Patient Welfare Implications of Indication-Specific Value-Based Pricing of Multi-Indication Drugs.

OBJECTIVES: Indication-specific value-based pricing (ISVBP) is a mechanism that allows the prices of multi-indication drugs to vary across indications by aligning the drug prices with value. However, the overall impact of ISVBP on patients across indications is uncertain. This study examines the theoretical welfare effects of ISVBP for multi-indication drugs and compares consumer surplus under ISVBP and single pricing, the latter of which is based on the weighted average value. METHODS: We considered a healthcare system with government-negotiated drug prices based on the value of drugs. We assumed a drug with 2 indications and 1 relevant comparator for each indication. The value of the drug was uniformly distributed among the patients of each indication in the base case. We also considered alternative scenarios with exponentially and Pareto distributed drug values. Numerical simulations were conducted to explore potential settings where ISVBP was welfare-improving for patients compared with single pricing. RESULTS: The theoretical analysis showed that the consumer surplus change was strictly non-positive from single pricing to ISVBP. Therefore, it was not welfare-improving for patients in the settings of interest. Numerical simulations confirmed this result across various scenarios of value distributions. CONCLUSIONS: This study provides insights into the patient welfare implications of ISVBP for multi-indication drugs. We did not identify conditions under which ISVBP can enhance overall patient well-being, suggesting that it should be implemented cautiously. Future research should examine dynamic welfare implications related to innovation incentives because they may significantly affect population health in the future.

Concentrated Formic Acid from CO2 Electrolysis for Directly Driving Fuel Cell.

The production of formic acid via electrochemical CO2 reduction may serve as a key link for the carbon cycle in the formic acid economy, yet its practical feasibility is largely limited by the quantity and concentration of the product. Here we demonstrate continuous electrochemical CO2 reduction for formic acid production at 2 M at an industrial-level current densities (i.e., 200 mA cm-2 ) for 300 h on membrane electrode assembly using scalable lattice-distorted bismuth catalysts. The optimized catalysts also enable a Faradaic efficiency for formate of 94.2 % and a highest partial formate current density of 1.16 A cm-2 , reaching a production rate of 21.7 mmol cm-2 h-1 . To assess the practicality of this system, we perform a comprehensive techno-economic analysis and life cycle assessment, showing that our approach can potentially substitute conventional methyl formate hydrolysis for industrial formic acid production. Furthermore, the resultant formic acid serves as direct fuel for air-breathing formic acid fuel cells, boasting a power density of 55 mW cm-2 and an exceptional thermal efficiency of 20.1 %.

Impact of combination preventative interventions on hospitalization and death under the pandemic of SARS-CoV-2 Omicron variant in China.

With a large population most susceptible to Omicron and emerging SARS-CoV-2 variants, China faces uncertain scenarios if reopening its border. Thus, we aimed to predict the impact of combination preventative interventions on hospitalization and death. An age-stratified susceptible-infectious-quarantined-hospitalized-removed-susceptible (SIQHRS) model based on the new guidelines of COVID-19 diagnosis and treatment (the ninth edition) was constructed to simulate the transmission dynamics of Omicron within 365 days. At baseline, we assumed no interventions other than 60% booster vaccination in individuals aged ≤60 years and 80% in individuals aged >60 years, quarantine and hospitalization. Oral antiviral medications for COVID-19 and nonpharmaceutical interventions (NPIs) such as social distancing and antigen self-testing were considered in subsequent scenarios. Sensitivity analyses were conducted to reflect different levels of interventions. A total of 0.73 billion cumulative quarantines (95% CI 0.53-0.83), 33.59 million hospitalizations (22.41-39.31), and 0.62 million deaths (0.40-0.75) are expected in 365 days. The case fatality rate with pneumonia symptoms (moderate, severe and critical illness) is expected to be 1.83% (1.68-1.99%) and the infected fatality rate is 0.38‰ (0.33-0.4‰). The highest existing hospitalization and ICU occupations are 3.11 (0.30-3.85) and 20.33 (2.01-25.20) times of capacity, respectively. Sensitivity analysis showed that interventions can be adjusted to meet certain conditions to reduce the total number of infections and deaths. In conclusion, after sufficient respiratory and ICU beds are prepared and the relaxed NPIs are in place, the SARS-CoV-2 Omicron variant would not seriously impact the health system.

