Towards an actionable One Health approach.

BACKGROUND: Despite the increasing focus on strengthening One Health capacity building on global level, challenges remain in devising and implementing real-world interventions particularly in the Asia-Pacific region. Recognizing these gaps, the One Health Action Commission (OHAC) was established as an academic community for One Health action with an emphasis on research agenda setting to identify actions for highest impact. MAIN TEXT: This viewpoint describes the agenda of, and motivation for, the recently formed OHAC. Recognizing the urgent need for evidence to support the formulation of necessary action plans, OHAC advocates the adoption of both bottom-up and top-down approaches to identify the current gaps in combating zoonoses, antimicrobial resistance, addressing food safety, and to enhance capacity building for context-sensitive One Health implementation. CONCLUSIONS: By promoting broader engagement and connection of multidisciplinary stakeholders, OHAC envisions a collaborative global platform for the generation of innovative One Health knowledge, distilled practical experience and actionable policy advice, guided by strong ethical principles of One Health.

Vaccine confidence mediates the association between a pro-social pay-it-forward intervention and improved influenza vaccine uptake in China: A mediation analysis.

INTRODUCTION: A Chinese clinical trial has demonstrated that a prosocial pay-it-forward intervention that offered subsidized vaccination and postcard messages effectively increased influenza vaccine uptake and vaccine confidence. This secondary analysis explored the potential mediating role of vaccine confidence on the association between a pay-it-forward intervention and influenza vaccine uptake, and how this might vary by individual annual income levels. METHODS: Data from 300 participants (150 standard-of-care and 150 pay-it-forward participants) were included in the analysis. We conducted descriptive analysis of demographic and vaccine confidence variables. Multivariable regression and mediation analysis on interventions, vaccine confidence and vaccine uptake were conducted. A sub-group analysis was conducted to further understand whether associations between these variables vary by income levels (<=$1860 or >$1860). RESULTS: The pay-it-forward intervention was significantly associated with greater levels of perceived influenza vaccine importance (adjusted odds ratio (aOR) = 3.60, 95 %CI: 1.77-7.32), effectiveness (aOR = 3.37, 95 %CI: 1.75-6.52) and safety (aOR = 2.20, 95 %CI: 1.17-4.15). Greater perceived influenza vaccine importance was associated with increased vaccine uptake (aOR = 8.51, 95 %CI: 3.04-23.86). The indirect effect of the pay-it-forward intervention on vaccination was significant through improved perceived influenza vaccine importance (indirect effect1 = 0.07, 95 %CI: 0.02-0.11). This study further revealed that, irrespective of the individual income level, the pay-it-forward intervention was associated with increased vaccine uptake when compared to the standard-of-care approach. CONCLUSIONS: Pay-it-forward intervention may be a promising strategy to improve influenza vaccine uptake. Perceived confidence in vaccine importance appears to be a potential mediator of the association between pay-it-forward and vaccine uptake.

Development and Validation of a Prediction Model for Hepatitis B Virus-Related Hepatocellular Carcinoma Patients Receiving Postoperative Adjuvant Transarterial Chemoembolization.

Background: Hepatocellular carcinoma (HCC) patients who are at significant risk of tumor recurrence and mortality can benefit from postoperative adjuvant transarterial chemoembolization (PA-TACE). However, the benefits of PA-TACE remain unclear. Herein, we aimed to develop a model for predicting the prognosis of HBV-related patients who undergo PA-TACE and endeavored to guide individualized clinical treatment. Methods: We included 432 HBV-related patients who underwent PA-TACE after curative resection were included. The dataset was divided into a training set (n=216) and an internal validation set (n=216). For identifying independent risk factors, the least absolute shrinkage and selection operator and univariate and multivariate Cox analyses were performed. We derived a prognostic model from the training set that was internally validated. The concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and risk stratification were used to evaluate the performance of the nomogram. Results: Patients undergoing PA-TACE had significantly longer overall survival (OS) than those who did not undergo PA-TACE. Age, albumin levels, macrovascular invasion, tumor size, and, stages of Barcelona Clinic Liver Cancer were identified as independent risk variables and concluded into the nomogram to predict the OS of HBV-related patients who received PA-TACE. The nomogram's C-index values OS were 0.710 and 0.652 in the training and internal validation sets, respectively. Both time-dependent AUC and the calibration curve showed good discrimination and model fitness. The risk score -0.12 was kept as the cut-off value that would accurately divide patients into high-risk and low-risk groups; furthermore, the Kaplan-Meier curve showed a high discriminative ability of the model. Conclusion: We developed a predictive model. comprising a formula and nomogram to predict the OS and provide risk stratification for HBV-related patients undergoing PA-TACE, which could contribute to suitable treatment options for this patient population.

BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models.

OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

Is hepatectomy feasible for hepatocellular carcinoma patients with clinically significant portal hypertension and beyond the Milan criteria?

BACKGROUND: Hepatocellular carcinoma (HCC) patients with clinically significant portal hypertension (CSPH) and beyond the Milan criteria undergoing hepatectomy were previously considered to be at high risk and to have a poor prognosis, especially for major hepatectomy. The aim of this study was to investigate the safety and efficacy of hepatectomy in those patients. METHODS: Data were collected on HCC patients with CSPH treated at a single centre from January 2010 to October 2021. Propensity score-matched (PSM) analysis was used to balance the bias between groups. RESULTS: Of the included patients, 556 underwent hepatectomy and 172 underwent transcatheter arterial chemoembolization (TACE). Comparison of patients beyond the Milan criteria and those with Milan criteria underwent hepatectomy, the 90-day mortality and complication rates were similar in the two groups. However, the overall survival (OS) and recurrence-free survival (RFS) of patients within the Milan criteria were significantly better than those beyond the Milan criteria (p < 0.001). In HCC patients beyond the Milan criteria, OS of performing hepatectomy was significantly longer than TACE (p < 0.001). Within HCC patients beyond the Milan criteria underwent hepatectomy, there was no significant difference in 90-day mortality and complications between minor and major hepatectomy in patients beyond the Milan criteria and no significant difference in RFS and OS after PSM. CONCLUSIONS: Hepatectomy for HCC patients with CSPH and beyond the Milan criteria is safe and feasible, with an acceptable prognosis and no significant difference between minor and major hepatectomy.

Pay-it-forward to increase uptake among 15-18-year-old adolescent girls compared with user-paid vaccination: The pilot results of a two-arm randomized controlled trial in China.

Background: China has low human papillomavirus(HPV) vaccination rate due to lack of public funding and mistrust in domestic vaccines. This pilot study evaluated the feasibility and preliminary effectiveness of an innovative pay-it-forward strategy, which has a participant receive a subsidized vaccine and offers her an opportunity to donate to support other girls, in improving HPV vaccine uptake among 15-18-year-old adolescent girls. Methods: A two-arm randomized controlled pilot trial was performed in one vaccination clinic in Western China. Adolescent girls (via caregivers) were invited to participate the study via online dissemination of the pilot study. Eligible ones were then randomly allocated using a sealed envelope method into standard-of-care or pay-it-forward arm in a 1:1 ratio. Pay-it-forward participants received hand-written postcard messages, a subsidized vaccine, and an opportunity to donate and (or) write postcards for future recipient girls. Standard-of-care participants self-paid for vaccines. The primary outcome was the first-dose HPV vaccine uptake, which was calculated using multivariable logistic regression, presented as crude/adjusted odds ratios (cORs/aORs) and 95% con dence intervals (CIs). Standard scales were used to assess the feasibility of the program. Results: A total of 100 participants (50 in each arm) were recruited from Jan 4, 2022 to Feb 18, 2022. The HPV vaccine uptake rate was 98% (49/50) in the pay-it-forward arm and 82% (41/50) in the standard-of-care arm (cOR = 10.76, 95% CI: 1.31-88.47, P = 0.027; aOR = 12.12, 95% CI: 1.37-107.29, P = 0.025). The completion rate of full schedule of HPV vaccination in the two arms was 100% (49/49) and 95.1% (39/41), respectively. Of all 49 vaccinated girls in the pay-it-forward arm, 38 (77.6%) donated to support future participants, and the total donation accounted for 33.3% of prepaid subsidization. Among caregivers in the pay-it-forward arm, 97.6% (41/42) believed that this strategy was feasible. Conclusions: The pilot showed feasibility and preliminary effectiveness of a pay-it-forward strategy to increase HPV vaccination rate. The high uptake rate in the standard-of-care arm is likely caused by the selection bias associated with the online dissemination approach and secured vaccine supply through the program. Further adaption of the intervention package and a population-based recruitment pathway are needed to better reflect local contexts and enhance the generalizability of the subsequent formal trial. Trial registration: Chinese Clinical Trial Registry (ChiCTR), ChiCTR2200055542. Retrospectively registered on 11 January 2022, https://www.chictr.org.cn/showproj.html?proj=139738.

