The autoactivation of human single-chain urokinase-type plasminogen activator (uPA).

Most serine proteases are synthesized as inactive zymogens that are activated by cleavage by another protease in a tightly regulated mechanism. The urokinase-type plasminogen activator (uPA) and plasmin cleave and activate each other, constituting a positive feedback loop. How this mutual activation cycle begins has remained a mystery. We used hydrogen deuterium exchange mass spectrometry to characterize the dynamic differences between the inactive single-chain uPA (scuPA) and its active form two-chain uPA (tcuPA). The results show that the C-terminal ß-barrel and the area around the new N terminus have significantly reduced dynamics in tcuPA as compared with scuPA. We also show that the zymogen scuPA is inactive but can, upon storage, become active in the absence of external proteases. In addition to plasmin, the tcuPA can activate scuPA by cleavage at K158, a process called autoactivation. Unexpectedly, tcuPA can cleave at position 158 even when this site is mutated. TcuPA can also cleave scuPA after K135 or K136 in the disordered linker, which generates the soluble protease domain of uPA. Plasmin cleaves scuPA exclusively after K158 and at a faster rate than tcuPA. We propose a mechanism by which the uPA receptor dimerization could promote autoactivation of scuPA on cell surfaces. These results resolve long-standing controversies in the literature surrounding the mechanism of uPA activation.

Cost-effectiveness analysis of tislelizumab vs. camrelizumab for the treatment of second-line locally advanced or metastatic esophageal squamous cell carcinoma.

BACKGROUND: Esophageal carcinoma is a type of cancer that occurs in the esophagus. For patients with locally advanced or metastatic esophageal squamous cell carcinoma who have either experienced disease progression following first-line standard chemotherapy or are intolerant to it, the prognosis is typically poor. Additionally, these patients often bear a substantial economic burden during the course of their treatment. Tislelizumab is a selective PD-1 inhibitor with efficacy proven in locally advanced or metastatic esophageal squamous cell carcinoma. The study aims to evaluate the cost-effectiveness of tislelizumab versus camrelizumab as the second-line treatment in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients in China. METHODS: From the perspective of China's healthcare system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime horizon. Anchored matching adjusted indirect comparison was used for survival analyses based on individual patient data from RATIONALE 302 trial and the published ESCORT study due to the lack of head-to-head clinical trials. Only direct medical costs were included. Costs and utility values were derived from local charges, the published literature, and related databases. Sensitivity analyses and a scenario analysis were also performed to verify the robustness of the model results. RESULTS: Compared with camrelizumab monotherapy, tislelizumab monotherapy incurred a lower lifetime cost ($8,346 vs. $8,851) and yielded higher quality-adjusted life-years (QALYs) (0.87 vs. 0.63), which resulted in an incremental cost-effectiveness ratio (ICER) of -$2,051/QALY. Tislelizumab monotherapy is a dominant option over camrelizumab monotherapy in China. The three primary parameters upon which this result was most sensitive were the unit cost of camrelizumab, the unit cost of tislelizumab, and the duration of reactive cutaneous capillary endothelial proliferation (RCCEP). According to the probabilistic sensitivity analysis (PSA), tislelizumab monotherapy was 100% cost-effective when the WTP was 1-3 times GDP per capita in China($11,207/QALY∼$33,621/QALY). Scenario analysis showed that the result was consistent. CONCLUSION: Tislelizumab monotherapy is a dominant option compared with camrelizumab monotherapy as the second-line treatment for locally advanced or metastatic ESCC in China.

Alteration of the Gut Microbiota in Missed Abortion.

