA methyltransferase 3 beta (DNMT3B) rather than DNA methyltransferase 1 (DNMT1) in ERα-positive BC cells. Subsequent enrichment analysis illustrated that ESR1 methylation is strongly correlated with cell adhesion and junction. Knocking down DNMT3B could partially reverse SNAI2 overexpression-induced cell proliferation, migration, and invasion. Moreover, high DNMT3B expression predicted poor relapse-free survival and overall survival in ERα-positive BC patients. In conclusion, this study demonstrated the novel mechanisms of the ESR1 methylation mediated with the SNAI2/DNMT3B complex and enhanced awareness of ESR1 methylation's role in promoting epithelial-mesenchymal transition in BC.

A Study Against Colon Cancer Mechanism of Xanthium Sibiricum Herba Based on Computer Simulation and Bioinformatics.

INTRODUCTION: Cancer is one of the leading causes of death worldwide, accounting for nearly one in six deaths in 2020. As a folk medicine, Xanthium sibiricum Herba (XSH) has been used many times in clinical practice for the treatment of various diseases. With the increasing number of cancer patients, there is a clinical need to find effective anti-cancer drugs. AIM: This study aims to explores the bioactivity and the anti-cancer mechanism of XSH. METHODS: In this study, bioinformatics, network pharmacology, molecular docking, molecular dynamics simulation techniques, and apoptosis assay were used to explore the bioactivity and the anti-cancer mechanism of XSH. RESULTS: Finally, seven active ingredients in XSH after the screening were obtained, the two most active compounds were ß-sitosterol and aloe-emodin, and good anti-cancer activity of XSH was predicted. DISCUSSION: Four core targets were obtained from the PPI network map, namely Caspase-3 (CASP3), Transcription factor AP-1 (JUN), Myc proto-oncogene protein (MYC), and cellular tumor antigen p53 (TP53). GO and KEGG analyses showed that the mechanism of XSH anti-cancer is mainly related to the apoptosis process, and the main signaling pathways are enriched in the p53 signaling pathway, Apoptosis, and MAPK signaling. The molecular docking and molecular dynamics simulation results showed that CASP3, JUN, MYC, and TP53 had a high affinity with ß-sitosterol and aloe-emodin. Bioinformatics analyses demonstrated the importance of core targets. Apoptosis assay showed that XSH could significantly promote the apoptosis of cancer cells, and inhibit their proliferation and migration, especially colon cancer cells. CONCLUSION: This study uncovered the main active components, bioactivities, and potential targets of XSH, and further revealed the multi-component, multi-target, and multi-pathway mechanism of XSH for cancer treatment and promoting apoptosis.

Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer.

OBJECTIVES: De novo mesenchymal-to-epithelial transition (MET) gene fusions in non-small cell lung cancer (NSCLC) are a promising target for MET tyrosine kinase inhibitors (TKIs). We aimed to examine the response to targeted therapy with MET TKIs and resistance mechanisms in de novo MET fusion-positive NSCLC as these have not been comprehensively explored. MATERIALS AND METHODS: We examined the MET fusions in 4,429 patients with advanced-stage NSCLC using targeted next-generation sequencing and validated the results using RT-PCR. We analyzed cellular models harboring MET fusions and established a patient-derived organoid (PDO) model. RESULTS: We identified 13 (0.29 %, 13/4429) patients with de novo MET fusions and found EPHB4, THAP5, TNPO3, and DST as novel MET fusion partners. The most common concomitant gene with MET fusions was TP53 mutations. Among 12 patients receiving MET TKI treatment, two achieved stable disease, six achieved partial response, and four underwent progressive disease. An in vitro study showed that EPHB4-MET is a functional driver gene. MET inhibitors significantly inhibited the proliferation and phosphorylation of downstream STAT3, AKT, and ERK1/2 in EPHB4-MET overexpressing cells. Acquired MET D1228H/N or D1246N mutations were found in patients harboring MET fusions after acquiring resistance to MET TKIs. Tivantinib showed optimal suppression efficacy in a PDO model with an acquired MET D1228N mutation. CONCLUSION: MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions.

iTRAQ Quantitative Proteomic Analysis of Different Expressed Proteins and Signal Pathways in Bakuchiol-Induced Hepatotoxicity.

