Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

Fixed-Duration Pirtobrutinib plus Venetoclax with or without Rituximab in Relapsed/Refractory CLL: Phase 1b BRUIN Trial.

Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial (NCT03740529). Prior covalent BTKi therapy was allowed, but not prior venetoclax. Patients were assigned to receive PV (n=15) or PVR (n=10) for 25 cycles. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4), and 17 (68%) patients had received prior covalent BTKi. At the data-cutoff date (May 5, 2023), median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% CI:68.1-99.8%) for PV and 100% (95% CI:69.2-100.0%) for PVR, with 10 complete responses (PV:7; PVR:3). After 12 cycles of treatment, 85.7% (95% CI:57.2-98.2%) of PV and 90.0% (95% CI:55.5-99.7%) of PVR patients achieved undetectable minimal residual disease assessed in peripheral blood by clonoSEQ® assay at a sensitivity of <1x10-4. Progression-free survival at 18 months was 92.9% (95% CI: 59.1-99.0) for PV patients and 80.0% (95% CI: 40.9-94.6) for PVR patients. No DLTs were observed in either treatment combination during the 5-week assessment period. The most common grade ≥3 adverse events for all patients included neutropenia (52%) and anemia (16%). Adverse events led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi.

Transcription factor GmAlfin09 regulates endoplasmic reticulum stress in soybean via peroxidase GmPRDX6.

Soybean (Glycine max [L.] Merr.) is a valuable oil crop but is also highly susceptible to environmental stress. Thus, developing approaches to enhance soybean stress resistance is vital to soybean yield improvement. In previous studies, transcription factor Alfin has been shown to serve as an epigenetic regulator of plant growth and development. However, no studies on Alfin have yet been reported in soybean. In this study, the endoplasmic reticulum (ER) stress- and reactive oxygen species (ROS)-related GmAlfin09 was identified. Screening of genes co-expressed with GmAlfin09 unexpectedly led to the identification of soybean peroxidase 6 (GmPRDX6). Further analyses revealed that both GmAlfin09 and GmPRDX6 were responsive to ER stress, with GmPRDX6 localizing to the ER under stress. Promoter binding experiments confirmed the ability of GmAlfin09 to bind to the GmPRDX6 promoter directly. When GmAlfin09 and GmPRDX6 were overexpressed in soybean, enhanced ER stress resistance and decreased ROS levels were observed. Together, these findings suggest that GmAlfin09 promotes the upregulation of GmPRDX6, and GmPRDX6 subsequently localizes to the ER, reduces ROS levels, promotes ER homeostasis, and ensures the normal growth of soybean even under ER stress. This study highlights a vital target gene for future molecular breeding of stress-resistant soybean lines.

Construction of Binder-Free, Self-Supported, Hetero-Core-Shell Honeycomb Structured CuCo2 O4 @Ni0.5 Co0.5 (OH)2 with Abundant Mesopores and High Conductivity for High-Performance Energy Storage.

Clever and rational design of structural hierarchy, along with precise component adjustment, holds profound significance for the construction of high-performance supercapacitor electrode materials. In this study, a binder-free self-supported CCO@N0.5 C0.5 OH/NF cathode material is constructed with hierarchical hetero-core-shell honeycomb nanostructure by first growing CuCo2 O4 (CCO) nanopin arrays uniformly on highly conductive nickel foam (NF) substrate, and then anchoring Ni0.5 Co0.5 (OH)2 (N0.5 C0.5 OH) bimetallic hydroxide nanosheet arrays on the CCO nanopin arrays by adjusting the molar ratio of Ni(OH)2 and Co(OH)2 . The constructed CCO@N0.5 C0.5 OH/NF electrode material showcases a wealth of multivalent metal ions and mesopores, along with good electrical conductivity, excellent electrochemical reaction rates, and robust long-term performance (capacitance retention rate of 87.2%). The CCO@N0.5 C0.5 OH/NF electrode, benefiting from the hierarchical structure of the material and the exceptional synergy between multiple components, demonstrates an excellent specific capacitance (2553.6 F g-1 at 1 A g-1 ). Furthermore, the assembled asymmetric CCO@N0.5 C0.5 OH/NF//AC/NF supercapacitor demonstrates a high energy density (70.1 Wh kg-1 at 850 W kg-1 ), and maintains robust capacitance cycling stability performance (83.7%) after undergoing 10 000 successive charges and discharges. It is noteworthy that the assembled supercapacitor exhibits an operating voltage (1.7 V) that is well above the theoretical value (1.5 V).

