Cost-Effectiveness Analysis of Pan-Genotypic Sofosbuvir-Based Regimens for Treatment of Chronic Hepatitis C Genotype 1 Infection in China.

Background: Hepatitis C virus (HCV) genotype 1 is the most prevalent HCV infection in China. Sofosbuvir-based direct antiviral agent (DAA) regimens are the current mainstays of treatment. Sofosbuvir/velpatasvir (SOF/VEL) and sofosbuvir/ledipasvir (SOF/LDV) regimens became reimbursable in China in 2020. Thus, this study aimed to identify the optimal SOF-based regimen and to inform efficient use of healthcare resources by optimizing DAA use in treating HCV genotype 1. Methods and Models: A modeling-based cost-utility analysis was conducted from the payer's perspective targeting adult Chinese patients with chronic HCV genotype 1 infection. Direct medical costs and health utilities were inputted into a Markov model to simulate lifetime experiences of chronically infected HCV patients after receiving SOF/LDV, SOF/VEL or the traditional strategy of pegylated interferon (pegIFN) + ribavirin (RBV). Discounted lifetime cost and quality adjusted life years (QALYs) were computed and compared to generate the incremental cost utility ratio (ICUR). An ICUR below the threshold of 31,500 $/QALY suggests cost-effectiveness. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of model findings. Results: Both SOF/LDV and SOF/VEL regimens were dominant to the pegIFN + RBV regimen by creating more QALYs and incurring less cost. SOF/LDV produced 0.542 more QALYs but cost $10,390 less than pegIFN + RBV. Relative to SOF/LDV, SOF/VEL had an ICUR of 168,239 $/QALY which did not meet the cost-effectiveness standard. Therefore SOF/LDV was the optimal strategy. These findings were robust to linear and random variations of model parameters. However, reducing the SOF/VEL price by 40% would make this regimen the most cost-effective option. Conclusions: SOF/LDV was found to be the most cost-effective treatment, and SOF/VEL was also economically dominant to pegIFN + RBV. These findings indicated that replacing pegIFN + RBV with DAA regimens could be a promising strategy.

Elabela prevents angiotensin II-induced apoptosis and inflammation in rat aortic adventitial fibroblasts via the activation of FGF21-ACE2 signaling.

Apoptosis, inflammation, and fibrosis contribute to vascular remodeling and injury. Elabela (ELA) serves as a crucial regulator to maintain vascular function and has been implicated in the pathogenesis of hypertensive vascular remodeling. This study aims to explore regulatory roles and underlying mechanisms of ELA in rat aortic adventitial fibroblasts (AFs) in response to angiotensin II (ATII). In cultured AFs, exposure to ATII resulted in marked decreases in mRNA and protein levels of ELA, fibroblast growth factor 21 (FGF21), and angiotensin-converting enzyme 2 (ACE2) as well as increases in apoptosis, inflammation, oxidative stress, and cellular migration, which were partially blocked by the exogenous replenishment of ELA and recombinant FGF21, respectively. Moreover, treatment with ELA strikingly reversed ATII-mediated the loss of FGF21 and ACE2 levels in rat aortic AFs. FGF21 knockdown with small interfering RNA (siRNA) significantly counterbalanced protective effects of ELA on ATII-mediated the promotion of cell migration, apoptosis, inflammatory, and oxidative injury in rat aortic AFs. More importantly, pretreatment with recombinant FGF21 strikingly inhibited ATII-mediated the loss of ACE2 and the augmentation of cell apoptosis, oxidative stress, and inflammatory injury in rat aortic AFs, which were partially prevented by the knockdown of ACE2 with siRNA. In summary, ELA exerts its anti-apoptotic, anti-inflammatory, and anti-oxidant effects in rat aortic AFs via activation of the FGF21-ACE2 signaling. ELA may represent a potential candidate to predict vascular damage and targeting the FGF21-ACE2 signaling may be a promising therapeutic intervention for vascular adventitial remodeling and related disorders.

Plasma levels of Elabela are associated with coronary angiographic severity in patients with acute coronary syndrome.

