List prices and clinical value of anticancer drugs in China, Japan, and South Korea: a retrospective comparative study.

Background: High prices of anticancer drugs have raised concerns due to their financial impact on patients and healthcare systems. This study aimed to assess the initial and latest list prices and clinical value of reimbursed anticancer drugs in China, Japan, and South Korea. Methods: We identified anticancer drugs newly approved by the National Medical Products Administration of China from January 2012 to June 2022, and by the Pharmaceuticals and Medical Devices Agency of Japan and the Ministry of Food and Drug Safety of South Korea up until June 2022. We compared initial and latest treatment prices between countries and assessed clinical value using patients' survival, quality of life (QoL), and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). We calculated Spearman rank correlation coefficients of treatment prices with clinical value for individual countries and employed regression analyses to investigate whether the relationship between prices and clinical value was modified by the country setting. Findings: Our cohort included 91 anticancer drug indications, with 60 listed for reimbursement in China, 91 in Japan, and 87 in South Korea. Median treatment prices were highest in Japan, followed by South Korea, and lowest in China, both for initial prices (US$64082 vs. US$45529 vs. US$19144, p < 0.0001) and latest prices (US$50859 vs. US$31611 vs. US$18666, p < 0.0001). Over time, China (ß = -0.047, p < 0.0001) and South Korea (ß = -0.049, p < 0.0001) witnessed more significant price reductions compared to Japan (ß = -0.013, p = 0.011). The correlations between both initial and latest treatment prices and clinical value (QoL and ESMO-MCBS) were more significant and stronger in China and South Korea than in Japan, although Japan exhibited slightly stronger correlations in terms of survival compared to China and South Korea. The relationship between clinical value and treatment prices may not be modified by the country setting. Interpretation: In comparison, South Korea's list prices and their correlations with clinical value appear reasonable. Policymakers in Japan could enhance efficiency by controlling prices and aligning them with clinical value, while China would need to take substantial steps to expand anticancer drug coverage. Funding: National Natural Science Foundation of China (72374149 and 72074163), and China Center for South Asian Studies, Sichuan University.

Price negotiation and pricing of anticancer drugs in China: An observational study.

BACKGROUND: While China has implemented reimbursement-linked drug price negotiation annually since 2017, emphasizing value-based pricing to achieve a value-based strategic purchase of medical insurance, whether drug prices became better aligned with clinical value after price negotiation has not been sufficiently established. This study aimed to assess the changes in prices and their relationship with the clinical value of anticancer drugs after the implementation of price negotiations in China. METHODS AND FINDINGS: In this observational study, anticancer drug indications that were negotiated successfully between 2017 and 2022 were identified through National Reimbursement Drug Lists (NRDL) of China. We excluded extensions of indications for drugs already listed in the NRDL, indications for pediatric use, and indications lacking corresponding clinical trials. We identified pivotal clinical trials for included indications by consulting review reports or drug labels issued by the Center for Drug Evaluation, National Medical Products Administration. We calculated treatment costs as outcome measures based on publicly available prices and collected data on clinical value including safety, survival, quality of life, and overall response rate (ORR) from publications of pivotal clinical trials. The associations between drug costs and clinical value, both before and after negotiation, were analyzed using regression analyses. We also examined whether price negotiation has led to a reduction in the variation of treatment costs for a given value. We included 103 anticancer drug indications, primarily for the treatment of blood cancer, lung cancer, and breast cancer, with 76 supported by randomized controlled trials and 27 supported by single-arm clinical trials. The median treatment costs over the entire sample have been reduced from US$34,460.72 (interquartile range (IQR): 19,990.49 to 55,441.66) to US$13,688.79 (IQR: 7,746.97 to 21,750.97) after price negotiation (P < 0.001). Before price negotiation, each additional month of survival gained was associated with an increase in treatment costs of 3.4% (95% confidence interval (CI) [2.1, 4.8], P < 0.001) for indications supported by randomized controlled trials, and a 10% increase in ORR was associated with a 6.0% (95% CI [1.6, 10.3], P = 0.009) increase in treatment costs for indications supported by single-arm clinical trials. After price negotiation, the associations between costs and clinical value may not have changed significantly, but the variation of drug costs for a given value was reduced. Study limitations include the lack of transparency in official data, missing data on clinical value, and a limited sample size. CONCLUSIONS: In this study, we found that the implementation of price negotiation in China has led to drug pricing better aligned with clinical value for anticancer drugs even after substantial price reductions. The achievements made in China could shed light on the price regulation in other countries, particularly those with limited resources and increasing drug expenditures.

