Quality control of elbow joint radiography using a YOLOv8-based artificial intelligence technology.

BACKGROUND: To explore an artificial intelligence (AI) technology employing YOLOv8 for quality control (QC) on elbow joint radiographs. METHODS: From January 2022 to August 2023, 2643 consecutive elbow radiographs were collected and randomly assigned to the training, validation, and test sets in a 6:2:2 ratio. We proposed the anteroposterior (AP) and lateral (LAT) models to identify target detection boxes and key points on elbow radiographs using YOLOv8. These identifications were transformed into five quality standards: (1) AP elbow positioning coordinates (XA and YA); (2) olecranon fossa positioning distance parameters (S17 and S27); (3) key points of joint space (Y3, Y4, Y5 and Y6); (4) LAT elbow positioning coordinates (X2 and Y2); and (5) flexion angle. Models were trained and validated using 2,120 radiographs. A test set of 523 radiographs was used for assessing the agreement between AI and physician and to evaluate clinical efficiency of models. RESULTS: The AP and LAT models demonstrated high precision, recall, and mean average precision for identifying boxes and points. AI and physicians showed high intraclass correlation coefficient (ICC) in evaluating: AP coordinates XA (0.987) and YA (0.991); olecranon fossa parameters S17 (0.964) and S27 (0.951); key points Y3 (0.998), Y4 (0.997), Y5 (0.998) and Y6 (0.959); LAT coordinates X2 (0.994) and Y2 (0.986); and flexion angle (0.865). Compared to manual methods, using AI, QC time was reduced by 43% for AP images and 45% for LAT images (p < 0.001). CONCLUSION: YOLOv8-based AI technology is feasible for QC of elbow radiography with high performance. RELEVANCE STATEMENT: This study proposed and validated a YOLOv8-based AI model for automated quality control in elbow radiography, obtaining high efficiency in clinical settings. KEY POINTS: QC of elbow joint radiography is important for detecting diseases. Models based on YOLOv8 are proposed and perform well in image QC. Models offer objective and efficient solutions for QC in elbow joint radiographs.

Clinical characteristics and risk factors of osteoporosis among older Asian men with type-2 diabetes mellitus, hypertension, or hyperlipidaemia.

This study investigated osteoporosis risk factors among older Asian men with type-2 diabetes mellitus, hypertension, or hyperlipidaemia in primary care. Advanced age, dementia, depression, and polypharmacy were associated with higher risks for osteoporosis. Screening strategies targeting these factors are crucial for improving bone health as part of comprehensive preventive care. PURPOSE: Asian patients with type-2 diabetes mellitus (T2DM), hypertension, or hyperlipidaemia (DHL) are predominantly managed in primary care. They are also at risk of osteoporosis, but men are often under-screened and under-treated for this preventable bone disorder. This study aimed to identify the clinical characteristics and risk factors of osteoporosis among older men with DHL in primary care for early intervention. METHODS: This retrospective study included men aged 65 years and older managed in public primary care clinics for their DHL between 1st July 2017 and 30th June 2018. Demographic, clinical, laboratory, and imaging data were extracted from their electronic medical records based on their International Classification of Diseases-10 (ICD-10) diagnosis codes. Descriptive statistical analyses, with statistical significance set at p < 0.05, were conducted, followed by generalized estimating equation (GEE) modelling. RESULTS: Medical records of 17,644 men (83.1% Chinese, 16.9% minority ethnic groups, median age 71 years) were analysed. 2.3% of them had diagnosis of osteoporosis, 0.15% had fragility fracture, and 26.0% of those diagnosed with osteoporosis were treated with bisphosphonates. Their mean HbA1c was 6.9%; mean systolic and diastolic blood pressure were 133 and 69 mmHg. The GEE model showed that age (OR = 1.07, 95%CI = 1.05-1.09, p < 0.001), dementia (OR = 2.24, 95%CI = 1.33-3.77, p = 0.002), depression (OR = 2.38, 95%CI = 1.03-5.50, p = 0.043), and polypharmacy (OR = 6.85, 95%CI = 3.07-15.26, p < 0.001) were significantly associated with higher risks for osteoporosis. CONCLUSION: Age, dementia, depression, and polypharmacy are associated with osteoporosis risks in men with DHL. Strategies to incorporate osteoporosis screening among older men with these risk factors are needed to improve their bone health.

