New light on ω-3 polyunsaturated fatty acids and diabetes debate: a population pharmacokinetic-pharmacodynamic modelling and intake threshold study.

OBJECTIVE: ω-3 polyunsaturated fatty acids (PUFA) are a key modifiable factor in the intervention of type 2 diabetes, yet recommendations for dietary consumption of ω-3 PUFA in type 2 diabetes remain ambiguous and controversial. Here, we revisit the subject in the light of population pharmacokinetic-pharmacodynamic (PPK-PD) modeling and propose a threshold for intake. RESEARCH DESIGN AND METHODS: Plasma levels of ω-3 PUFA and glycosylated hemoglobin (HbA1c) were measured as pharmacokinetic and pharmacodynamic indicator, respectively. The nonlinear mixed effect analysis was used to construct a PPK-PD model for ω-3 PUFA and to quantify the effects of FADS gene polymorphism, age, liver and kidney function, and other covariables. RESULTS: Data from 161 patients with type 2 diabetes in the community were modeled in a two-compartment model with primary elimination, and HDL was a statistically significant covariate. The simulation results showed that HbA1c showed a dose-dependent decrease of ω-3 PUFA plasma level. A daily intake of ω-3 PUFA at 0.4 g was sufficient to achieve an HbA1c level of 7% in more than 95% of patients. CONCLUSIONS: PPK/PD modeling was proposed as a multilevel analytical framework to quantitatively investigate finer aspects of the complex relationship between ω-3 PUFA and type 2 diabetes on genetic and non-genetic influence factors. The results support a beneficial role for ω-3 PUFA in type 2 diabetes and suggested the intake threshold. This new approach may provide insights into the interaction of the two and an understanding of the context in which changes occur.

Universal screening and treatment towards the elimination of chronic hepatitis C in China: an economic evaluation.

OBJECTIVES: China has the largest number of hepatitis C virus (HCV) infection in the world, but current levels of diagnosis and treatment are low. The objective of this study was to assess the cost-effectiveness of various universal HCV screening and treatment strategies in China and inform decisions on health policy. STUDY DESIGN: A cost-effectiveness analytical study. METHODS: We developed a Markov model to investigate cost-effectiveness of different HCV screening and treatment strategies in China. We simulated several screening scenarios for Chinese people aged 18-70 years. We estimated incremental cost-effectiveness ratios (ICERs) of different intervention scenarios compared with status quo. RESULTS: Expanded HCV screening and treatment strategy with prioritisation for high-risk groups (Scenario S5) was the most cost-effective strategy (ICER: USD $11,667.71/quality-adjusted life-year [QALY] gained), which resulted in great reduction in HCV-related diseases and deaths, with a 67.11% reduction in cases of chronic HCV. Universal HCV screening and treatment implementation remains a cost-effective strategy when delayed until 2025 (ICER: USD $17,093.69/QALY), yet the delayed strategy is less effective in reducing HCV-related deaths. CONCLUSIONS: Expanded HCV screening and treatment strategy with prioritisation for high-risk groups is the most cost-effective strategy and has lead to a significant reduction in both HCV morbidity and mortality in China, which would essentially eliminate HCV as a public threat.

5-FU promotes HBV replication through oxidative stress-induced autophagy dysfunction.

BACKGROUND & AIMS: Hepatitis B virus (HBV) reactivation is a major problem that must be overcome during chemotherapy for HBV-related hepatocellular carcinoma (HCC). However, the mechanism underlying chemotherapy-associated HBV reactivation is still not fully understood, hindering the development of improved HBV-related HCC treatments. METHODS: A meta-analysis was performed to assess the HBV reactivation risk during transcatheter arterial chemoembolization (TACE). To investigate the regulatory effects and mechanisms of 5-FU on HBV replication, an HBV mouse model was established by pAAV-HBV1.2 hydrodynamic injection followed by intraperitoneal 5-FU injection, and different in vitro models (HepG2.2.15 or Huh7 cells) were established. Realtime RT‒qPCR, western blotting, luciferase assays, and immunofluorescence were used to determine viral parameters. We also explored the underlying mechanisms by RNA-seq, oxidative stress evaluation and autophagy assessment. RESULTS: The pooled estimated rate of HBV reactivation in patients receiving TACE was 30.3 % (95 % CI, 23.1%-37.4 %). 5-FU, which is a chemotherapeutic agent commonly used in TACE, promoted HBV replication in vitro and in vivo. Mechanistically, 5-FU treatment obviously increased autophagosome formation, as shown by increased LC3-II levels. Additionally, 5-FU impaired autophagic degradation, as shown by marked p62 and mCherry-GFP-LC3 upregulation, ultimately promoting HBV replication and secretion. Autophagy inhibition by 3-methyladenine or chloroquine significantly altered 5-FU-induced HBV replication. Furthermore, 5-FU-induced autophagy and HBV replication were markedly attenuated with a reactive oxygen species (ROS) scavenger. CONCLUSIONS: Together, our results indicate that ROS-induced autophagosome formation and autophagic degradation play a critical role in 5-FU-induced HBV reactivation.