How Poor Is Your Sample? A Simple Approach for Estimating the Relative Economic Status of Small and Nonrepresentative Samples.

BACKGROUND: Asset-based indices of living standards, or wealth indices, are widely used proxies for economic status; however, such indices are not readily available for small and nonrepresentative samples. METHODS: We describe a simple out-of-sample prediction approach that uses estimates from large and representative "reference" samples to calculate measures of relative economic status (e.g., wealth index scores) for small and/or nonrepresentative "target" samples. The method relies on the availability of common variables and assumptions about comparable associations between these variables and the underlying construct of interest (e.g., household wealth). We provide 2 sample applications that use Demographic and Health Surveys (DHS) from 5 countries as reference samples. Using ordinary least squares regression, we estimate associations between household characteristics and the DHS wealth index. We use parameter estimates to predict wealth index scores for small nonrepresentative target samples. Comparisons of wealth distributions in the reference and target samples highlight selection effects. RESULTS: Applications of the approach to diverse populations, including populations at high risk of HIV infection and households with orphaned and separated children, demonstrate its usefulness for characterizing the economic status of small and nonrepresentative samples relative to existing reference samples. Women and men in northern Tanzania at high risk of HIV infection were concentrated in the upper half of the wealth distribution. By contrast, the relative distribution of household wealth among households with orphaned and separated children varied greatly across countries and rural versus urban settings. CONCLUSIONS: Public health professionals who implement, manage, and evaluate programs in low- and middle-income countries may find this approach applicable because of the simplicity of the estimation methods, low marginal cost of primary data acquisition, and availability of established measures of relative economic status in many publicly available household surveys (e.g., those administered by the DHS Program, World Bank, International Labour Organization, and UNICEF).

Influenza vaccine uptake among children and older adults in China: a secondary analysis of a quasi-experimental study.

BACKGROUND: Influenza vaccination is the key to prevent influenza-related disease, especially among high-risk populations. However, influenza vaccine uptake in China is low. This secondary analysis of a quasi-experimental trial aimed to understand factors associated with influenza vaccine uptake among children and older people stratified by funding context. METHODS: A total of 225 children (aged 0.5-8 years) and 225 older people (aged 60 years or above) were recruited from three clinics (rural, suburban and urban) in Guangdong Province. Participants were allocated into two groups based on funding contexts: a self-paid group (N = 150, 75 children and 75 older adults) in which participants paid full price for their vaccination; and a subsidized group (N = 300, 150 children and 150 older adults) in which varying levels of financial support was provided. Univariate and multivariable logistic regressions were conducted stratified by funding contexts. RESULTS: Overall, 75.0% (225/300) of participants in the subsidized group and 36.7% (55/150) in the self-paid group got vaccinated. Older adults had lower vaccination rates than children in both funding groups, while both age groups showed much higher uptake in the subsidized group than in the self-paid group (aOR = 5.96, 95% CI: 3.77-9.42, p = 0.001). In the self-paid group, having prior influenza vaccination history of children (aOR:2.61, 95%CI: 1.06-6.42) or older people (aOR:4.76, 95%CI: 1.08-20.90) was associated with increased influenza vaccine uptake compared to those who had no prior vaccination experiences in the family. While in the subsidized group, participants who got married or lived with partners (aOR = 0.32, 0.10-0.98) had lower vaccination uptake than single ones. Trust in providers' advice (aOR = 4.95, 95%CI:1.99, 12.43), perceived effectiveness of the vaccine (aOR: 12.18, 95%CI: 5.21-28.50), and experienced influenza-like illnesses in the family in the past year (aOR = 46.52, 4.10, 533.78) were associated with higher vaccine uptake. CONCLUSIONS: Older people had suboptimal vaccine uptake compared to children in both contexts and need more attention to enhance influenza vaccination. Tailoring interventions to different vaccine funding contexts may help improve influenza vaccination: In self-paid context, motivating people to accept their first ever influenza vaccination may be a promising strategy. In subsidized context, improving public confidence in vaccine effectiveness and providers' advice would be useful.