Effectiveness of Inactivated COVID-19 Vaccines Against Illness Caused by the B.1.617.2 (Delta) Variant During an Outbreak in Guangdong, China : A Cohort Study.

BACKGROUND: Real-world evidence on inactivated COVID-19 vaccines against the highly transmissible B.1.617.2 (Delta) variant of SARS-CoV-2 is limited, leaving an important gap in the evidence base about inactivated COVID-19 vaccines for use by immunization programs. OBJECTIVE: To estimate inactivated vaccine effectiveness (VE) against the B.1.617.2 variant. DESIGN: Retrospective cohort study. SETTING: The study was based on the first outbreak of the B.1.617.2 variant in mainland China that was discovered and traced in Guangdong in May and June 2021. PARTICIPANTS: 10 805 adult case patients with laboratory-confirmed infection and close contacts. MEASUREMENTS: Participants were categorized as unvaccinated, partially vaccinated (1 dose), and fully vaccinated (2 doses). We estimated VE against the primary outcome of pneumonia and the secondary outcomes of infections, symptomatic infections, and severe or critical illness associated with the B.1.617.2 variant. RESULTS: Results are reported in the order of outcome severity. Of 10 805 participants, 1.3% contracted infections, 1.2% developed symptomatic infections, 1.1% had pneumonia, and 0.2% had severe or critical illness. The adjusted VEs of full vaccination were 51.8% (95% CI, 20.3% to 83.2%) against infection, 60.4% (CI, 31.8% to 88.9%) against symptomatic infection, and 78.4% (CI, 56.9% to 99.9%) against pneumonia. Also, full vaccination was 100% (CI, 98.4% to 100.0%) effective against severe or critical illness. By contrast, the adjusted VEs of partial vaccination against infection, symptomatic infection, and pneumonia were 10.7% (CI, -41.2% to 62.6%), 6.8% (CI, -47.4% to 61.0%), and 11.6% (CI, -42.6% to 65.8%), respectively. LIMITATION: Observational study with possible unmeasured confounders; insufficient data to do reliable subgroup analyses by age and vaccine brand. CONCLUSION: Full vaccination with inactivated vaccines is effective against the B.1.617.2 variant. Effort should be made to ensure full vaccination of target populations. PRIMARY FUNDING SOURCE: National Natural Science Foundation of China and Key-Area Research and Development Program of Guangdong Province.

Poria cocos Polysaccharide Ameliorated Antibiotic-Associated Diarrhea in Mice via Regulating the Homeostasis of the Gut Microbiota and Intestinal Mucosal Barrier.

