Impact of medical insurance access negotiation on the utilization of innovative anticancer drugs in China: an interrupted time series analysis.

BACKGROUND: The high costs of innovative anticancer drugs hinder a number of cancer patients' access to these drugs in China. To address this problem, in 2018, the medical insurance access negotiation (MIAN) policy was implemented, when the prices of 17 innovative anticancer drugs were successfully negotiated and they were therefore included in the reimbursement list. This study aimed to explore the impact of the MIAN policy on the utilization of innovative anticancer drugs. METHODS: With monthly data on drug expenditures and defined daily doses (DDDs) of each innovative anticancer drug from January 2017 to December 2019, interrupted time series analysis was employed to estimate both the instant (change in the level of outcome) and long-term (change in trends of outcomes) impacts of the MIAN policy on drug utilization in terms of drug expenditures and DDDs. Our sample consists of 12 innovative anticancer drugs. RESULTS: From January 2017 to December 2019, the monthly drug expenditures and DDDs of 12 innovative anticancer drugs increased by about 573% (from US$8,931,809.30 to US$51,138,331.09) and 1400% (from 47,785 to 668,754), respectively. Overall, the implementation of the MIAN policy led to instant substantial increases of US$8,734,414 in drug expenditures and 158,192.5 in DDDs. Moreover, a sharper upward trend over time was reported, with increases of US$2,889,078 and 38,715.3 in the monthly growth rates of drug expenditures and DDDs, respectively. Regarding individual innovative anticancer drugs, the most prominent instant change and trend change in drug utilization were found for osimertinib, crizotinib, and ibrutinib. In contrast, the utilization of pegaspargase was barely affected by the MIAN policy. CONCLUSIONS: The MIAN policy has effectively promoted the utilization of innovative anticancer drugs. To ensure the continuity of the effects and eliminate differentiation, supplementary measures should be carried out, such as careful selection of drugs for medical insurance negotiations, a health technology assessment system and a multichannel financing mechanism.

Synthesis of Pd/Carbon Hollow Spheres by the Microwave Discharge Method for Catalytic Debenzylation.

Pd/C catalysts have been widely applied in the debenzylation process due to their excellent ability of hydrogenolysis. However, they have been suffering from the problems of agglomeration and loss of active components, which lead to decreased and unstable activity. Thus, it is still a challenge to achieve Pd/C catalysts with high activity and stability. Herein, we propose a strategy for preparing Pd/C catalysts on porous carbon hollow spheres by a microwave discharge method. Due to the high-temperature property and reducibility of microwave discharge, Pd precursors can be rapidly reduced, resulting in well-dispersed Pd nanoparticles with a small size on the carbon carrier. Besides, the matched mesopores in the carbon hollow spheres can anchor Pd nanoparticles and effectively reduce the agglomeration and loss of Pd nanoparticles during the catalytic reaction. As a result, the as-prepared Pd/mesoporous carbon hollow spheres exhibit high and stable activity in the debenzylation reaction.

The association of serum toxic metals and essential elements during early pregnancy with body mass index trajectory of infants during the first years: A prospective study.

To the best of our knowledge, prior research has yet to delve into the combined and interactive relationships between maternal exposure to essential elements and toxic metals and infancy's continuous growth and trajectories. This study aims to discern infant growth trajectories in the first year of life and to determine the associations of maternal serum levels of essential elements and toxic metals with growth trajectory. Within a Chinese prospective cohort in 2019 - 2021, 407 mother-infant pairs were included, and the serum levels of five essential elements (zinc, calcium, copper, magnesium and iron) and two toxic metals (cadmium and lead) in early pregnancy were assessed. The growth trajectory of infants was followed until age one year. Raw BMI and height values were transformed to age- and sex-specific BMI and height standard deviation (SD) scores. Latent-class group-based trajectory models and piecewise linear mixed regression were estimated to determine infant growth trajectories and growth velocity, respectively. The individual relationship between maternal metallic element levels and infant growth trajectory was examined using multinomial logistic regression models and linear mixed regression, while joint associations and interactive relationships were explored using Bayesian kernel machine regression (BKMR) following confounder adjustments. Four distinct trajectory patterns based on BMI-z score (low-rapid BMI gain group, normal-stable BMI group, very low-rapid BMI gain group and normal-rapid BMI gain group) and length-for-age (high-stable length group, low-stable length group, normal-rapid length gain group, very low-rapid length gain group) were identified during the first year post-birth, respectively. In single-metal and multiple-metal models, infants born to mothers with higher serum Zn and lower serum Cu levels were associated with a normal-rapid BMI gain trajectory during the first year. Serum Cu exhibited a positive correlation with the rate of BMI change solely in infants aged 6-12 months. Further, the BKMR analysis revealed a statistically significant and negative joint effect of the five essential elements on the likelihood of normal-rapid BMI/length gain trajectory when serum levels of these elements fell below the 70th percentile compared to median levels. In addition, high levels of serum copper and calcium interactively affect the rates of BMI change during 6-12 months old (ß: -0.21, 95% CI: -0.44, -0.03, P = 0.04, P-interaction=0.04). In conclusion, maternal trace elements at early pregnancy are linked to infant growth patterns and growth velocity in the first year of life.