The efficacy and safety of low-dose rituximab in the treatment of pemphigus vulgaris: a cohort study.

BACKGROUND: Rituximab (RTX) is considered the first-line treatment for pemphigus vulgaris (PV), which is a B-cell-mediated acquired autoimmune disease. However, no consensus on the optimum dosage has been achieved. OBJECTIVES: To investigate the efficacy and safety of low-dose RTX (a single infusion of 500 mg) for the treatment of PV, a cohort study was conducted for patients with PV, along with a 12-month follow-up following the administration of RTX. METHODS: Patients with moderate or severe PV were divided into group A (low-dose RTX combined with corticosteroids) and group B (corticosteroids alone). Data on complete remission (CR) rates, doses of corticosteroids, cumulative doses of corticosteroids at the third, sixth, and twelfth months, pemphigus disease area index and adverse effects (AEs) were collected. RESULTS: Forty-four patients with moderate or severe PV were enrolled in this study (19 in group A and 25 in group B). Patients treated with low-dose RTX had higher CR rates, lower doses of corticosteroids at the third, sixth, and twelfth months, lower cumulative doses of corticosteroids at the sixth and twelfth months, and fewer AEs than those who received corticosteroids alone. CONCLUSIONS: This study indicated that low-dose RTX may be a beneficial and secure therapy option for patients with moderate to severe PV.

Measuring low-value care in hospital discharge records: evidence from China.

Background: Plenty of efforts have been made to reduce the use of low-value care (the care that is not expected to provide net benefits for patients) across the world, but measures of low-value care have not been developed in China. This study aims to develop hospital discharge records-based measures of low-value surgical procedures, evaluate their annual use and associated expenditure, and analyze the practice patterns by characterizing its temporal trends and correlations across rates of different low-value procedures within hospitals. Methods: Informed by evidence-based lists including Choosing Wisely, we developed 11 measures of low-value surgical procedures. We evaluated the count and proportion of low-value episodes, as well as the proportion of expenditure and medical insurance payouts for these episodes, using hospital discharge records in Sichuan Province, China during a period of 2016-2022. We compared the count and expenditure detected by different versions of these measures, which varied in sensitivity and specificity. We characterized the temporal trends in the rate of low-value surgical procedures and estimated the annual percent change using joint-point regression. Additionally, we calculated the Spearman correlation coefficients between the risk-standardized rates of low-value procedures which were estimated by multilevel models adjusting for case mix across hospitals. Findings: Low-value episodes detected by more specific versions of measures accounted for 3.25% (range, 0.11%-71.66%), and constituted 6.03% (range, 0.32%-84.63%) and 5.90% (range, 0.33%-82.86%) of overall expenditure and medical insurance payouts, respectively. The three figures accounted for 5.90%, 8.41%, and 8.38% in terms of more sensitive versions of measures. Almost half of the low-value procedures (five out of eleven) experienced an increase in rates during the period of 2016-2022, with four of them increasing over 20% per year. There was no significant correlation across risk-standardized rates of different low-value procedures within hospitals (mean r for pairwise, 0.03; CI, -0.02, 0.07). Interpretation: Despite overall low-value practices detected by the 11 developed measures was modest, certain clinical specialties were plagued by widespread low-value practices which imposed heavy economic burdens for the healthcare system. Given the pervasive and significant upward trends in rates of low-value practices, it has become increasingly urgent to reduce such practices. Interventions in reducing low-value practices in China would be procedure-specific as practice patterns of low-value care varied by procedures and common drivers of low-value practices may not exist. Funding: The National Science Foundation of China (72074163), Taikang Yicai Public Health and Epidemic Control Fund, Sichuan Science and Technology Program (2022YFS0052 and 2021YFQ0060), and Sichuan University (2018hhf-27 and SKSYL201811).

Integration of GWAS and RNA-Seq Analysis to Identify SNPs and Candidate Genes Associated with Alkali Stress Tolerance at the Germination Stage in Mung Bean.