There is a symbiotic relationship between gut microbiota and human beings. Imbalance of the gut microbiota will cause pathological damages to humans. Although many risk factors are associated with missed abortion (MA), the pathological mechanism of it is still unclear. Here, we analyzed gut flora of the patients with MA by S16 high-throughput sequencing. The possible pathogenic mechanisms of the MA were explored. Fecal samples from 14 healthy controls and 16 MA patients were collected to do 16S rRNA gene high-throughput sequencing analysis. The abundance of the Bacteroidetes, Proteobacteria, Actinobacteria, Escherichia, Streptococcus_ Salivarius, and Lactobacillus was significantly reduced in the MA group, while, the abundance of the Klebsiella was significantly increased in the MA patients. The Ruminococcaceae and [Eubacterium]_coprostanoligenes_group were found only in the specimens of the MA patients. The Fabrotax function prediction analysis showed that four photosynthesis function bacteria (cyanobateria, oxygenic_photoautotrophy, photoautotrophy, and phototrophy) only existed in the MA group. In the analysis of the BugBase microbiome function prediction, the Escherichia of the MA group is significantly reduced compared to that of the healthy controls in the items of that Contains_Mobile_Elements, Facultatively_Anaerobic, Forms_Biofilms, Potentially_Pathogenic.png, Gram_Nagative, and Stress_Tolerant_relabundance. These alterations may affect the stability of the host's immune, neural, metabolic and other systems by interfering with the balance of the gut microbiota or by the metabolites of those bacteria, causing the MA. This study explored the possible pathogenic factors of the gut microbiota of the MA. The results provide evidence to figure out the pathogenesis of the MA.

Health utilities in pediatric cancer patients and survivors: a systematic review and meta-analysis for clinical implementation.

PURPOSE: Health utility (HU) is a useful metric for evaluating cost and utility of cancer therapies or prioritizing healthcare resources. We conducted a meta-analysis to compare HUs in association with clinical parameters and identify missing cancer-related themes from the extant HU measures for pediatric cancer patients and survivors. METHODS: Studies published in the PubMed, Embase, Web of Science, and Cochrane Library were identified. Meta-analyses were performed to estimate weighted means of HUs assessed by self- and proxy-responses. Mixed-effects meta-regressions were applied to compare HUs between cancer patients/survivors and general populations. Missing themes in the extant measures were identified based on established patient-reported outcomes frameworks. RESULTS: Of 123 selected studies included pediatric cancer populations, 44% used the Health Utilities Index version 2 (HUI2), and 48% used version 3 (HUI3). Compared to general populations, cancer patients undergoing therapies for acute lymphoblastic leukemia (ALL) had 0.129 (95% CI - 0.183 to - 0.075) and brain tumor had 0.257 (95% CI - 0.354 to - 0.160) lower HUs per proxy-reported HUI3, whereas survivors of ALL had 0.028 (95% CI - 0.062 to 0.007) and brain tumor had 0.188 (95% CI - 0.237 to - 0.140) lower HUs per proxy-reported HUI3. Compared to general populations, cancer patients treated with multimodality therapy and survivors off therapy 2-5 years had significantly poorer HUs (p's < 0.05). Missing cancer-specific contents from the HU measures were identified. CONCLUSION: Pediatric cancer patients and survivors had poorer HUs than general populations. It is important to select appropriate HUs for economic evaluations, and offer interventions to minimize HU deficits for particular cancer populations.

A comparison of self-reported and proxy-reported health utilities in children: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to conduct a systematic review and meta-analysis to compare differences in health utilities (HUs) assessed by self and proxy respondents in children, as well as to evaluate the effects of health conditions, valuation methods, and proxy types on the differences. METHODS: Eligible studies published in PubMed, Embase, Web of Science, and Cochrane Library up to December 2019 were identified according to PRISMA guidelines. Meta-analyses were performed to calculate the weighted mean differences (WMDs) in HUs between proxy- versus self-reports. Mixed-effects meta-regressions were applied to explore differences in WMDs among each health condition, valuation method and proxy type. RESULTS: A total of 30 studies were finally included, comprising 211 pairs of HUs assessed by 15,294 children and 16,103 proxies. This study identified 34 health conditions, 10 valuation methods, and 3 proxy types. In general, proxy-reported HUs were significantly different from those assessed by children themselves, while the direction and magnitude of these differences were inconsistent regarding health conditions, valuation methods, and proxy types. Meta-regression demonstrated that WMDs were significantly different in patients with ear diseases relative to the general population; in those measured by EQ-5D, Health utility index 2 (HUI2), and Pediatric asthma health outcome measure relative to Visual analogue scale method; while were not significantly different in individuals adopting clinician-proxy and caregiver-proxy relative to parent-proxy. CONCLUSION: Divergence existed in HUs between self and proxy-reports. Our findings highlight the importance of selecting appropriate self and/or proxy-reported HUs in health-related quality of life measurement and economic evaluations.

Renoprotective effect of combining pentoxifylline with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in advanced chronic kidney disease.

