Cost-effectiveness of camrelizumab plus chemotherapy versus chemotherapy alone as first-line therapy in advanced or metastatic esophageal squamous cell carcinoma.

OBJECTIVE: Camrelizumab combination therapy for advanced or metastatic esophageal squamous cell carcinoma (ESCC) has considerable survival benefits. This study investigated the cost-effectiveness of camrelizumab combination therapy versus chemotherapy alone as a first-line treatment for patients with ESCC from the perspective of the Chinese healthcare system. METHODS: A three-state partitioned survival model was developed to estimate total costs, life years (LYs), quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs) and incremental net health benefits (INHBs) over a 20-year time horizon. Sensitivity and scenario analyses were also performed. RESULTS: Camrelizumab plus chemotherapy increased QALYs by 0.30 (0.43 LYs), with an incremental cost of $9,272. The ICERs for camrelizumab plus chemotherapy vs chemotherapy alone was $31,062/QALY ($21,599/LY), and the INHB was 0.05 QALY at the cost-effective threshold of $37,653/QALY (3 times China's GDP per capita). One-way sensitivity analyses showed that the ICER was the most sensitive to utility values in the PFS state. Probabilistic sensitivity analyses suggested that camrelizumab combination therapy had a probability of 74.04% cost-effectiveness at a threshold of $37,653/QALY. Scenario analyses confirmed that the findings were robust. CONCLUSIONS: Camrelizumab combination therapy is likely to have a cost-effectiveness advantage over chemotherapy alone for previously untreated advanced or metastatic ESCC in China.

Molecular mechanism of Ginkgo biloba in treating type 2 diabetes mellitus combined with non-alcoholic fatty liver disease based on network pharmacology, molecular docking, and experimental evaluations.

Ginkgo biloba has gained increasing attention owing to its remarkable effects against cardiovascular disease. However, the role of G. biloba in hepatic lipid metabolism disorders in type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms have not been elucidated. Here, the effective ingredients and mechanisms of action of G. biloba in T2DM combined with NAFLD were investigated via an integrated strategy of network pharmacology and molecular docking. Thirty-four core targets for the alleviation of T2DM combined with NAFLD were identified and retrieved from multiple open-source databases, after validating the ameliorative effect of G. biloba on lipid accumulation in vitro. The targets IL6, IL1B, VEGFA, PTGS2, and CCL2, among others, with high network association values, were screened using Cytoscape. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that 34 compounds derived from G. biloba may exert therapeutic effects via response to molecule of bacterial origin, cellular response to lipid, and response to the hormone. In addition, the AGE-RAGE and IL-17 signaling pathways were predicted to be most significantly affected. Meanwhile, the outcomes of the molecular docking experiment showed that the most effective ingredients in G. biloba showed a strong binding affinity to the potential target active sites. Findings from further in vitro experiments confirmed that G. biloba treatment decreased the level of IL6, IL1B, and VEGFA protein. In conclusion, our findings provided novel insights into the mechanisms underlying the therapeutic effect of G. biloba in T2DM combined with NAFLD. PRACTICAL APPLICATIONS: As a medicinal food plant, G. biloba has been shown to exert benefits in cardiovascular diseases. However, the pharmacological material basis and complex mechanism of action in G. biloba in T2DM combined with NAFLD remain unknown. Here, the mechanism by which G. biloba could ameliorate T2DM combined with NAFLD was investigated, and the potential target and molecular mechanism were explored, through a comprehensive strategy combining network pharmacology and molecular docking. Our findings indicate that G. biloba exerts synergistic effects in treating T2DM combined with NAFLD through multi-ingredients, multi-targets, and multi-pathways; the findings also elucidate the nutritional and therapeutic potential of G. biloba in preventing and treating T2DM combined with NAFLD and provides robust evidence for its clinical application.

Evaluation of CD4/CD8 ratio in children with immune thrombocytopenic purpura (ITP) after treatment with intravenous immunoglobulin (IVIG).