One step toward precision dosing of caffeine in preterm infants: An external evaluation of published population pharmacokinetic models.

BACKGROUND: Several population pharmacokinetic (PopPK) models of caffeine in preterm infants have been published, but the extrapolation of these models to facilitate model-informed precision dosing (MIPD) in clinical practice is uncertain. This study aimed to comprehensively evaluate their predictive performance using an external, independent dataset. METHODS: Data used for external evaluation were based on an independent cohort of preterm infants. Currently available PopPK models for caffeine in preterm infants were identified and re-established. Prediction- and simulation-based diagnostics were used to assess model predictability. The influence of prior information was assessed using Bayesian forecasting. RESULTS: 120 plasma samples from 76 preterm infants were included in the evaluation dataset. Twelve PopPK models of caffeine in preterm infants were re-established based on our previously published study. Although two models showed superior predictive performance, none of the 12 PopPK models met all the clinical acceptance criteria of these external evaluation items. Besides, the external predictive performances of most models were unsatisfactory in prediction- and simulation-based diagnostics. Nevertheless, the application of Bayesian forecasting significantly improved the predictive performance, even with only one prior observation. CONCLUSIONS: Two models that included the most covariates had the best predictive performance across all external assessments. Inclusion of different covariates, heterogeneity of preterm infant characteristics, and different study designs influenced predictive performance. Thorough evaluation is needed before these PopPK models can be implemented in clinical practice. The implementation of MIPD for caffeine in preterm infants could benefit from the combination of PopPK models and Bayesian forecasting as a helpful tool.

Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction.

Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.

Development and application of a population pharmacokinetic model repository for caffeine dose tailoring in preterm infants.

BACKGROUND: Considerable interindividual variability for the pharmacokinetics of caffeine in preterm infants has been demonstrated, emphasizing the importance of personalized dosing. This study aimed to develop and apply a repository of currently published population pharmacokinetic (PopPK) models of caffeine in preterm infants to facilitate model-informed precision dosing (MIPD). RESEARCH DESIGN AND METHODS: Literature search was conducted using PubMed, Embase, Scopus, and Web of Science databases. Relevant publications were screened, and their quality was assessed. PopPK models were reestablished to develop the model repository. Covariate effects were evaluated and the concentration-time profiles were simulated. An online simulation and calculation tool was developed as an instance. RESULTS: Twelve PopPK models were finally included in the repository. Preterm infants' age and body size, especially the postnatal age and current weight, were identified as the most clinically critical covariates. Simulated blood concentration-time profiles across these models were comparable. Caffeine citrate-dose regimen should be adjusted according to the age and body size of preterm infants. The developed online tool can be used to facilitate clinical decision-making. CONCLUSIONS: The first developed repository of PopPK models for caffeine in preterm infants has a wide range of potential applications in the MIPD of caffeine.

Original antigenic sin: A potential double-edged effect for vaccine improvement.

Original antigenic sin (OAS) influences the immune response to subsequent infections with related variants following initial pathogen exposure. This phenomenon is characterized by cross-reactivity, which, although it may worsen infections, also provides a degree of protection against immune evasion caused by variations. This paradox complicates the development of creating universal vaccinations, as they frequently show diminished effectiveness against these emerging variants. This review aims to elucidate the diverse impacts of OAS on the immune response to various infections, emphasizing the complicated balance between beneficial and harmful outcomes. Moreover, we evaluate the influence of adjuvants and other variables on the extent of OAS, hence affecting the effectiveness of vaccines. Understanding the mechanisms of OAS that cause persistent infections and evasion of the immune system is crucial for the developing innovative vaccines. And it has significant potential for clinical applications.

Youths' awareness and attitudes towards raising the minimum legal age of smoking and passive smoking in Singapore.