FURIN suppresses the progression of atherosclerosis by promoting macrophage autophagy.

FURIN, a member of the mammalian proprotein convertases (PCs) family, can promote the proteolytic maturation of proproteins. It has been shown that FURIN plays an important role in the progression of atherosclerosis (AS). Current evidence indicates that autophagy widely participates in atherogenesis. This study aimed to explore whether FURIN could affect atherogenesis via autophagy. The effect of FURIN on autophagy was studied using aortic tissues from aortic dissection patients who had BENTALL surgery, as well as macrophages and ApoE-/- mice. In atherosclerotic plaques of aortic tissues from patients, FURIN expression and autophagy were elevated. In macrophages, FURIN-shRNA and FURIN-overexpression lentivirus were used to intervene in FURIN expression. The results showed that FURIN overexpression accelerated LC3 formation in macrophages during the autophagosome formation phase. Furthermore, FURIN-induced autophagy resulted in lower lipid droplet concentrations in macrophages. The western blot revealed that FURIN regulated autophagy via the AMPK/mTOR/ULK1/PI3KIII signaling pathway. In vivo, FURIN overexpression resulted in increased macrophage LC3 formation in ApoE-/- mice atherosclerotic plaques, confirming that FURIN could inhibit the progression of AS by promoting macrophage autophagy. The present study demonstrated that FURIN suppressed the progression of AS by promoting macrophage autophagy via the AMPK/mTOR/ULK1/PI3KIII signaling pathway, which attenuated atherosclerotic lesion formation. Based on this data, current findings add to our understanding of the complexity of AS.

PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway.

OBJECTIVE: Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication. Phospholipase D2 (PLD2) is crucial in mediating inflammatory reactions and is associated with the prognosis of patients with sepsis. Whether PLD2 is involved in the pathophysiology of SICM remains unknown. This study aimed to investigate the effect of PLD2 knockout on SICM and to explore potential mechanisms. METHODS: The SICM model was established using cecal ligation and puncture in wild-type and PLD2-knockout mice and lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Transfection with PLD2-shRNA lentivirus and a PLD2 overexpression plasmid were used to interfere with PLD2 expression in H9C2 cells. Cardiac pathological alterations, cardiac function, markers of myocardial injury, and inflammatory factors were used to evaluate the SICM model. The expression of pyroptosis-related proteins (NLRP3, cleaved caspase 1, and GSDMD-N) was assessed using western blotting, immunofluorescence, and immunohistochemistry. RESULTS: SICM mice had myocardial tissue damage, increased inflammatory response, and impaired heart function, accompanied by elevated PLD2 expression. PLD2 deletion improved cardiac histological changes, mitigated cTNI production, and enhanced the survival of the SICM mice. Compared with controls, PLD2-knockdown H9C2 exhibits a decrease in inflammatory markers and lactate dehydrogenase production, and scanning electron microscopy results suggest that pyroptosis may be involved. The overexpression of PLD2 increased the expression of NLRP3 in cardiomyocytes. In addition, PLD2 deletion decreased the expression of pyroptosis-related proteins in SICM mice and LPS-induced H9C2 cells. CONCLUSION: PLD2 deletion is involved in SICM pathogenesis and is associated with the inhibition of the myocardial inflammatory response and pyroptosis through the NLRP3/caspase 1/GSDMD pathway.

GOLPH3 inhibits erastin-induced ferroptosis in colorectal cancer cells.

