Alteration of Thyroid Hormones in Mouse Models of Alzheimer's Disease and Aging.

INTRODUCTION: Aging is characterized by the deterioration of a wide range of functions in tissues and organs, and Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. Hypothyroidism occurs when there is insufficient production of thyroid hormones (THs) by the thyroid. The relationship between hypothyroidism and aging as well as AD is controversial at present. METHODS: We established an animal model of AD (FAD4T) with mutations in the APP and PSEN1 genes, and we performed a thyroid function test and RNA sequencing (RNA-Seq) of the thyroid from FAD4T and naturally aging mice. We also studied gene perturbation correlation in the FAD4T mouse thyroid, bone marrow, and brain by further single-cell RNA sequencing (scRNA-seq) data of the bone marrow and brain. RESULTS: In this study, we found alterations in THs in both AD and aging mice. RNA-seq data showed significant upregulation of T-cell infiltration- and cell proliferation-related genes in FAD4T mouse thyroid. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that upregulated genes were enriched in the functional gene modules of activation of immune cells. Downregulated energy metabolism-related genes were prominent in aging thyroids, which reflected the reduction in THs. GSEA showed a similar enrichment tendency in both mouse thyroids, suggesting their analogous inflammation state. In addition, the regulation of leukocyte activation and migration was a common signature between the thyroid, brain, and bone marrow of FAD4T mice. CONCLUSIONS: Our findings identified immune cell infiltration of the thyroid as the potential underlying mechanism of the alteration of THs in AD and aging.

Recent advances in food waste-derived nanoporous carbon for energy storage.

Affordable and environmentally friendly electrochemically active raw energy storage materials are in high demand to switch to mass-scale renewable energy. One particularly promising avenue is the feasibility of utilizing food waste-derived nanoporous carbon. This material holds significance due to its widespread availability, affordability, ease of processing, and, notably, its cost-free nature. Over the years, various strategies have been developed to convert different food wastes into nanoporous carbon materials with enhanced electrochemical properties. The electrochemical performance of these materials is influenced by both intrinsic factors, such as the composition of elements derived from the original food sources and recipes, and extrinsic factors, including the conditions during pyrolysis and activation. While current efforts are dedicated to optimizing process parameters to achieve superior performance in electrochemical energy storage devices, it is timely to take stock of the current state of research in this emerging field. This review provides a comprehensive overview of recent developments in the fabrication and surface characterisation of porous carbons from different food wastes. A special focus is given on the applications of these food waste derived porous carbons for energy storage applications including batteries and supercapacitors.

This review compiles very recent literature on the synthesis of porous carbon from food waste biomass and their efficient utilisation as electrode material for energy storage applications in supercapacitor devices.

Strategies for Improving the Photocatalytic Hydrogen Evolution Reaction of Carbon Nitride-Based Catalysts.

Due to the depletion of fossil fuels and their-related environmental issues, sustainable, clean, and renewable energy is urgently needed to replace fossil fuel as the primary energy resource. Hydrogen is considered as one of the cleanest energies. Among the approaches to hydrogen production, photocatalysis is the most sustainable and renewable solar energy technique. Considering the low cost of fabrication, earth abundance, appropriate bandgap, and high performance, carbon nitride has attracted extensive attention as the catalyst for photocatalytic hydrogen production in the last two decades. In this review, the carbon nitride-based photocatalytic hydrogen production system, including the catalytic mechanism and the strategies for improving the photocatalytic performance is discussed. According to the photocatalytic processes, the strengthened mechanism of carbon nitride-based catalysts is particularly described in terms of boosting the excitation of electrons and holes, suppressing carriers recombination, and enhancing the utilization efficiency of photon-excited electron-hole. Finally, the current trends related to the screening design of superior photocatalytic hydrogen production systems are outlined, and the development direction of carbon nitride for hydrogen production is clarified.

Morphology regulation of zero-valent iron nanosheets supported on microsilica for promoting peroxymonosulfate activation.