Objectives: Early smoking initiation has been associated with a higher risk of developing long-term smoking habit. There is a growing global consensus that demands raising the minimum legal age (MLA) for smoking as an approach to address this problem. Singapore successfully raised the MLA from 18 to 21 years in 2021. This study aimed to evaluate the awareness and attitude of multi-ethnic Asian youth (aged 15-24) on raising MLA to 21 and passive smoking. Methods: A cross-sectional survey comprising of 23 items was circulated via a secure internet-based platform, FORMSG between September and November 2022. Data were analyzed for descriptive statistics. Categorical variables were compared for association with receptivity toward change in MLA using Chi-Squared test and multivariable logistic regression analysis using Rstudio. Post-hoc Bonferroni correction were further utilized for pairwise comparison. Results: Majority (80.3%) of the 608 participants expressed their support for MLA 21 implementation. Participants' age was a significant variable as those aged 15-17 years old (OR = 2.1, 95%CI = 1.01-4.32, p = 0.048) showed a higher likelihood of supporting MLA implementation compared to those aged 21 and above. In addition, majority (89.8%) of them were also aware of the harmful effects of passive smoking. When it came to discouraging smoking among youth, family influence (64%) and school education (55.6%) emerged as the top strategies. Conclusion: Most of the youth express strong support for raising the MLA to 21, with over 80% in favor of such change, reflects a significant harmony among youth in favor of tobacco-free environment.

Population pharmacokinetics of valproic acid in children with epilepsy: Implications for dose tailoring when switching from oral syrup to sustained-release tablets.

Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady-state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20-50 kg. As a result, the PK characteristics of VPA were described using a one-compartment model with first-order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h-1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.

Molecular Mechanism of Interaction between DNA Aptamer and Receptor-Binding Domain of Severe Acute Respiratory Syndrome Coronavirus 2 Variants Revealed by Steered Molecular Dynamics Simulations.

The ongoing SARS-CoV-2 pandemic has underscored the urgent need for versatile and rapidly deployable antiviral strategies. While vaccines have been pivotal in controlling the spread of the virus, the emergence of new variants continues to pose significant challenges to global health. Here, our study focuses on a novel approach to antiviral therapy using DNA aptamers, short oligonucleotides with high specificity and affinity for their targets, as potential inhibitors against the spike protein of SARS-CoV-2 variants Omicron and JN.1. Our research utilizes steered molecular dynamics (SMD) simulations to elucidate the binding mechanisms of a specifically designed DNA aptamer, AM032-4, to the receptor-binding domain (RBD) of the aforementioned variants. The simulations reveal detailed molecular insights into the aptamer-RBD interaction, demonstrating the aptamer's potential to maintain effective binding in the face of rapid viral evolution. Our work not only demonstrates the dynamic interaction between aptamer-RBD for possible antiviral therapy but also introduces a computational method to study aptamer-protein interactions.

A Brillouin microscopy analysis of the crystalline lenses of Chinese adults with myopia.

To evaluate lenticular biomechanical and geometric parameters in Chinese adults with myopia and identify relevant factors using Brillouin microscopy (BM) and Pentacam. The biomechanical and geometric properties of the ocular lenses of Chinese adults with myopia were quantified using BM. Anterior segment images were acquired using a Pentacam. Correlated factors including age, sex, spherical equivalent (SE), intraocular pressure (IOP), axial length (AL), white-to-white ratio (WTW), central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber volume (ACV), and anterior chamber angle (ACA) were analyzed. We studied 65 eyes from 65 participants (mean age, 25.23 ± 6.12 years). Width of Top Plateau (WTP), Width of Bottom Plateau (WBP), Slope of Anterior Cortex (SAC), Slope of Posterior Cortex (SPC), and Height of Plateau (Height) metrics obtained using BM showed mean values of 2.597 ± 0.393 mm, 4.310 ± 0.535 mm, 1.344 ± 0.549 GPa/mm, -1.343 ± 0.480 GPa/mm, and 3.373 ± 0.048 GPa, respectively. No significant correlation was found between these parameters and sex, SE, IOP, CCT, ACA, or Height. Interestingly, WBP (r = 0.467, P < 0.001), SAC (r = 0.412, P = 0.001), and SPC (r = -0.280, P = 0.024) were significantly associated with age, and an age-related increase of WBP (slope of 35.36 ± 10.08 µm per year) was identified. Both ACD and ACV showed significant correlations with SAC (r = 0.329 and 0.380, P = 0.008 and 0.002, respectively), but not with SPC. BM provided a novel perspective on lenticular biomechanical and geometric properties in Chinese adults with myopia, which correlated with age, AL, WTW, ACD, and ACV.

Upgrading Gel Electrolytes Through Electrostatic-Induced Dual-Salt Paradigm for Superior Zn-Ion Battery Performance.