Intra Venous Immunoglobulin (IVIG) is a plasma-derived product used to treat many autoimmune diseases, including thrombocytopenia, immunodeficiency, and infectious diseases. In this study, the effect of IVIG injection was evaluated on the number of white blood cells, neutrophils, lymphocytes, and platelets. The effect of IVIG was also considered on the percentage of CD4 and CD8 positive cells T cell lymphocytes and their absolute number in pediatric patients with immune thrombocytopenic purpura. The study was a cross-sectional study performed on 32 patients with ITP. In these patients, a blood sample was taken before and one hour after the start of the IVG injection. For all samples, a complete blood cell, platelet count, and differential blood leukocyte count were performed by Sysmex kx-21. Then labeled anti-CD4 and anti-CD8 markers were used to evaluate the type of lymphocytes. SPSS software version 15 and a t-test with a significant level of p <0.05 were used for statistical analysis of the obtained results. Pearson correlation coefficient was also used to evaluate the relationship between patients' age and the total volume of injected IVIG results. Examination of blood cell counts showed a significant decrease in the mean of white blood cells, neutrophils, and lymphocytes after intravenous immunoglobulin injection. However, these changes were not statistically significant for platelets. A comparison of the mean percentage of CD4 and CD8 cells shows a significant increase in the CD4 / CD8 cell ratio after injection. The absolute number of CD4 and CD8 lymphocytes one hour after IVIG injection was significantly decreased, but their proportion increased after injection. Generally, IVIG reduces the absolute number of neutrophils, but this reduction is not associated with infection problems. This decrease is also seen in the number of lymphocytes. However, the change in the number and percentage of CD4 and CD8 cells depends on the sampling time following IVIG injection.

Trends of Antibiotic Use and Expenditure After an Intensified Antimicrobial Stewardship Policy at a 2,200-Bed Teaching Hospital in China.

Objective: This study aimed to evaluate the effects of intensified Chinese special rectification activity on clinical antibiotic use (CSRA) policy on a tertiary-care teaching hospital. Methods: A 48-month longitudinal dataset involving inpatients, outpatients, and emergency patients were collected. Study period included pre-intervention stage (adopting soft measures like systemic training) and post-intervention stage (applying antibiotic control system to intensify CSRA policy). Antibiotic use was evaluated by antibiotic use rate (AUR) or antibiotic use density (AUD). Economic indicator was evaluated by antibiotic cost in prescription or antibiotic expenditure in hospitalization. Data was analyzed by interrupted time series (ITS) analysis. Results: The medical quality indicators remained stable or improved during the study period. AUR of inpatients (AURI) declined 0.553% per month (P = 0.025) before the intervention and declined 0.354% per month (P = 0.471) after the intensified CSRA policy was implemented. AUD, expressed as defined daily doses per 100 patients per day (DDDs/100PD), decreased by 1.102 DDDs/100PD per month (P = 0.021) before and decreased by 0.597 DDDs/100PD per month (P = 0.323) thereafter. The ratio of antibiotic expenditure to medication expenditure (AE/ME) decreased by 0.510% per month (P = 0.000) before and fell by 0.096% (P = 0.000) per month thereafter. AE per patient decreased by 25.309 yuan per month (P = 0.002) before and decreased by 7.987 yuan per month (P = 0.053) thereafter. AUR of outpatient (AURO) decreased by 0.065% per month before (P = 0.550) and decreased by 0.066% per month (P = 0.994) thereafter. The ratio of antibiotic cost to prescription cost in outpatient (ACO/PCO) decreased by 0.182% per month (P = 0.506) before and decreased by 0.216% per month (P = 0.906) thereafter. AUR of emergency patient (AURE) decreased by 0.400% per month (P = 0.044) before and decreased by 0.092% per month (P = 0.164) thereafter. The ratio of antibiotic cost to prescription cost in emergency patient (ACE/PCE) decreased by 0.616% per month (P < 0.001) before and decreased by 0.151% per month (P < 0.001) thereafter. Conclusions: Implementation of CSRA policy was associated with declining antibiotic use and antibiotic expenditure in inpatients, outpatients, and emergency patients. However, it is also important to note that the declining trend of antibiotic consumption slowed due to the limited capacity for decline in the later stages of CSRA intervention.

Cost-Effectiveness Analysis of Anlotinib as Third- or Further-Line Treatment for Relapsed Small Cell Lung Cancer (SCLC) in China.