Bakuchiol (BAK) is an abundant natural compound. BAK has been reported to have several biological activities such as anticancer, antiaging, anti-inflammatory, and prevention of bone loss. However, it causes hepatotoxicity, the mechanism of which is not known. In this study, we explored the mechanism of BAK hepatotoxicity by treating rats with 52.5 mg/kg and 262.5 mg/kg of BAK, administered continuously for 6 weeks. We examined the liver pathology and biochemical composition of bile to determine toxicity. Mechanisms of BAK hepatotoxicity were analyzed based on relative and absolute quantification (iTRAQ) protein equivalent signatures and validated in vitro using LO2 cells. iTRAQ analysis revealed 281 differentially expressed proteins (DEPs) in liver tissue of the BAK-treated group, of which 215 were upregulated, and 66 were downregulated. GO and KEGG enrichment analysis revealed that bile secretion, lipid metabolism, and cytochrome P450 signaling pathways were enriched in DEPs. Among them, peroxisome proliferator-activated receptor α (PPARα), farnesoid X receptor (FXR), and cholesterol 7α-hydroxylase (CYP7a1) were closely associated with the development and progression of BAK-induced hepatic metabolic dysfunction and abnormal bile metabolism. This study shows that BAK can induce hepatotoxicity through multiple signaling pathways.

Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in Low-risk Patients: A Meta-Analysis Based on a 2-Year Follow-Up.

BACKGROUND: Previous studies have shown that transcatheter aortic valve implantation is the best alternative therapy to surgical aortic valve replacement in high-risk surgical patients with aortic stenosis. However, it is not clear whether transcatheter aortic valve implantation can be utilized in low-risk surgical patients with aortic stenosis. This studyaimed to evaluate the safety and efficacy of transcatheter aortic valve implantation in low-risk patients. METHODS: From the outset of our initiative until April 2022, PubMed, EMBASE, and the Cochrane database were thoroughly searched, yielding the selection of 3 randomized controlled trials including 2644 patients with aortic stenosis, to assess outcome measures at distinct follow-up time. RESULTS: The mean Society of Thoracic Surgeons Predicted Risk of Mortality score of patients was 2.2. At the 30-day and 1-year follow-up, transcatheter aortic valve implan- tation was associated with a lower incidence of all-cause mortality, cardiovascular mor- tality, acute kidney injury (stage 2 or 3), life-threatening or significant bleeding, and new atrial fibrillation but an increased risk of permanent pacemaker implantation. At the 2-year follow-up, transcatheter aortic valve implantation only had an advantage in new atrial fibrillation (relative risk, 0.27; 95% CI, 0.14-0.51; P < .0001), with no significant differ- ence in all-cause mortality or cardiovascular mortality. CONCLUSIONS: For low-risk surgical patients with aortic stenosis, compared to surgical aortic valve replacement, transcatheter aortic valve implantation was associated with lower all-cause mortality at 30-day follow-up and lower cardiovascular mortality at 1-year follow-up. Except for the advantages in new atrial fibrillation, transcatheter aor- tic valve implantation had no significant impact on mortality at 2-year follow-up.

Hypericin nanoparticles for self-illuminated photodynamic cytotoxicity based on bioluminescence resonance energy transfer.

The purpose of this study was to investigate the self-sensitization of photosensitizer without an external light source to produce a photodynamic therapy (PDT) effect based on the principle of bioluminescence resonance energy transfer (PDT-BRET). First, we demonstrated that HeLa cells could efficiently express firefly luciferase (FLase) after the firefly luciferase gene was transfected with the FLase-gene plasmid (FLase-GP), and proved that FLase could act on the substrate firefly D-luciferin (FLuc) to produce photons. The generated photons activate the photosensitizer hypericin (Hyp) and induce cytotoxicity. Then, we successfully prepared carboxymethyl chitosan-modified poly(lactic-co-glycolic acid) nanoparticles (CPNPs) loaded with FLuc (FLuc-CPNPs) and with loaded Hyp (Hyp-CPNPs). Their physicochemical and pharmaceutical characteristics indicated that they were an excellent drug delivery system. Characterization of the biological effects showed that they could be located in the mitochondrial, had higher ROS generation and stronger cytotoxicity. In vivo results also showed that PDT-BRET was as effective as classic PDT. PDT-BRET and the related drug delivery system are expected to become a new platform for anticancer therapy.

