Overcoming Secondary Mutations of Type II Kinase Inhibitors.

Type II kinase inhibitors bind in the "DFG-out" kinase conformation and are generally considered to be more potent and selective than type I inhibitors, which target a DFG-in conformation. Nine type II inhibitors are currently clinically approved, with more undergoing clinical development. Resistance-conferring secondary mutations emerged with the first series of type II inhibitors, most commonly at residues within the kinase activation loop and at the "gatekeeper" position. Recently, new inhibitors have been developed to overcome such mutations; however, mutations activating other pathways (and/or other targets) have subsequently emerged on occasion. Here, we systematically summarize the secondary mutations that confer resistance to type II inhibitors, the structural basis for resistance, newer inhibitors designed to overcome resistance, as well as the challenges and opportunities for the development of new inhibitors to overcome secondary kinase domain mutations.

GYY4137-induced p65 sulfhydration protects synovial macrophages against pyroptosis by improving mitochondrial function in osteoarthritis development.

INTRODUCTION: Osteoarthritis (OA) is the most common arthritis that is characterized by the progressive synovial inflammation and loss of articular cartilage. Although GYY4137 is a novel and slow-releasing hydrogen sulfide (H2S) donor with potent anti-inflammatory properties that may modulate the progression of OA, its underlying mechanism remains unclear. OBJECTIVES: In this study, we validated the protective role of GYY4137 against OA pathological courses and elucidated its underlying regulatory mechanisms. METHODS: Cell transfection, immunofluorescence staining, EdU assay, transmission electron microscopy, mitochondrial membrane potential measurement, electrophoretic mobility shift assay, sulfhydration assay, qPCR and western blot assays were performed in the primary mouse chondrocytes or the mouse macrophage cell line raw 264.7 for in vitro study. DMM-induced OA mice model and Macrophage-specific p65 knockout (p65f/f LysM-CreERT2) mice on the C57BL/6 background were used for in vivo study. RESULTS: We found that GYY4137 can alleviate OA progress by suppressing synovium pyroptosis in vivo. Moreover, our in vitro data revealed that GYY4137 attenuates inflammation-induced NLRP3 and caspase-1 activation and results in a decrease of IL-1ß production in macrophages. Mechanistically, GYY4137 increased persulfidation of NF-kB p65 in response to inflammatory stimuli that results in a decrease of cellular reactive oxygen species (ROS) accumulation and ameliorates mitochondrial dysfunctions. Using site-directed mutagenesis, we showed that H2S persulfidates cysteine38 in p65 protein and hampers p65 transcriptional activity, and p65 mutant impaired macrophage responses to GYY4137. CONCLUSION: These findings suggest a mechanism by which GYY4137 through redox modification of p65 participates in inhibiting NLRP3 activation by OA to regulate inflammatory responses. Thus, we propose that GYY4137 represents a promising novel therapeutic strategy for the treatment of OA.

Extracellular vesicles as modifiers of epigenomic profiles.

Extracellular vesicles (EVs), emerging as novel mediators between intercellular communication, encapsulate distinct bioactive cargoes to modulate multiple biological events, such as epigenetic remodeling. In essence, EVs and epigenomic profiles are tightly linked and reciprocally regulated. Epigenetic factors, including histone and DNA modifications, noncoding RNAs, and protein post-translational modifications (PTMs) dynamically regulate EV biogenesis to contribute to EV heterogeneity. Alternatively, EVs actively modify DNA, RNA, and histone profiles in recipient cells by delivering RNA and protein cargoes for downstream epigenetic enzyme regulation. Moreover, EVs display great potential as diagnostic markers and drug-delivery vehicles for therapeutic applications. The combination of parental cell epigenomic modification with single EV characterization would be a promising strategy for EV engineering to enhance the epidrug loading efficacy and accuracy.

Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and ß-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.

Antimicrobial resistance and genome characteristics of Salmonella enteritidis from Huzhou, China.