Combing the assisted dispersion strategy of support with the wet chemical reduction method, a novel nano-zero valent iron/microsilica (nZVI/M) composite was successfully fabricated, where the 2D nZVI nanosheets were uniformly anchored and covered on the surface of microsilica. The introduction of microsilica notably relieved the agglomeration effect of nZVI nanosheets, which induced the improvement of specific surface area (45.68 m2/g) and pore volume (0.172 cm3/g), and thereby exposing more active sites for bisphenol A (BPA) removal. The optimized nZVI/M-0.6 displayed the superior catalytic performance in the presence of peroxymonosulfate (PMS) with the degradation rate of BPA reached above 97% within 3 min and a higher constant rate of 0.659 min-1, which was approximately 3.9 times as high as that of nZVI/PMS system. The homogeneously dispersion of nZVI nanosheets on microsilica benefited for the assembly of the pollutants and boosting the kinetics of the catalytic degradation process. As a highly efficient PMS activator, it could well maintain the catalytic activity in different real water samples. The quenching experiments verified that SO4•- played the dominate role for BPA removal. This work offered novel insights for designing and preparing iron-based persulfate activator for wastewater treatment.

Optimal sensor placement for the routine monitoring of urban drainage systems: A re-clustering method.

The construction of an efficient monitoring network is critical for the effective and safe management of urban drainage systems. This study developed a re-clustering methodology that incorporates additional perspectives beyond node similarity to improve the traditional clustering process for optimal sensor placement. Instead of targeting event-specific water quality or hydraulic monitoring, the method integrates the water hydraulic and quality characteristics of nodes in response to the demand for routine monitoring. The implementation of this method first applies model simulation to generate the attribute datasets required for clustering analysis, and then re-clusters the initial clustering result according to the constructed re-clustering potential indices. And the information theory-based evaluation metrics were introduced to quantitatively assess the sensor deployment scheme obtained by amalgamating the two clustering results. Two networks with different drainage systems and sizes were chosen as case studies to illustrate the application of the framework. The results demonstrate that the clustering process enables to expand the information contained in the monitoring network, and that the re-clustering strategy can generate more comprehensive and practical solutions upon this basis.

Defect Engineering Modulated Iron Single Atoms with Assist of Layered Clay for Enhanced Advanced Oxidation Processes.

Single-atom catalysts (SACs) feature maximum atomic utilization efficiency; however, the loading amount, dispersibility, synthesis cost, and regulation of the electronic structure are factors that need to be considered in water treatment. In this study, kaolinite, a natural layered clay mineral, is applied as the support for g-C3 N4 and single Fe atoms (FeSA-NGK). The FeSA-NGK composite exhibits an impressive degradation performance toward the target pollutant (>98% degradation rate in 10 min), and catalytic stability across consecutive runs (90% reactivity maintained after three runs in a fluidized-bed catalytic unit) under peroxymonosulfate (PMS)/visible light (Vis) synergetic system. The introduction of kaolinite promotes the loading amount of single Fe atoms (2.57 wt.%), which is a 14.2% increase compared to using a bare catalyst without kaolinite, and improved the concentration of N vacancies, thereby optimizing the regulation of the electronic structure of the single Fe atoms. It is discovered that the single Fe atoms successfully occupied five coordinated N atoms and combined with a neighboring N vacancy. Consequently, this regulated the local electronic structure of single Fe atoms, which drives the electrons of N atoms to accumulate on the Fe centers. This study opens an avenue for the design of clay-based SACs for water purification.

Global burden of lung cancer attributable to ambient fine particulate matter pollution in 204 countries and territories, 1990-2019.