BACKGROUND/PURPOSE: Several studies have shown the renoprotective effects of pentoxifylline in the treatment of chronic kidney disease (CKD). This study was conducted to examine whether there was an increased benefit of including pentoxifylline with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in the treatment of CKD. METHODS: A single-center retrospective analysis was conducted. A total of 661 Stage 3B-5 CKD patients who received ACEI or ARB treatment were recruited. The patients were divided into the pentoxifylline use group and the no pentoxifylline group. Renal survival analysis of the two groups was compared. Subgroup analysis was performed by dividing the patients into lower [urine protein to creatinine ratio (UPCR)<1 g/g] and higher (UPCR ≥ 1 g/g) proteinuria subgroups. RESULTS: There was no between-groups difference regarding mortality and cardiovascular events. Addition of pentoxifylline showed a better renal outcome (p = 0.03). The protective effect of add-on pentoxifylline was demonstrated in the higher proteinuria subgroup (p = 0.005). In the multivariate Cox regression model, pentoxifylline use also showed a better renal outcome [hazard ratio (HR): 0.705; 95% confidence interval (CI): 0.498-0.997; p = 0.048]. This effect was more prominent in the higher proteinuria subgroup (HR: 0.602; 95% CI: 0.413-0.877; p = 0.008). CONCLUSION: In the advanced stages of CKD, patients treated with a combination of pentoxifylline and ACEI or ARB had a better renal outcome than those treated with ACEI or ARB alone. This effect was more prominent in the higher proteinuria subgroup. More large randomized control trials are needed to provide concrete evidence of the add-on effect of pentoxifylline.

Cost-effectiveness of edaravone dexborneol versus human urinary kallidinogenase for acute ischemic stroke in China.

BACKGROUND: Clinical trials have demonstrated the efficacy of edaravone dexborneol in the treatment of acute ischemic stroke. This study aims to determine the cost-effectiveness of edaravone dexborneol compared with human urinary kallidinogenase from China's healthcare system perspective. METHODS: A combination of the decision tree and Markov model was constructed to evaluate the cost-effectiveness of edaravone dexborneol versus human urinary kallidinogenase in the treatment of acute ischemic stroke over a lifetime horizon. Efficacy data were derived from pivotal clinical trials of edaravone dexborneol and human urinary kallidinogenase (TASTE trial and RESK trial, respectively) and adjusted using matching-adjusted indirect comparison. Cost and health utility inputs were extracted from published literature and open databases. One-way deterministic sensitivity and probabilistic sensitivity analyses were performed to examine the robustness of the results. RESULTS: Compared with human urinary kallidinogenase, edaravone dexborneol generated 0.153 incremental quality-adjusted life years (QALYs) with an incremental cost of ¥856, yielding an incremental cost-effectiveness ratio of ¥5,608 per QALY gained under the willingness-to-pay threshold (one-time gross domestic product per capita). Both one-way deterministic sensitivity analysis and probabilistic sensitivity analysis demonstrated the robustness of the base case results. CONCLUSIONS: Edaravone dexborneol is a cost-effective treatment choice for acute ischemic stroke patients compared with human urinary kallidinogenase in China.

Methods for Economic Evaluations of Novel Oral Anticoagulants in Patients with Atrial Fibrillation: A Systematic Review.