Ferroptosis is a novel form of programmed cell death and is considered to be a druggable target for colorectal cancer (CRC) therapy. However, the role of ferroptosis in CRC and its underlying mechanism are not fully understood. In the present study we found that a protein enriched in the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3), was overexpressed in human CRC tissue and in several CRC cell lines. The expression of GOLPH3 was significantly correlated with the expression of ferroptosis-related genes in CRC. The overexpression of GOLPH3 in Erastin-induced Caco-2 CRC cells reduced ferroptotic phenotypes, whereas the knockdown of GOLPH3 potentiated ferroptosis in HT-29 CRC cells. GOLPH3 induced the expression of prohibitin-1 (PHB1) and prohibitin-2 (PHB2), which also inhibited ferroptosis in Erastin-treated CRC cells. Moreover, GOLPH3 interacted with PHB2 and nuclear factor erythroid 2-related factor 2 (NRF2) in Caco-2 cells. These observations indicate that GOLPH3 is a negative regulator of ferroptosis in CRC cells. GOLPH3 protects these cells from ferroptosis by inducing the expression of PHB1 and PHB2, and by interacting with PHB2 and NRF2.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Characteristic and mechanism of biological nitrogen and phosphorus removal facilitated by biogenic manganese oxides (BioMnOx) at various concentrations of Mn(II).

Biogenic manganese oxides (BioMnOx) have attracted considerable attention as active oxidants, adsorbents, and catalysts. However, characteristics and mechanisms of nitrification-denitrification in biological redox reactions mediated by different concentrations of BioMnOx are still unclear. Fate of nutrients (e.g., NH4+-N, TP, NO3--N) and COD were investigated through different concentrations of BioMnOx produced by Mn(II) in the moving bed biofilm reactor (MBBR). 34% and 89.2%, 37.8% and 89.8%, 57.3% and 88.9%, and 62.1% and 90.4% of TN and COD by MBBR were synchronously removed in four phases, respectively. The result suggested that Mn(II) significantly improved the performance of simultaneous nitrification and denitrification (SND) and TP removal based on manganese (Mn) redox cycling. Characteristics of glutathione peroxidase (GSH-Px), reactive oxygen species (ROS), and electron transfer system activity (ETSA) were discussed, demonstrating that ROS accumulation reduced the ETSA and GSH-Px activities when Mn(II) concentration increased. Extracellular polymeric substance (EPS) function and metabolic pathway of Mn(II) were explored. Furthermore, effect of cellular components on denitrification was evaluated including BioMnOx performances, indicating that Mn(II) promoted the non-enzymatic action of cell fragments. Finally, mechanism of nitrification and denitrification, denitrifying phosphorus and Mn removal was further elucidated through X-ray photoelectron spectroscopy (XPS), high throughput sequencing, and fourier transform infrared reflection (FTIR). This results can bringing new vision for controlling nutrient pollution in redox process of Mn(II).

Microcystin-RR promote lipid accumulation through CD36 mediated signal pathway and fatty acid uptake in HepG2 cells.

Microcystins (MC)-RR is a significant analogue of MC-LR, which has been identified as a hepatotoxin capable of influencing lipid metabolism and promoting the progression of liver-related metabolic diseases. However, the toxicity and biological function of MC-RR are still not well understood. In this study, the toxic effects and its role in lipid metabolism of MC-RR were investigated in hepatoblastoma cells (HepG2cells). The results demonstrated that MC-RR dose-dependently reduced cell viability and induced apoptosis. Additionally, even at low concentrations, MC-RR promoted lipid accumulation through up-regulating levels of triglyceride, total cholesterol, phosphatidylcholines and phosphatidylethaolamine in HepG2 cells, with no impact on cell viability. Proteomics and transcriptomics analysis further revealed significant alterations in the protein and gene expression profiles in HepG2 cells treated with MC-RR. Bioinformatic analysis, along with subsequent validation, indicated the upregulation of CD36 and activation of the AMPK and PI3K/AKT/mTOR in response to MC-RR exposure. Finally, knockdown of CD36 markedly ameliorated MC-RR-induced lipid accumulation in HepG2 cells. These findings collectively suggest that MC-RR promotes lipid accumulation in HepG2 cells through CD36-mediated signal pathway and fatty acid uptake. Our findings provide new insights into the hepatotoxic mechanism of MC-RR.

Epidemiology of plaque-induced gingivitis among 12-15-year-old Chinese schoolchildren: A study based on the 2018 case definition.