Poria cocos polysaccharides (PCP) have been validated for several biological activities, including antitumor, anti-inflammatory, antioxidant, immunomodulatory, hepatoprotective and modulation on gut microbiota. In this research, we aim to demonstrate the potential prebiotic effects and the therapeutic efficacies of PCP in the treatment of antibiotic-associated diarrhea (AAD), and confirm the beneficial effects of PCP on gut dysbiosis. Antibiotic-associated diarrhea mice models were established by treating them with broad-spectrum antibiotics in drinking water for seven days. Mice in two groups treated with probiotics and polysaccharide were given Bifico capsules (4.2 g/kg/d) and PCP (250 mg/kg/d) for seven days using intragastric gavage, respectively. To observe the regulatory effects of PCP on gut microbiota and intestinal mucosal barrier, we conducted the following experiments: intestinal flora analysis (16S rDNA sequencing), histology (H&E staining) and tight junction proteins (immunofluorescence staining). The levels of mRNA expression of receptors associated with inflammation and gut metabolism were assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR). The study revealed that PCP can comprehensively improve the clinical symptoms of AAD mice, including fecal traits, mental state, hair quality, etc., similar to the effect of probiotics. Based on histology observation, PCP significantly improved the substantial structure of the intestine of AAD mice by increasing the expression levels of colonic tight junction protein zonula-occludens 1 (ZO-1) and its mRNA. Moreover, PCP not only increased the abundance of gut microbiota, but also increased the diversity of gut microbiota in AAD mice, including alpha diversity and beta diversity. Further analysis found that PCP can modulate seven characteristic species of intestinal flora in AAD mice, including Parabacteroides_distasonis, Akkermansia_muciniphila, Clostridium_saccharolyticum, Ruminoc-occus_gnavus, Lactobacillus_salivarius, Salmonella_enterica and Mucispirillum_schaedleri. Finally, enrichment analysis predicted that PCP may affect intestinal mucosal barrier function, host immune response and metabolic function by regulating the microbiota. RT-PCR experiments showed that PCP can participate in immunomodulatory and modulation on metabolic by regulating the mRNA expression of forkhead-box protein 3 (FOXP3) and G protein-coupled receptor 41 (GPR41). These results indicated that Poria cocos polysaccharide may ameliorate antibiotic-associated diarrhea in mice by regulating the homeostasis of the gut microbiota and intestinal mucosal barrier. In addition, polysaccharide-derived changes in intestinal microbiota were involved in the immunomodulatory activities and modulation of the metabolism.

Industrial-Current-Density CO2-to-C2+ Electroreduction by Anti-swelling Anion-Exchange Ionomer-Modified Oxide-Derived Cu Nanosheets.

CO2 electroreduction to high-energy-density C2+ products is highly attractive, whereas the C2+ selectivity under industrial current densities is still unsatisfying. Here, an anti-swelling anion exchange ionomer (AEI) was first proposed to optimize the local environment for promoting industrial-current-density CO2-to-C2+ electroreduction. Taking the anti-swelling AEI-modified oxide-derived Cu nanosheets as an example, in situ Raman spectroscopy and contact angle measurements revealed that the OH--accumulated -N(CH3)3+ groups and anti-swelling backbone of AEI could synergistically regulate the local pH level and water content. In situ Fourier-transform infrared spectroscopy and theoretical calculations demonstrated that the higher local pH value could lower the energy barrier for the rate-limiting COCO* hydrogenated to COCOH* from 0.08 to 0.04 eV, thereby boosting the generation of C2+ products. Owing to the anti-swelling backbone, the optimized water content of 3.5% could suppress the competing H2 evolution and hence facilitate the proton-electron transfer step for C2+ production. As a result, the anti-swelling AEI-modified oxide-derived Cu nanosheets achieved a C2+ Faradaic efficiency of 85.1% at a current density up to 800 mA cm-2 with a half-cell power conversion efficiency exceeding 50%, outperforming most reported powder catalysts.

Identifying an Interfacial Stabilizer for Regeneration-Free 300 h Electrochemical CO2 Reduction to C2 Products.

The electrochemical CO2 reduction reaction (CO2RR) to produce high value-added hydrocarbons and oxygenates presents a sustainable and compelling approach toward a carbon-neutral society. However, uncontrollable migration of active sites during the electrochemical CO2RR limits its catalytic ability to simultaneously achieve high C2 selectivity and ultradurability. Here, we demonstrate that the generated interfacial CuAlO2 species can efficiently stabilize the highly active sites over the Cu-CuAlO2-Al2O3 catalyst under harsh electrochemical conditions without active sites regeneration for a long-term test. We show that this unique Cu-CuAlO2-Al2O3 catalyst exhibits ultradurable electrochemical CO2RR performance with an 85% C2 Faradaic efficiency for a 300 h test. Such a simple interfacial engineering design approach unveiled in this work would be adaptable to develop various ultradurable catalysts for industrial-scale electrochemical CO2RR.