BACKGROUND: Atrial fibrillation (AF) is a severe epidemiological and public health concern among the elderly population worldwide, with substantial economic and social burdens. Economic evaluations can play an essential role in optimizing the utilization of scarce resources. In recent years, the number of economic evaluation studies related to AF has increased due to the rising number of AF patients, the continuous updating of clinical data, and the emergence of real-world evidence. However, there are still deficiencies in model settings and parameter sources in relevant studies. OBJECTIVE: This study aims to review the existing economic evaluations of novel oral anticoagulants (NOACs) in patients with AF and summarize the evidence and methods applied. METHODS: A comprehensive and systematic search was conducted on electronic databases, including PubMed, Embase, Web of Science (WOS), and The Cochrane Library, from the date of database creation to November 2022. The reporting quality of included literature was assessed using the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement. RESULTS: A total of 102 studies were included in the review, with 200 comparisons between NOACs and vitamin K antagonists (VKAs), as well as 58 comparisons between different NOACs. The healthcare sector and payer perspectives were the most common, and accordingly, the majority of the evaluations considered only direct medical costs. Most studies used Markov cohort models with the number of health states ranging from 4 to 29. Of included studies, 80 (78%) considered event recurrence and complications, and 78 (76%) considered discontinuation and second-line therapy. All of the studies applied uncertainty analysis to explore the robustness of the results. Of all 200 NOACs-VKAs comparisons, 149 (75%) showed that NOACs were more cost-effective; this proportion was 84% (139 out of 165) in high-income countries but decreased to 29% (10 out of 35) in middle- and low-income countries. Most (82%) of the 28 items in the CHEERS 2022 checklist were elucidated in the majority of included studies. A minority (only 39%) of included studies demonstrated high reporting quality. CONCLUSION: NOACs may be more cost-effective than VKAs in patients with AF, but this conclusion applies to high-income countries, whereas VKAs may be more cost-effective in middle- and low-income countries. The reporting quality of included studies was variable, and certain methodological issues were presented. This study highlights the economic evaluation methodology of NOACs in patients with AF and provides recommendations for modeling methods and future studies.

Comparison of the EQ-5D-Y and the CHU-9D instruments in a general child population based on self-reports and proxy-reports.

OBJECTIVE: This study utilized the EQ-5D-Y and the Child Health Utility 9D (CHU-9D) instruments to empirically investigate a general child population aged 7-8 years in China, with the aim of assessing and comparing the performance, correlation, and agreement between these two instruments. Both self-reported and proxy-reported versions of the instruments were considered in the analysis. METHODS: Data were collected from 7-8-year-old students in the second grade from four schools in Guangxi and Guiyang provinces, China. Children and their proxies independently completed their respective versions of the questionnaires, including the EQ-5D-Y, the CHU-9D, and other socio-demographic information. The psychometric properties of the EQ-5D-Y and the CHU-9D were assessed, including ceiling effects, internal consistency, and known-group validity. Spearman's correlation coefficient, Intraclass Correlation Coefficient (ICC), and Bland-Altman plots were calculated and plotted to assess the correlation and agreement between the EQ-5D-Y and CHU-9D. RESULTS: A total of 369 pairs of valid questionnaires were collected from both children and proxies. Due to the study's focus on a general child population, both EQ-5D-Y and CHU-9D yielded high utility values, with a significant ceiling effect observed, particularly in the EQ-5D-Y proxy-reported results. Compared to the EQ-5D-Y, the CHU-9D demonstrated a higher Cronbach's alpha coefficient and better internal consistency. Both instruments also demonstrated known-group validity, distinguishing different health status groups, except for EQ-5D-Y proxy-reported results. Spearman's correlation coefficient indicated some correlations in similar dimensions and utility values between the EQ-5D-Y and CHU-9D. The ICC of the EQ-5D-Y and CHU-9D utility values was 0.290 for self-reports and 0.383 for proxy-reports, indicating poor agreement between the two instruments. The Bland-Altman plots showed that the mean utility values obtained from EQ-5D-Y were significantly higher than those from CHU-9D. CONCLUSION: The EQ-5D-Y and the CHU-9D demonstrated acceptable performance within the general child population aged 7-8 years in China, except for the EQ-5D-Y proxy-reported version. It suffered from a notable ceiling effect, poor internal consistency, as well as weak known-group validity and discriminative ability. Moreover, although there existed a certain degree of correlation between the EQ-5D-Y and CHU-9D, their utility values exhibited significant differences. Therefore, these instruments are not interchangeable in practice.

Measuring the environmental efficiency of countries: a directional distance function metafrontier approach.

This paper measures environmental efficiency (EE) in 63 countries over the period 1981-2005 and analyzes whether the adoption of the Kyoto Protocol is accompanied by an increase in environmental efficiency during the same period. Differences in EE across countries under distinct country-specific production frontiers are measured using a directional distance function model, which incorporates a desirable output (GDP) and an undesirable output (CO2 emissions). It is further assumed that a stochastic meta-technology-frontier exists and represents potential outputs available to all countries given inputs. The metafrontier for four country groups, high income countries, upper-middle income countries, low-middle income countries, and low income countries, are estimated using balanced panel data for the sample countries over the study period. The overall results indicate that the four country groups operated under distinct stochastic production frontiers and therefore used different production technologies. It is found that high income countries achieved the highest progress in their average environmental efficiency relative to the metafrontier, while lower-middle income countries and low income countries recorded negative growth in their average EE relative to the metafrontier.