Clinicopathological features and resistance mechanisms in HIP1-ALK-rearranged lung cancer: A multicenter study.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.

Association between body mass index, waist circumference, and age at natural menopause: a population-based cohort study in Chinese women.

The purpose of the study was to investigate whether premenopausal body mass index (BMI) and waist circumference (WC) influence age at menopause. A total of 2116 women aged 35-64 years from two communities of the CMCS Beijing cohort were recruited in 1992 and followed up to 2018. Of 1439 premenopausal women at baseline, 6 women data were missing. Finally, 1433 women were included for analysis. Overweight was defined as BMI 24-27.99 kg/m2. Central obesity was defined as WC ≥80 cm. Age at menopause was categorized as <45 years, 45-49 years, 50-51 years (reference), and >51 years. Multinomial logistic regression models were used to estimate relative odds ratios (RORs) and 95% confidence intervals (CIs). Compared to women with normal weight and normal WC, overweight women with normal WC had higher risk of menopause at >51 years (ROR 1.64, 95% CI 1.10-2.45; P = .01); and overweight women with central obesity had higher risk of menopause at not only >51 years (ROR 1.82, 95% CI 1.13-2.93; P = .01) but also <45 years (ROR 3.13, 95% CI 1.20-8.43; P = .02) and 45-49 years (ROR 2.76, 95% CI 1.71-4.46; P < .001). When overweight women combine with central obesity, the risk of early menopause will increase in some of them.

Effect of sequential high-flow nasal cannula oxygen therapy and non-invasive positive-pressure ventilation in patients with difficult weaning from mechanical ventilation after extubation on respiratory mechanics.

BACKGROUND: Patients with difficult weaning who undergo mechanical ventilation are more likely to be at risk of reintubation and the sequential use of oxygen therapy after extubation is a concern for clinicians. Therefore, the aim of the present study was to compare the effects of transnasal high-flow nasal cannula (HFNC) oxygen therapy and non-invasive positive-pressure ventilation (NIV) on respiratory mechanics in patients with difficult weaning. METHODS: The present study was a single-center, retrospective, observational study. Twenty-nine patients with difficult weaning off invasive mechanical ventilation from the Department of Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, from December 2018 to April 2021, were included. Within 48 h after extubation, alternate respiratory support with HFNC and NIV was provided. Relevant indicators were recorded after each support mode had been maintained for at least 60 min. These included esophageal pressure (Pes), gastric pressure (Pga), transdiaphragmatic pressure (Pdi), pressure-time product of Pes (PTPes), pressure-time product of Pga (PTPga), pressure-time product of Pdi (PTPdi), ratio of the PTPdi to the PTPes (PTPdi/PTPes), and ratio of the Pes to the Pdi (Pes/Pdi), diaphragmatic electromyogram (EMGdi), percentage of esophageal pressure coefficient of variation (CVes%),diaphragmatic electromyogram coefficient of variation (CVEMG),inspiratory time (Ti), expiratory time (Te) and respiratory cycle time (Ttot). RESULTS: Of the 29 patients included, 22 were males and 7 were females [age: 63.97±15.34 years, Acute Physiological and Chronic Health Estimation II (APACHE II) score: 18.00±5.63]. The CVes% and the Pes/Pdi were significantly higher in patients with NIV than HFNC using 40 L/min, CVes%: 9 (-6, 20) vs. -7 (-23, 6) and Pes/Pdi: 0.17 (-0.1, 0.53), vs. -0.12 (-0.43, 0.08) (P<0.05). The remaining indicators were not statistically different. CONCLUSIONS: The sequential NIV and HFNC can be tolerated in patients with such difficult weaning off mechanical ventilation after extubation, and more patients tend to choose HFNC subjectively. Compared with HFNC, NIV reduces the work of adjunctive respiratory muscle, but the patient's Pes dispersion is high when NIV is used, and it is necessary to pay attention to patient-ventilator coordination in clinical practice. We recommend alternating HFNC and NIV during the sequential respiratory therapy after extubation.