Proportion of liver cancer cases and deaths attributable to potentially modifiable risk factors in China.

BACKGROUND: Understanding the differences in the burden of liver cancer due to different risk factors across provinces is critical to informing and improving liver cancer prevention and control. In this study, we estimated the population attributable fractions (PAFs) of liver cancer in all 31 provinces of China in 2016. METHODS: Prevalence estimates of risk factors were derived from representative surveys. We used pooled relative risks obtained from several recent large-scale pooled analyses or high-quality meta-analyses. We calculated PAFs using multiple formulas which included exposure prevalence and relative risk data stratified by sex, age and province, and then combined and created overall PAFs by sex, risk factors and risk factor groups. RESULTS: Approximately 252 046 liver cancer cases {69.5% [95% confidence interval (CI) 52.6, 76.5]} and 212 704 deaths [67.7% (95% CI 50.9, 74.6)] were attributable to modifiable risk factors in China in 2016. The overall PAF for liver cancer was approximately 1.5 times higher in men than in women, with the top three risk factors in men being hepatitis B virus (HBV), smoking and alcohol drinking, whereas in women, they were HBV, excess body weight and hepatitis C virus (HCV). Among the risk factor groups, infectious agents had the highest PAF, followed by behavioural factors and metabolic factors. CONCLUSIONS: The PAF for liver cancer caused by modifiable risk factors varies widely among provinces and socioeconomic and geographical regions in China. The use of tailored primary prevention strategies across provinces and socioeconomic and geographical regions has great potential to reduce the burden and disparities of liver cancer.

Global variability of influenza activity and virus subtype circulation from 2011 to 2023.

BACKGROUND: Although decreased influenza activity has been reported in many countries during the COVID-19 pandemic, it remains unknown how global influenza activity has changed. We described the global variability of influenza activity and virus subtype circulation from 2011 to 2023 to prepare for the potential influenza outbreak with the control of the COVID-19 pandemic. METHODS: Influenza virological surveillance data between 2011 and 2023 were obtained from the WHO-FluNet database. We first calculated and compared the influenza activity before and during the COVID-19 pandemic. For countries whose influenza activity has recovered, we also described changes in the duration of influenza epidemics. We then determined the proportion of influenza cases caused by the different influenza virus types. RESULTS: In total, 73 countries with 2.17 million influenza cases were included. In the early stage of the COVID-19 pandemic, decreased influenza activity was observed in all WHO regions. In 2022 and 2023, rebound in influenza activity was observed in all WHO regions, especially in Western Pacific Region. At the same time, a change in the duration of the influenza epidemic was observed in several Southern Hemisphere countries. Moreover, in all WHO regions, few B/Yamagata viruses were detected during the COVID-19 pandemic. CONCLUSIONS: Lack of exposure to influenza will diminish population immunity and increase the severity of large epidemics on a future global resurgence. Ongoing monitoring of the changes in the duration of the influenza epidemic and circulation subtypes should be the focus of future work.

Derivation and validation of a risk score to predict acute kidney injury in critically ill cirrhotic patients.