Effects of baloxavir and oseltamivir antiviral therapy on the transmission of seasonal influenza in China: A mathematical modeling analysis.

New antiviral influenza treatments can effectively alleviate illness while reducing viral shedding. However, how such effects can translate into lower population infections of seasonal influenza in China remains unknown. To shed light on the public health impacts of novel antiviral agents for influenza, we constructed a dynamic transmission model to simulate the seasonal influenza epidemics in China. Two antivirus treatments, baloxavir and oseltamivir, were evaluated by estimating their impacts on the incidences of influenza infection in a single flu season. In the base-case analysis of a 10% antiviral treatment uptake rate, 2760 and 3420 per 10 000 persons contracted influenza under the treatment of baloxavir and oseltamivir, respectively. These incidence rates amounted to an 18.90% relative risk reduction (RRR) of infection associated with baloxavir in relation to oseltamivir. The corresponding RRR was 82.16% when the antiviral treatment uptake rate was increased to 35%. In addition, the peak of the prevalence of infected individuals per 10 000 persons under the baloxavir treatment was 177 (range: 93-274) fewer than that of oseltamivir. Our analyses suggest that the baloxavir treatment strategy reduces the incidence of influenza in China compared with oseltamivir in the setting of a seasonal flu epidemic. Also, increasing the uptake rate of antiviral treatment can potentially prevent millions of infections during a single flu season.

Vaccination strategy for preventing the spread of SARS-CoV-2 in the limited supply condition: A mathematical modeling study.

To mitigate SARS-CoV-2 transmission, vaccines have been urgently approved. With their limited availability, it is critical to distribute the vaccines reasonably. We simulated the SARS-CoV-2 transmission for 365 days over four intervention periods: free transmission, structural mitigation, personal mitigation, and vaccination. Sensitivity analyses were performed to obtain robust results. We further evaluated two proposed vaccination allocations, including one-dose-high-coverage and two-doses-low-coverage, when the supply was low. 33.35% (infection rate, 2.68 in 10 million people) and 40.54% (2.36) of confirmed cases could be avoided as the nonpharmaceutical interventions (NPIs) adherence rate rose from 50% to 70%. As the vaccination coverage reached 60% and 80%, the total infections could be reduced by 32.72% and 41.19%, compared to the number without vaccination. When the durations of immunity were 90 and 120 days, the infection rates were 2.67 and 2.38. As the asymptomatic infection rate rose from 30% to 50%, the infection rate increased 0.92 (SD, 0.16) times. Conditioned on 70% adherence rate, with the same amount of limited available vaccines, the 20% and 40% vaccination coverage of one-dose-high-coverage, the infection rates were 2.70 and 2.35; corresponding to the two-doses-low-coverage with 10% and 20% vaccination coverage, the infection rates were 3.22 and 2.92. Our results indicated as the duration of immunity prolonged, the second wave of SARS-CoV-2 would be delayed and the scale would be declined. On average, the total infections in two-doses-low-coverage was 1.48 times (SD, 0.24) as high as that in one-dose-high-coverage. It is crucial to encourage people in order to improve vaccination coverage and establish immune barriers. Particularly when the supply is limited, a wiser strategy to prevent SARS-CoV-2 is equally distributing doses to the same number of individuals. Besides vaccination, NPIs are equally critical to the prevention of widespread of SARS-CoV-2.

UHRF1 Controls Thymocyte Fate Decisions through the Epigenetic Regulation of EGR1 Expression.