Multi-level determinants of failure to receive timely and complete measles vaccinations in Southwest China: a mixed methods study.

BACKGROUND: Measles outbreaks re-emerged in 2013-2014 in Guangxi Zhuang Autonomous Region of China, where measles immunisation coverage is high. The discrepancy between the vaccination coverage and outbreaks indicates that timeliness is crucial, yet there is limited knowledge on the health system barriers to timely vaccination. Using integrated evidence at the household, village clinic, and township hospital levels, this study aimed to identify the determinants of failure in receiving timely measles vaccinations among children in rural Guangxi. METHODS: A multi-stage stratified cluster sampling survey with a nested qualitative study was conducted among children aged 18-54 months in Longan, Zhaoping, Wuxuan, and Longlin counties of Guangxi from June to August 2015. The status of timely vaccinations for the first dose of measles-containing vaccine (MCV1) and the second dose of measles-containing vaccine (MCV2) was verified via vaccination certificates. Data on household-level factors were collected using structured questionnaires, whereas data on village and township-level factors were obtained through in-depth interviews and focus group discussions. Determinants of untimely measles vaccinations were identified using multilevel logistic regression models. RESULTS: A total of 1216 target children at the household level, 120 villages, and 20 township hospitals were sampled. Children were more likely to have untimely vaccination when their primary guardian had poor vaccination knowledge [MCV1, odds ratio (OR) = 1.72; MCV2, OR = 1.51], had weak confidence in vaccines (MCV1, OR = 1.28-4.58; MCV2, OR = 1.42-3.12), had few practices towards vaccination (MCV1, OR = 12.5; MCV2, OR = 3.70), or had low satisfaction with vaccination service (MCV1, OR = 2.04; MCV2, OR = 2.08). This trend was also observed in children whose village doctor was not involved in routine vaccination service (MCV1, OR = 1.85; MCV2, OR = 2.11) or whose township hospital did not provide vaccination notices (MCV1, OR = 1.64; MCV2, OR = 2.05), vaccination appointment services (MCV1, OR = 2.96; MCV2, OR = 2.74), sufficient and uniformly distributed sessions for routine vaccination (MCV1, OR = 1.28; MCV2, OR = 1.17; MCV1, OR = 2.08), or vaccination service on local market days (MCV1, OR = 2.48). CONCLUSIONS: Guardians with poor knowledge, weak beliefs, and little practice towards vaccination; non-involvement of village doctors in routine vaccinations; and inconvenient vaccination services in township hospitals may affect timely measles vaccinations among children in rural China.

Timeliness, completeness, and timeliness-and-completeness of serial routine vaccinations among rural children in Southwest China: A multi-stage stratified cluster sampling survey.

INTRODUCTION: Vaccination coverage is widely used as metric of vaccination programme performance. However, VPDs outbreaks were reported in areas with high vaccination coverage. Timeliness and completeness have been considered more important assessment indicators of routine vaccination than overall vaccination coverage, but little is known in rural China. This study aimed to assess the timeliness and completeness of serial routine vaccinations among children in rural Southwest China. METHODS: A multi-stage stratified cluster survey was conducted among 1062 children aged 18-48 months in rural Guangxi. Vaccination status was obtained from child's vaccination certificate. We calculated timely vaccination coverage, complete vaccination coverage, timely-and-complete vaccination coverage and 95% CI for routine vaccination through weighted estimation analysis. Weighted Kaplan-Meier analyses were applied to estimate the median delay periods for each dose of serial routine vaccines, including one-dose BCG, three-dose HepB, three-dose OPV, four-dose DTP, two-dose MCV, two-dose JEV and two-dose MPV-A. Complete coverage, and timely-and-complete coverage for combined 5-vaccine series were calculated. RESULTS: For each dose of routine vaccines, overall vaccination coverages were over 90%, but timely vaccination coverage ranged from the lowest of 44.4% for JEV1 to the highest of 92.5% for MPV-A1. For multi-dose routine vaccines, complete vaccination coverages varied from the lowest of 92.9% for MCV to the highest of 100% for HepB, and timely-and-complete vaccination coverages were lower than 80%, ranging from the lowest of 30% for JEV to the highest of 77.2% for MPV-A. For combined 5-vaccine series, complete coverage was 77%, while timely-and-complete coverage was 12.1%. MPV-A1 had the longest median delay of 176 days, but BCG and HepB1 had the shortest of 1 day. CONCLUSIONS: The overall coverages of serial routine vaccinations were high, but the timeliness and completeness were poor. Relevant agencies of vaccination service should address timeliness-and-completeness into the assessment indicators of routine vaccination service quality.