Contribution of a WRKY Transcription Factor, ShWRKY81, to Powdery Mildew Resistance in Wild Tomato.

Tomato powdery mildew, caused by Oidium neolycopersici, is a destructive fungal disease that damages almost all of the aerial parts of tomato, causing devastating losses in tomato production worldwide. WRKY transcription factors are key regulators of plant immunity, but the roles of ShWRKYs in wild tomato Solanum habrochaites LA1777 against O. neolycopersici still remain to be uncovered. Here, we show that ShWRKY81 is an important WRKY transcription factor from wild tomato Solanum habrochaites LA1777, contributing to plant resistance against O. neolycopersici. ShWRKY81 was isolated and identified to positively modulate tomato resistance against On-Lz. The transient overexpression of the ShWRKY81-GFP (green fluorescent protein) fusion protein in Nicotiana benthamiana cells revealed that ShWRKY81 was localized in the nucleus. ShWRKY81 responded differentially to abiotic and biotic stimuli, with ShWRKY81 mRNA accumulation in LA1777 seedlings upon On-Lz infection. The virus-induced gene silencing of ShWRKY81 led to host susceptibility to On-Lz in LA1777, and a loss of H2O2 formation and hypersensitive response (HR) induction. Furthermore, the transcripts of ShWRKY81 were induced by salicylic acid (SA), and ShWRKY81-silenced LA1777 seedlings displayed decreased levels of the defense hormone SA and SA-dependent PRs gene expression upon On-Lz infection. Together, these results demonstrate that ShWRKY81 acts as a positive player in tomato powdery mildew resistance.

The effectiveness of pay-it-forward in addressing HPV vaccine delay and increasing uptake among 15-18-year-old adolescent girls compared to user-paid vaccination: a study protocol for a two-arm randomized controlled trial in China.

BACKGROUND: Human papillomavirus (HPV) vaccination could prevent cervical and other HPV-associated cancers attributable to vaccine-associated HPV types. However, HPV vaccination coverage among women aged 9-18 years old is low in China. Common barriers include poor financial affordability, minimal public engagement, and low confidence in domestically produced HPV vaccines. Pay-it-forward offers an individual a free or subsidized service then an opportunity to voluntarily donate and/or create a postcard message to support future people. This study aims to assess the effectiveness of pay-it-forward as compared to standard-of-care self-paid vaccination to improve HPV vaccine uptake among adolescent girls aged 15-18 years, who are left out in the current pilot free HPV vaccination task force in some parts of China. METHODS: This is a two-arm randomized controlled trial in Chengdu, China. Eligible adolescent girls (via caregivers) will be randomly selected and recruited through four community health centers (one in the most developed urban areas, one in higher middle-income and one in lower middle-income suburban areas, and one in the least developed rural areas) using the resident registration list. A total of 320 participants will be randomized into two study arms (user-paid versus pay-it-forward vaccination) in a 1:1 ratio. The intervention assignment will be blinded to recruiters and participants using envelop concealment until the research assistants open the envelop to determine which treatment to deliver to each individual. The primary outcome of the study will be HPV vaccine uptake by administrative data. Secondary outcomes include costs, vaccine hesitancy, and the completion rates of the 3-dose HPV vaccination series. DISCUSSION: This study will investigate an innovative pay-it-forward strategy's effectiveness and economic costs to improve HPV vaccination among 15-18-year-old adolescent girls. Study findings will have implications for increasing HPV vaccine uptake in places where HPV vaccines are provided for a fee. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR), ChiCTR2200055542. Registered on 11 January 2022.

Developing and Validating an Autophagy Gene-Set-Based Prognostic Signature in Hepatocellular Carcinoma Patients.