AIM: To explore the epidemiology of plaque-induced gingivitis and related factors among Chinese adolescents. MATERIALS AND METHODS: This cross-sectional survey comprised 118,601 schoolchildren in the 12-15-year age group. Data came from the National Oral Health Survey in mainland China. The field investigation was conducted according to the World Health Organization guidelines. The new 2018 case definition for plaque-induced gingivitis was used. Participants underwent clinical examinations and completed a structured questionnaire. Bleeding on probing (BOP) was performed on all teeth. Multinomial logistic regression was used to explore the factors related to the extent of gingivitis. RESULTS: Nearly half of the study population (47.3%) had plaque-induced gingivitis; 23.9% and 23.3% presented with localised and generalised gingivitis, respectively. The first molars were the most affected by BOP. Well-established factors, such as demographic characteristics, socioeconomic status, local factors and smoking habits, were significantly associated with the extent of gingivitis. Odds ratios for localised and generalised gingivitis increased with the decrease in frequency of toothbrushing with a fluoride dentifrice. CONCLUSIONS: The study population had high plaque-induced gingivitis prevalence. The extent of gingivitis appeared to have a dose-response relationship with the frequency of toothbrushing with a fluoride dentifrice.

Long-term exposure to ambient fine particulate matter and periodontitis: An observational study using nationally representative survey data.

AIM: The rising prevalence of periodontitis imposes substantial burdens on individuals and society. Identifying environmental risk factors for periodontitis may contribute to tackling the global public health burden of it. This study aimed to assess the association between long-term exposure to PM2.5 and periodontitis in a nationally representative population from China. MATERIALS AND METHODS: In this multi-centre cross-sectional study of 372 communities in 31 provinces of Mainland China, we used data from the Fourth National Oral Health Survey of China in 2015-2016, in combination with high-resolution gridded concentrations of fine particulate matter (PM2.5). Logistic regression was applied to assess the relationship between long-term PM2.5 exposure and the risk of periodontitis. In addition, we examined whether the association varied by individual characteristics, and estimated the exposure-response relationship and the risk of damaged tooth in each tooth quadrant. RESULTS: A total of 8391 participants from 96 cities were diagnosed with periodontitis, accounting for 60.04% (8391/13,459) of the participants. For each 10 µg/m3 increment in 1-, 3- and 5-year average concentrations of PM2.5, the risk of total periodontitis increased by 9.0% (95% confidence interval: 6.0%, 12.0%), 8.0% (6.0, 11·0) and 7.0% (5.0, 10.0), respectively. Mild periodontitis was more strongly associated with PM2.5 exposure than moderate and severe periodontitis. The teeth in the lower anterior, lower posterior or upper anterior are more susceptible to the effect of PM2.5 on the periodontal pocket, calculus and bleeding gums. CONCLUSIONS: Long-term exposure to PM2.5 is significantly associated with an increased risk of periodontitis in the nationally representative Chinese population. Considering the rising prevalence of periodontitis, considerable costs of treatment, and substantially adverse effects on individuals and society, these findings suggest that stricter air quality regulations may help ease the burden of periodontal disease.

Epidemiology of mental health comorbidity in patients with atopic dermatitis: An analysis of global trends from 1998 to 2022.

The prevalence rates of attention deficit hyperactivity disorder (ADHD), depression, anxiety and suicide are increasing in patients with atopic dermatitis (AD), although no research has systematically examined these trends yet. Here, we explore the prevalence of the occurrence of comorbidities, such as ADHD, depression, anxiety and suicide with AD. We searched seven electronic databases from inception to October 2022 to identify relevant studies, and the Agency for Healthcare Research and Quality (AHRQ) and Newcastle-Ottawa Scale (NOS) tools were used to assess the quality of observational studies. Statistical analysis was performed using R software. Publication bias was evaluated using Egger's and Begg's linear tests. The global prevalence rates of ADHD, depression, anxiety and suicidal ideation in patients with AD were 7%, 17%, 21% and 13%, respectively, between 1998 and October 2022. Among children (aged <18 years), North American children with AD had the highest prevalence rates of ADHD (10%), depression (13%) and anxiety (20%). Among the adult (aged ≥18 years) population, patients with AD in Africa had the highest prevalence rates of depression (36%) and anxiety (44%), while Asian adults with AD had the highest prevalence rates of ADHD (7%) and suicidal ideation (20%). These results highlight the high prevalence and comorbidity rates of mental illnesses with AD, which should be brought to the attention of patients with AD and their physicians.