Soil salt-alkalization seriously impacts crop growth and productivity worldwide. Breeding and applying tolerant varieties is the most economical and effective way to address soil alkalization. However, genetic resources for breeders to improve alkali tolerance are limited in mung bean. Here, a genome-wide association study (GWAS) was performed to detect alkali-tolerant genetic loci and candidate genes in 277 mung bean accessions during germination. Using the relative values of two germination traits, 19 QTLs containing 32 SNPs significantly associated with alkali tolerance on nine chromosomes were identified, and they explained 3.6 to 14.6% of the phenotypic variance. Moreover, 691 candidate genes were mined within the LD intervals containing significant trait-associated SNPs. Transcriptome sequencing of alkali-tolerant accession 132-346 under alkali and control conditions after 24 h of treatment was conducted, and 2565 DEGs were identified. An integrated analysis of the GWAS and DEGs revealed six hub genes involved in alkali tolerance responses. Moreover, the expression of hub genes was further validated by qRT-PCR. These findings improve our understanding of the molecular mechanism of alkali stress tolerance and provide potential resources (SNPs and genes) for the genetic improvement of alkali tolerance in mung bean.

Effects of ambient temperature on atopic dermatitis and attributable health burden: a 6-year time-series study in Chengdu, China.

Background: Despite increasing public concerns about the widespread health effects of climate change, the impacts of ambient temperature on atopic dermatitis (AD) remain poorly understood. Objectives: We aimed to explore the effect of ambient temperature on AD and to estimate the burdens of AD attributed to extreme temperature. Methods: Data on outpatients with AD and climate conditions in Chengdu, China were collected. A distributed lag nonlinear model (DLNM) was adopted to explore the association between daily mean temperature and AD outpatient visits. Subgroup analysis was used to identify vulnerable populations. Attributable burden was estimated by the epidemiological attributable method. Results: We analyzed 10,747 outpatient visits from AD patients at West China Hospital in Chengdu between January 1, 2015, and December 31, 2020. Both low (<19.6 °C) and high temperatures (>25.3 °C) were associated with increased AD outpatient visits, with the increase being more pronounced at low temperature, as evidenced by a 160% increase in visits when the temperature dropped below zero from the minimum mortality temperature (22.8 °C). Children and males were the most susceptible populations. Approximately 25.4% of AD outpatient visits were associated with temperatures, causing an excessive 137161.5 US dollars of health care expenditures during this 6-year period. Conclusions: Both high and low temperatures, particularly low temperatures, were significantly associated with an increased risk of AD, with children and males showing the strongest associations. Extreme environmental temperature has been identified as one of the major factors promoting the development of AD. However, individual patient-level exposures still needed to be investigated in future studies to confirm the causality between temperature and AD.

Identifying the causal effects of long-term exposure to PM2.5 and ground surface ozone on individual medical costs in China-evidence from a representative longitudinal nationwide cohort.

BACKGROUND: There is little evidence on whether PM2.5 and ground surface ozone have consistent effects on increased individual medical costs, and there is a lack of evidence on causality in developing countries. METHODS: This study utilized balanced panel data from 2014, 2016, and 2018 waves of the Chinese Family Panel Study. The Tobit model was developed within a counterfactual causal inference framework, combined with a correlated random effects and control function approach (Tobit-CRE-CF), to explore the causal relationship between long-term exposure to air pollution and medical costs. We also explored whether different air pollutants exhibit comparable effects. RESULTS: This study encompassed 8928 participants and assessed various benchmark models, highlighting the potential biases from failing to account for air pollution endogeneity or overlooking respondents without medical costs. Using the Tobit-CRE-CF model, significant effects of air pollutants on increased individual medical costs were identified. Specifically, margin effects for PM2.5 and ground-level ozone signifying that a unit increase in PM2.5 and ground-level ozone results in increased total medical costs of 199.144 and 75.145 RMB for individuals who incurred fees in the previous year, respectively. CONCLUSIONS: The results imply that long-term exposure to air pollutants contributes to increased medical costs for individuals, offering valuable insights for policymakers aiming to mitigate air pollution's consequences.

The Contributions of Population Distribution, Healthcare Resourcing, and Transportation Infrastructure to Spatial Accessibility of Health Care.