Salmonella enteritidis is a main pathogen responsible for sporadic outbreaks of gastroenteritis, and therefore is an important public health problem. This study investigated the drug resistance and genomic characteristics of S. enteritidis isolated from clinical and food sources in Huzhou, Zhejiang Province, China, from February 1, 2021, to December 30, 2023. In total, 43 S. enteritidis strains isolated during the study period were subjected to virulence gene, drug resistance gene, genetic correlation, antibiotic resistance, and multilocus sequence typing analyses. All 43 isolates were identified as ST11, and contained 108 virulence-related genes. Drug sensitivity analysis of the 43 isolates showed resistance rates of 100% to nalidixic acid and 90.70% to ampicillin and ampicillin/sulbactam. Multidrug resistance is a serious issue, with 81.40% of strains resistant to three or more antibacterial drugs. Genome sequencing indicated that S. enteritidis possessed 23 drug resistance genes, of which 14 were common to all 43 isolates. Phylogenetic analysis based on core genome single-nucleotide polymorphisms divided the 43 S. enteritidis strains into three clusters, with the 10 samples from an outbreak forming an independent branch located in cluster 3.

Distinct roles of excitatory and inhibitory neurons in the medial prefrontal cortex in the expression and reconsolidation of methamphetamine-associated memory in male mice.

Methamphetamine, a commonly abused drug, is known for its high relapse rate. The persistence of addictive memories associated with methamphetamine poses a significant challenge in preventing relapse. Memory retrieval and subsequent reconsolidation provide an opportunity to disrupt addictive memories. However, the key node in the brain network involved in methamphetamine-associated memory retrieval has not been clearly defined. In this study, using the conditioned place preference in male mice, whole brain c-FOS mapping and functional connectivity analysis, together with chemogenetic manipulations of neural circuits, we identified the medial prefrontal cortex (mPFC) as a critical hub that integrates inputs from the retrosplenial cortex and the ventral tegmental area to support both the expression and reconsolidation of methamphetamine-associated memory during its retrieval. Surprisingly, with further cell-type specific analysis and manipulation, we also observed that methamphetamine-associated memory retrieval activated inhibitory neurons in the mPFC to facilitate memory reconsolidation, while suppressing excitatory neurons to aid memory expression. These findings provide novel insights into the neural circuits and cellular mechanisms involved in the retrieval process of addictive memories. They suggest that targeting the balance between excitation and inhibition in the mPFC during memory retrieval could be a promising treatment strategy to prevent relapse in methamphetamine addiction.

The Effects of Irradiation on the Improvement in Oxidation Behavior of MX-ODS Steel in Liquid Pb.

Lead-cooled fast reactors exhibit strong inherent safety performance and good economic features, while material degradation due to corrosion and irradiation is still challenging. Oxide dispersion-strengthened steels are one of the promising candidates for fuel cladding materials. The effects of both irradiation and corrosion on ODS steel need to be further studied. In this work, MX-ODS steel was irradiated by Fe ions at 500 °C up to 46 dpa. Later, the as-received specimen and the irradiated specimen were used to conduct corrosion tests in oxygen-saturated Pb at 550 °C for 1 h. In the as-received specimen, discontinuous oxides penetrated by Pb and Pb in contact with steel matrix were observed, demonstrating unsatisfactory corrosion resistance of the material. However, in the irradiated specimen after corrosion experiment, a protective oxide layer formed and prevented Pb attack. The oxidation behavior differences between the two specimens can be attributed to the defects produced by irradiation and the structural discrepancy in oxides caused by the formation process. A possible mechanism of irradiation on the corrosion is discussed. In the as-received specimen, Fe atoms loss led to voids in the oxides, and lead penetrated the oxides through these voids. In the irradiated specimen, defects left by previous irradiation helped to form a more uniform oxide layer. The adhesive outer magnetite oxide and the Fe ions generated from where grain boundary oxidation developed retarded the presence of voids and made the oxide layer protective.

Impact of Type 2 Diabetes Mellitus on Left Atrioventricular Coupling and Left Atrial Deformation in Patients with Essential Hypertension: An MRI Feature Tracking Study.