Combined exposure to multiple essential elements and cadmium at early pregnancy on gestational diabetes mellitus: a prospective cohort study.

Background: Minerals and trace elements were involved in the pathogenesis and progression of diabetes. However, the association of mixed exposure to essential elements and toxic elements with gestational diabetes mellitus (GDM) is poorly understood. Objective: This study aims to examine the associations between serum calcium (Ca), iron (Fe), zinc (Zn), copper (Cu), magnesium (Mg), and cadmium (Cd) concentrations in early pregnancy and GDM risk in Chinese pregnant women. Method: A total of 1,168 pregnant women were included in this prospective cohort study. The concentrations of serum elements were measured using the polarography method before 14 gestational weeks and an oral glucose tolerance test was conducted at 24-28 gestational weeks to diagnose GDM. Binary logistic regression analysis and restricted cubic spline were applied to evaluate the association between serum individual element and GDM. Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression were used to assess the associations between mixed essential elements and Cd exposure and GDM risk. Results: The mean concentrations of Zn (124.65 vs. 120.12 µmol/L), Fe (135.26 vs. 132.21 µmol/L) and Cu (23.33 vs. 23.03 µmol/L) in the GDM group were significantly higher than those in the control group. Single-element modeling results suggested that second and fourth-quartile maternal Zn and Fe concentration, third and fourth-quartile Cu concentration and fourth-quartile Ca concentration were associated with an increased risk of GDM compared to first-quartile values. Restricted cubic spline analysis showed U-shaped and non-linear relationships between Cd and GDM. According to the BKMR models and WQS analyses, a six-element mixture was significantly and positively associated with the risk of GDM. Additionally, Cd, Zn, and Cu contributed the most strongly to the association. Conclusion: Serum Zn, Cu, Fe, and Ca exposure during early pregnancy showed a positive association with GDM in the individual evaluation. The multiple-evaluation showed that high levels of elements mixture, particularly Cd, Zn, and Cu, may promote the development of GDM.

Knockdown of lncRNA MALAT1 induces pyroptosis by regulating the miR­124/SIRT1 axis in cervical cancer cells.

The aim of the present study was to elucidate the role and downstream mechanism of long non­coding RNA (lncRNA) metastasis­associated lung adenocarcinoma transcript 1 (MALAT1) in the process of cervical cancer cell pyroptosis. The effect of inhibiting lncRNA MALAT1 on cervical cancer cells was determined using primary cells isolated from patients and U14 cervical tumor­bearing nude mice. The level of lncRNA MALAT1 expression and cell viability were determined for relationship analysis. Pyroptosis was then investigated in HeLa cells with lncRNA MALAT1 knockdown or overexpression with or without lipopolysaccharide (LPS) treatment. Bioinformatics tools were used to identify downstream factors of lncRNA MALAT1, which were subsequently verified by gain­ or loss­of­function analyses in the process of cervical cancer cell pyroptosis. It was observed that the level of lncRNA MALAT1 was markedly higher in cervical carcinoma cells compared with expression in paracarcinoma cells, and knockdown of lncRNA MALAT1 induced cervical cancer cell death through pyroptosis. By contrast, overexpression of lncRNA MALAT1 blocked LPS­induced pyroptosis. These results, combined with bioinformatics statistical tools, demonstrated that the microRNA (miR)­124/sirtuin 1 (SIRT1) axis may affect the progression of cervical cancer at least partly by mediating the effect of lncRNA MALAT1 on the pyroptosis of cervical cancer cells. In conclusion, the lncRNA MALAT1/miR­124/SIRT1 regulatory axis in cervical cancer cells may mediate pyroptosis and may provide potential targets against the progression of cervical cancer.