Gel electrolytes are gaining attention for rechargeable Zn-ion batteries because of their high safety, high flexibility, and excellent comprehensive electrochemical performances. However, current gel electrolytes still perform at mediocre levels due to incomplete Zn salts dissociation and side reactions. Herein, an electrostatic-induced dual-salt strategy is proposed to upgrade gel electrolytes to tackle intrinsic issues of Zn metal anodes. The competitive coordination mechanism driven by electrostatic repulsion and steric hindrance of dual anions promotes zinc salt dissociation at low lithium salt addition levels, improving ion transport and mechanical properties of gel electrolytes. Li+ ions and gel components coordinate with H2O, reducing active H2O molecules and inhibiting associated side reactions. The dual-salt gel electrolyte enables excellent reversibility of Zn anodes at both room and low temperatures. Zn||Polyaniline cells using the dual-salt gel electrolyte exhibit a high discharge capacity of 180 mAh g-1 and long-term cycling stability over 180 cycles at -20 °C. The dual-salt strategy offers a cost-effective approach to improving gel electrolytes for high-performance flexible Zn-ion batteries.

Proteomic Identification of Small Extracellular Vesicle Proteins LAMB1 and Histone H4 for Prostate Cancer Diagnosis and Risk Stratification.

Diagnosis and stratification of prostate cancer (PCa) patients using the prostate-specific antigen (PSA) test is challenging. Extracellular vesicles (EVs), as a new star of liquid biopsy, has attracted interest to complement inaccurate PSA screening and invasiveness of tissue biopsy. In this study, a panel of potential small EV (sEV) protein biomarkers is identified from PCa cell lines using label-free LC-MS/MS proteomics. These biomarkers underwent further validation with plasma and urine samples from different PCa stages through parallel reaction monitoring-based targeted proteomics, western blotting, and ELISA. Additionally, a tissue microarray containing cancerous and noncancerous tissues is screened to provide additional evidence of selected sEV proteins associated with cancer origin. Results indicate that sEV protein LAMB1 is highly expressed in human plasma of metastatic PCa patients compared with localised PCa patients and control subjects, while sEV protein Histone H4 is highly expressed in human urine of high-risk PCa patients compared to low-risk PCa patients and control subjects. These two sEV proteins demonstrate higher specificity and sensitivity than the PSA test and show promise for metastatic PCa diagnosis, progression monitoring, and risk stratification.

Effect of different iron ratios on interaction and thermodynamic stability of bound whey protein isolate.

Whey protein isolates (WPI) are known to have mineral-binding capacity to promote iron absorption. The aim of this study was to investigate the effect of iron ratio on the conformational structure of iron-bound whey protein isolate (WPI-Fe) and its thermodynamic stability. It was shown that the iron to protein ratio affects both the iron binding capacity of WPI and the iron valence state on the surface of WPI-Fe complexes. As the iron content increases, aggregation between protein molecules occurs. In addition, WPI-Fe nanoparticles have thermodynamic stability and Fe2+ has a high affinity with WPI for spontaneous exothermic reactions. This study demonstrates that WPI-Fe complexes can be used to efficiently deliver high-quality iron source (Fe2+) for future iron supplements.

Literacy and attitude of Asian youths on dengue and its prevention in an endemic developed community.

Background: Over the past few decades, the incidence of dengue fever has considerably increased. Effective vector control strategies and specific protection using dengue vaccine are thought to be the key elements to combat dengue. The dengue incidence among the Singapore youths (15-24 years) was second only to that of adults (25-44 years). This study evaluated the knowledge and attitude of Singapore youths on dengue and its preventive measures. Methods: A cross-sectional study using online-based questionnaire survey was conducted among Singapore youths from September to November 2022. Data were analyzed for descriptive statistics whereas Chi-squared test, linear regression analysis and Pearson correlation were used to determine the association between demographic factors and youth's attitude on dengue prevention using Rstudio. Results: A total of 624 respondents completed the survey out of 1822 surveys distributed nation-wide, with a response rate of 34.2% (mean age 17.4 years ± 1.84; 59.3% female; 89.9% Chinese). The mean dengue knowledge scores of participants were 14.1 ±2.8. Univariate analysis showed that teenagers (15-19 years) had significantly higher knowledge score than the young adults (20-24 years) (ß=0.82,95%CI = 0.13-1.51, p = 0.021). Majority of them were aware of the Mozzie Wipeout campaign (90.2%) followed by the release of Wolbachia mosquitos (69.1%). Two-thirds of the youths who were aware of Wolbachia and Gravitrap considered that it was effective in reducing dengue infection rates. Participants suggested information about the current dengue infection rate (71.9%) as the most effective of the five proposed strategies to improve uptake of dengue preventive measures. In comparison to young adults, teenagers were more likely to uptake dengue preventive measures if widespread mosquito control practices were implemented (69.1% vs. 42.3%). Conclusion: The overall knowledge of the youths on dengue and its prevention was satisfactory. Future health promotion campaigns targeting the youths should focus on transforming the knowledge into practice.