BACKGROUND: Hypertension (HTN) and type 2 diabetes mellitus (T2DM) are both associated with left ventricular (LV) and left atrial (LA) structural and functional abnormalities; however, the relationship between the left atrium and ventricle in this population is unclear. PURPOSE: To identify differences between hypertensive patients with and without T2DM as the basis for further investigation the atrioventricular coupling relationship. STUDY TYPE: Cross-sectional, retrospective study. POPULATION: 89 hypertensive patients without T2DM [HTN (T2DM-)] (age: 58.4 +/- 11.9 years, 48 male), 62 hypertensive patients with T2DM [HTN (T2DM+)] (age: 58.5 +/- 9.1 years, 32 male) and 70 matched controls (age: 55.0 +/- 9.6 years, 37 male). FIELD STRENGTH/SEQUENCE: 2D balanced steady-state free precession cine sequence at 3.0 T. ASSESSMENT: LA reservoir, conduit, and booster strain (εs, εe, and εa) and strain rate (SRs, SRe, and SRa), LV radial, circumferential and longitudinal peak strain (PS) and peak systolic strain rate and peak diastolic strain rate (PSSR and PDSR) were derived from LA and LV cine images and compared between groups. STATISTICAL TESTS: Chi-square or Fisher's exact test, one-way analysis of variance, analysis of covariance, Pearson's correlation, multivariable linear regression analysis, and intraclass correlation coefficient. A P value <0.05 was considered significant. RESULTS: Compared with controls, εs, εe, SRe and PS-longitudinal, PDSR-radial, and PDSR-longitudinal were significantly lower in HTN (T2DM-) group, and they were even lower in HTN (T2DM+) group than in both controls and HTN (T2DM-) group. SRs, εa, SRa, as well as PS-radial, PS-circumferential, PSSR-radial, and PSSR-circumferential were significantly lower in HTN (T2DM+) compared with controls. Multivariable regression analyses demonstrated that: T2DM and PS-circumferential and PS-longitudinal (ß = -4.026, -0.486, and -0.670, respectively) were significantly associated with εs; T2DM and PDSR-radial and PDSR-circumferential were significantly associated with εe (ß = -3.406, -3.352, and -6.290, respectively); T2DM and PDSR-radial were significantly associated with SRe (ß = 0.371 and 0.270, respectively); T2DM and PDSR-longitudinal were significantly associated with εa (ß = -1.831 and 5.215, respectively); and PDSR-longitudinal was significantly associated with SRa (ß = 1.07). DATA CONCLUSION: In hypertensive patients, there was severer LA dysfunction in those with coexisting T2DM, which may be associated with more severe LV dysfunction and suggests adverse atrioventricular coupling. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 3.

The Application Effect of Evidence-Based Targeted Nursing in Severe Preeclamptic Women and Its Impact on Maternal Psychological Status, Quality of Life, and Maternal-Infant Outcomes.

Objective: To analyze the application effect of evidence-based targeted nursing in severe preeclamptic women and its impact on maternal psychological status, quality of life, and maternal-infant outcomes. Methods: A retrospective analysis was conducted on clinical data of 97 severe preeclamptic patients admitted to our hospital from June 2021 to June 2023. All patients met the complete inclusion and exclusion criteria. Based on the different nursing intervention plans received by the patients, they were divided into a control group (n=47) and an observation group (n=50). Patients in the control group received routine nursing intervention, while patients in the observation group received evidence-based targeted nursing. A comparison was made between the two groups in terms of levels of psychological status indicators, quality of life, maternal pregnancy outcomes, neonatal outcomes, Apgar scores, and nursing satisfaction. Results: (1) Psychological status indicators: Before the intervention, the two groups had no significant difference in EPDS scores and SAS scores (P > .05). After the intervention, the EPDS scores and SAS scores in the observation group were significantly lower than those in the control group (P < .05, effect size d = 0.65 for EPDS scores and d = 0.72 for SAS scores), indicating a substantial reduction in depression and anxiety levels. (2) Quality of life: Before the intervention, there was no significant difference in the scores for health status, physiological function, and mental status between the two groups (P > .05). After the intervention, the scores for health status, physiological function, and mental status in the observation group were significantly higher than in the control group (P < .05, effect size d = 0.58 for health status, d = 0.63 for physiological function, and d = 0.61 for mental status), suggesting a notable improvement in the overall quality of life for patients. (3) Maternal pregnancy outcomes: The incidence of adverse pregnancy outcomes in the control group was 42.55%, while in the observation group, it was 18.00%. The incidence of adverse pregnancy outcomes in the observation group was significantly lower than in the control group (P < .05, effect size d = 0.82), indicating a substantial reduction in adverse outcomes. (4) Neonatal outcomes and Apgar scores: The incidence of adverse neonatal outcomes in the control group was 46.81%, with an Apgar score of (7.13±1.05), while in the observation group, it was 22.00%, with an Apgar score of (7.96±1.17). The incidence of adverse neonatal outcomes in the observation group was significantly lower, and the Apgar scores were significantly higher than those in the control group (P < .05, effect size d = 0.73 for adverse neonatal outcomes, and d = 0.68 for Apgar scores), indicating improved neonatal outcomes. (5) Nursing satisfaction: The nursing satisfaction in the control group was 80.85%, whereas in the observation group, it was 96.00%. The nursing satisfaction in the observation group was significantly higher than that in the control group (P < .05, effect size d = 0.86), reflecting a higher level of satisfaction with the evidence-based targeted nursing intervention. Conclusion: Evidence-based targeted nursing intervention in severe preeclamptic women demonstrates significant benefits in improving maternal psychological well-being, quality of life, and maternal-infant outcomes. The intervention effectively reduces depression and anxiety levels, enhances overall quality of life, and reduces the incidence of adverse pregnancy and neonatal outcomes. The use of personalized care plans and enhanced patient education may contribute to these positive outcomes. Furthermore, evidence-based targeted nursing intervention promotes higher levels of nursing satisfaction and fosters better doctor-patient relationships. These findings highlight the importance of implementing evidence-based targeted nursing as a standard approach in the management of severe preeclampsia, ultimately improving the holistic care and well-being of both mothers and infants.