Background: Hepatocellular carcinoma (HCC), a major type of cancer affecting the lives of people across the world, is one of many diseases whose advancement is thought to be influenced by autophagy dysfunction. Here, the prognostic significance of autophagy in HCC will be investigated. Methods: The Cancer Genome Atlas (TCGA) database was employed in this work to identify 62 differentially-expressed Autophagy-Related Genes (ARGs) in HCC patients. Functional enrichment studies revealed that autophagy played a tumor-promoting role in the advancement of HCC. Based on RNA sequencing of 116 tumor samples and 114 paracancerous tissue samples acquired from HCC patients at the Guangxi Medical University Cancer Hospital, 866 differentially expressed prognosis-related genes were identified. Using lasso regression analysis, two ARGs (BIRC5 and BAK1) linked to prognosis were discovered after intersecting the differential genes derived from the prognosis-related groups. A risk score based on ARGs was developed using a Cox proportional hazards regression model. RNA sequencing data were used to construct this model. Finally, the TCGA and The Human Protein Atlas Databases (THPA) were used to validate the clinical data of 116 HCC patients. Results: Elevated expression level of the BAK1 and BIRC5 genes is linked to poor prognosis. The two ARGs were used to calculate the risk score as follows: (0.0253*BAK1) + (0.0051*BIRC5). Risk score served as the independent prognostic factor as per the multivariate analysis. TCGA, THPA, and data from the Guangxi Medical University Cancer Hospital were used to confirm the predictive validity of risk scores for the prognosis of HCC patients. Conclusion: This study offers molecular insights regarding the involvement of autophagy in HCC patients, along with a probable prognostic signature for determining the outcome (prognosis) of HCC patients.

Case Report: A case of HNF1B mutation patient with first presentation of diabetic ketosis.

Background: Maturity-onset diabetes of the young 5 (MODY5), a rare diabetes syndrome of young adults, is associated with variants in hepatocyte nuclear factor 1B (HNF1B) gene. Case Presentation: We reported a case of MODY5, which presented with diabetic ketosis, multiple renal cysts, and hypokalemia. In this case, the HNF1B score was estimated as 13 and a heterozygous variant of HNF1B in exon 4 (c.826C>T, p.Arg276*) was identified through Sanger sequencing. Conclusions: Multiple renal cysts and youth-onset diabetes are common manifestations in patients with HNF1B mutations, and insufficient insulin secretion may be a potential cause of diabetic ketosis in MODY5.

Combining stereotactic body radiotherapy with camrelizumab for unresectable hepatocellular carcinoma: a single-arm trial.

PURPOSE: Stereotactic body radiotherapy (SBRT) may have significant immunomodulatory effects that enhance tumor response to immune checkpoint inhibitors. This phase 2 clinical trial was conducted to evaluate the safety and efficacy of combining palliative SBRT with camrelizumab (an anti-PD1 monoclonal antibody) in patients with unresectable hepatocellular carcinoma (uHCC). METHODS: Patients with uHCC, Child-Pugh A/B liver function, and at least one measurable lesion were enrolled between April 2020 and August 2022. Patients were administered 200 mg camrelizumab intravenously from the first day of palliative SBRT and then every 3 weeks. Palliative SBRT was delivered daily over five fractions per week, with a dose range of 30-50 Gy. The primary endpoints were objective response rate (ORR) and safety. This trial was registered at ClinicalTrials.gov (NCT04193696). RESULTS: Twenty-one patients were enrolled; the median radiation dose was 40 Gy, and the median number of cycles of camrelizumab was five. The ORR was 52.4%. After a median follow-up of 19.7 months, the median progression-free and overall survival were 5.8 and 14.2 months, respectively. The overall survival probability was 85.7% at 6 months, 76.2% at 9 months, and 59.9% at 12 months. All grade 3 treatment-related adverse events (TRAEs) occurred in five patients (23.8%) and were manageable. No grade 4/5 TRAEs were observed. CONCLUSION: Palliative SBRT plus camrelizumab showed promising antitumor activity against uHCC. Toxicities were manageable with no unexpected safety issues. This study provides evidence of a new therapeutic method for the treatment of uHCC.

Clinical implications and biological features of a novel postoperative recurrent HCC classification: A multi-centre study.