Thymocyte differentiation is a highly complex process that is accompanied by epigenetic changes. Ubiquitin-like containing PHD ring finger 1 (UHRF1) is a critical epigenetic modifier involved in various cellular processes. In this study, we demonstrated that it is highly expressed in T cell precursors of the thymus. Further, its deficiency results in significantly reduced thymocyte cellularity and thymus size in mice. Through systematic analysis based on single-cell RNA sequencing, we found that UHRF1 deficiency thwarts αß T cell lineage development, whereas biasing γδ T lineage differentiation dampens the progression of immature single-positive cells. UHRF1 deficiency promotes the IL-17 secreting and RORγt expression in γδ T cell, indicating a Tγδ17 phenotype. Further, the analysis of gene-regulatory networks demonstrated that UHRF1 controls the expression of early growth response 1 (EGR1). UHRF1 interacts with DNA methyltransferase 1 (DNMT1) at the CpG promoter region of Egr1 loci and affects the nearby chromatin modifications of H3K9me3 and H3K4me3. Taken together, our results demonstrate that UHRF1 is a key factor that mediates the epigenetic regulation of EGR1 and, consequently, thymocyte fate decisions.

Title: the impact of a pilot integrated care model on the quality and costs of inpatient care among chinese elderly: a difference-in-difference analysis of repeated cross-sectional data.

BACKGROUND: Recently, integrated care has received tremendous popularity in China, a leading example of which is the Luohu model. In the present analysis, we aimed to examine the impacts of the Luohu model on the quality and costs of inpatient care. METHODS: We conducted a retrospective analysis using administrative claims databases of Shenzhen City (the city that the Luohu district sits) from Jan 2015-Apr 2017, which encompassed the time before and after the implementation of the pilot model. The outcomes were 30-day readmission, inpatient costs, and length of stay (LOS). Multivariable difference-in-difference analyses were conducted. RESULTS: In the first year following the integration, the Luohu model did not have impacts on any of the outcomes. Although its effect on readmission (ratio of odds ratio: 1.082; 95% CI: 0.865 to 1.353) was still not identified in the first four months of the second post-integration year, it decreased inpatient costs by CN¥ 1224.1 (95% CI: 372.7 to 2075.5) and LOS by 0.938 days (95% CI: 0.0416 to 1.835) per hospitalization episode during the same period. CONCLUSIONS: The Luohu model may reduce costs and LOS in the long term. It is potentially a viable approach to improve the value of inpatient care in China.

Outness and its correlates among gay and bisexual men attending university in China: a cross-sectional study.

BACKGROUND: Disclosure of sexual orientation to others (outness) might be associated with sexual and mental health among gay and bisexual men (GBM) attending university. We aimed to characterise outness and investigate factors correlated with outness among GBM attending university in China. METHODS: Between September 2018 and March 2019, GBM attending university were recruited in six cities in China. Information on sociodemographic characteristics, outness and sexual behaviours were collected using a self-administered questionnaire. Each participant was tested for HIV/STIs. Correlates of outness were assessed using multivariable logistic regression. RESULTS: A total of 400 GBM attending university were recruited, of whom 251 (62.8%) had disclosed their sexual orientation. Men who served as student leaders (adjusted odds ratio [AOR]=2.28, 95% CI: 1.46-3.54) and donated blood (AOR 1.85, 95% CI: 1.05-3.24) were more likely to disclose their sexual orientation, whereas men who had sex with a female (AOR 0.19, 95% CI: 0.05-0.74) and had group sex (AOR 0.52, 95% CI: 0.30-0.89) were less likely to disclose their sexual orientation. Mental health status, HIV/STI infections were not associated with outness. CONCLUSIONS: GBM attending university who disclosed their sexual orientation were more likely to be involved with student work and less likely to engage in high-risk sexual behaviours. More attention and education could focus on non-disclosing GBM men attending university through peer education or other ways.

Effectiveness of remdesivir for the treatment of hospitalized COVID-19 persons: A network meta-analysis.