Development of a growth-coupled selection platform for directed evolution of heme biosynthetic enzymes in Corynebacterium glutamicum.

Heme is an important tetrapyrrole compound, and has been widely applied in food and medicine industries. Although microbial production of heme has been developed with metabolic engineering strategies during the past 20 years, the production levels are relatively low due to the multistep enzymatic processes and complicated regulatory mechanisms of microbes. Previous studies mainly adopted the strategies of strengthening precursor supply and product transportation to engineer microbes for improving heme biosynthesis. Few studies focused on the engineering and screening of efficient enzymes involved in heme biosynthesis. Herein, a growth-coupled, high-throughput selection platform based on the detoxification of Zinc-protoporphyrin IX (an analogue of heme) was developed and applied to directed evolution of coproporphyrin ferrochelatase, catalyzing the insertion of metal ions into porphyrin ring to generate heme or other tetrapyrrole compounds. A mutant with 3.03-fold increase in k cat/K M was selected. Finally, growth-coupled directed evolution of another three key enzymes involved in heme biosynthesis was tested by using this selection platform. The growth-coupled selection platform developed here can be a simple and effective strategy for directed evolution of the enzymes involved in the biosynthesis of heme or other tetrapyrrole compounds.

Association of gut microbiota, plasma and fecal metabolite profiles with intellectual development in school-age children.

Background: Little is known about how the gut microbiota and metabolic profiles are related to cognitive outcomes in young children until now. It was hypothesized that the gut microbiota, the plasma and fecal metabolites significantly correlated with intelligence quotient (IQ) in school-age children in current study. Methods: This cross-sectional study enrolled 452 children aged 6-9 years old. IQ was measured using the Wechsler Intelligence Scale for Children-Fourth Edition. Fecal microbiota, plasma and fecal metabolites were analyzed using 16S rRNA amplicon sequencing and targeted metabolomic technologies, respectively. Results: Restricted maximum likelihood (REML) analyses showed that microbiota composition and fecal metabolites were associated with neither subscale nor full-scale IQ (P: 0.059-0.500). However, plasma metabolites were significantly correlated with the processing speed (P=0.008). In multiple regression analysis after adjusting for confounders and multiple test correction, benzoic acid, azelaic acid, adipic acid, suberic acid and malonic acid selected by the multivariate methods with unbiased variable selection were positively associated with processing speed index (PSI) [Pfalse discovery rate (FDR): 0.006-0.024], whereas pyruvic acid was negatively associated with the PSI and full-scale IQ (PFDR: 0.014-0.030). Conclusions: In normal school-age children, certain plasma metabolites concentrations but not the gut microbiota composition nor fecal metabolites are correlated with intelligence.

Sustainable and high-level microbial production of plant hemoglobin in Corynebacterium glutamicum.

BACKGROUND: Plant hemoglobin shows great potential as a food additive to circumvent the controversy of using animal materials. Microbial fermentation with engineered microorganisms is considered as a promising strategy for sustainable production of hemoglobin. As an endotoxin-free and GRAS (generally regarded as safe) bacterium, Corynebacterium glutamicum is an attractive host for hemoglobin biosynthesis. RESULTS: Herein, C. glutamicum was engineered to efficiently produce plant hemoglobin. Hemoglobin genes from different sources including soybean and maize were selected and subjected to codon optimization. Interestingly, some candidates optimized for the codon usage bias of Escherichia coli outperformed those for C. glutamicum regarding the heterologous expression in C. glutamicum. Then, saturated synonymous mutation of the N-terminal coding sequences of hemoglobin genes and fluorescence-based high-throughput screening produced variants with 1.66- to 3.45-fold increase in hemoglobin expression level. To avoid the use of toxic inducers, such as isopropyl-ß-D-thiogalactopyranoside, two native inducible expression systems based on food additives propionate and gluconate were developed. Promoter engineering improved the hemoglobin expression level by 2.2- to 12.2-fold. Combination of these strategies and plasmid copy number modification allowed intracellular production of hemoglobin up to approximately 20% of total protein. Transcriptome and proteome analyses of the hemoglobin-producing strain revealed the cellular response to excess hemoglobin accumulation. Several genes were identified as potential targets for further enhancing hemoglobin production. CONCLUSIONS: In this study, production of plant hemoglobin in C. glutamicum was systematically engineered by combining codon optimization, promoter engineering, plasmid copy number modification, and multi-omics-guided novel target discovery. This study offers useful design principles to genetically engineer C. glutamicum for the production of hemoglobin and other recombinant proteins.