BACKGROUND & AIMS: The multiplicity of hepatocellular carcinoma (HCC) recurrence patterns is the most important determinant of patients' postsurgical survival. A systematic HCC recurrence classification is needed to help prevent and treat postoperative HCC recurrence in the era of precision medicine. METHODS: A total of 1319 patients with recurrent HCC from four hospitals were enrolled and divided into a development cohort (n = 916), internal validation cohort (n = 225) and external validation cohort (n = 178). A comprehensive study of patients' clinicopathological factors and biological features was conducted. RESULTS: Four subtypes of recurrence were identified, which integrated recurrence features, survival, effects on systemic and liver function and potential therapeutics after recurrence: type I (solitary-intrahepatic oligorecurrence); type II (multi-intrahepatic oligorecurrence); type III (progression recurrence) and type IV (hyper-progression recurrence). Type III~IV recurrence indicated exceptionally poor prognosis. Subsequently, two nomogram models were established for type III~IV recurrence prediction, and both demonstrated excellent predictive performance and applicability of pre and postoperative strategy formulation. Multiple biological analyses revealed that HCC cases with type III~IV recurrence were characterized by enrichment in p53 mutations, CCND1 amplification, high proliferation/metastasis potential, inactive metabolism and immune exhaustion features. Over-expression of high mobility group protein 2 (HMGA2) enhanced the highly malignant behaviour of HCC through multiple molecular pathways, making it a potential prognostic predictor and therapeutic target. CONCLUSIONS: This 'recurrent HCC classification' has important potential value in identifying patients with surgical benefit, predicting postsurgical survival and guiding treatment strategies. Multidimensional biological insights also increased knowledge of factors associated with HCC recurrence.

Effectiveness of a pay-it-forward intervention compared with user-paid vaccination to improve influenza vaccine uptake and community engagement among children and older adults in China: a quasi-experimental pragmatic trial.

BACKGROUND: China has low seasonal influenza vaccination rates among priority populations. In this study, we aimed to evaluate a pay-it-forward strategy to increase influenza vaccine uptake in rural, suburban, and urban settings in China. METHODS: We performed a quasi-experimental pragmatic trial to examine the effectiveness of a pay-it-forward intervention (a free influenza vaccine and an opportunity to donate financially to support vaccination of other individuals) to increase influenza vaccine uptake compared with standard-of-care user-paid vaccination among children (aged between 6 months and 8 years) and older people (≥60 years) in China. Recruitment took place in the standard-of-care group until the expected sample size was reached and then in the pay-it-forward group in primary care clinics from a rural site (Yangshan), a suburban site (Zengcheng), and an urban site (Tianhe). Participants were introduced to the influenza vaccine by project staff using a pamphlet about influenza vaccination and were either asked to pay out-of-pocket at the standard market price (US$8·5-23·2; standard-of-care group) or to donate any amount anonymously (pay-it-forward group). Participants had to be eligible to receive an influenza vaccine and to have not received an influenza vaccine in the past year. The primary outcome was vaccine uptake. Secondary outcomes were vaccine confidence and costs (from the health-care provider perspective). Regression methods compared influenza vaccine uptake and vaccine confidence between the two groups. This trial is registered with ChiCTR, ChiCTR2000040048. FINDINGS: From Sept 21, 2020, to March 3, 2021, 300 enrolees were recruited from patients visiting three primary care clinics. 55 (37%) of 150 people in the standard-of-care group (40 [53%] of 75 children and 15 [20%] of 75 older adults) and 111 (74%) of 150 in the pay-it-forward group (66 [88%] of 75 children and 45 [60%] of 75 older adults) received an influenza vaccine. People in the pay-it-forward group were more likely to receive an influenza vaccine compared with those in the standard-of-care group (adjusted odds ratio [aOR] 6·7 [95% CI 2·7-16·6] among children and 5·0 [2·3-10·8] among older adults). People in the pay-it-forward group had greater confidence in vaccine safety (aOR 2·2 [95% CI 1·2-3·9]), importance (3·1 [1·6-5·9]), and effectiveness (3·1 [1·7-5·7]). In the pay-it-forward group, 107 (96%) of 111 participants donated money for subsequent vaccinations. The pay-it-forward group had a lower economic cost (calculated as the cost without subtraction of donations) per person vaccinated (US$45·60) than did the standard-of-care group ($64·67). INTERPRETATION: The pay-it-forward intervention seemed to be effective in improving influenza vaccine uptake and community engagement. Our data have implications for prosocial interventions to enhance influenza vaccine uptake in countries where influenza vaccines are available for a fee. FUNDING: Bill & Melinda Gates Foundation and the UK National Institute for Health Research.

Genetic Relationships of Puccinia striiformis f. sp. tritici in Southwestern and Northwestern China.