EPR-ENDOR characterization of (17O, 1H, 2H) water in manganese catalase and its relevance to the oxygen-evolving complex of photosystem II.

The synthesis of efficient water-oxidation catalysts demands insight into the only known, naturally occurring water-oxidation catalyst, the oxygen-evolving complex (OEC) of photosystem II (PSII). Understanding the water oxidation mechanism requires knowledge of where and when substrate water binds to the OEC. Mn catalase in its Mn(III)-Mn(IV) state is a protein model of the OEC's S(2) state. From (17)O-labeled water exchanged into the di-µ-oxo di-Mn(III,IV) coordination sphere of Mn catalase, CW Q-band ENDOR spectroscopy revealed two distinctly different (17)O signals incorporated in distinctly different time regimes. First, a signal appearing after 2 h of (17)O exchange was detected with a 13.0 MHz hyperfine coupling. From similarity in the time scale of isotope incorporation and in the (17)O µ-oxo hyperfine coupling of the di-µ-oxo di-Mn(III,IV) bipyridine model (Usov, O. M.; Grigoryants, V. M.; Tagore, R.; Brudvig, G. W.; Scholes, C. P. J. Am. Chem. Soc. 2007, 129, 11886-11887), this signal was assigned to µ-oxo oxygen. EPR line broadening was obvious from this (17)O µ-oxo species. Earlier exchange proceeded on the minute or faster time scale into a non-µ-oxo position, from which (17)O ENDOR showed a smaller 3.8 MHz hyperfine coupling and possible quadrupole splittings, indicating a terminal water of Mn(III). Exchangeable proton/deuteron hyperfine couplings, consistent with terminal water ligation to Mn(III), also appeared. Q-band CW ENDOR from the S(2) state of the OEC was obtained following multihour (17)O exchange, which showed a (17)O hyperfine signal with a 11 MHz hyperfine coupling, tentatively assigned as µ-oxo-(17)O by resemblance to the µ-oxo signals from Mn catalase and the di-µ-oxo di-Mn(III,IV) bipyridine model.

Economic evaluation of sintilimab plus chemotherapy vs. pembrolizumab plus chemotherapy for the treatment of first-line advanced or metastatic squamous NSCLC.

Background and objective: Sintilimab has superior efficacy and safety in patients with advanced or metastatic squamous non-small cell lung cancer (NSCLC), but its cost-effectiveness in China is unclear. This study is to evaluate the cost-effectiveness of sintilimab plus chemotherapy vs. pembrolizumab plus chemotherapy for locally advanced or metastatic squamous NSCLC in China. Methods: From the perspective of the Chinese health system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime time horizon. The two-stage method was used to estimate the overall survival hazard ratios to avoid the bias by crossover design in ORIENT-12 and KEYNOTE-407 studies. The anchored matching adjusted indirect comparison method (MAIC) was used for indirect comparison based on the individual patient data from ORIENT-12 and the publicly published KEYNOTE-407 study due to the lack of head-to-head clinical trials. Only direct medical costs were included, and utilities were derived from the published literature in the base case analysis. Sensitivity analysis was also performed to verify the robustness of the model results. In addition, the scenario analysis where the utilities were derived from the Quality of Life Questionnaire-Core 30 (QLQ-C30) scale in the ORIENT-12 by mapping to the EuroQol-5-dimension 5-level (EQ-5D-5L) was carried out to explore the uncertainty of the results. Results: Compared with pembrolizumab + chemotherapy, sintilimab + chemotherapy incurred a lower lifetime cost ($12,321 vs. 36,371) and yielded fewer quality-adjusted life-years (QALYs) (0.9902 vs. 1.0085), which resulted in an incremental cost-effectiveness ratio (ICER) of $1,314,208/QALY. A sintilimab strategy is a cost-effectiveness option under the WTP of 1-3 times the GDP per capita in China ($11,250/QALY~$33,749/QALY). The utility value of the post-progression, the unit cost of albumin paclitaxel, and the utility value of the progression-free state were the main drivers in the deterministic sensitivity analysis (DSA). According to the probabilistic sensitivity analysis (PSA), sintilimab + chemotherapy was 100% cost-effective when the WTP was 1-3 times China's per capita GDP. The results of the scenario analysis showed that sintilimab + chemotherapy obtained more QALYs (1.2319 vs. 1.1815) and lower costs ($12,321 vs. 36,371), which implied that sintilimab + chemotherapy may dominate the pembrolizumab + chemotherapy. Conclusion: Compared with pembrolizumab + chemotherapy, sintilimab + chemotherapy is more cost-effective for first-line treatment in Chinese patients with locally advanced or metastatic squamous NSCLC.

Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: The current influenza pandemic calls for a safe and effective vaccine. We assessed the safety and immunogenicity of eight formulations of 2009 pandemic influenza A H1N1 vaccine produced by ten Chinese manufacturers. METHODS: In this multicentre, double-blind, randomised trial, 12 691 people aged 3 years or older were recruited in ten centres in China. In each centre, participants were stratified by age and randomly assigned by a random number table to receive one of several vaccine formulations or placebo. The study assessed eight formulations: split-virion formulation containing 7.5 microg, 15 microg, or 30 microg haemagglutinin per dose, with or without aluminium hydroxide adjuvant, and whole-virion formulation containing 5 microg or 10 microg haemagglutinin per dose, with adjuvant. All formulations were produced from the reassortant strain X-179A (A/California/07/2009-A/PR/8/34). We analysed the safety (adverse events), immunogenicity (geometric mean titre [GMT] of haemagglutination inhibition antibody), and seroprotection (GMT >or=1:40) of the formulations. Analysis was by per protocol. Two sites registered their trial with ClinicalTrials.gov, numbers NCT00956111 and NCT00975572. The other eight studies were registered with the State Food and Drug Administration of China. FINDINGS: 12 691 participants received the first dose on day 0, and 12 348 participants received the second dose on day 21. The seroprotection rate 21 days after the first dose of vaccine ranged from 69.5% (95% CI 65.9-72.8) for the 7.5 microg adjuvant split-virion formulation to 92.8% (91.9-93.6) for the 30 microg non-adjuvant split-virion formulation. The seroprotection rate was 86.5% (796 of 920; 84.1-88.7) in recipients of one dose of the 7.5 microg non-adjuvant split-virion vaccine compared with 9.8% (140 of 1432; 8.3-11.4) in recipients of placebo (p<0.0001). One dose of the 7.5 microg non-adjuvant split-virion vaccine induced seroprotection in 178 of 232 children (aged 3 years to <12 years; 76.7%, 70.7-82.0), 211 of 218 adolescents (12 years to <18 years; 96.8%, 93.5-98.7), 289 of 323 adults (18-60 years; 89.5%, 85.6-92.6), and 118 of 147 adults older than 60 years (80.3%, 72.9-86.4), meeting the European Union's licensure criteria for seroprotection in all age-groups. In children, a second dose of the 7.5 microg formulation increased the seroprotection rate to 97.7% (215 of 220, 94.8-99.3). Adverse reactions were mostly mild or moderate, and self-limited. Severe adverse effects occurred in 69 (0.6%, 0.5-0.8) recipients of vaccine compared with one recipient (0.1%, 0-0.2) of placebo. The most common severe adverse reaction was fever, which occurred in 25 (0.22%; 0.14-0.33) recipients of vaccine after the first dose and four (0.04%; 0.01-0.09) recipients of vaccine after the second dose compared with no recipients of placebo after either dose. INTERPRETATION: One dose of non-adjuvant split-virion vaccine containing 7.5 microg haemagglutinin could be promoted as the formulation of choice against 2009 pandemic influenza A H1N1 for people aged 12 years or older. In children (aged <12 years), two 7.5 mug doses might be needed. FUNDING: Sinovac Biotech, Hualan Biological Bacterin, China National Biotec Group, Beijing Tiantan Biological Products, Changchun Institute of Biological Products, Changchun Changsheng Life Sciences, Jiangsu Yanshen Biological Technology Stock, Zhejiang Tianyuan Bio-Pharmaceutical, Lanzhou Institute of Biological Products, Shanghai Institute of Biological Products, and Dalian Aleph Biomedical.