Triptolide suppresses the growth and metastasis of non-small cell lung cancer by inhibiting ß-catenin-mediated epithelial-mesenchymal transition.

Non-small cell lung cancer (NSCLC) is characterized by a high incidence of metastasis and poor survival. As epithelial-mesenchymal transition (EMT) is well recognized as a major factor initiating tumor metastasis, developing EMT inhibitor could be a feasible treatment for metastatic NSCLC. Recent studies show that triptolide isolated from Tripterygium wilfordii Hook F attenuated the migration and invasion of breast cancer, colon carcinoma, and ovarian cancer cells, and EMT played important roles in this process. In the present study we investigated the effect of triptolide on the migration and invasion of NSCLC cell lines. We showed that triptolide (0.5, 1.0, 2.0 nM) concentration-dependently inhibited the migration and invasion of NCI-H1299 cells. Triptolide treatment concentration-dependently suppressed EMT in NCI-H1299 cells, evidenced by significantly elevated E-cadherin expression and reduced expression of ZEB1, vimentin, and slug. Furthermore, triptolide treatment suppressed ß-catenin expression in NCI-H1299 and NCI-H460 cells, overexpression of ß-catenin antagonized triptolide-caused inhibition on EMT, whereas knockout of ß-catenin enhanced the inhibitory effect of triptolide on EMT. Administration of triptolide (0.75, 1.5 mg/kg per day, ip, every 2 days) for 18 days in NCI-H1299 xenograft mice dose-dependently suppressed the tumor growth, restrained EMT, and decreased lung metastasis, as evidence by significantly decreased expression of mesenchymal markers, increased expression of epithelial markers as well as reduced number of pulmonary lung metastatic foci. These results demonstrate that triptolide suppresses NSCLC metastasis by targeting EMT via reducing ß-catenin expression. Our study implies that triptolide may be developed as a potential agent for the therapy of NSCLC metastasis.

Combined effect of menopause and cardiovascular risk factors on death and cardiovascular disease: a cohort study.

BACKGROUND: Observational studies suggest that early menopause is associated with increased risk of death and cardiovascular disease (CVD); however, the results of these studies have been inconsistently. We aimed to assess the association of menopause with death and CVD and whether this association was modified by cardiovascular risk factors. METHODS: The study population was women age 35-64 years living in two communities of Beijing who were enrolled in the Chinese Multi-provincial Cohort Study in 1992. Participants were followed until first cardiovascular event, death, or the end of follow-up (2018). Self-reported age at menopause was recorded. Multivariate Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of death and CVD after adjusting for baseline covariates of age, family history of CVD, and white blood cell count, as well as time-varying covariates of menopause, use of oral estrogen, and conventional risk factors. Additionally, we assessed the combined effect of age at menopause and risk factors on the primary endpoint. RESULTS: Of 2104 eligible women, 124 died and 196 had a first CVD event (33 fatal CVD and 163 non-fatal CVD). Compared with women who experienced menopause at age 50-51 years, the risk of death was higher in women with menopause at age 45-49 years (HR 1.99, 95% CI 1.24-3.21; P = 0.005), and the risk of ischemic stroke was higher in women with menopause at age < 45 years (HR 2.16, 95% CI 1.04-4.51; P = 0.04) and at age 45-49 years (HR 2.05, 95% CI 1.15-3.63; P = 0.01). Women who had menopause before age 50 years and at least one elevated risk factor at baseline had a higher risk of death (HR 11.10, 95% CI 1.51-81.41; P = 0.02), CVD (HR 3.98, 95% CI 1.58-10.01; P = 0.003), ischemic CVD (HR 4.53, 95% CI 1.63-12.62; P = 0.004), coronary heart disease (HR 8.63, 95% CI 1.15-64.50; P = 0.04), and stroke (HR 2.92, 95% CI 1.03-8.29; P = 0.04) than those with menopause at age 50-51 years and optimal levels of all risk factors. CONCLUSIONS: Earlier menopause may predict death and ischemic stroke. Furthermore, there is a combined effect of earlier menopause and elevated risk factors on death and CVD.