INTRODUCTION: Understanding the latest global spatio-temporal pattern of lung cancer burden attributable to ambient fine particulate matter pollution (PM2.5) is crucial to prioritize global lung cancer prevention, as well as environment improvement. METHODS: Data on lung cancer attributable to ambient PM2.5 were downloaded from the Global Burden of Disease Study (GBD) 2019. The numbers and age-standardized rates on lung cancer mortality (ASMR) and disability-adjusted life years (ASDR) were estimated by age, sex, region, and country. We used estimated annual percentage change (EAPC) to quantify the temporal trends of ASMR and ASDR from 1990 to 2019. RESULTS: In 2019, the number of global lung cancer deaths and DALYs attributable to ambient PM2.5 was approximately 0.31 million and 7.02 million respectively, among which more deaths and DALYs occurred in males. At GBD region level, the heaviest burden occurred in East Asia, accounting for over 50% worldwide, with China ranked first worldwide. The number of ambient PM2.5 attributable lung cancer deaths and DALYs has over doubled from 1990 to 2019, but high sociodemographic index (SDI) region had a rapid decrease, with EAPC -2.21 in ASMR (95% CI: -2.32, -2.09). The age-specific mortality rate or DALY rate has increased in all age groups in low to middle SDI regions from 1990 to 2019. The ASMR or ASDR showed an inverted V-shaped association with SDI. The EAPC in ASMR or ASDR was highly negatively correlated with ASMR or ASDR in 1990 and SDI in 2019, with coefficients around 0.70. CONCLUSIONS: The number of ambient PM2.5-related lung cancer deaths and DALYs has largely increased because of the increase of exposure to PM2.5, population growth, and aging. Local governments should do economic activities under the consideration of public health, especially in high-burden areas.

A Wide Dynamic Range Sigma-Delta Modulator for EEG Acquisition Using Randomized DWA and Dynamic-Modulated Scaling-Down Techniques.

This paper proposes a wide dynamic range (DR) and high-resolution discrete-time (DT) 2-order 4-bit sigma-delta modulator with a novel dynamic-modulated scaling-down (DM-SD) technology for non-invasive electroencephalogram (EEG) acquisition. The DM-SD technology can expand the input dynamic range and suppress large input offsets at the same time. The modulator was designed with 180nm CMOS technology with an area of 0.49 mm2. We achieve a 118.1 dB SNDR when the input signal is 437.5 Hz and the signal bandwidth is 1500 Hz. Due to the proposed DM-SD technology, the DR is expanded to 126 dB. The power consumption of the whole modulator is 1.6 mW and a 177.8 dB Schreier figure-of-merit (FoMs) is realized.

Prognostic value of the extent of lymphadenectomy for esophageal cancer-specific survival among T1 patients.

BACKGROUND: Clinically, there are no clear guidelines on the extent of lymphadenectomy in patients with T1 esophageal cancer. Studying the minimum number of lymph nodes for resection may increase cancer-specific survival. METHODS: Patients who underwent esophagectomy and lymphadenectomy at T1 stage were selected from the Surveillance, Epidemiology and End Results Program (United States, 1998-2014). Maximally selected rank and Cox proportional hazard models were used to examine three variables: the number of lymph nodes examined, the number of negative lymph nodes and the lymph node ratio. RESULTS: Approximately 18% had lymph node metastases, where the median values were 10, 10 and 0 for the number of lymph nodes examined, the number of negative lymph nodes and the lymph node ratio, respectively. All three examined variables were statistically associated with cancer-specific survival probability. Dividing patients into two groups shows a clear difference in cancer-specific survival compared to four or five groups for all three variables: there was a 29% decrease in the risk of death with the number of lymph nodes examined ≥14 vs < 14 (hazard ratio 0.71, 95% confidence interval: 0.57-0.89), a 35% decrease in the risk of death with the number of negative lymph nodes ≥13 vs < 13 (hazard ratio 0.65, 95% confidence interval: 0.52-0.81), and an increase of 1.21 times in the risk of death (hazard ratio 2.21, 95% confidence interval: 1.76-2.77) for the lymph node ratio > 0.05 vs ≤ 0.05. CONCLUSIONS: The extent of lymph node dissection is associated with cancer-specific survival, and the minimum number of lymph nodes that need to be removed is 14. The number of negative lymph nodes and the lymph node ratio also have prognostic value after lymphadenectomy among T1 stage patients.

A new mixed-ligand coordination polymer: protective activity on influenza a virus-induced COPD via regulating tlr3 gene expression on alveolar epithelial cells.