Triphenyl phosphate (TPP) exposure promotes proliferation and migration capabilities of gastric cancer cells: Insights from gene expression and pathway analysis.

BACKGROUND: Gastric cancer is a leading cause of cancer-related deaths influenced by both genetic and environmental factors. Triphenyl phosphate (TPP) is a prevalent flame retardant, but its health implications remain to be thoroughly understood. OBJECTIVE: To explore the link between TPP exposure and gastric cancer by examining gene expression patterns and developing a predictive model. METHODS: Gene expression data were sourced from The Cancer Genome Atlas (TCGA) and the Comparative Toxicogenomics Database (CTD). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were employed for analysis. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to obtain phosphate flame retardant-related scores. A predictive model was constructed through differential analysis, univariate COX regression, and LASSO regression. Molecular docking was performed to assess protein interactions with TPP. RESULTS: ssGSEA identified scores related to phosphate flame retardants in gastric cancer, which had a strong association with immune-related traits. Several genes associated with TPP were identified and used to develop a prognostic model that has clinical significance. Molecular docking showed a high binding affinity of TPP with MTTP, a gene related to lipid metabolism. Pathway analysis indicated that TPP exposure contributes to gastric cancer through lipid metabolic processes. CONCLUSION: The study establishes a potential correlation between TPP exposure and gastric cancer onset, pinpointing key genes and pathways involved. This underscores the significance of environmental factors in gastric cancer research and presents a potential diagnostic tool for clinical application.

Heavy metals in drinking water and periodontitis: evidence from the national oral health survey from China.

BACKGROUND: Periodontitis has become an increasingly important public health issue, coupled with a high economic burden for prevention and treatment. Exposure to essential trace heavy metals has been associated with various diseases; however, the relationships between essential trace heavy metals and periodontitis remain inconclusive. OBJECTIVES: To investigate the association between essential trace heavy metals in tap water and periodontitis in a nationally representative sample in China. METHODS: We conducted a nationwide study including 1348 participants from the Fourth National Oral Health Survey in the 2015-2016 period. The trace heavy metals concentration was measured in the local pipeline terminal tap water. Periodontitis was diagnosed according to the classification scheme proposed at the 2018 world workshop on the classification of periodontal and peri-implant diseases and conditions. We used weighted multivariable logistic regression to estimate the association between essential trace heavy metals and the risk of periodontitis. We additionally used spline analysis to explore the possible nonlinear dose-response associations. RESULTS: Periodontitis patients were exposed to higher concentrations of essential trace heavy metals. In adjusted models, for 1 SD increase in the concentration of iron, manganese, and copper in tap water, the risk of periodontitis increased by 30% (OR: 1.30, 95%CI: 1.12-1.50), 20% (OR: 1.20, 95%CI: 1.03-1.41), and 20% (OR: 1.20, 95%CI: 1.04-1.39), respectively. Stratified analyses demonstrated that the associations between essential trace heavy metals and periodontitis were higher in females, elders, and rural residents. Spline analysis revealed nonlinear exposure-response relationships between periodontitis and exposure to iron, manganese, and copper in tap water. CONCLUSIONS: Exposures to essential trace heavy metals in drinking water were associated with greater odds of periodontitis. Given the growing burden of periodontitis, our study sheds light on tailored public health policies for improving drinking water standards to alleviate periodontitis impairment.

On the urban resource and environment carrying capacity in China: A sustainable development paradigm.