Cost-Effectiveness Analysis of Oral Direct-Acting Antivirals for Chinese Patients with Chronic Hepatitis C.

BACKGROUND AND OBJECTIVE: All oral direct-acting antivirals (DAAs) have shown excellent efficacy and safety in Chinese patients with chronic hepatitis C (CHC). However, the cost of DAAs used to be expensive; therefore, large numbers of patients had no access to DAAs in China. Recently, prices have been greatly reduced. The objective of this study was to evaluate the cost-effectiveness of ledipasvir/sofosbuvir (LDV/SOF), sofosbuvir/velpatasvir (SOF/VEL), elbasvir/grazoprevir (EBR/GZR) and glecaprevir/pibrentasvir (GLE/PIB) in Chinese CHC patients stratified by hepatitis C virus (HCV) genotype (GT), cirrhosis status, and treatment history. METHODS: On the basis of a Chinese healthcare perspective, a Markov model was constructed to estimate the lifetime costs and health outcomes of patients treated with different DAA regimens. Chinese-specific clinical, cost, and utility inputs were obtained or calculated from published sources and expert opinions. Costs, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were reported as primary outcomes. Base-case analysis and sensitivity analysis were conducted. RESULTS: At a willing-to-pay (WTP) threshold of US$30,081/QALY (calculated by three times the GDP per capita in China), SOF/VEL was cost-effective in patients with HCV GT 1, 3, and 6 infections, and the probabilities that SOF/VEL was cost-effective were 9.7-75.7%, 39.1-63.9%, and 35.6-88.0%, respectively. For GT2 patients, noncirrhotic patients, treatment-naïve patients, and treatment-experienced patients, LDV/SOF was the most cost-effective regimen, and the probabilities of cost-effectiveness for each of these groups was 92.1-99.8%, 89.9-99.0%, 61.6-91.2%, and 99.3-100.0%, respectively below the WTP threshold. The GLE/PIB regimen (12-week duration) was the most cost-effective in cirrhotic patients, whereas the probability of its cost-effectiveness varied with that of EBR/GZR (4.1-93.8% versus 6.2-93.3%) below the WTP threshold. CONCLUSIONS: Overall, SOF/VEL and LDV/SOF regimens are more likely to be cost-effective among various subgroups of Chinese patients with CHC.

Cost-Effectiveness Analysis of Abemaciclib Plus Fulvestrant in the Second-Line Treatment of Women With HR+/HER2- Advanced or Metastatic Breast Cancer: A US Payer Perspective.

Introduction: This study evaluated the cost-effectiveness of abemaciclib plus fulvestrant (ABE + FUL) vs. palbociclib plus fulvestrant (PAL + FUL), ribociclib plus fulvestrant (RIB + FUL) and fulvestrant monotherapy (FUL) as second-line treatment for hormone receptor-positive and human epidermal growth factor receptor 2- negative advanced or metastatic breast cancer in the US. Methods: The 3 health states partitioned survival (PS) model was used over the lifetime. Effectiveness and safety data were derived from the MONARCH 2 trial, MONALEESA-3 trial, and PALOMA-3 trial. Parametric survival models were used for four treatments to explore the long-term effect. Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from published studies. Sensitivity analyses including one-way sensitivity analysis, probabilistic sensitivity analysis and scenario analysis were performed to observe model stability. Results: In the PS model, compared with PAL + FUL, ABE + FUL yielded 0.44 additional QALYs at an additional cost of $100,696 for an incremental cost-utility ratio (ICUR) of $229,039/QALY. Compared with RIB + FUL, ABE + FUL yielded 0.03 additional QALYs at an additional cost of $518 for an ICUR of $19,314/QALY. Compared with FUL, ABE + FUL yielded 0.68 additional QALYs at an additional cost of $260,584 for ICUR of $381,450/QALY. From the PS model, the ICUR was $270,576 /QALY (ABE + FUL vs. PAL + FUL), dominated (ABE + FUL vs. RIB + FUL) and $404,493/QALY (ABE + FUL vs. FUL) in scenario analysis. In the probabilistic sensitivity analysis, the probabilities that ABE + FUL was cost-effective vs. PAL + FUL, RIB + FUL and FUL at thresholds of $50,000, $100,000, and $200,000 per QALY gained were 0% and the probabilities that ABE + FUL was cost-effective vs. PAL + FUL and RIB + FUL at thresholds of $50,000, $100,000, and $200,000 per QALY gained were 0.2, 0.6, and 7.3%. Conclusions: The findings from the present analysis suggest that ABE + FUL might be cost-effective compared with RIB + FUL and not cost-effective compared with PAL + FUL and FUL for second-line treatment of patients with HR+/HER2- advanced or metastatic breast cancer in the US.