BACKGROUND: Elabela (ELA) was newly discovered as a novel endogenous ligand of the apelin receptor (APJ) which has demonstrated to be crucial for cardiovascular disease such as myocardial infarction, hypertension and heart failure. Previous experiments have revealed that ELA reduced arterial pressure and exerted positive inotropic effects on the heart. However, the role of plasma ELA levels in patients with acute coronary syndrome (ACS) and its relationship with severity of coronary arteries have not been investigated. METHODS: Two hundred and one subjects who were hospitalized for chest pain and underwent coronary angiography were recruited in this study. One hundred and seventy five patients were diagnosed with ACS and twenty-six subjects with negative coronary angiography were included in the control group. Plasma ELA levels, routine blood test, blood lipid, liver and kidney functions were measured. The number of coronary arteries and SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score of coronary lesions were used to evaluate the extent of coronary artery stenosis. RESULTS: ELA in patients with ACS was significantly higher than that in the control group (P < 0.01). There was no significant difference in plasma ELA levels among patients with single-, double- and triple-vessel diseases. However, in the generalized additive model (GAM), there was a threshold nonlinear correlation between the ELA levels and Syntax I score (P < 0.001). Plasma ELA levels were positively correlated with the Syntax I score when the ELA levels ranged from 63.47 to 85.49 ng/mL. There was no significant association between the plasma ELA levels and the extent of coronary artery stenosis when the ELA levels were less than 63.47 ng/mL or higher than 85.49 ng/mL. CONCLUSION: The present study demonstrates for the first time that plasma ELA levels are increased in patients with ACS. The rise in endogenous ELA levels was associated with severity of coronary stenosis and may be involved in the pathogenesis of ACS.

The association between orthostatic blood pressure changes and subclinical target organ damage in subjects over 60 years old.

BACKGROUND: Although recent studies have indicated that both orthostatic hypotension and orthostatic hypertension independently predict cardiovascular events, the underlying mechanisms are still controversial. The aim of the study was to investigate the relationships between orthostatic changes and organ damage in subjects over 60 years old. METHODS: This is a prospective observational cohort study. One thousand nine hundred and ninety-seven subjects over 60 years old were enrolled. Participants were grouped according to whether they had a drop ≥ 20 mmHg in systolic or ≥ 10 mmHg in diastolic BP (orthostatic hypotension), an increase in mean orthostatic systolic blood pressure ≥ 20 mm Hg (orthostatic hypertension), or normal changes within 3 min of orthostatism. Multiple regression modeling was used to investigate the relationship between orthostatic hypotension, orthostatic hypertension and subclinical organ damage with adjustment for confounders. RESULTS: Orthostatic hypotension and orthostatic hypertension were found in 461 (23.1%) and 189 (9.5%) participants, respectively. Measurement of carotid intima-media thickness (IMT), brachial-ankle pulse wave velocity (baPWV), clearance of creatinine, and microalbuminuria were associated with orthostatic hypotension; measurement of IMT and baPWV were associated with orthostatic hypertension in a cruse model. After adjustment, IMT [odds ratio (OR), 95% confidence interval (CI) per one-SD increment: 1.385, 1.052-1.823; P = 0.02], baPWV (OR = 1.627, 95% CI: 1.041-2.544; P = 0.033) and microalbuminuria (OR = 1.401, 95% CI: 1.002-1.958; P = 0.049) were still associated with orthostatic hypotension, while orthostatic hypertension was only associated with IMT (OR = 1.730, 95% CI: 1.143-2.618; P = 0.009). CONCLUSIONS: Orthostatic hypotension seems to be independently correlated with increased carotid atherosclerosis, arterial stiffness and renal damage in subjects over 60 years old. Orthostatic hypertension correlates with carotid atherosclerosis only.

Smart MMP2-Responsive Nanoprobe for Activatable Fluorescence Imaging-Guided Local Triple-Combination Therapies with Single Light.

Elaborately designed stimuli-responsive smart systems simultaneously enabling activatable imaging and selective treatment are highly desirable for precise diagnosis and therapy of cancer. Herein, such a smart theranostic nanoprobe composed of hollow gold nanospheres (HAuNs), photosensitizer (PS), matrix metalloproteinase 2 (MMP2) substrate peptide, and model drug doxorubicin (DOX) was designed. In the design, HAuNs served as the acceptor of Förster resonance energy transfer (FRET), photothermal therapy (PTT) reagent, and nanocarrier. The fluorescence and 1O2 generation of PS were inhibited by HAuNs through FRET effect, avoiding phototoxicity to normal tissues during circulation. Meanwhile, owing to the MMP2-triggered peptide cleavage, the PS could be efficiently activated in a tumor for selective fluorescence imaging and photodynamic therapy (PDT). The recovered fluorescence could be applied for detecting MMP2, locating tumor in vivo, and further guiding the local triple-combination therapies including PDT, PTT, and chemotherapy. The synergistic treatments of activated PDT, PTT, and controlled DOX release were achieved with single light, which provided the best therapeutic effects with enhanced stability and remarkably reduced nonspecific toxicity of PS and anticancer drug. This study helps to design novel stimuli-responsive systems for precise molecular sensing and site-specific cancer treatment.