Ideal cardiovascular health index and high-normal blood pressure in elderly people: evidence based on real-world data.

Limited information is available on the cardiovascular health (CVH) index and risk of high-normal blood pressure (HNBP) in elderly people. Randomized cluster sampling, multivariate logistic regression, and mediating effects analysis were used in this study analyze the relationship between CVH index and HNBP in the elderly. 1089 non-hypertensive residents aged 65 years or older completed the study. The positive rate of HNBP was 75.85% (male vs. female: 76.13% vs. 75.64%, P = 0.852); The ideal rate of CVH (ideal CVH index ≥ 5 items) was 14.51% (male vs. female: 15.91% vs. 13.46%, P = 0.256). Compared with people with 0-2 ideal CVH index, the risk of HNBP in people with 4 ideal indexes and ≥ 5 ideal indexes decreased by 50% and 63%, respectively, and their OR (95% CI) were 0.50 (0.31, 0.81) and 0.37 (0.21, 0.66), respectively. The results of the trend test showed that the risk of HNBP decreased by 32% for every increase in the ideal CVH index (trend P < 0.001) and TyG index does not play a mediating role in this relationship. That is, increasing the number of ideal CVH index may effectively reduce the risk of HNBP in elderly by one-third.

Emerging approaches to male contraception.

BACKGROUND: Currently, approximately half of all pregnancies worldwide are unintended. Contraceptive use significantly reduces the risk of unintended pregnancy; however, options for men are particularly limited. Consequently, efforts are underway to develop novel, safe, and effective male contraceptives. RESULTS: This review discusses research into emerging male contraceptive methods that either inhibit sperm production or impair sperm function. It focuses on those in the preclinical or early clinical stages of development.

Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC), a prevalent solid carcinoma of significant concern, is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes. The etiology and pathological progression of non-alcoholic steatohepatitis (NASH)-related HCC is multifactorial and multistage. However, no single animal model can accurately mimic the full NASH-related HCC pathological progression, posing considerable challenges to transition and mechanistic studies. Herein, a novel conditional inducible wild-type human HRAS overexpressed mouse model (HRAS-HCC) was established, demonstrating 100% morbidity and mortality within approximately one month under normal dietary and lifestyle conditions. Advanced symptoms of HCC such as ascites, thrombus, internal hemorrhage, jaundice, and lung metastasis were successfully replicated in mice. In-depth pathological features of NASH- related HCC were demonstrated by pathological staining, biochemical analyses, and typical marker gene detections. Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on protein-protein interaction (PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC. Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

Chlorogenic acid improves the development of porcine parthenogenetic embryos by regulating oxidative stress and ameliorating mitochondrial function.

Chlorogenic acid (CGA) is an effective phenolic antioxidant that can scavenge hydroxyl radicals and superoxide anions. Herein, the protective effects and mechanisms leading to CGA-induced porcine parthenogenetic activation (PA) in early-stage embryos were investigated. Our results showed that 50 µM CGA treatment during the in vitro culture (IVC) period significantly increased the cleavage and blastocyst formation rates and improved the blastocyst quality of porcine early-stage embryos derived from PAs. Then, genes related to zygotic genome activation (ZGA) were identified and investigated, revealing that CGA can promote ZGA in porcine PA early-stage embryos. Further analysis revealed that CGA treatment during the IVC period decreased the abundance of reactive oxygen species (ROS), increased the abundance of glutathione and enhanced the activity of catalase and superoxide dismutase in porcine PA early-stage embryos. Mitochondrial function analysis revealed that CGA increased mitochondrial membrane potential and ATP levels and upregulated the mitochondrial homeostasis-related gene NRF-1 in porcine PA early-stage embryos. In summary, our results suggest that CGA treatment during the IVC period helps porcine PA early-stage embryos by regulating oxidative stress and improving mitochondrial function.