Culture-Related Health Disparities in Quality of Life: Assessment of Instrument Dimensions Among Chinese.

Background: Health-related quality of life (HRQoL) is one of the major focuses of primary care. However, HRQoL instruments used in China are mainly developed from Western countries. Such instruments may not cover all important health concepts valued by the Chinese as health is a culture-specific concept. Objectives: The objectives of this study are to identify culture-specific health dimensions and culture-related health disparities in primary care that are considered important by Chinese living in China. Methods: A purposive sample of 164 adult Chinese (67 healthy persons and 97 patients) were interviewed face to face. In-depth open-ended questions were asked to elicit culture-specific dimensions of quality of life in primary care settings in China. Results: Twelve health dimensions were identified. Five most frequently mentioned dimensions were: mood (N = 52, 31.71%), physical activities (N = 48, 29.27%), work (N = 40, 24.39%), diet (N = 32, 19.51%), and vitality (N = 28, 17.07%). Significantly more healthy persons reported mood (49.25 vs. 19.59%, P < 0.001), mindset (16.42 vs. 0.00%, P < 0.001), and self-care (11.94 vs. 2.06%, P = 0.016) characterizing good HRQoL, while more patients emphasized on work (4.48 vs. 38.14%, P < 0.001). Diet and vitality appeared to be culture-specific dimensions related to health among Chinese. Conclusions: To better adapt or develop HRQoL instruments for Chinese, dimensions or items regarding diet might be included and disparities in the meaning of vitality between Chinese and Western cultures should be considered.

Predictors of Quality of Life in Patients With Myocardial Infarction Combined With Dyslipidemia.

Background: Dyslipidemia is an important risk factor for myocardial infarction (MI). This study aimed to examine the health-related quality of life (HRQoL) and its predictors of patients with MI combined with dyslipidemia in China. Methods: Information on patients' sociological characteristics, lifestyle, clinical characteristics, and quality of life were collected by electronic medical records and questionnaires. Tobit regression model was used to investigate the predictors of quality of life. Results: There were 756 patients responded. The average EQ-5D score of all the patients was 0.95 (SD: 0.11). For all patients, factors such as age, high-fat and high-cholesterol diet, sports, family history of dyslipidemia, history of peripheral artery disease significantly affected HRQoL. Conclusions: Post-discharge care of the elderly group should be paid more attention to and suggestions on the healthy lifestyle (fat control) of the patients should be encouraged to improve the quality of life of these population.

Economic Burden of Myocardial Infarction Combined With Dyslipidemia.

Background: Dyslipidemia is a common comorbidity and an important risk factor for myocardial infarction (MI). This study aimed to examine the economic burden of MI combined with dyslipidemia in China. Methods: Patients who were hospitalized due to MI combined with dyslipidemia in 2016 were enrolled. Costs were measured based on electronic medical records and questionnaires. The annual costs were analyzed by conducting descriptive statistics, univariable, and multivariable analyses. Results: Data of 900 patients were analyzed, and 144 patients were dead during the follow-up. The majority of patients were aged 51-70 years (n = 563, 62.55%) and males (n = 706, 78.44%). For all-cause costs, the median annual direct medical costs, direct non-medical costs, indirect costs, and total costs were RMB 13,168 (5,212-29,369), RMB 600 (0-1,750), RMB 676 (0-1,787), RMB 15,361 (6,440-33,943), respectively; while for cardiovascular-related costs, the corresponding costs were RMB 12,233 (3,795-23,746), RMB 515 (0-1,680), RMB 587 (0-1,655), and RMB 14,223 (4,914-28,975), respectively. Lifestyle and complications significantly affected both all-cause costs and cardiovascular-related costs. Conclusions: Increasing attention should be paid to encourage healthy lifestyle, and evidence-based medicine should focus on optimal precautions and treatments for complications, to reduce the economic burden among MI patients with a comorbid dyslipidemia.