A new Cu(II) coordination polymer (CP) of [Cu5(µ3-OH)2(bcpt)4(bib)2] (1, bib = 1,4-bis(1-imidazoly)benzene and H2bcpt = 3,5-bis(3'-carboxyphenyl)-1,2,4-triazole) was synthesized by reaction of Cu(NO3)2·3H2O reacting with 3,5-bis(3'-carboxyphenyl)-1,2,4-triazole in the existence of 1,4-bis(1-imidazoly)benzene as the second ligand. The treatment activity of the compound on influenza A virus induced chronic obstructive pulmonary disease (COPD) was evaluated. First, the biological function of the lung was assessed by measuring the partial pressure for the carbon dioxide (PaCO2) and oxygen (PaO2) via the analysis of blood gas. Next, the inflammatory cytokines released by alveolar epithelial cells were determined via the ELISA test kit. In addition to this, the real-time RT-PCR was carried out to determine the inflammatory response relative expression in the alveolar epithelial cells. Finally, the relative expression of the TLR3 on the alveolar epithelial cells was revealed by western blot. Possible binding patterns were acquired from the post scoring software and molecular docking, which exhibited two possible functional side chain binding sites of TLR3 to compounds binding, possibly offering distinct regulatory mechanisms.

Roles of large aggregating proteoglycans in human intervertebral disc degeneration.

Degeneration of the intervertebral discs, a natural progression of the aging process, is strongly implicated as a cause of low back pain. Aggrecan is the major structural proteoglycan in the extracellular matrix of the intervertebral disc. It is large, possessing numerous glycosaminoglycan chains and the ability to form aggregates in association with hyaluronan. The negatively charged glycosaminoglycan side chains in aggrecan in the nucleus pulposus of the intervertebral discs can bind electrostatically to polar water molecules, which are crucial for maintaining the well-hydrated state that enables the discs to undergo reversible deformation under compressive loading. A more in-depth understanding of the molecular basis of disc degeneration is essential to the design of therapeutic solutions to treat degenerative discs. Within this scope, we discuss the current knowledge concerning the structure and function of aggrecan in intervertebral disc degeneration. These data suggest that aggrecan plays a central role in the function and degeneration of the intervertebral disc, which may suggest potential aggrecan-based therapies for disc regeneration.

How do policies promote the sustainable development of older-adult care industry? A configuration analysis based on policy tools.

Background: Under the background of population aging in China, the demand for older-adult care services and products is growing, and the older-adult care industry has great development prospects. A sound older-adult care policy system, that is, an effective policy tool mix, plays an important role in improving the sustainable development of older-adult care industry. Materials and methods: Based on older-adult care policy documents from 31 Chinese provinces, this research extracts older-adult care policy tools via text mining. Then extracted policy tools are taken as conditional variables, and the development of older-adult care industry, which is manifested by the number of older-adult care companies across 31 regions is taken as the result variable. Through applying qualitative comparative analysis, the combined effect of different policy tools on the development of older-adult care industry is obtained. Results and discussions: Results show that a single policy tool cannot constitute the necessary condition to facilitate the older-adult care industry. Hence, policy tools should be applied in combination. Five sustainable policy tool mixes which can promote the development of older-adult care industry are summarized, namely supporting policy-driven mode, fiscal and tax support mode led by supply-oriented policy tools, double-team mode driven by fiscal and tax support and the consumer market, multi-subject joint force mode, and technology compensation mode. The overall findings of this study imply that exploring the policy tool combinations is of vital importance to the sustainable development of older-adult care industry.

The stabilization ability of NaA zeolite derived from fly ash for lead and cadmium in soil: Mechanisms and evaluation of effectiveness.

Developing technologies aimed at ecologically restoring is of great significance in addressing the problem of heavy metal pollution. In this study, NaA zeolites (FAZ) originated from fly ash with outstanding performance were prepared by alkali fusion hydrothermal method and used for the solidification and stabilization of heavy metals in soil. After systematic evaluation, it was found that FAZ may lower the leaching concentration of lead (Pb) in soil to <1 mg/kg and increase the stabilization rate of Pb to 80 % in the single Pb-contaminated soil, lower the leaching concentration of cadmium (Cd) in soil to <3 mg/kg and increase the stabilization rate of Cd to 60 % in the single Cd-contaminated soil, and lower the leaching concentration of Pb to 0.15 mg/kg and the leaching concentration of Cd to 0.74 mg/kg in PbCd complex polluted soil. Additionally, Pb stabilization rates reach 60 % and Cd stabilization rates reach 30 %, respectively. Ion exchange is primarily responsible for the adsorption and solidification of Pb and Cd in soil by FAZ. Generally, FAZ has a wide range of applications in the rehabilitation of contaminated soil and significantly lowers the level of heavy metal pollution in soil.