Orally administered Lactiplantibacillus plantarum OLL2712 decreased intestinal permeability, especially in the ileum: Ingested lactic acid bacteria alleviated obesity-induced inflammation by collaborating with gut microbiota.

Introduction: Chronic inflammation caused by dietary obesity has been considered to induce lifestyle-related diseases and functional ingredients with anti-inflammatory effects are attracting attention. Although multiple studies on obesity had proved the anti-inflammatory effects of ingestion of lactic acid bacteria (LAB) and other functional ingredients on adipose tissue, the precise effects on the intestine, especially on the individual intestinal segments have not been made clear. In this study, we elucidated the mechanisms of Lactiplantibacillus plantarum (basonym: Lactobacillus plantarum) OLL2712 in suppressing obesity-induced inflammation using high fat diet (HFD)-fed mice obesity model. Methods: We orally administered heat-treated LAB to HFD-fed mice model, and investigated the inflammatory changes in adipose tissue and intestinal immune cells. We also analyzed gut microbiota, and evaluated the inflammation and permeability of the duodenum, jejunum, ileum and colon; four intestinal segments differing in gut bacteria composition and immune response. Results: After 3-week LAB administration, the gene expression levels of proinflammatory cytokines were downregulated in adipose tissue, colon, and Peyer's patches (PP)-derived F4/80+ cells. The LAB treatment alleviated obesity-related gut microbiota imbalance. L. plantarum OLL2712 treatment helps maintain intestinal barrier function, especially in the ileum, possibly by preventing ZO-1 and Occludin downregulation. Discussion: Our results suggest that the oral administration of the LAB strain regulated the gut microbiota, suppressed intestinal inflammation, and improved the gut barrier, which could inhibit the products of obesity-induced gut dysbiosis from translocating into the bloodstream and the adipose tissue, through which the LAB finally alleviated the inflammation caused by dietary obesity. Barrier improvement was observed, especially in the ileum, suggesting collaborative modulation of the intestinal immune responses by ingested LAB and microbiota.

Theoretical basis and occurrence of internet fraud victimisation: Based on two systems in decision-making and reasoning.

The influencing factors of internet fraud, including demographics, psychology, experience and knowledge of susceptibility, have been widely studied. Research on the psychological mechanism of the victimisation process of internet fraud is relatively scarce but suggests a new research perspective. To summarise and unify the research in this field, this study systematically searched and analysed articles on the psychological decision-making mechanism of online fraud victims. We found that (a) previous researchers consistently believed that the heuristic processing mode was correlated with susceptibility to online fraud and that the systematic processing mode was helpful to detect and identify fraud. From the overall review results, we do not reject this conclusion, but the verification and intrinsic explanation of this relationship need to be further strengthened. (b) Under the heuristic-systematic model (HSM), with the exception of the trait of suspicion, there is no consensus on whether psychological factors (e.g., personality) influence the likelihood of online fraud through the mediating effect of the selection of the two systems. Objective knowledge and experience in specific fields have been found to be able to achieve this path. Information on the influential variables of equipment and habits is emerging, but how they affect network victimisation through the heuristic processing system needs to be further clarified. (c) The measurement of variables is conducted through simulation experiments. There may be a gap between the likelihood of internet fraud victimisation in the simulation experiment and in the real world. (d) The defence strategies under the HSM are intentional explorations, such as content-based cue recognition technology and simulated scene training.

Systems metabolic engineering of Escherichia coli for hyper-production of 5­aminolevulinic acid.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) is a promising biostimulant, feed nutrient, and photodynamic drug with wide applications in modern agriculture and therapy. Although microbial production of 5-ALA has been improved realized by using metabolic engineering strategies during the past few years, there is still a gap between the present production level and the requirement of industrialization. RESULTS: In this study, pathway, protein, and cellular engineering strategies were systematically employed to construct an industrially competitive 5-ALA producing Escherichia coli. Pathways involved in precursor supply and product degradation were regulated by gene overexpression and synthetic sRNA-based repression to channel metabolic flux to 5-ALA biosynthesis. 5-ALA synthase was rationally engineered to release the inhibition of heme and improve the catalytic activity. 5-ALA transport and antioxidant defense systems were targeted to enhance cellular tolerance to intra- and extra-cellular 5-ALA. The final engineered strain produced 30.7 g/L of 5-ALA in bioreactors with a productivity of 1.02 g/L/h and a yield of 0.532 mol/mol glucose, represent a new record of 5-ALA bioproduction. CONCLUSIONS: An industrially competitive 5-ALA producing E. coli strain was constructed with the metabolic engineering strategies at multiple layers (protein, pathway, and cellular engineering), and the strategies here can be useful for developing industrial-strength strains for biomanufacturing.