Several randomized clinical trials (RCTs) that investigated the effectiveness of remdesivir for the treatment of coronavirus disease-2019 (COVID-19) have generated inconsistent evidence. The present study aimed to synthesize available RCT evidence using network meta-analyses (NMAs). Both blinded and open-label RCTs in PubMed database from inception to 7 June 2020 that contained "remdesivir", "Covid-19", and "trial" in the abstracts conducted on hospitalized COVID-19 persons were identified and screened. The studies must have at least one remdesivir arm and evaluated one of the pre-specified outcomes. The outcomes were clinical improvement between days 10 to 15 after randomization and clinical recovery during the follow-up period. The identified literature was supplemented with relatively recent studies that were known to the researchers if not already included. Frequentist NMAs with random effects were conducted. Both 10-day and 5-day remdesivir regimens were associated with higher odds of clinical improvement (odds ratio [OR] of 10-day regimen: 1.35, 95% confidence interval [CI], 1.09-1.67); OR of 5-day regimen: 1.81, 95% CI, 1.32-2.45, and higher probabilities of clinical recovery (relative risk [RR] of 10-day regimen: 1.24, 95% CI, 1.07-1.43; RR of 5-day regimen: 1.47, 95% CI, 1.16-1.87 compared with placebo. Remdesivir may have clinical benefits among hospitalized COVID-19 persons.

Economic evaluation of remdesivir for the treatment of severe COVID-19 patients in China under different scenarios.

AIMS: The present study aimed to evaluate the cost-effectiveness of the 5-day remdesivir regimen compared with standard of care among severe COVID-19 patients in China, the evidence on which is essential to inform the necessity of securing access to remdesivir. METHODS: A dynamic transmission model that extended the susceptible-exposed-infected-recovered framework by incorporating asymptomatic, presymptomatic and waiting-to-be-diagnosed patients was constructed to conduct the cost-effectiveness analysis from the healthcare system perspective. To estimate epidemic parameters, the model was first calibrated to the observed epidemic curve in Wuhan from 23 January to 19 March 2020. Following the calibration, the infected compartment was replaced by 3 severity-defined health states to reflect differential costs and quality of life associated with disease gravity. Costs and quality-adjusted life year (QALY) outcomes of 9 million simulated people were accrued across time to evaluate the incremental cost-effectiveness ratio of remdesivir. As robustness checks, an alternative modelling technique using decision tree, additional epidemic scenarios representing different epidemic intensities, and 1-way parameter variations were also analysed. RESULTS: Remdesivir treatment cost CN¥97.93 million more than standard of care. Also, the net QALY gain from 5-day remdesivir treatment was 6947 QALYs. As such, the incremental cost-effectiveness ratio was CN¥14 098/QALY, substantially lower than the gross domestic product per capita threshold. The peak daily number of severe cases was 19% lower in the remdesivir treatment strategy. Overall, results were robust in alternative scenarios and sensitivity analyses. CONCLUSION: Given the cost-effectiveness profile, access to remdesivir for severe COVID-19 patients in China should be considered.

Cost-effectiveness analysis of ranibizumab for retinal vein occlusion patients in China from the societal perspective.

BACKGROUND: Clinical trials in China have demonstrated that ranibizumab can improve the clinical outcomes of branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). However, no economic evaluation of ranibizumab has been conducted among Chinese patient population. METHODS: To provide insights into the economic profile of ranibizumab among Chinese RVO population, a Markov state-transition model was used to predict the outcomes of ranibizumab comparing to laser photocoagulation and observational-only care from the societal perspective. This model simulated changes in patient visuality, quality-adjusted of life years (QALY), medical costs, and direct non-medical costs of individuals with visual impairment due to BRVO or CRVO in lifetime. The base-case analysis used an annual discount rate of 5% for costs and benefits following the China Guidelines for Pharmacoeconomic Evaluations. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the model. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) comparing ranibizumab to laser photocoagulation was ¥65,008/QALY among BRVO patients and was ¥65,815/QALY among CRVO patients, respectively. Comparing to the 2019 gross domestic product (GDP) per capita of ¥71,000, both two ICERs were far below the cost-effective threshold at three times of GDP per capita (¥213,000). The deterministic and probabilistic sensitivity analyses demonstrated the base-case results were robust in most of the simulation scenarios. CONCLUSION: The current Markov model demonstrated that ranibizumab may be cost-effective compared with laser photocoagulation to treat BRVO and cost-effective compared to observation-only care to treat CRVO in China from the societal perspective.