INTRODUCTION: The survival of patients with relapsed small cell lung cancer (SCLC) has achieved little progress in the last several decades. ALTER1202 confirmed the efficacy and safety of anlotinib as a third- or further-line option for relapsed SCLC. This study aimed to assess the cost-effectiveness of anlotinib compared with placebo as third- or further-line treatment for advanced SCLC in China. METHODS: A Markov model was developed to simulate the process of advanced SCLC and estimate the incremental cost-effectiveness ratio (ICER) of anlotinib versus placebo. The health outcomes and utilities were derived from the ALTER1202 (NCT03059797) and published sources, respectively. Total costs were calculated from the perspective of Chinese society. One-way and probabilistic sensitivity analyses (PSA) were conducted to explore the model uncertainties. RESULTS: Anlotinib was estimated to result in an additional 0.12 quality-adjusted life-years (QALYs) at an incremental cost of $2131.32, resulting in an ICER of $17,741.94/QALY. The ICER did not exceed the willingness-to-pay (WTP) threshold of $30,833 per QALY, which was three times the gross domestic product (GDP) per capita of China in 2019. One-way sensitivity analysis showed that the cost of anlotinib exerted the maximum influence on the result of the model, followed by the utility of progression-free survival (PFS) state in the anlotinib group and median overall survival (mOS) in the anlotinib group. In PSA, the probability of anlotinib being cost-effective was 26.6% and 78.5% when the WTP threshold was one and three times the GDP per capita, respectively. CONCLUSION: Anlotinib is likely to be a cost-effective option compared with placebo for patients with relapsed SCLC who experience failure of at least two lines of chemotherapy in China.

Evaluation of the variability and safety of serum trough concentrations of vancomycin in patients admitted to the intensive care unit.

OBJECTIVE: To examine the variability and safety of serum trough concentrations of vancomycin in patients admitted to the intensive care unit (ICU) and to analyze the factors influencing the trough concentration. METHODS: Data were collected retrospectively from ICU patients receiving vancomycin treatment at a fixed dose of 2g/day due to unobtainable weight data, at Changzhou No. 2 People's Hospital, between 2012 and 2015. Vancomycin trough concentrations were compared between groups stratified by sex, age, and estimated glomerular filtration rate (eGFR). RESULTS: The vancomycin trough concentration varied significantly among ICU patients on a fixed dose of 2g/day. Only 16.9% of ICU patients met the concentration target of 15-20mg/l, while 25% of patients showed supratherapeutic concentrations. A higher proportion of female patients than male patients showed supratherapeutic concentrations (40.4% vs. 15.5%). The trough concentration was positively correlated with age (y=0.279x-2.085; R2=0.186) and negatively correlated with eGFR (y=-0.2x+33.776; R2=0.366). Vancomycin-related nephrotoxicity occurred at an incidence of 5.9%. CONCLUSIONS: These results suggest that the fixed-dose regimen is not appropriate for ICU patients in view of the low incidence of target trough concentrations and the high incidence of supratherapeutic concentrations. The dose should be individualized based on weight, age, and renal function to improve outcomes and patient safety.

ZL006 promotes migration and differentiation of transplanted neural stem cells in male rats after stroke.

New strategies must be developed to resolve the problems of stroke treatment. In recent years, stem cell-based therapy after stroke has come into the public and academic lens. Previously we have shown that uncoupling neuronal nitric oxide synthase (nNOS) from the postsynaptic density protein-95 (PSD-95) by ZL006, a small molecular compound, can ameliorate ischemic damage and promote neuronal differentiation of endogenous neural stem cells (NSCs) in focal cerebral ischemic male rats. In this study, we transplanted exogenous NSCs into the ipsilateral hemisphere of male rats in combination with ZL006 treatment after ischemic stroke. We show that ZL006 treatment facilitates the migration of transplanted NSCs into the ischemia-injured area and promotes neuronal differentiation of these cells, which is not due to a direct effect of ZL006 on exogenous NSCs but is associated with increased phosphorylation of cAMP response element-binding protein (CREB) in neurons and favorable microenvironment. Moreover, improved functional outcome in the ZL006-treated group was also found. Taken together, our data indicate that ZL006, uncoupling nNOS-PSD-95 in neurons, positively regulates the fate of transplanted NSCs and benefits the functional outcome after stroke in male rats.

Phosphofructokinase-1 Negatively Regulates Neurogenesis from Neural Stem Cells.

Phosphofructokinase-1 (PFK-1), a major regulatory glycolytic enzyme, has been implicated in the functions of astrocytes and neurons. Here, we report that PFK-1 negatively regulates neurogenesis from neural stem cells (NSCs) by targeting pro-neural transcriptional factors. Using in vitro assays, we found that PFK-1 knockdown enhanced, and PFK-1 overexpression inhibited the neuronal differentiation of NSCs, which was consistent with the findings from NSCs subjected to 5 h of hypoxia. Meanwhile, the neurogenesis induced by PFK-1 knockdown was attributed to the increased proliferation of neural progenitors and the commitment of NSCs to the neuronal lineage. Similarly, in vivo knockdown of PFK-1 also increased neurogenesis in the dentate gyrus of the hippocampus. Finally, we demonstrated that the neurogenesis mediated by PFK-1 was likely achieved by targeting mammalian achaete-scute homologue-1 (Mash 1), neuronal differentiation factor (NeuroD), and sex-determining region Y (SRY)-related HMG box 2 (Sox2). All together, our results reveal PFK-1 as an important regulator of neurogenesis.