Catalpol counteracts the pathology in a mouse model of Duchenne muscular dystrophy by inhibiting the TGF-ß1/TAK1 signaling pathway.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by a mutation in the gene encoding the dystrophin protein. Catalpol is an iridoid glycoside found in Chinese herbs with anti-inflammatory, anti-oxidant, anti-apoptotic, and hypoglycemic activities that can protect against muscle wasting. In the present study we investigated the effects of catalpol on DMD. Aged Dystrophin-deficient (mdx) mice (12 months old) were treated with catalpol (100, 200 mg·kg-1·d-1, ig) for 6 weeks. At the end of the experiment, the mice were sacrificed, and gastrocnemius (GAS), tibialis anterior (TA), extensor digitorum longus (EDL), soleus (SOL) muscles were collected. We found that catalpol administration dose-dependently increased stride length and decreased stride width in Gait test. Wire grip test showed that the time of wire grip and grip strength were increased. We found that catalpol administration dose-dependently alleviated skeletal muscle damage, evidenced by reduced plasma CK and LDH activity as well as increased the weight of skeletal muscles. Catalpol administration had no effect on dystrophin expression, but exerted anti-inflammatory effects. Furthermore, catalpol administration dose-dependently decreased tibialis anterior (TA) muscle fibrosis, and inhibited the expression of TGF-ß1, TAK1 and α-SMA. In primary myoblasts from mdx mice, knockdown of TAK1 abolished the inhibitory effects of catalpol on the expression levels of TGF-ß1 and α-SMA. In conclusion, catalpol can restore skeletal muscle strength and alleviate skeletal muscle damage in aged mdx mice, thus may provide a novel therapy for DMD. Catalpol attenuates muscle fibrosis by inhibiting the TGF-ß1/TAK1 signaling pathway.

Association of menopause with risk of carotid artery atherosclerosis.

OBJECTIVES: Observational studies suggest that the risk of cardiovascular disease increases during menopause; however, the menopause-related risk of subclinical atherosclerosis is unclear. The aim of the current study is to evaluate menopause and the risk of subclinical carotid atherosclerosis through a retrospective analysis of data from a population-based prospective cohort study. STUDY DESIGN: The study sample comprised 879 women in the Beijing community enrolled in the Chinese Multi-provincial Cohort Study at baseline study in 1992 and followed up to at least one carotid ultrasound examination at three on-site follow-up surveys. Age at menopause was categorized as <40 years (premature menopause), 40-44 years (early menopause), 45-49 years (relatively early menopause), 50-51 years (reference), and >51 years (relatively late menopause). Menopause staging at baseline was categorized as: reproductive, menopausal transition/perimenopause, early postmenopause, and late postmenopause. Menopause as a time-varying covariate was calculated using waiting time to menopause and menopause status at the last follow-up (2012). MAIN OUTCOME MEASURES: The main outcome measures included carotid plaque and intima-media thickening. Gray's test was performed to assess the equality of cumulative incidence functions between age groups at menopause and between menopause stages. Multivariate Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) associated with menopause. RESULTS: Of the 879 women included (mean [SD] age at baseline, 48.6 [8.1] years), 573 (65.2%) developed carotid plaques and 430 (48.9%) developed intima-media thickening during follow-up. Menopause was significantly associated with risk of developing carotid plaques (HR 1.93, 95% CI 1.05-3.54; P = 0.03) after adjustment for age at baseline, age at menopause, use of oral estrogen due to menopause, and traditional cardiovascular risk factors at baseline. No significant association was found between age at menopause and risk of carotid atherosclerosis. CONCLUSION: Menopausal women, irrespective of age at menopause, had an increased risk of carotid plaque.