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a crucial disease for wheat worldwide and constantly threatens wheat production in southwestern and northwestern China, where the environment is a good fit for Pst oversummering and overwintering. However, the underlying genetic dynamics of spring epidemic Pst populations across large areas of continuous planting in the southwestern and northwestern regions are poorly understood. A total of 2,103 Pst isolates were sampled in the spring of 2019 from the two agroecosystems and grouped into three horizontal spatial scales (countywide, provincial, and regional subpopulations) and two vertical spatial scales that consisted of elevational and geomorphic subpopulations. A total of 776 multilocus genotypes were identified, with the highest genetic diversity found in the northern and Sichuan populations, particularly in the Ningxia and Sichuan Basins, while the lowest genetic diversity was found in the Yunnan and Guizhou populations. Multivariate discriminant analysis of principal components (DAPC) and STRUCTURE (STRUCTURE 2.3.4) analyses revealed variation in the genotypic compositions of the molecular groups on horizontal and vertical dimensions from north to south or vice versa and from low to high or vice versa, respectively. The regional neighbor-joining tree revealed three large spatial structures consisting of the southwestern, the northwestern, and the Xinjiang regions, while the Tibetan population connected the southwestern and northwestern regions. The isolates of the Sichuan Basin were scattered over the four quartiles by principal coordinate analysis, which indicated frequent genotype interchange with others. Greater genetic differentiation was observed between the southwestern and northwestern regions. Linkage equilibrium (P ≥ 0.05) was detected on different spatial scales, suggesting that Pst populations are using sexual reproduction or mixed reproduction (sexual and clonal reproduction) in southwestern and northwestern China. IMPORTANCE Understanding the epidemiology and population genetics of plant pathogens is crucial to formulate efficient predictions of disease outbreaks and achieve sustainable integrated disease management, especially for pathogens with migratory capability. Here, this study covers the genetic homogeneity and heterogeneity of different geographical Pst populations on broad to fine spatial scales from the key epidemic regions of the two agroecosystems in China, where wheat stripe rust occurs annually. We provide knowledge of the population genetics of Pst and reveal that, for instance, there is greater genetic diversity in northwestern China, there are close genetic relationships between Yunnan and Guizhou and between Gansu-Ningxia and Qinghai, and there are effects of altitude on genetic compositions, etc. All of these findings clarify the genetic relationships and expand the insights into the population dynamics and evolutionary mechanisms of Pst in southwestern and northwestern China, providing a theoretical basis for achieving sustainable control of wheat stripe rust in key epidemic regions.

Prognostic Value of Aspartate Transaminase/Alanine Transaminase Ratio in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma Undergoing Hepatectomy.

Background: Aspartate transaminase/alanine transaminase (De Ritis) ratio is a good predictor of liver function damage, but its prognostic value in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy remains unclear. This study aimed to assess the association of the De Ritis ratio with overall survival (OS) among hepatitis B virus (HBV)-related HCC patients undergoing hepatectomy. Methods: A total of 1,147 HCC patients were recruited. Cox regression analysis was used to identify the independent risk factors. Restricted cubic spline (RCS) was used to evaluate the association between the De Ritis ratio and mortality risk. Nomogram was constructed to determine the predictive power of the De Ritis ratio. Results: Multivariate Cox regression analysis revealed that the tertile of the De Ritis ratio was an independent risk factor for mortality. After adjustment for confounding factors, the adjusted hazard ratios (HRs) with corresponding 95% CIs of mortality for the 2nd tertile and 3rd tertile were 1.175 (0.889-1.554) and 1.567 (1.199-2.046), respectively. RCS confirmed a non-linear association between the natural logarithm of the De Ritis ratio and the risk of mortality (p for non-linearity = 0.0375). The nomogram showed that the natural logarithm of the De Ritis ratio contributed the most to the prediction of prognosis in HBV-related HCC patients, and Harrell's C-index was 0.680 with a 95% CI of 0.645-0.715. Conclusion: The De Ritis ratio is an independent predictor for OS in HBV-related HCC patients undergoing hepatectomy, which allows for prognostic stratification of patients, hence, individualized treatment and follow-up.

The transmission dynamics of Middle East Respiratory Syndrome coronavirus.