Photocatalytic CO2 conversion: What can we learn from conventional COx hydrogenation?

Solar-driven reduction of CO2 into fuels/feedstocks is a promising strategy for addressing energy and CO2 emission issues. Despite great research efforts, it still remains a grand challenge to achieve efficient and highly selective reduction of CO2 owing to the large bond energy of CO2 and the diversity of reduction products. In addition to the control of light harvesting and charge transfer like photocatalytic water splitting, the design of catalytically active sites is highly important to promote CO2 reduction activity and selectivity (e.g., C-C coupling). In fact, we can learn a lot from conventional CO2 hydrogenation and syngas conversion in terms of active site design. In this article, we demonstrate how to design catalytically active sites for efficient and highly selective photocatalytic reduction of CO2 by sorting out the rules from the existing research on conventional COx hydrogenation, with a focus on enhancing C[double bond, length as m-dash]O activation and C-C coupling to form value-added products. This article aims to highlight the challenges in the field of photocatalytic CO2 conversion and the connection of photocatalysis with conventional catalytic systems, providing the readers the opportunities to join the research.

Ultrastable Cu Catalyst for CO2 Electroreduction to Multicarbon Liquid Fuels by Tuning C-C Coupling with CuTi Subsurface.

Production of multicarbon (C2+ ) liquid fuels is a challenging task for electrocatalytic CO2 reduction, mainly limited by the stabilization of reaction intermediates and their subsequent C-C couplings. In this work, we report a unique catalyst, the coordinatively unsaturated Cu sites on amorphous CuTi alloy (a-CuTi@Cu) toward electrocatalytic CO2 reduction to multicarbon (C2-4 ) liquid fuels. Remarkably, the electrocatalyst yields ethanol, acetone, and n-butanol as major products with a total C2-4 faradaic efficiency of about 49 % at -0.8 V vs. reversible hydrogen electrode (RHE), which can be maintained for at least 3 months. Theoretical simulations and in situ characterization reveals that subsurface Ti atoms can increase the electron density of surface Cu sites and enhance the adsorption of *CO intermediate, which in turn reduces the energy barriers required for *CO dimerization and trimerization.

Performance of unanchored matching-adjusted indirect comparison (MAIC) for the evidence synthesis of single-arm trials with time-to-event outcomes.

BACKGROUND: The objectives of the present study were to evaluate the performance of a time-to-event data reconstruction method, to assess the bias and efficiency of unanchored matching-adjusted indirect comparison (MAIC) methods for the analysis of time-to-event outcomes, and to propose an approach to adjust the bias of unanchored MAIC when omitted confounders across trials may exist. METHODS: To evaluate the methods using a Monte Carlo approach, a thousand repetitions of simulated data sets were generated for two single-arm trials. In each repetition, researchers were assumed to have access to individual-level patient data (IPD) for one of the trials and the published Kaplan-Meier curve of another. First, we compared the raw data and the reconstructed IPD using Cox regressions to determine the performance of the data reconstruction method. Then, we evaluated alternative unanchored MAIC strategies with varying completeness of covariates for matching in terms of bias, efficiency, and confidence interval coverage. Finally, we proposed a bias factor-adjusted approach to gauge the true effects when unanchored MAIC estimates might be biased due to omitted variables. RESULTS: Reconstructed data sufficiently represented raw data in the sense that the difference between the raw and reconstructed data was not statistically significant over the one thousand repetitions. Also, the bias of unanchored MAIC estimates ranged from minimal to substantial as the set of covariates became less complete. More, the confidence interval estimates of unanchored MAIC were suboptimal even using the complete set of covariates. Finally, the bias factor-adjusted method we proposed substantially reduced omitted variable bias. CONCLUSIONS: Unanchored MAIC should be used to analyze time-to-event outcomes with caution. The bias factor may be used to gauge the true treatment effect.

A Cellular MicroRNA Facilitates Regulatory T Lymphocyte Development by Targeting the FOXP3 Promoter TATA-Box Motif.