Two-dimensional hyperchaos-based encryption and compression algorithm for agricultural UAV-captured planar images.

This study presents an approach that integrates compressed sensing technology with two-dimensional hyperchaotic coupled Fourier oscillator systems (2D-HCFOS) to address the challenge of slow encryption speeds in agricultural unmanned aerial vehicles (UAVs). The primary challenge in enhancing encryption speed lies in the limited capacity inherent in traditional chaotic-based systems and the computational complexity of their processes. The 2D-HCFOS utilizes a complex two-dimensional hybrid chaotic system, which significantly enhances the security of agricultural UAV image data. Notably, the image encryption process is performed on a personal computer connected to the drone, ensuring efficient processing. By integrating advanced Fourier series and nonlinear coupled oscillators, the model surpasses existing chaotic-based methods, improving both the pseudo-randomness and robustness of encryption. Additionally, incorporating Bonouille functions into the discrete cosine transform (DCT) domain results in a sparser measurement matrix, which is essential for efficient encryption on personal computers. The effectiveness of 2D-HCFOS in securely encrypting agricultural drone images has been rigorously validated through simulations and analytical evaluations using sophisticated row, rotation, and matrix encryption techniques. The improved security performance is further verified by comparative analysis. Compared with other models, the Lyapunov index of 2D-HCFOS is 15.1039, and the sample entropy is 2.4987, indicating that it possesses superior chaotic performance and encryption reliability.

Simultaneous inactivation of Microcystis aeruginosa and degradation of microcystin-LR in water by activation of periodate with sunlight.

Harmful algal blooms pose tremendous threats to ecological safety and human health. In this study, simulated solar light (SSL) irradiation was used to activate periodate (PI) for the inactivation of Microcystis aeruginosa and degradation of microcystin-LR (MC-LR). We found that PI-SSL system could effectively inactivate 5 × 106 cells·mL-1 algal cells below the limit of detection within 180 min. ·OH and iodine (IO3· and IO4·) radicals generated in PI-SSL system could rupture cell membranes, releasing intracellular substances including MC-LR into the reaction system. However, the released MC-LR could be degraded into non-toxic small molecules via hydroxylation and ring cleavage processes in PI-SSL system, reducing their environmental risks. High algae inactivation performance of PI-SSL system in solution with a wide pH range (3-9), with the coexisting anions (Cl-, NO3- and SO42-) and the copresence of natural organic matters (humic acid and fulvic acid), real water (lake water and river water), as well as in continuous-flow reactor (14 h) were also achieved. In addition, under natural sunlight irradiation, effective algae inactivation could also be achieved in an enlarged reactor (1 L). Overall, our study showed that PI-SSL system could avoid the inference by the background substances and could be employed as a feasible technique to treat algal bloom water.

Prediction of prognosis and immunotherapy efficacy based on metabolic landscape in lung adenocarcinoma by bulk, single-cell RNA sequencing and Mendelian randomization analyses.

Immunotherapy has been a remarkable clinical advancement in cancer treatment, but only a few patients benefit from it. Metabolic reprogramming is tightly associated with immunotherapy efficacy and clinical outcomes. However, comprehensively analyzing their relationship is still lacking in lung adenocarcinoma (LUAD). Herein, we evaluated 84 metabolic pathways in TCGA-LUAD by ssGSEA. A matrix of metabolic pathway pairs was generated and a metabolic pathway-pair score (MPPS) model was established by univariable, LASSO, multivariable Cox regression analyses. The differences of metabolic reprogramming, tumor microenvironment (TME), tumor mutation burden and drug sensitivity in different MPPS groups were further explored. WGCNA and 117 machine learning algorithms were performed to identify MPPS-related genes. Single-cell RNA sequencing and in vitro experiments were used to explore the role of C1QTNF6 on TME. The results showed MPPS model accurately predicted prognosis and immunotherapy efficacy of LUAD patients regardless of sequencing platforms. High-MPPS group had worse prognosis, immunotherapy efficacy and lower immune cells infiltration, immune-related genes expression and cancer-immunity cycle scores than low-MPPS group. Seven MPPS-related genes were identified, of which C1QTNF6 was mainly expressed in fibroblasts. High C1QTNF6 expression in fibroblasts was associated with more infiltration of M2 macrophage, Treg cells and less infiltration of NK cells, memory CD8+ T cells. In vitro experiments validated silencing C1QTNF6 in fibroblasts could inhibit M2 macrophage polarization and migration. The study depicted the metabolic landscape of LUAD and constructed a MPPS model to accurately predict prognosis and immunotherapy efficacy. C1QTNF6 was a promising target to regulate M2 macrophage polarization and migration.