Corneal Sub-Basal Nerve Plexus Regeneration Pattern following Implantable Collamer Lens Implantation for Myopia: A Prospective Longitudinal In Vivo Confocal Microscopy Study.

Implantable Collamer Lens (ICL) surgery has increasingly been adopted for myopia correction in recent decades. This study, employing in vivo confocal microscopy (IVCM), aimed to assess the impact of corneal incision during ICL surgery on the corneal sub-basal nerve plexus (SNP) and adjacent immune dendritiform cells (DCs). In this longitudinal study, eyes from 53 patients undergoing ICL surgery were assessed preoperatively and postoperatively over a twelve-month period. Quantification of seven SNP parameters was performed using ACCMetrics V.2 software. Ultimately, the final analysis was restricted to one eye from each of the 37 patients who completed a minimum of three months' postoperative follow-up. Preoperative investigations revealed a positive correlation of DC density with patient age and a negative association with corneal nerve fiber density (CNFD). Additionally, both DCs and CNFD were positively linked to spherical equivalent refraction (SER) and inversely related to axial length (AL). Intriguingly, preoperative DC density demonstrated an indirect relationship with both baseline and postoperative CNFD changes. Post-surgery, an initial surge in DC density was observed, which normalized subsequently. Meanwhile, parameters like CNFD, corneal nerve fiber length (CNFL), and corneal nerve fractal dimension (CNFrD) initially showed a decline following surgery. However, at one-year follow-up, CNFL and CNFrD displayed significant recovery, while CNFD did not return to its baseline level. This study thus delineates the regeneration pattern of SNP and alterations in DC density post-ICL surgery, highlighting that CNFD in the central cornea does not completely revert to preoperative levels within a year. Given these findings, practitioners are advised to exercise caution in older patients, those with high myopia, or elevated preoperative DCs who may undergo delayed SNP regeneration.

Unlocking the Potential of Pterostilbene: A Pharmaceutical Element for Aptamer-Based Nanomedicine.

Natural compounds like pterostilbene (PTE) have gained recognition for their various biological activities and potential health benefits. However, challenges related to bioavailability and limited clinical efficacy have prompted efforts to strengthen their therapeutic potential. To meet these challenges, we herein rationally designed and successfully synthesized a pharmaceutical phosphoramidite that allows for the programmable incorporation of PTE into oligonucleotides. The resultant aptamer-PTE conjugate can selectively bind to cancer cells, leading to a specific internalization and drug release. Moreover, compared with free PTE, the conjugate exhibits superior cytotoxicity in cancer cells. Specifically, in a zebrafish xenograft model, the nanomedicine effectively inhibits tumor growth and neovascularization, highlighting its potential for targeted antitumor therapy. This approach presents a promising avenue for harnessing the therapeutic potential of natural compounds via a nanomedicine solution.

Endothelial dysfunction of syphilis: Pathogenesis.

Treponema pallidum is the causative factor of syphilis, a sexually transmitted disease (STD) characterized by perivascular infiltration of inflammatory cells, vascular leakage, swelling and proliferation of endothelial cells (ECs). The endothelium lining blood and lymphatic vessels is a key barrier separating body fluids from host tissues and is a major target of T. pallidum. In this review, we focus on how T. pallidum establish intimate interactions with ECs, triggering endothelial dysfunction such as endothelial inflammation, abnormal repairment and damage of ECs. In addition, we summarize that migration and invasion of T. pallidum across vascular ECs may occur through two pathways. These two mechanisms of transendothelial migration are paracellular and cholesterol-dependent, respectively. Herein, clarifying the relationship between T. pallidum and endothelial dysfunction is of great significance to provide novel strategies for diagnosis and prevention of syphilis, and has a great potential prospect of clinical application.

Extrapolation study for determining the time since injury in a rat subcutaneous hematoma model utilizing ATR-FTIR spectroscopy.