AIM: Acute kidney injury (AKI) is a common complication in critically ill cirrhotic patients with substantial mortality. Given AKI can be prevented through early detection, it is urgent to develop an easy model to identify high-risk patients. METHODS: A total of 1149 decompensated cirrhotic (DC) patients from the eICU Collaborative Research Database were enrolled for model development and internal validation. The variables used for analysis mainly included laboratory tests. We first built an ensemble model (random forest, gradient boosting machine, K-nearest neighbor, and artificial neural network) named DC-AKI using machine learning methods. Based on the Akaike information criterion, we then constructed a risk score, which was externally validated in 789 DC patients from the Medical Information Mart for Intensive Care database. RESULTS: AKI developed in 212 (26%) of 804 patients in the derivation cohort, and 355 (45%) of 789 patients in the external validation cohort. DC-AKI identified the eight variables most strongly associated with the outcome: serum creatinine, total bilirubin, magnesium, shock index, prothrombin time, mean corpuscular hemoglobin, lymphocytes, and arterial oxygen saturation. Based on the smallest Akaike information criterion, a six-variable model was eventually used to construct the scoring system (serum creatinine, total bilirubin, magnesium, shock index, lymphocytes, and arterial oxygen saturation). The scoring system showed good discrimination, with the area under the receiver operating characteristics curve of 0.805 and 0.772 in two validation cohorts. CONCLUSIONS: The scoring system using routine laboratory data was able to predict the development of AKI in critically ill cirrhotic patients. The utility of this score in clinical care requires further research.

The associations of tobacco use, sexually transmitted infections, HPV vaccination, and screening with the global incidence of cervical cancer: an ecological time series modeling study.

OBJECTIVES: We aimed to quantify the temporal associations between cervical cancer incidence and cervical cancer-related factors and to predict the number of new cervical cancer cases averted under counterfactual scenarios compared to the status quo scenario. METHODS: We described temporal trends in cervical cancer and associated factors globally from 1990 to 2019. We then used generalized linear mixed models to explore the impact of tobacco use, sexually transmitted infections (STIs), human papillomavirus (HPV) vaccination, and cervical screening on cervical cancer incidence. A counterfactual analysis was performed to simulate the most effective scenario for reducing cervical cancer incidence. RESULTS: The worldwide incidence of cervical cancer showed a downward trend over the past 3 decades (estimated annual percentage change, -0.72%), although the incidence remained high (>30 cases per 100,000 persons) in sub-Saharan Africa, Latin America, and the Caribbean. Higher smoking and STI prevalence showed significant direct associations with the incidence of cervical cancer, whereas HPV vaccination and screening coverage showed significant inverse associations. If the strategic goals for accelerating the elimination of cervical cancer and tobacco control programs had been achieved in 2019, the largest decrease in the number of new cervical cancer cases would have been observed, with 54,169 fewer new cases of cervical cancer in 2019. CONCLUSIONS: Our counterfactual analysis found that a comprehensive intervention program emphasizing scaled-up cervical screening coverage (70%), HPV vaccination coverage (90%), and tobacco control (30% relative reduction) would be the most effective program for reducing cervical cancer incidence.

Development and validation of a prognostic nomogram model for ICU patients with alcohol-associated cirrhosis.

BACKGROUND: The prognosis of patients with alcohol-associated cirrhosis (ALC) admitted to the intensive care unit (ICU) is poor. We developed and validated a nomogram (NIALC) for ICU patients with ALC. METHODS: Predictors of mortality were defined by a machine learning method in a cohort of 394 ICU patients with ALC from the Medical Information Mart for Intensive Care database. Then the nomogram (NIALC) was constructed and evaluated using the AUC. The MELD, MELD-sodium, Child-Pugh, and CLIF-SOFA scores were then compared with NIALC. Two datasets of 394 and 501 ICU patients with ALC were utilized for model validation. RESULTS: In-hospital mortality was 41% and 21% in the training and external validation sets. Predictors included were blood urea nitrogen, total bilirubin, prothrombin time, serum creatinine, lactate, partial thromboplastin time, phosphate, mean arterial pressure, lymphocytes, fibrinogen, and albumin. The AUCs for the NIALC were 0.767 and 0.760 in the two validation cohorts, which were better than those of the MELD, MELD-sodium, Child-Pugh, and CLIF-SOFA. CONCLUSION: We developed a nomogram for ICU patients with ALC, which demonstrated better discriminative ability than previous prognostic scores. This nomogram could be conveniently used to facilitate the individualized prediction of death in ICU patients with ALC.