Transcriptomic analysis of Paraoxonase 1 expression in hepatocellular carcinoma and its potential impact on tumor immunity.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by a complex pathogenesis that confers aggressive malignancy, leading to a lack of dependable biomarkers for predicting invasion and metastasis, which results in poor prognoses in patients with HCC. Glycogen storage disease (GSD) is an uncommon metabolic disorder marked by hepatomegaly and liver fibrosis. Notably, hepatic adenomas in GSD patients present a heightened risk of malignancy compared to those in individuals without the disorder. In this investigation, PON1 emerged as a potential pivotal gene for HCC through bioinformatics analysis. METHODS: Transcriptomic profiling data of liver cancer were collected and integrated from TCGA and GEO databases. Bioinformatics analysis was conducted to identify mutated mRNAs associated with GSD, and the PON1 gene was selected as a key gene. Patients were grouped based on the expression levels of PON1, and differences in clinical characteristics, biological pathways, immune infiltration, and expression of immune checkpoints were compared. RESULTS: The expression levels of the PON1 gene showed significant differences between the high-expression group and the low-expression group in HCC patients. Further analysis indicated that the PON1 gene at different expression levels might influence the clinical manifestations, biological processes, immune infiltration, and expression of immune checkpoints in HCC. Additionally, immunohistochemistry (IHC) results revealed high expression of PON1 in normal tissues and low expression in HCC tissues. These findings provide important clues and future research directions for the early diagnosis, prognosis, immunotherapy, and potential molecular interactions of HCC. CONCLUSION: Our investigation underscores the noteworthy prognostic significance of PON1 in HCC, suggesting its potential pivotal role in modulating tumor progression and immune cell infiltration. These findings establish PON1 as a novel tumor biomarker with significant implications for the prognosis, targeted therapy, and immunotherapy of patients with HCC.

Oxygen vacancy-dependent synergistic disinfection of antibiotic-resistant bacteria by BiOBr nanoflower induced H2O2 activation.

Antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs) pose a significant threat to both ecosystems and human health. Owing to the excellent catalytic activity, eco-safety, and convenience for defect engineering, BiOBr with oxygen vacancies (OVs) of different density thus were fabricated and employed to activate H2O2 for ARB disinfection/ARGs degradation in present study. We found that BiOBr with OVs of appropriate density induced via ethanol reduction (BOB-E) could effectively activate H2O2, achieving excellent ARB disinfection and ARGs degradation efficiency. Moreover, this disinfection system exhibited remarkable tolerance to complex water environments and actual water conditions. In-situ characterization and theoretical calculations revealed that OVs in BOB-E could effectively capture and activate aqueous H2O2 into HO· and O2·-. The generated reactive oxygen species combined with electron transfer could damage the cell membrane system and degrade genetic materials of ARB, leading to effective disinfection. The impressive reusability, high performance achieved in two immobilized reaction systems (packed column and baffled ditch reactor), excellent degradation of emerging organic pollutants supported the feasibility of BOB-E/H2O2 system towards practical water decontamination. Overall, this study not only provides insights into fabrication of bismuth-based catalysts for efficient ARB disinfection/ARGs degradation via OVs regulation, but also paves the way for their practical applications.

Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomised phase 3 trial.