As urbanization progresses, the number of resource and environmental problems that impede sustainable growth in cities is increasing. The urban resource and environment carrying capacity (URECC) serves as a crucial indicator for understanding the interaction between human activities and urban resource and environmental systems, guiding the practice of sustainable urban development. Thus, accurately comprehending and analyzing the URECC and coordinating the balanced growth of the economy and the URECC is essential to ensure cities' sustainable development. In this research, we combine DMSP/OLS and NPP/VIIRS night-time light data to assess the economic growth of Chinese cities using panel data for 282 prefecture-level cities in China from 2007 to 2019. The findings reveal the following outcomes: (1) Economic growth significantly contributes to the enhancement of the URECC, and the economic expansion of neighboring areas also promotes the URECC within the region. Economic growth can indirectly improve the URECC by fostering internet development, industrial upgrading, technological progress, opening up opportunities, and educational advancements. (2) The results from the threshold regression analysis suggest that as the level of internet development improves, the influence of economic growth on the URECC is initially constrained and then facilitated. Similarly, as financial development improves, the effect of economic growth on the URECC is initially constrained and subsequently promoted, with the promotion effect gradually increasing. (3) The relationship between economic expansion and the URECC varies across regions with different geographic locations, administrative levels, scales, and resource endowments.

Identifying the nexus among environmental performance, digital finance, and green innovation: New evidence from prefecture-level cities in China.

Globally, nations are increasingly focusing on green innovation in their environmental protection efforts as part of sustainable development, and digital finance is playing a vital role in enhancing green innovation. Employing annual data from 220 prefecture-level cities between 2011 and 2019, we empirically analyze the connections among environmental performance, digital finance, and green innovation via the Karavias panel unit root test with structural breaks, the Gregory-Hansen structural break cointegration test and pooled mean group (PMG) estimation. The following four points are the key conclusions: (1) The results support cointegration links between these variables when structural breaks are considered. (2) The PMG estimation outcomes indicate that green innovation and digital finance may have a favorable long-term effect on environmental performance. (3) For better environmental performance and more green innovation, the level of digitalization of digital finance is crucial. (4) The potential of digital finance and green innovation to improve environmental performance has not been fully realized in the western region of China.

Tooth brushing with fluoridated toothpaste and associated factors among Chinese adolescents: a nationwide cross-sectional study.

BACKGROUND: Tooth brushing with fluoridated toothpaste has become the most important way to provide the anti-caries effect of fluoride around the world. China has promoted the use of fluoridated toothpaste since 1989. However, there are few studies on the national profile of use of fluoridated toothpaste and related factors in Chinese adolescents. We carried out this study to investigate oral hygiene behaviours, especially the status of tooth brushing with fluoridated toothpaste and its correlates among adolescents, based on data from the latest Nation Oral Health Survey in mainland China. METHODS: This cross-sectional study recruited 118,601 participants aged 12-15 years using multistage stratified sampling. Questionnaires were completed by students at school. Data employed in analyses were extracted from the questionnaire, including information on tooth brushing, fluoridated toothpaste, dental floss, sociodemographic factors, fluoride knowledge and attitude towards regular dental check-ups. A binary logistic regression was performed to compute the odds ratios (OR). Tooth brushing twice daily with fluoridated toothpaste was the dependent variable. Sociodemographic factors, fluoride knowledge, attitude towards regular dental check-ups, dental visit experience and perceived oral health were the independent variables. P < 0.05 was considered statistically significant. RESULTS: A total of 32.6% of participants brushed their teeth twice daily, 7.4% used fluoridated toothpaste, and 3.9% cleaned their teeth twice daily with fluoridated toothpaste. The logistic regression showed the probability of twice-a-day tooth brushing with fluoridated toothpaste was higher among these groups: females (OR: 1.141; 95%CI: 1.072-1.214), 15-year-olds (OR: 1.786; 95%CI: 1.634-1.952), from urban areas (OR: 1.389; 95%CI: 1.288-1.497), without siblings (OR: 1.351; 95%CI: 1.259-1.450), with an educated father (OR: 1. 605; 95%CI: 1.442-1.788) and mother (OR: 1.706; 95%CI: 1.530-1.903), having dental visit experiences (OR: 1.702; 95%CI: 1.589-1.823), rating one's oral health as good (OR: 2.341; 95%CI: 2.083-2.631), having fluoride knowledge (OR: 4.345; 95%CI: 4.034-4.678) and having a positive attitude towards regular dental check-ups (OR: 1.589; 95%CI: 1.460-1.729). CONCLUSIONS: The oral hygiene behaviours of Chinese adolescents were undesirable. Twice daily tooth brushing with fluoridated toothpaste was significantly associated with sociodemographic factors, fluoride knowledge, and attitudes towards regular dental check-ups.