Genetic Correction of Induced Pluripotent Stem Cells From a Deaf Patient With MYO7A Mutation Results in Morphologic and Functional Recovery of the Derived Hair Cell-Like Cells.

UNLABELLED: The genetic correction of induced pluripotent stem cells (iPSCs) induced from somatic cells of patients with sensorineural hearing loss (caused by hereditary factors) is a promising method for its treatment. The correction of gene mutations in iPSCs could restore the normal function of cells and provide a rich source of cells for transplantation. In the present study, iPSCs were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T; P-iPSCs), the asymptomatic father of the patient (MYO7A c.1184G>A mutation; CF-iPSCs), and a normal donor (MYO7A(WT/WT); C-iPSCs). One of MYO7A mutation sites (c.4118C>T) in the P-iPSCs was corrected using CRISPR/Cas9. The corrected iPSCs (CP-iPSCs) retained cell pluripotency and normal karyotypes. Hair cell-like cells induced from CP-iPSCs showed restored organization of stereocilia-like protrusions; moreover, the electrophysiological function of these cells was similar to that of cells induced from C-iPSCs and CF-iPSCs. These results might facilitate the development of iPSC-based gene therapy for genetic disorders. SIGNIFICANCE: Induced pluripotent stem cells (iPSCs) were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T). One of the MYO7A mutation sites (c.4118C>T) in the iPSCs was corrected using CRISPR/Cas9. The genetic correction of MYO7A mutation resulted in morphologic and functional recovery of hair cell-like cells derived from iPSCs. These findings confirm the hypothesis that MYO7A plays an important role in the assembly of stereocilia into stereociliary bundles. Thus, the present study might provide further insight into the pathogenesis of sensorineural hearing loss and facilitate the development of therapeutic strategies against monogenic disease through the genetic repair of patient-specific iPSCs.

Interaction of nNOS with PSD-95 negatively controls regenerative repair after stroke.

Stroke is a major public health concern. The lack of effective therapies heightens the need for new therapeutic targets. Mammalian brain has the ability to rewire itself to restore lost functionalities. Promoting regenerative repair, including neurogenesis and dendritic remodeling, may offer a new therapeutic strategy for the treatment of stroke. Here, we report that interaction of neuronal nitric oxide synthase (nNOS) with the protein postsynaptic density-95 (PSD-95) negatively controls regenerative repair after stroke in rats. Dissociating nNOS-PSD-95 coupling in neurons promotes neuronal differentiation of neural stem cells (NSCs), facilitates the migration of newborn cells into the injured area, and enhances neurite growth of newborn neurons and dendritic spine formation of mature neurons in the ischemic brain of rats. More importantly, blocking nNOS-PSD-95 binding during the recovery stage improves stroke outcome via the promotion of regenerative repair in rats. Histone deacetylase 2 in NSCs may mediate the role of nNOS-PSD-95 association. Thus, nNOS-PSD-95 can serve as a target for regenerative repair after stroke.

Effects of BMP-2 and FGF2 on the osteogenesis of bone marrow-derived mesenchymal stem cells in hindlimb-unloaded rats.

Hindlimb unloading, as a simulation of microgravity, decreases the osteogenic potential of mesenchymal stem cells (MSCs) from hindlimb femur of rat. We simulated the microgravity by 28-day of hindlimb unloading for male Sprague-Dawley rat, and performed intramuscular injection of BMP-2 and FGF2 at a given interval during hindlimb unloading. Then, the bone marrow (BM) was collected from hindlimb femur of rat. MSCs were isolated from BM, cultured for four passages, and then induced for osteogenesis. The results revealed that the hindlimb unloading decreased the osteogenic potential of MSCs and also the expression of osteoblast gene marker mRNAs in cells induced by osteogenic conditions. Hindlimb unloading for 28 days resulted in the decrease of vinculin-containing focal adhesion in MSCs. During hindlimb unloading, the interval intramuscular injection of BMP-2 or FGF2 alone could increase the osteogenic potential of MSCs and the expression of osteoblast gene marker mRNA. However, the effect of BMP-2 or FGF2 injection alone was significantly lower than that of combination injection of both factors. The further examination showed that the intramuscular injection of BMP-2 promoted the expression of Runx2 mRNA and that the intramuscular injection of FGF2 increased the phosphorylation of ERK and Runx2. Nevertheless, the intramuscular injection of any factor could not increase the formation of vinculin-containing focal adhesions in MSCs. This suggests that BMP-2 should increase the expression of Runx2, and that the activation of Runx2 should be promoted by the FGF2 signaling pathway which activated ERK/Runx2. The activation of this signaling pathway should not lie on the formation of vinculin-containing focal adhesions.