Population demand, healthcare resourcing, and transportation linkage are considered as major determinants of spatial access to health care. Temporal changes of the 3 determinants would result in gain or loss of spatial access to health care. As a remarkable milestone achieved by Targeted Poverty Reduction Project launched in China, the significant improvements in spatial access to health care served as an ideal context for investigating the relative contributions of these 3 determinants to the changes in spatial access to health care in a rural county. A national level poverty-stricken county, Chishui county from Guizhou province, China, was chosen as our study area. The enhanced two-step floating catchment area model and the chain substitution method were employed for analysis. The relative contributions of the 3 determinants demonstrated variations with villages. The relative contributions of healthcare resourcing were positive in all villages as indicated by sharp increases in healthcare resources. Population changes and transportation infrastructure expansion had both negative and positive effects on spatial access to health care for different villages. Decisionmakers should take into account the duration of travel time spent between where people live, where transport hubs are located, and where healthcare services are delivered in the process of formulating policies toward rural healthcare planning. For villages with poorly-established infrastructure, the optimization of population distribution and healthcare resourcing should be considered as the priority. A stronger marginal effect would be induced by transportation infrastructure expansion with increased spatial accessibility. This study provides empirical evidences to inform healthcare planning in low- and middle-income countries.

Floods and diarrheal morbidity: Evidence on the relationship, effect modifiers, and attributable risk from Sichuan Province, China.

Background: Although studies have provided the estimates of floods-diarrhoea associations, little is known about the lag effect, effect modification, and attributable risk. Based on Sichuan, China, an uneven socio-economic development province with plateau, basin, and mountain terrains spanning different climatic zones, we aimed to systematically examine the impacts of floods on diarrheal morbidity. Methods: We retrieved information on daily diarrheal cases, floods, meteorological variables, and annual socio-economic characteristics for 21 cities in Sichuan from January 1, 2017 to December 31, 2019. We fitted time-series Poisson models to estimate the city-specific floods-diarrhoea relation over the lags of 0-14 days, and then pooled them using meta-analysis for cumulative and lag effects. We further employed meta-regression to explore potential effect modifiers and identify effect modification. We calculated the attributable diarrheal cases and fraction of attributable morbidity within the framework of the distributed lag model. Results: Floods had a significant cumulative association with diarrhoea at the provincial level, but varied by regions and cities. The effects of the floods appeared on the second day after the floods and lasted for 5 days. Floods-diarrhoea relations were modified by three effect modifiers, with stronger flood effects on diarrhoea found in areas with higher air pressure, lower diurnal temperature range, or warmer temperature. Floods were responsible for advancing a fraction of diarrhoea, corresponding to 0.25% within the study period and 0.48% within the flood season. Conclusions: The impacts imposed by floods were mainly distributed within the first week. The floods-diarrhoea relations varied by geographic and climatic conditions. The diarrheal burden attributable to floods is currently low in Sichuan, but this figure could increase with the exposure more intensive and the effect modifiers more detrimental in the future. Our findings are expected to provide evidence for the formulation of temporal- and spatial-specific strategies to reduce potential risks of flood-related diarrhoea.

Exploring the effect of the primary care health workers number on infectious diarrhea morbidity and where the health resources should go.

We aimed to explore the association between the number of primary healthcare workers and infectious diarrhea morbidity at community levels and to provide evidence-based implications for optimizing primary healthcare manpower resource allocations. We collected annual infectious diarrhea morbidity and relevant data of 4321 communities in Sichuan Province, China, from 2017 to 2019. Global and local Moran's I were calculated to detect the spatial clustering of infectious diarrhea morbidity and to identify areas where increased primary healthcare manpower resources should be allocated. The spatial lag fixed effects panel data model was adopted to explore the association between the number of primary healthcare workers per 1000 residents and infectious diarrhea morbidity. Significantly high-high and low-low clusters of infectious diarrhea cases were found to be mainly distributed in underdeveloped and developed areas during the studied period years, respectively. The infectious diarrhea morbidity was found to be statistically negatively associated with the number of primary healthcare workers per 1000 residents with a coefficient of - 0.172, indicating that a 0.172 reduction of infectious diarrhea morbidity (1/10,000) was associated with doubled amounts of primary healthcare workers per 1000 residents. Our findings highlighted the role of primary healthcare in the process of infectious diarrhea prevention and control, and implied that constant efforts should be addressed to facilitate infectious diarrhea prevention and control, especially in the underdeveloped areas.