Acupuncture for hot flashes in women with breast cancer: A systematic review.

BACKGROUND: Acupuncture is applied worldwide in treating hot flashes (HFs), which may be a common complication experienced by women with breast cancer (BC). Although researches associated with the effect of acupuncture for HFs have been done by many people, there is a lack of comprehensive evaluation of the effect of this therapy. OBJECTIVE: The aim of this systematic review is to assess the effectiveness of acupuncture for HFs in women with BC. METHODS: Seven databases (Cochrane Central Register of Controlled Trials, Embase, PubMed, Web of Science, Chinese National Knowledge Infrastructure Database, Chinese Biomedical Literature Database, and Wan Fang Database) were searched from their inceptions to June 2015 without language restrictions. Randomized controlled trials (RCTs) were aggregated to evaluate the therapeutic effect of acupuncture for HFs in women with BC. RESULTS: Twelve RCTs were identified at last, and all of the studies agreed on the potential therapeutic effect of acupuncture for HFs in women with BC. However, three trials showed significant difference compared with the controls. One research demonstrated an encouraging trend, and six did not find any difference between acupuncture and controls. Another two trials got a negative result compared with hormone therapy. The meta-analysis indicated a difference in the number of HFs after treatment and during follow-up compared with the controls. Three trials reported Kupperman index scores, and meta-analysis showed significant difference between acupuncture and controls after treatment and during follow-up. CONCLUSION: Acupuncture seems to be an effective therapy for HFs in women with BC; however, there was insufficient evidence to support the efficacy of acupuncture. However, the results should be interpreted cautiously, because of the poor quality and small number of included studies.

The Effects of Needling Fenglong (ST40) and Neiguan (PC6) on IL-17 of ApoE-Gene-Knockout Mice's Liver.

The aim of the present paper was to observe the effects of needling ST40 and PC6 on IL-17 of ApoE(-/-) mice with fatty liver. Forty male ApoE(-/-) mice were randomized into Needling-Acupoint Group, Simvastatin Intragastric Administration Group, Needling Nonacupoint Group, and Model Group. Each was fed with high fat diet for 8 weeks since 16 weeks of age; after 8 weeks of intervention, mice were sacrificed and tested for various examinations. Result showed that the body weight, TC, and serum IL-17 in Needling-Acupoint Group decreased. Compared with Model Group, the immunohistochemical expressions of IL-17 in liver tissue were significantly decreased among the other three groups. In conclusion, acupuncture was able to lower the expression of IL-17 level both in serum and liver tissue in ApoE(-/-) mice, which is helpful to reduce the inflammation and defers the progress from fatty liver to cirrhosis.

Characterization of mouse brain microRNAs after infection with cyst-forming Toxoplasma gondii.

BACKGROUND: The obligate intracellular parasite Toxoplasma gondii can interfere with host cell signaling pathways, alter host defense systems and cell cycle control, and establish a chronic infection in the central nervous system. T. gondii infection may alter the expression profile of host microRNAs (miRNAs) which have key regulatory functions at the post-transcriptional level. METHODS: Using high-throughput sequencing and real-time quantitative PCR technology, we compared the miRNA expression profiles of uninfected mouse brains with brains from mice at 14 days and 21 days after infection with cyst-forming T. gondii (Type II). RESULTS: A total of 51.30 million raw reads were obtained from all samples and 495 (14d infected mouse sample), 511 (14d sham-infected control), 504 (21d infected mouse sample) and 514 (21d sham-infected control) miRNA candidates identified. Among these, 414 miRNAs were consistent across all the studied groups, 17 were specific to the 14d infected group and 32 were specific to the 21d infected group. In addition, 9 miRNAs were common to both the 14d- and 21d-infected groups. Enrichment analysis for the targets of these miRNAs showed a high percentage of "protein tag" functions. Immune related targets including chemokines, cytokines, growth factors and interleukins were also found. CONCLUSIONS: These results not only showed that the miRNA expression of the host can be changed by the invasion of cyst-forming T. gondii, but also indicated that the host attempts to respond using two tactics: marking proteins with "protein tags" and adaptation of immune related systems.