Lean body mass but not body fat mass is related with leukocyte telomere length in children.

OBJECTIVES: The aim of this study was to investigate the relationship between body composition and leukocyte telomere length (LTL) in healthy Chinese children aged 6-11 years. METHODS: This cross-sectional study enrolled 406 healthy children (175 girls and 231 boys). The relative telomere length in their peripheral blood leukocytes was determined via quantitative polymerase chain reaction. Dual-energy X-ray absorptiometry was used to determine body fat content and regional fat distribution, appendicular skeletal muscle mass (ASM), bone mineral density (BMD) and bone mineral content (BMC) at the total body (TB) and total body less head (TBLH) levels, and total body lean mass (TBLM) was then determined. ASM/height2 (ASMI) was also calculated. RESULTS: After adjusting for potential covariates, multiple linear regression analyses revealed that neither body fat content nor regional body fat distribution were significantly associated with LTL (ß = -8.48 × 10-6-1.44 × 10-1, p = 0.227-0.959). However, ASM, ASMI, TB BMC/TB BMD, TBLH BMC/TBLH BMD and TBLM were positively associated with LTL (ß = 8.95 × 10-6-4.95 × 10-1, p = 0.005-0.035). Moreover, analysis of covariance revealed there was a statistically significant dose-dependent positive association between LTL and ASM, TB BMC/BMD, TBLH BMC/BMD, and TBLM (p-trend = 0.002-0.025). CONCLUSIONS: Skeletal muscle mass and bone mass but not body fat content or distribution were significantly associated with LTL in this pediatric population.

Directed evolution of linker helix as an efficient strategy for engineering LysR-type transcriptional regulators as whole-cell biosensors.

Whole-cell biosensors based on transcriptional regulators are powerful tools for rapid measurement, high-throughput screening, dynamic metabolic regulation, etc. To optimize the biosensing performance of transcriptional regulator, its effector-binding domain is commonly engineered. However, this strategy is encumbered by the limitation of diversifying such a large domain and the risk of affecting effector specificity. Molecular dynamics simulation of effector binding of LysG (an LysR-type transcriptional regulator, LTTR) suggests the crucial role of the short linker helix (LH) connecting effector- and DNA-binding domains in protein conformational change. Directed evolution of LH efficiently produced LysG variants with extended operational range and unaltered effector specificity. The whole-cell biosensor based on the best LysGE58V variant outperformed the wild-type LysG in enzyme high-throughput screening and dynamic regulation of l-lysine biosynthetic pathway. LH mutations are suggested to affect DNA binding and facilitate transcriptional activation upon effector binding. LH engineering was also successfully applied to optimize another LTTR BenM for biosensing. Since LTTRs represent the largest family of prokaryotic transcriptional regulators with highly conserved structures, LH engineering is an efficient and universal strategy for development and optimization of whole-cell biosensors.

Vitamin A Nutritional Status Is a Key Determinant of Bone Mass in Children.

The bone mass increases that occur during the period of childhood are of great significance for maximizing the peak bone mass in adults and preventing for osteoporosis. Studies have reported that VA can improve the bone health in adults. Moreover, limited studies have assessed such associations in children. In this cross-sectional study including 426 children, we assessed the children's plasma retinol concentration by liquid chromatography-mass spectrometry and the dietary intake of VA and carotenoids using a structured Food Frequency Questionnaire. Their bone mineral content and bone mineral density (BMD) were measured using dual-energy X-ray absorptiometry. After adjusting for potential confounders, the restricted cubic spline revealed an inverted U-shaped association between plasma retinol concentration and BMD; the estimated effects on the TBLH BMD per µmol/L increase in the plasma retinol concentration were 1.79 × 10-2 g/cm2 below 1.24 µmol/L and -5.78 × 10-3 g/cm2 above this point (p for non-linearity = 0.046). A multiple linear regression analysis revealed a positive association between the plasma retinol concentration and the TBLH BMC (ß = 1.89, 95% CI: 1.64 × 10-1-3.62, p = 0.032). In conclusion, an appropriate plasma retinol concentration and greater intakes of dietary VA and ß-carotene may enhance the bone mineral status of children who are aged 6-9 years.