Effect of NUDT15 polymorphisms on early hematological safety of low-dose azathioprine in Chinese patients with pemphigus vulgaris: A prospective cohort study.

Azathioprine (AZA) is the preferred immunosuppressant for treating pemphigus vulgaris (PV), with discontinuation mainly attributed to hematological adverse events (AE). Reportedly, nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) polymorphisms have been strongly associated with thiopurine-induced leukopenia. To investigate hematological AE of low-dose AZA based on NUDT15 genotypes among patients with PV, a prospective cohort study was conducted in patients with PV, followed-up for the first 8 weeks after AZA administration. All patients were divided into wild homozygous and heterozygous NUDT15 groups. Both groups initiated AZA at low dose (50 mg/day) and continued with different dose-escalating approaches. Bone marrow suppression was considered the principal outcome. Overall, 62 patients with PV were enrolled (48 in the wild homozygous NUDT15 group vs. 14 in the heterozygous NUDT15 group). Except for median maintenance doses of AZA, no statistically significant differences were observed between the two groups in terms of age, sex, white blood cells, neutrophil count, platelet count, hemoglobin level, median final doses of corticosteroids (mg prednisone equivalent), pemphigus disease area index, and anti-desmoglein 1/3 autoantibodies. In both groups, patients presented similar hematological AE and treatment responses after administration of different low-dose AZA treatment strategies. Low-dose AZA based on NUDT15 genotypes can reduce the risk of early hematological AE among patients with PV.

Governmental Investments in Hospital Infrastructure Among Regions and Its Efficiency in China: An Assessment of Building Construction.

Hospital infrastructure has been addressed as the prerequisite of healthcare delivery which intensively affects medical quality. Over the past decade, China has proposed a series of investment plans for hospital infrastructure in order to promote healthcare development in underdeveloped regions. Focusing on the construction of hospital buildings as the key component of hospital infrastructure, this study aims to examine whether the investment efficiency is lower where a government prioritizes equity and to explore what kind of geographical predispositions should be embedded in governmental investment plans for hospital infrastructures from the perspectives of both investment equity and efficiency. Relevant data from 330 governmental-invested hospital building construction projects in Sichuan province, China, from 2009 to 2018 were collected. Concentration index was used to evaluate the equity in the distribution of the investments. Tobit model was employed to explore the relationship between regional economic development and investment efficiency measured by an integrated approach of principal component analysis and data envelopment analysis. The results demonstrated a slight concentration of governmental investments in economically developed regions, while a negative association with regional economic development was identified with investment efficiency. Our study illustrated the investment efficiency was higher where a government prioritized equity and provided empirical evidences on switching governmental investment predisposition in the aspect of healthcare infrastructure construction toward less developed regions in China from the perspectives of both investment allocation equity and efficiency, which would further assist in the formulation of region-specific policies and strategies for underdeveloped regions.

Risk Factors for Progression from Subclinical to Clinical Phase of Psoriatic Arthritis: A Case-Control Study.

INTRODUCTION: The objective of this study is to identify the potential risk factors for progression from subclinical to clinical psoriatic arthritis (PsA). METHODS: A retrospective, longitudinal, case-control study was conducted at a single hospital, including 25 patients with clinically confirmed PsA in the case group and 137 controls without confirmed PsA. All patients in both groups had a medical history of subclinical PsA. Various baseline covariates were collected from all patients when they had a status of subclinical PsA. Univariate, multivariate, stratified, and interaction analyses were employed to identify potential risk factors of transiting to clinical PsA from subclinical PsA. RESULTS: In multivariate logistic regression analysis, older age (OR 10.15, 95% CI 2.79-36.91, p = 0.00), alcohol drinking (OR 3.43, 95% CI 1.17-10.12, p = 0.03), elevated high-sensitivity C-reactive protein (hs-CRP) (OR 1.05, 95% CI 1.01-1.09, p = 0.03) were identified as risk factors for transition from subclinical to clinical PsA. Stratified and logistic regression analyses suggest a significant interaction between age and fatty liver. For patients aged less than 45 years old, the association between fatty liver and clinical PsA was statistically significant. CONCLUSIONS: Older age, alcohol drinking, elevated hs-CRP, and the presence of fatty liver at less than 45 years old appear to increase the risk of transition from subclinical to clinical PsA. These findings call for a need to manage these risk factors.