BACKGROUND: Maintenance treatment of patients with advanced non-small-cell lung cancer (NSCLC) without disease progression after first-line chemotherapy is a subject of ongoing research. The aim of the randomised, double-blind, placebo-controlled, INFORM study was to investigate the efficacy, safety, and tolerability of the EGFR-tyrosine-kinase inhibitor gefitinib in the maintenance setting. METHODS: Patients were aged 18 years or older, were of east Asian ethnic origin, had a life expectancy of more than 12 weeks, histologically or cytologically confirmed stage IIIb or IV NSCLC, a WHO performance status of 0-2, and had completed four cycles of first-line platinum-based doublet chemotherapy without disease progression or unacceptable toxic effects. Between Sept 28, 2008 and Aug 11, 2009, 296 patients were randomly assigned 1:1 to receive either gefitinib (250 mg per day orally) or placebo (orally) within 3-6 weeks after chemotherapy until progression or unacceptable toxic effects. Randomisation was done via an interactive web response system with computer-generated randomisation codes. Our primary endpoint was progression-free survival assessed in the intention-to-treat population. This completed study is registered with Clinicaltrials.gov, number NCT00770588. FINDINGS: Progression-free survival was significantly longer with gefitinib (n=148) than with placebo (148) (median progression-free survival 4·8 months [95% CI 3·2-8·5] vs 2·6 months [1·6-2·8]; hazard ratio [HR] 0·42, 95% CI 0·33-0·55; p<0·0001). Adverse events occurred more frequently with gefitinib than with placebo; the most common adverse events of any grade were rash (73 [50%] of 147 in the gefitinib group vs 14 [9%] of 148 in the placebo group), diarrhoea (37 [25%] vs 13 [9%]), and alanine aminotransferase increase (31 [21%] vs 12 [8%]). The most commonly reported grade 3 or 4 adverse event was alanine aminotransferase increase (3 [2%] of 147 in the gefitinib group, none of 148 in the placebo group). Ten of 147 (7%) patients given gefitinib and five of 148 (3%) patients given placebo had serious adverse events. Three deaths were thought to be related to treatment with gefitinib: one from interstitial lung disease; one from lung infection; and one from pneumonia. INTERPRETATION: Maintenance treatment with gefitinib significantly prolonged progression-free survival compared with placebo in patients from east Asia with advanced NSCLC who achieved disease control after first-line chemotherapy. Clinicians should consider these data when making decisions about maintenance treatment in such patients. FUNDING: AstraZeneca.

The epidemiology and evolutionary dynamics of massive dengue outbreak in China, 2019.

Introduction: In 2019, China experienced massive dengue outbreaks with high incidence and expanded outbreak areas. The study aims to depict dengue's epidemiology and evolutionary dynamics in China and explore the possible origin of these outbreaks. Methods: Records of confirmed dengue cases in 2019 were obtained from the China Notifiable Disease Surveillance System. The sequences of complete envelope gene detected from the outbreak provinces in China in 2019 were retrieved from GenBank. Maximum Likelihood trees were constructed to genotype the viruses. The median-joining network was used to visualize fine-scale genetic relationships. Four methods were used to estimate the selective pressure. Results: A total of 22,688 dengue cases were reported, 71.4% of which were indigenous cases and 28.6% were imported cases (including from abroad and from other domestic provinces). The abroad cases were predominantly imported from Southeast Asia countries (94.6%), with Cambodia (3,234 cases, 58.9%), and Myanmar (1,097 cases, 20.0%) ranked as the top two. A total of 11 provinces with dengue outbreaks were identified in the central-south of China, of which Yunnan and Guangdong provinces had the highest number of imported and indigenous cases. The primary source of imported cases in Yunnan was from Myanmar, while in the other ten provinces, the majority of imported cases were from Cambodia. Guangdong, Yunnan and Guangxi provinces were China's primary sources of domestically imported cases. Phylogenetic analysis of the viruses in outbreak provinces revealed three genotypes: (I, IV, and V) in DENV 1, Cosmopolitan and Asian I genotypes in DENV 2, and two genotypes (I and III) in DENV 3. Some genotypes concurrently circulated in different outbreak provinces. Most of the viruses were clustered with those from Southeast Asia. Haplotype network analysis showed that Southeast Asia, possibly Cambodia and Thailand, was the respective origin of the viruses in clade 1 and 4 for DENV 1. Positive selection was detected at codon 386 in clade 1. Conclusion: Dengue importation from abroad, especially from Southeast Asia, resulted in the dengue epidemic in China in 2019. Domestic transmission between provinces and positive selection on virus evolution may contribute to the massive dengue outbreaks.