Timing Matters: A Longitudinal Study Examining the Effects of Physical Activity Intensity and Timing on Adolescents' Mental Health Outcomes.

Physical activity is universally acknowledged for its benefits to mental health; however, the specific intensities and timings that best benefit adolescents' mental health, crucial due to their significant influence on daily schedules, have not been thoroughly investigated. This study addresses the substantive research gap by exploring the varied effects of physical activity intensity (light versus moderate to vigorous) and timing (weekdays versus weekends and holidays) on adolescent mental health. Utilizing a large-scale longitudinal dataset (NT1 = 84,054; NT2 = 44,623) from 158 schools, this research describes the current state of adolescent physical activity and investigates the effects of physical activity on mental health outcomes, including positive (i.e., life satisfaction, positive mental health) and negative indicators (depression, anxiety), over a 6-month period. Participants were adolescents aged 9-19 years (mean age = 12.73 ± 2.43 years, 48.9% female), with the analysis adjusted for potential confounding factors. Results showed that as adolescents grow older, their engagement in moderate-to-vigorous physical activity during both weekdays and weekends/holidays tends to decrease, while light physical activity during weekdays increases. Multilevel regression analysis indicated that moderate-to-vigorous physical activity during weekends/holidays at Time 1 positively correlated with better mental health outcomes at Time 2 (six months later), featuring enhanced positive indicators and reduced negative ones. Moderate-to-vigorous physical activity on weekdays at Time 1 was positively linked to mental health at Time 2. Light physical activity during weekends/holidays at Time 1 positively predicted life satisfaction and positive mental health at Time 2. In contrast, light physical activity on weekdays at Time 1 negatively correlated with life satisfaction at Time 2. The study underscores the importance of promoting moderate-to-vigorous physical activity, particularly on weekends and holidays, to improve mental health outcomes among adolescents.

Improving the Prognostic Evaluation Precision of Hospital Outcomes for Heart Failure Using Admission Notes and Clinical Tabular Data: Multimodal Deep Learning Model.

BACKGROUND: Clinical notes contain contextualized information beyond structured data related to patients' past and current health status. OBJECTIVE: This study aimed to design a multimodal deep learning approach to improve the evaluation precision of hospital outcomes for heart failure (HF) using admission clinical notes and easily collected tabular data. METHODS: Data for the development and validation of the multimodal model were retrospectively derived from 3 open-access US databases, including the Medical Information Mart for Intensive Care III v1.4 (MIMIC-III) and MIMIC-IV v1.0, collected from a teaching hospital from 2001 to 2019, and the eICU Collaborative Research Database v1.2, collected from 208 hospitals from 2014 to 2015. The study cohorts consisted of all patients with critical HF. The clinical notes, including chief complaint, history of present illness, physical examination, medical history, and admission medication, as well as clinical variables recorded in electronic health records, were analyzed. We developed a deep learning mortality prediction model for in-hospital patients, which underwent complete internal, prospective, and external evaluation. The Integrated Gradients and SHapley Additive exPlanations (SHAP) methods were used to analyze the importance of risk factors. RESULTS: The study included 9989 (16.4%) patients in the development set, 2497 (14.1%) patients in the internal validation set, 1896 (18.3%) in the prospective validation set, and 7432 (15%) patients in the external validation set. The area under the receiver operating characteristic curve of the models was 0.838 (95% CI 0.827-0.851), 0.849 (95% CI 0.841-0.856), and 0.767 (95% CI 0.762-0.772), for the internal, prospective, and external validation sets, respectively. The area under the receiver operating characteristic curve of the multimodal model outperformed that of the unimodal models in all test sets, and tabular data contributed to higher discrimination. The medical history and physical examination were more useful than other factors in early assessments. CONCLUSIONS: The multimodal deep learning model for combining admission notes and clinical tabular data showed promising efficacy as a potentially novel method in evaluating the risk of mortality in patients with HF, providing more accurate and timely decision support.

Exploring the convergence of ICT, digital financial inclusion, environmental pressures, and free trade and their significance in driving sustainable green investment initiatives under carbon neutrality targets.