Plant-based diets and body composition in Chinese omnivorous children aged 6-9 years old: A cross-sectional study.

Evidence suggests that plant-based diets are beneficial for alleviating metabolic diseases. Childhood is a crucial period for body growth and development. However, it is unknown whether adherence to a plant-based diet is related to a healthy body composition in children. We aimed to assess the relationship between a plant-based diet and body composition in children. A total of 452 Chinese children aged 6-9 years old participated in this cross-sectional study. Lean mass (LM), fat mass, and fat mass percentage (FMP) were assessed via dual-energy X-ray absorptiometry. An age- and sex-specific abdominal FMP ≥85th percentile was defined as abdominal obesity. Handgrip strength was measured using a hydraulic hand dynamometer. A validated 79-item food frequency questionnaire was used to collect dietary information. Overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI) scores were calculated. After adjusting for potential covariates, a higher hPDI score (per 10-score increment) was associated with a higher LM in the android area (0.038 kg, 3.2%), gynoid area (0.048 kg, 1.9%), and trunk (0.102 kg, 1.2%) and with a lower FMP (1.18%) in the android area. In contrast, a higher uPDI score (per 10-score increment) was associated with a lower LM in the trunk (0.091 kg, 1.1%) and android area (0.023 kg, 1.9%) and with a higher FMP (0.74%) in the android area. No significant associations were observed between the overall PDI and body composition or abdominal obesity. After stratifying by sex, higher (vs. lower) hPDI scores was associated with lower abdominal obesity risk in girls and higher handgrip strength in boys. In conclusion, in this cross-sectional study, we found that stronger adherence to a healthful plant-based diet, and less adherence to an unhealthful plant-based diet was associated with better body composition in Chinese omnivorous children aged 6-9 years old. Our results highlight the need to distinguish between healthy and unhealthy plant foods within investigating how to obtain a healthy body composition in children.

Synthesis of High-Loading Pt/C Electrocatalysts Using a Surfactant-Assisted Microwave Discharge Method for Oxygen Reduction Reactions.

High-loading Pt/C catalysts play an important role in the practical application of metal-air batteries and fuel cells because of their superior activity, high conductivity, and commercial availability. It is well known that high loadings always lead to the agglomeration of Pt nanoparticles, resulting in a loss of catalytic activity and stability; thus, it still remains a challenge to prepare high-loading Pt/C catalysts with high dispersion and small particle sizes. Here, we introduce a surfactant-assisted microwave discharge method to prepare high-loading (>40 wt %) Pt/C electrocatalysts with ultrafine particle sizes (∼3.19 nm) and good dispersion. Benefitting from the high-temperature property and reducibility of carbon-induced-arc, the surfactant and Pt precursors undergo rapid decomposition, reduction, and carbonization, generating the structure of Pt@C on carbon black. The carbon derived from the surfactant can not only inhibit the agglomeration of Pt nanoparticles but also prevent the Pt core from toxication, ensuring high activity and stability of the high-loading Pt/C catalyst. When evaluated in the oxygen reduction reaction, the as-prepared Pt/C catalyst demonstrates a comparable activity and better methanol resistance to commercial Pt/C.

Impact of the National Reimbursement Drug List Negotiation Policy on Accessibility of Anticancer Drugs in China: An Interrupted Time Series Study.