The CD4+CD25+FOXP3+ regulatory T cells (Tregs) mediate immunological self-tolerance and suppress various immune responses. FOXP3 is a key transcriptional factor for the generation and development of Tregs. Its expression is regulated by various cytokines including TGF-ß, IL-2, and IL-10. It is important to further identify the regulatory factors for Tregs. Given that many microRNAs (miRNAs) could specifically interact with the core promoter region and specifically enhance the transcription of many target genes, we searched for any possible miRNA(s) targeting the core promoter region of the FOXP3 gene. We found that miR-4281, an miRNA specifically expressed in hominids, can potently and specifically upregulate FOXP3 expression by directly interacting with the TATA-box motif in the human FOXP3 promoter. Consequently, miR-4281 significantly accelerated the differentiation of human naive cells to induced Tregs (iTregs) that possess immune suppressor functions and weaken the development of graft-versus-host disease in a humanized mouse model. Interestingly, iTregs induced by the combination of TGF-ß, IL-2, and chemically synthesized miR-4281 were more stable and functional than those induced by TGF-ß and IL-2 alone. Moreover, we found that the IL-2/STAT5 signal transduction upregulates FOXP3 expression not only through the classical pathway, but also by enhancing the expression of the miR-4281 precursor gene (SNCB) and, correspondingly, miR-4281. This study reveals a novel mechanism regulating FOXP3 expression and human iTreg development and, therefore, offers a new therapeutic target to manipulate immunosuppressive system.

Impact of Systematic Factors on the Outbreak Outcomes of the Novel COVID-19 Disease in China: Factor Analysis Study.

BACKGROUND: The novel COVID-19 disease has spread worldwide, resulting in a new pandemic. The Chinese government implemented strong intervention measures in the early stage of the epidemic, including strict travel bans and social distancing policies. Prioritizing the analysis of different contributing factors to outbreak outcomes is important for the precise prevention and control of infectious diseases. We proposed a novel framework for resolving this issue and applied it to data from China. OBJECTIVE: This study aimed to systematically identify national-level and city-level contributing factors to the control of COVID-19 in China. METHODS: Daily COVID-19 case data and related multidimensional data, including travel-related, medical, socioeconomic, environmental, and influenza-like illness factors, from 343 cities in China were collected. A correlation analysis and interpretable machine learning algorithm were used to evaluate the quantitative contribution of factors to new cases and COVID-19 growth rates during the epidemic period (ie, January 17 to February 29, 2020). RESULTS: Many factors correlated with the spread of COVID-19 in China. Travel-related population movement was the main contributing factor for new cases and COVID-19 growth rates in China, and its contributions were as high as 77% and 41%, respectively. There was a clear lag effect for travel-related factors (previous vs current week: new cases, 45% vs 32%; COVID-19 growth rates, 21% vs 20%). Travel from non-Wuhan regions was the single factor with the most significant impact on COVID-19 growth rates (contribution: new cases, 12%; COVID-19 growth rate, 26%), and its contribution could not be ignored. City flow, a measure of outbreak control strength, contributed 16% and 7% to new cases and COVID-19 growth rates, respectively. Socioeconomic factors also played important roles in COVID-19 growth rates in China (contribution, 28%). Other factors, including medical, environmental, and influenza-like illness factors, also contributed to new cases and COVID-19 growth rates in China. Based on our analysis of individual cities, compared to Beijing, population flow from Wuhan and internal flow within Wenzhou were driving factors for increasing the number of new cases in Wenzhou. For Chongqing, the main contributing factor for new cases was population flow from Hubei, beyond Wuhan. The high COVID-19 growth rates in Wenzhou were driven by population-related factors. CONCLUSIONS: Many factors contributed to the COVID-19 outbreak outcomes in China. The differential effects of various factors, including specific city-level factors, emphasize the importance of precise, targeted strategies for controlling the COVID-19 outbreak and future infectious disease outbreaks.