Due to its rapid economic development over the past few decades, China is now at the forefront of environmental issues, necessitating creative solutions that combine ICT, digital financial inclusion, environmental pressure, and free trade to encourage green investment. This study aims to investigate the linkage between ICT, digital financial inclusion, environmental pressure, free trade, and green investment in China from 1996 to 2022 by employing the Partial least squares structural equation modelling (PLS-SEM). As per our results, the statistical values of Cronbach's alpha, composite reliability, and average variance are all above the cutoff point, demonstrating the applicability of this methodology. According to the structural model's results, the path coefficients between digital financial inclusion and green investment, environmental pressure and green investment, and GDP and green investment are positively significant, implying that these three factors are crucial for boosting green investment in China. In addition, our vector autoregressive model results suggest that ICT, digital financial inclusion, environmental pressures, free trade, and GDP cause green investment to rise in China. Thus, the policymakers in China should focus on developing comprehensive policies to encourage green investment in China, which is crucial for economic and environmental sustainability.

Utility of waist-to-height ratio, waist circumference and body mass index in predicting clustered cardiometabolic risk factors and subclinical vascular phenotypes in children and adolescents: A pooled analysis of individual data from 14 countries.

AIMS: The clinical utility of waist-to-height ratio (WHtR) in predicting cardiometabolic risk factors (CMRFs) and subclinical markers of cardiovascular disease remains controversial. We aimed to compare the utility of WHtR with waist circumference (WC) and body mass index (BMI) in identifying children and adolescents (youths) at risk for cardiometabolic outcomes, including clustered CMRFs, high carotid intima-media thickness (cIMT), and arterial stiffness (assessed as high pulse wave velocity, PWV). METHODS: We analyzed data from 34,224 youths (51.0 % boys, aged 6-18 years) with CMRFs, 5004 (49.5 % boys, aged 6-18 years) with cIMT measurement, and 3100 (56.4 % boys, aged 6-17 years) with PWV measurement from 20 pediatric samples across 14 countries. RESULTS: WHtR, WC, and BMI z-scores had similar performance in discriminating youths with ≥3 CMRFs, with the area under the curve (AUC) (95 % confidence interval, CI)) ranging from 0.77 (0.75-0.78) to 0.78 (0.76-0.80) using the modified National Cholesterol Education Program (NCEP) definition, and from 0.77 (0.74-0.79) to 0.77 (0.74-0.80) using the International Diabetes Federation (IDF) definition. Similarly, all three measures showed similar performance in discriminating youths with subclinical vascular outcomes, with AUC (95 % CI) ranging from 0.67 (0.64-0.71) to 0.70 (0.66-0.73) for high cIMT (≥P95 values) and from 0.60 (0.58-0.66) to 0.62 (0.58-0.66) for high PWV (≥P95 values). CONCLUSIONS: Our findings suggest that WHtR, WC, and BMI are equally effective in identifying at-risk youths across diverse pediatric populations worldwide. Given its simplicity and ease of use, WHtR could be a preferable option for quickly screening youths with increased cardiometabolic risk in clinical settings.

Synergistic Effect of ZIF-8 and Pt-Functionalized NiO/In2O3 Hollow Nanofibers for Highly Sensitive Detection of Formaldehyde.

A rapid and accurate monitoring of hazardous formaldehyde (HCHO) gas is extremely essential for health protection. However, the high-power consumption and humidity interference still hinder the application of HCHO gas sensors. Hence, zeolitic imidazolate framework-8 (ZIF-8)-loaded Pt-NiO/In2O3 hollow nanofibers (ZPNiIn HNFs) were designed via the electrospinning technique followed by hydrothermal treatment, aiming to enable a synergistic advantage of the surface modification and the construction of a p-n heterostructure to improve the sensing performance of the HCHO gas sensor. The ZPNiIn HNF sensor has a response value of 52.8 to 100 ppm HCHO, a nearly 4-fold enhancement over a pristine In2O3 sensor, at a moderately low temperature of 180 °C, along with rapid response/recovery speed (8/17 s) and excellent humidity tolerance. These enhanced sensing properties can be attributed to the Pt catalysts boosting the catalytic activity, the p-n heterojunctions facilitating the chemical reaction, and the appropriate ZIF-8 loading providing a hydrophobic surface. Our research presents an effective sensing material design strategy for inspiring the development of cost-effective sensors for the accurate detection of indoor HCHO hazardous gas.