Decomposing socioeconomic inequalities in dental caries among Chinese adults: findings from the 4th national oral health survey.

OBJECTIVE: This cross-sectional study aimed to investigate socioeconomic inequalities in dental caries among adults (35 years and older) in China and explore the contributions of various factors to these inequalities. METHODS: This study included 10,983 adults (3,674 aged 35-44 years, 3,769 aged 55-64 years and 3,540 aged 65-74 years) who participated in the 4th National Oral Health Survey (2015-2016) in China. Dental caries status was evaluated by the decayed, missing and filled teeth (DMFT) index. Concentration indices (CIs) were applied to quantify the different degrees of socioeconomic-related inequality in DMFT, decayed teeth with crown or root caries (DT), missing teeth due to caries or other reasons (MT), and filled teeth without any primary or secondary caries (FT) among adults of different age groups. Decomposition analyses were conducted to identify the determinants and their associations with inequalities in DMFT. RESULTS: The significant negative CI indicated that DMFT for the total sample were concentrated among socioeconomically disadvantaged adults (CI = - 0.06; 95% confidence interval [CI], - 0.073 to - 0.047). The CIs for DMFT for adults aged 55-64 and 65-74 years were - 0.038 (95% CI, - 0.057 to - 0.018) and - 0.039 (95% CI, - 0.056 to - 0.023), respectively, while the CI for DMFT for adults aged 35-44 years was not statistically significant (CI = - 0.002; 95% CI, - 0.022 to 0.018). The concentration indices of DT were negative and concentrated in disadvantaged populations, while FT showed pro-rich inequalities in all age groups. Decomposition analyses showed that age, education level, toothbrushing frequency, income and type of insurance contributed substantially to socioeconomic inequalities, accounting for 47.9%, 29.9%, 24.5%,19.1%, and 15.3%, respectively. CONCLUSION: Dental caries was disproportionately concentrated among socioeconomically disadvantaged adults in China. The results of these decomposition analyses are informative for policy-makers attempting to develop targeted health policy recommendations to reduce dental caries inequalities in China.

Ramucirumab for Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha Fetoprotein Following Non-Sorafenib Systemic Therapy: An Expansion Cohort of REACH-2.

BACKGROUND: Ramucirumab is indicated for patients with advanced hepatocellular carcinoma (HCC) and α-fetoprotein (AFP) ≥400 ng/mL following sorafenib. Here, we prospectively studied ramucirumab following non-sorafenib systemic therapies. MATERIALS AND METHODS: This open-label, non-comparative cohort of REACH-2 enrolled patients with advanced HCC, Child-Pugh class-A liver disease, and AFP ≥400 ng/mL who had received 1-2 lines of therapy, excluding sorafenib or chemotherapy. Ramucirumab was administered 8 mg/kg intravenously Q2W. The primary endpoint was safety. Secondary endpoints were overall survival, progression-free survival, objective response rate (RECIST v1.1), time to progression, pharmacokinetics, and patient-reported outcomes. Final analysis occurred after all enrolled patients completed ≥3 treatment cycles or discontinued treatment. RESULTS: Between April 27, 2018, and March 29, 2021, 47 patients were treated at 21 investigative sites in Asia, Europe, and USA. The most frequently reported grade ≥3 adverse events, regardless of causality, were hypertension (11%), proteinuria (6%), hyponatremia (6%), and AST increased (6%). Two patients died from adverse events (myocardial infarction and upper gastrointestinal hemorrhage), deemed related to treatment. Median progression-free survival, time to progression, and overall survival were 1.7 months, 2.8 months, and 8.7 months, respectively. The objective response rate was 10.6% with a median duration response of 8.3 months. Median time to deterioration in FHSI-8 total score was 4.4 months. CONCLUSION: Ramucirumab demonstrated consistent and meaningful clinical activity with no new safety signals following non-sorafenib therapies in patients with advanced HCC and AFP ≥400 ng/mL. This represents one of the first sequencing studies for patients with advanced HCC not treated with sorafenib.