Biocompatibility and bone-repairing effects: comparison between porous poly-lactic-co-glycolic acid and nano-hydroxyapatite/poly(lactic acid) scaffolds.

Copolymer composite scaffolds and bioceramic/polymer composite scaffolds are two representative forms of composite scaffolds used for bone tissue engineering. Studies to compare biocompatibility and bone-repairing effects between these two scaffolds are significant for selecting or improving the scaffold for clinical application. We prepared two porous scaffolds comprising poly-lactic-acid/poly-glycolic-acid (PLGA) and poly-lactic-acid/nano-hydroxyapatite (nHAP/PLA) respectively, and examined their biocompatibility with human bone marrow-derived mesenchymal stem cells (hMSCs) through evaluating adhesion, proliferation and osteogenic differentiation potentials of hMSCs in the scaffold. Then, the PLGA scaffold with hMSCs (PM construct) and the nHAP/PLA scaffold with hMSCs (HPM construct) were transplanted into the rat calvarial defect areas to compare their effects on the bone reconstruction. The results showed that the nHAP/PLA scaffold was in favor of adhesion, matrix deposition and osteogenic differentiation of hMSCs. For in vivo transplantation, both HPM and PM constructs led to mineralization and osteogenesis in the defect area of rat. However, the area grafted with PM construct showed a better formation of mature bone than that with HPM construct. In addition, the evaluation of in vitro and in vivo degradation indicated that the degradation rate of nHAP/PLA scaffold was much lower than that of PLGA scaffold. It is inferred that the lower degradation of nHAP/PLA scaffold should result in its inferior bone reconstruction in rat calvaria. Therefore, the preparation of an ideal composite scaffold for bone tissue engineering should be taken into account of the balance between its biocompatibility, degradation rate, osteoconductivity and mechanical property.

[Effects of shenghua decoction on hemorheology, thrombosis and microcirculation].

OBJECTIVE: To investigate the effects of Shenghua decoction on hemorheology, thrombosis and microcirculation, and explore its approach and mechanism. METHOD: The main hemorheological indexes and endothelial function were detected in acute stress blood stasis rats. The thrombus wet weight and thrombus dry weight were measured in the rat model of venous thrombosis, and the inhibitory rates in the formation of venous thrombosis were calculated. The number of paralysis or dead after 1-15 min was calculated in mice, induced by tail intravenous injection of a mixture of collagen and Epinephrine. Blood flow and the across netting were also determined on capillary vessel of uterus microcirculation. RESULT: Shenghua decoction reduce blood viscidity of the rats, reduce the thrombosis of the murine, and promote the microcirculation of the uterus in rats. CONCLUSION: Shenghua decoction has the ability of blood-activating and stasis-eliminating. It also has an anti-thrombotic effect and can promote microcirculation.

[Efficacy of 5-nitroimidazole derivatives in treatment of bacterial vaginosis].

OBJECTIVE: To evaluate the efficacy and adverse effects of 5-nitroimidazole derivatives in treatment of bacterial vaginosis (BV). METHODS: 278 BV patients were randomly divided into 8 groups to be treated with (1) oral metronidazole sustained release tablet 750 mg/day for 7 days, (2) oral metronidazole sustained release tablet 750 mg/day for 7 days and vaginal tinidazole 250 mg for 7 days, (3) oral tinidazole 1 g/day for 3 days (2 g for the first dose), (4) oral tinidazole 1 g/day for 3 days (2 g for the first dose), (5) oral ornidazole 2 x 500 mg/day for 3 days and vaginal tinidazole 250 mg for 7 days, (6) oral ornidazole 2 x 500 mg/day for 3 days, (7) oral secnidazole 2 g in a single dose and vaginal tinidazole 250 mg for 7 days, and (8) oral secnidazole 2 g in a single dose. RESULTS: The clinical cure rates of the oral administration groups were 56.76% - 62.50%, all significantly lower than those of the oral/vaginal combination groups (80.00% - 86.11%, all P < 0.05). There was nit significantly difference in efficacy level among the only oral treatment groups and the oral/vaginal combination groups (all P > 0.05). CONCLUSION: Combination of oral and vaginal administration of 5-nitroimidazole derivatives is more effective in treatment of BV than oral administration only.