The Association of Market Mix of Hospital Ownership With Medical Disputes: Evidence From China.

The prevalence and severity of medical disputes in China have attracted the attention of society and academia, and how to alleviate medical disputes has become a major concern. Following the implementation of a series of policies, the private sector in China's hospital market has expanded rapidly over the past decade. It remains unknown whether the market mix of hospital ownership could alleviate medical disputes, this study aims to bridge the gap. Data are collected from all hospitals (2171) in Sichuan province, China, from 2012 to 2015. Using a negative binomial hurdle model, the results show that for hospitals with disputes, the private hospital market share has an inverted U-shaped relationship with the number of disputes. However, no significant relationship is found between the private hospital market share and the probability of dispute occurrence. For hospitals with disputes, competition plays a protective role in the effect of the private hospital market share on the number of disputes, hindering the increase in the number of disputes and facilitating a more rapid drop. However, medical quality is found to play an insignificant role in that effect. The findings also support encouraging new private hospitals in China rather than privatizing existing public hospitals.

Complete remission of refractory pemphigus vulgaris in a Chinese patient with mutated NUDT15 by combination of minimal doses of azathioprine and prednisone.

Although azathioprine (AZA) combined with corticosteroids remains the first-line therapy to treat patients with pemphigus vulgaris (PV), there are increasing reports of AZA-induced leukopenia, which provides the rationale for monitoring the blood cell count and testing the genotypes at the thiopurine methyltransferase (TPMT) and the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) genes. Here, we reported a case of persistent refractory PV in a Chinese patient with three runs of AZA-corticosteroids treatment. In the first two runs he received AZA-corticosteroids at standard or slightly reduced doses and developed leukopenia. In the third run of treatment, he was found to have NUDT15 mutation (rs116855232) and wild-type homozygous TPMT*3C (rs1142345), treatment with minimal doses of AZA and prednisone resulted in a complete remission of PV without any side effects including leukopenia. Our observations not only highlight the benefits of testing the TPMT and NUDT15 genotypes and monitoring the dynamic changes of the white blood cell count in guiding the AZA therapy, but also suggest the potential of using the AZA-corticosteroids combination at very low doses in the treatment of refractory PV.

The modification effect of the diurnal temperature range on the exposure-response relationship between temperature and pediatric hand, foot and mouth disease.

BACKGROUND: Growing evidence suggests that the diurnal temperature range (DTR) could modify the temperature-disease relationship for those environmentally-related infectious diseases. However, there is a lack of evidence on the hand, foot and mouth disease (HFMD). In this study, we thoroughly examined this hypothesis via a nationwide study. METHOD: We collected the daily time series of HFMD cases and meteorological factors of 143 cities in mainland China from 2009 to 2014. For each city, we calculated the arithmetic average of the meteorological factors as a proxy for the climatic differences. We then performed two-stage time series analyses for four different climatic regions. Specifically, a distributed lag nonlinear model was applied to estimate the temperature-HFMD relationship for each city, and then a multivariate meta-regression was implemented to examine whether the DTR could explain the potential heterogeneity as an effect modifier. In addition, we compared the modification effect of the DTR with those of other climatic factors. RESULT: We found a significant modification effect of DTR on the temperature-HFMD relationship in the moderate-temperature region. Besides, the modification effect was only observed at hot temperatures. Comparing the maximum temperature (32.2 °C) to the median temperature (11.9 °C), the risk ratio was 1.60 (1.33, 1.92) when DTR was in the 10th percentile (6.8 °C) and 0.81 (0.69, 0.96) when the DTR was in the 90th percentile (11.8 °C). By comparing DTR with other climatic variables, we found that the DTR had the best performance in improving the model fit (ΔQAIC= 10.1) and reducing the heterogeneity (ΔI2 = 3.1%) in the multivariate meta-regression. CONCLUSION: Our findings verified that DTR can modify the temperature-HFMD relationship. Besides, our findings also implied that DTR could be used as a proxy variable to comprehensively reflect the modification effects of multiple climatic factors.