Global cirrhosis prevalence trends and attributable risk factors-an ecological study using data from 1990-2019.

BACKGROUND AND AIMS: Cirrhosis is a major public health issue worldwide with significant morbidity and mortality. We aimed to explore the time series associations between varying levels of risk factors and cirrhosis prevalence and predict the cirrhosis prevalence under alternative scenarios to consolidate evidence for further intervention plans. METHODS: We collected data of cirrhosis and its risk factors from 1990 to 2019 across 178 countries and used a generalized linear mixed model to explore the time series associations between cirrhosis and risk factors. We simulated scenarios with varying levels of risk factors and investigated benefits gained from the control of risk factors compared with the status quo. RESULTS: The global cirrhosis prevalence varied geographically, with the highest observed in East and Southeast Asia, mainly due to high hepatitis prevalence. Our study revealed that each 1% increase in prevalence of hepatitis B and C, cirrhosis prevalence would correspondingly increase 0.028% and 0.288%. There would be approximately 392.15 million fewer cirrhosis patients if the goals of a 65% reduction in prevalence of hepatitis and a 10% reduction in alcohol consumption were achieved. CONCLUSIONS: Given that cirrhosis prevalence has different risk factors depending on geography, it is important to identify an appropriate set of interventions for cirrhosis that are adapted to the epidemiological situation in a specific country. Interventions targeting hepatitis may have a significant impact on global cirrhosis prevalence, therefore, the adoption of specific interventions for hepatitis in high-burden regions and high-risk groups is warranted to lower the global burden of cirrhosis.

Changes in Influenza Activity and Circulating Subtypes During the COVID-19 Outbreak in China.

Background: Non-pharmaceutical interventions (NPIs) to mitigate COVID-19 can impact the circulation of influenza viruses. There is a need to describe the activity of influenza and its subtypes during the COVID-19 pandemic to aid in the development of influenza prevention and control measures in the next influenza season. Method: Data from pathogenic surveillance performed by the Chinese National Influenza Center from January 2016 to August 2021 were extracted and stratified by type and subtype for northern China and southern China. The distribution of influenza activity and circulating subtypes were described during the COVID-19 pandemic, and data from 2016 to 2019 were used for comparisons. Results: Influenza activity declined rapidly and then rose slowly during the COVID-19 pandemic in China. The distribution of influenza subtypes changed from A-dominant to B/Victoria-dominant after the COVID-19 outbreak. Discussion: Whether the B/Yamagata lineage has disappeared from China deserves more attention in future virologic monitoring programs. The influenza vaccination campaign in the 2021-2022 season is an important means by which to reduce the proportion of susceptible people and limit the damage that potentially greater and earlier circulation of the virus could cause.

Barriers to and Facilitators of Human Papillomavirus Vaccination Among People Aged 9 to 26 Years: A Systematic Review.

BACKGROUND: Cervical and oropharyngeal cancers are associated with human papillomavirus (HPV) infection, which can be prevented with the vaccines. However, uptake of the HPV vaccine remains low in many countries. There is a need to better understand the barriers to and facilitators of HPV vaccination from young people's perspectives. METHODS: Five electronic databases were searched for original publications (dated January, 2006-December, 2019) reporting barriers to and facilitators of HPV vaccination among young people. All articles were screened against prespecified eligibility criteria, and data were extracted against prespecified form. RESULTS: A total of 13 studies that were published in international peer-reviewed journals and met the stated eligibility criteria were identified. The barriers reported were centralized around lack of knowledge about HPV and the HPV vaccine, fear about the safety and efficacy of the HPV vaccine, fear about not being able to pay for the HPV vaccine, and discrimination regarding to the HPV vaccine. The facilitators reported were centralized around trust in the efficacy and safety of the HPV vaccine, discounted price of vaccination, positive recommendations from others, perceived risk of HPV infection, and benefits of vaccine. CONCLUSIONS: After their introduction 14 years ago, knowledge deficiency of the HPV vaccine is still a critical barrier to vaccination. Educational initiatives aimed at adolescents and young adults were urgently needed. Understanding factors that arbitrate in early HPV vaccination is critical for improving the HPV vaccination rate.