Objective: Since 2016, the Chinese government has been regularly implementing the National Reimbursement Drug List Negotiation (NRDLN) to improve the accessibility of drugs. In the second round of NRDLN in July 2017, 18 anticancer drugs were included. This study analyzed the impact of the NRDLN on the accessibility of these 18 anticancer drugs in China. Methods: National hospital procurement data were collected from 2015 to 2019. As measurements of drug accessibility, monthly average of drug availability or defined daily dose cost (DDDc) was calculated. Interrupted time series (ITS) analysis was employed to evaluate the impact of NRDLN on drug accessibility. Multilevel growth curve models were estimated for different drug categories, regions or levels of hospitals. Results: The overall availability of 18 anticancer drugs increased from about 10.5% in 2015 to slightly over 30% in 2019. The average DDDc dropped from 527.93 CNY in 2015 to 401.87 CNY in 2019, with a reduction of 23.88%. The implementation of NRDLN was associated with higher availability and lower costs for all 18 anticancer drugs. We found an increasing level in monthly drug availability (ß2 = 2.1126), which ascended more sharply after the implementation of NRDLN (ß3 = 0.3656). There was a decreasing level in DDDc before July 2017 (ß2 = -108.7213), together with a significant decline in the slope associated with the implementation of NRDLN (ß3 = -4.8332). Compared to Traditional Chinese Medicines, the availability of Western Medicines was higher and increased at a higher rate (ß3 = 0.4165 vs. 0.1108). Drug availability experienced a larger instant and slope increase in western China compared to other regions, and in secondary hospitals than tertiary hospitals. Nevertheless, regional and hospital-level difference in the effect of NRDLN on DDDc were less evident. Conclusion: The implementation of NRDLN improves the availability and reduces the cost of some anticancer drugs in China. It contributes to promoting accessibility of anticancer drugs, as well as relieving regional or hospital-level disparities. However, there are still challenges to benefit more patients sufficiently and equally. It requires more policy efforts and collaborative policy combination.

ß-elemene regulates M1-M2 macrophage balance through the ERK/JNK/P38 MAPK signaling pathway.

Macrophages are classified into classically activated M1 macrophages and alternatively activated M2 macrophages, and the two phenotypes of macrophages are present during the development of various chronic diseases, including obesity-induced inflammation. In the present study, ß-elemene, which is contained in various plant substances, is predicted to treat high-fat diet (HFD)-induced macrophage dysfunction based on the Gene Expression Omnibus (GEO) database and experimental validation. ß-elemene impacts the imbalance of M1-M2 macrophages by regulating pro-inflammatory cytokines in mouse white adipose tissue both in vitro and in vivo. In addition, the RAW 264 cell line, which are macrophages from mouse ascites, is used to identify the effects of ß-elemene on inhibiting bacterial endotoxin lipopolysaccharide (LPS)-induced phosphorylation of mitogen-activated protein kinase (MAPK) pathways. These pathways both induce and are activated by pro-inflammatory cytokines, and they also participate in the process of obesity-induced inflammation. The results highlight that ß-elemene may represent a possible macrophage-mediated therapeutic medicine.

Associations of the Gut Microbiota Composition and Fecal Short-Chain Fatty Acids with Leukocyte Telomere Length in Children Aged 6 to 9 Years in Guangzhou, China: A Cross-sectional Study.

BACKGROUND: Telomere length (TL) serves as a marker of cellular senescence and appears to plateau between the age of 4 y and young adulthood, after which the gut microbiota are supposed to be established. However, scarce data are available regarding the correlation between gut microbiota composition and TL in the pediatric population. OBJECTIVES: We aimed to investigate whether the gut microbiota and the concentrations of SCFAs in feces are associated with leukocyte TL in children. METHODS: In total, 401 children aged 6-9 y from Guangzhou were enrolled in this cross-sectional study. qPCR was used to determine relative TL in peripheral blood leukocytes. The gut microbiota was characterized by 16S ribosomal RNA amplicon sequencing and the fecal concentrations of total SCFAs and SCFA subtypes were determined using HPLC. The multivariate methods with an unbiased variable selection (MUVR) algorithm and partial least square models were used to select predictable operational taxonomic units (OTUs). Further correlation analyses were performed based on multiple linear regression models with adjustment for covariates and false discovery rate. RESULTS: With the use of MUVR, 35 relevant and minimal optimal OTUs were finally selected. Multiple linear regression analysis showed that the abundance of several OTUs, including OTU334 (belonging to the genus Family XIII AD3011 group), OTU726 (belonging to the species Lachnoclostridium phocaeense), OTU1441 (belonging to the genus Ruminococcus torques group), OTU2553 (belonging to the genus Lachnospiraceae UCG-010), and OTU3375 (belonging to the family Lachnospiraceae), was negatively associated with leukocyte TL (ß: -0.187 to -0.142; false discovery rate (FDR)-corrected P value (PFDR) = 0.009-0.035]. However, neither SCFA subtype nor total SCFA content in feces exhibited significant associations with TL (ß: -0.032 to 0.048; PFDR = 0.915-0.969). CONCLUSIONS: The gut microbiota, but not fecal SCFA concentration, was significantly associated with TL in this pediatric population.