The determination of the time of an injury has been a major problem in forensic science due to the lack of objective, reliable and portable methods. In this study, a subcutaneous hemorrhage model in rats was established over six days, and attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy coupled with chemometrics was used to determine the time since injury. Initial principal component analysis (PCA) showed variance among hematoma sites. Subsequently, spectral data were acquired to establish a dependable partial least square (PLS) regression model with predictive abilities. The root mean square error of cross-validation (RMSECV) and the root mean square error of prediction (RMSEP) values produced by a genetic algorithm (GA) were 0.64 d (R2 = 0.88) and 0.57 d (R2 = 0.90), respectively. Few variables were involved in the model, and significantly better results were obtained in comparison to the conventional full-spectrum PLS model. In combination with the results of variable importance in projection (VIP) scores, all components, including proteins, nucleic acids and phospholipids, provided inferences regarding the samples at different time points; additionally, amide I and II bands represented the secondary structure of proteins and provided the largest contribution. Based on our preliminary study, the combination of swift and nondamaging ATR-FTIR spectroscopy with chemometrics could prove to be an advantageous approach for gauging the age of an injury in the forensic field.

Low-Electronegativity Cationic High-Entropy Doping to Trigger Stable Anion Redox Activity for High-Ni Co-Free Layered Cathodes in Li-Ion Batteries.

LiNi0.8 Co0.1 Mn0.1 O2 (NCM-811) exhibits the highest capacity in commercial lithium-ion batteries (LIBs), and the high Ni content (80 %) provides the only route for high energy density. However, the cationic structure instability arisen from the increase of Ni content (>80 %) limits the further increase of the capacity, and inevitable O2 release related to anionic structure instability hinders the utilization of anion redox activity. Here, by comparing various combinations of high-entropy dopants substituted Co element, we propose a low-electronegativity cationic high-entropy doping strategy to fabricate the high-Ni Co-free layered cathode (LiNi0.8 Mn0.12 Al0.02 Ti0.02 Cr0.02 Fe0.02 O2 ) that exhibits much higher capacity and cycling stability. Configurational disorder originated from cationic high-entropy doping in transition metal (TM) layer, anchors the oxidized lattice oxygen ((O2 )n- ) to preserve high (O2 )n- content, triggering the anion redox activity. Electron transfer induced by applying TM dopants with lower electronegativity than that of Co element, increases the electron density of O in TM-O octahedron (TM-O6 ) configuration to reach higher (O2 )n- content, resulting in the higher anion redox activity. With exploring the stabilization effect on both cations and anions of high-entropy doping and low-electronegativity cationic modified anion redox activity, we propose an innovative and variable pathway for rationally tuning the properties of commercial cathodes.

From "wet" matrices to "dry" blood spot sampling strategy: a versatile LC-MS/MS assay for simultaneous monitoring caffeine and its three primary metabolites in preterm infants.

OBJECTIVES: To update traditional "wet" matrices to dried blood spot (DBS) sampling, based on the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technique, and develop a method for simultaneous analyzing caffeine and its three primary metabolites (theobromine, paraxanthine, and theophylline), supporting routine therapeutic drug monitoring (TDM) for preterm infants. METHODS: DBS samples were prepared by a two-step quantitative sampling method, i.e., volumetric sampling of a quantitative 10 µL volume of peripheral blood and an 8 mm diameter whole punch extraction by a methanol/water (80/20, v/v) mixture containing 125 mM formic acid. Four paired stable isotope labeled internal standards and a collision energy defect strategy were applied for the method optimization. The method was fully validated following international guidelines and industrial recommendations on DBS analysis. Cross validation with previously developed plasma method was also proceeded. The validated method was then implemented on the TDM for preterm infants. RESULTS: The two-step quantitative sampling strategy and a high recovery extraction method were developed and optimized. The method validation results were all within the acceptable criteria. Satisfactory parallelism, concordance, and correlation were observed between DBS and plasma concentrations of the four analytes. The method was applied to provide routine TDM services to 20 preterm infants. CONCLUSIONS: A versatile LC-MS/MS platform for simultaneous monitoring caffeine and its three primary metabolites was developed, fully validated, and successfully applied into the routine clinical TDM practices. Sampling method switching from "wet" matrices to "dry" DBS will facilitate and support the precision dosing of caffeine for preterm infants.