BACKGROUND: In this study, we aimed to quantify the contribution of different transmission routes of the Middle East respiratory syndrome (MERS) and determine its transmissibility. METHODS: Based on the natural history and transmission features of MERS in different countries, a susceptible-exposed-symptomatic-asymptomatic-recovered/death (SEIARD) model and a multi-route dynamic model (MMDM). The SEIARD model and MMDM were adopted to simulate MERS in South Korea and Saudi Arabia, respectively. Data on reported MERS cases in the two countries were obtained from the World Health Organization. Thereafter, the next generation matrix method was employed to derive the equation for the basic reproduction number (R0), and the model fitting procedure was adopted to calculate the R0 values corresponding to these different countries. RESULTS: In South Korea, 'Person-to-Person' transmission was identified as the main mode of MERS transmission in healthcare settings, while in Saudi Arabia, in addition to 'Person-to-Person' transmission, 'Host-to-Host' and 'Host-to-Person' transmission also occurred under certain scenarios, with camels being the main host. Further, the fitting results showed that the SEIARD model and MMDM fitted the data well. The mean R0 value was 8.59 (95% confidence interval [CI]: 0-28.02) for MERS in South Korea, and for MERS in Saudi Arabia, it was 1.15 and 1.02 (95% CI: 0.86-1.44) for the 'Person-to-Person' and 'Camel-to-Camel' transmission routes, respectively. CONCLUSIONS: The SEIARD and MMDM model can be used to simulate the transmission of MERS in different countries. Additionally, in Saudi Arabia, the transmissibility of MERS was almost the same among hosts (camels) and humans.

Lenvatinib with or without immune checkpoint inhibitors for patients with unresectable hepatocellular carcinoma in real-world clinical practice.

BACKGROUND: Lenvatinib is regarded as the first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of lenvatinib with or without immune checkpoint inhibitors (ICIs) in patients with unresectable HCC. METHODS: In this multicentric retrospective study, patients with unresectable HCC who treated with lenvatinib with or without ICIs would be enrolled. Overall survival, progression-free survival, objective response rate, and disease control rate were calculated to assess the antitumor response. RESULTS: Between January 2019 and August 2020, 65 patients received lenvatinib plus ICIs while other 45 patients received lenvatinib. The baseline characteristics were comparable between the two groups. Lenvatinib plus ICIs provided significantly higher overall survival (hazard ratio = 0.47, 95% CI 0.26-0.85; p = 0.013) and progression-free survival (hazard ratio = 0.35, 95% CI 0.20-0.63; p < 0.001) than lenvatinib monotherapy. Moreover, patients with lenvatinib plus ICIs had significantly higher objective response rate (41.5% vs 20.0%, p = 0.023) and disease control rate (72.3% vs 46.7%, p = 0.009) per RECIST v1.1 than those with lenvatinib. No treatment-related deaths were observed. Grade 3 or greater adverse events occurring in 10% or more of patients in either treatment group were hypertension [13 (20.0%) of 65 patients treated with lenvatinib plus ICIs vs 8 (17.8%) of 45 patients treated with lenvatinib], and palmar-plantar erythrodysesthesia [seven (10.8%) vs two (4.4%)]. CONCLUSIONS: In this real-world study, lenvatinib combined with ICIs showed significantly promising efficacy and manageable safety than lenvatinib alone in patients with unresectable HCC.

Impact of immunization programs on 11 childhood vaccine-preventable diseases in China: 1950-2018.

To evaluate the achievements of China's immunization program between 1950 and 2018, we chose 11 vaccine-preventable diseases (VPDs) as representative notifiable diseases and used annual surveillance data obtained between 1950 and 2018 to derive disease incidence and mortality trends. Quasi-Poisson and polynomial regression models were used to estimate the impacts of specific vaccine programs, and life-table methods were used to calculate the loss of life expectancy, years of life lost, and loss of working years. The total notification number for the 11 VPDs was 211,866,000 from 1950 to 2018. The greatest number occurred in 1959, with a total incidence of 1,723 per million persons. From 1978 to 2018, a substantial decline was observed in the incidence of major infectious diseases. The incidence of pertussis fell 98% from 126.35 to 1.58 per million, and the incidences of measles, meningococcal meningitis, and Japanese encephalitis fell 99%, 99%, and 98%, respectively. The regression models showed that most of the 11 diseases exhibited dramatic declines in morbidity after their integration into the Expanded Program on Immunization (EPI), while varicella and paratyphoid fever, which were not integrated into the EPI, showed increased morbidity. From 1978 to 2018, the total life expectancy for the 11 VPDs increased by 0.79 years, and similar results were obtained for different age groups. China has had great success in controlling VPDs in recent decades, and improving vaccination coverage is a key aspect of controlling VPDs in China.