Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

Optimized production of full-length PCV2d virus-like particles in Escherichia coli: A cost-effective and high-yield approach for potential vaccine antigen development.

Porcine circovirus type 2 (PCV2) is a globally prevalent infectious pathogen affecting swine, with its capsid protein (Cap) being the sole structural protein critical for vaccine development. Prior research has demonstrated that PCV2 Cap proteins produced in Escherichia coli (E. coli) can form virus-like particles (VLPs) in vitro, and nuclear localization signal peptides (NLS) play a pivotal role in stabilizing PCV2 VLPs. Recently, PCV2d has emerged as an important strain within the PCV2 epidemic. In this study, we systematically optimized the PCV2d Cap protein and successfully produced intact PCV2d VLPs containing NLS using E. coli. The recombinant PCV2d Cap protein was purified through affinity chromatography, yielding 7.5 mg of recombinant protein per 100 ml of bacterial culture. We augmented the conventional buffer system with various substances such as arginine, ß-mercaptoethanol, glycerol, polyethylene glycol, and glutathione to promote VLP assembly. The recombinant PCV2d Cap self-assembled into VLPs approximately 20 nm in diameter, featuring uniform distribution and exceptional stability in the optimized buffer. We developed the vaccine and immunized pigs and mice, evaluating the immunogenicity of the PCV2d VLPs vaccine by measuring PCV2-IgG, IL-4, TNF-α, and IFN-γ levels, comparing them to commercial vaccines utilizing truncated PCV2 Cap antigens. The HE staining and immunohistochemical tests confirmed that the PCV2 VLPs vaccine offered robust protection. The results revealed that animals vaccinated with the PCV2d VLPs vaccine exhibited high levels of PCV2 antibodies, with TNF-α and IFN-γ levels rapidly increasing at 14 days post-immunization, which were higher than those observed in commercially available vaccines, particularly in the mouse trial. This could be due to the fact that full-length Cap proteins can assemble into more stable PCV2d VLPs in the assembling buffer. In conclusion, our produced PCV2d VLPs vaccine elicited stronger immune responses in pigs and mice compared to commercial vaccines. The PCV2d VLPs from this study serve as an excellent candidate vaccine antigen, providing insights for PCV2d vaccine research.

A Bayesian approach based on discounting factor for consistency assessment in multi-regional clinical trial.

Multi-regional clinical trial (MRCT) has become an increasing trend for its supporting simultaneous global drug development. After MRCT, consistency assessment needs to be conducted to evaluate regional efficacy. The weighted Z-test approach is a common consistency assessment approach in which the weighting parameter W does not have a good practical significance; the discounting factor approach improved from the weighted Z-test approach by converting the estimation of W in original weighted Z-test approach to the estimation of discounting factor D. However, the discounting factor approach is an approach of frequency statistics, in which D was fixed as a certain value; the variation of D was not considered, which may lead to un-reasonable results. In this paper, we proposed a Bayesian approach based on D to evaluate the treatment effect for the target region in MRCT, in which the variation of D was considered. Specifically, we first took D random instead of fixed as a certain value and specified a beta distribution for it. According to the results of simulation, we further adjusted the Bayesian approach. The application of the proposed approach was illustrated by Markov Chain Monte Carlo simulation.

Trends by age and sex and projections of disease prevalence from studying hypertensive heart disease in China over the past three decades.

BACKGROUND: Hypertensive heart disease (HHD) is a common cause of cardiovascular disease and mortality worldwide, and its burden is increasing with aging populations. OBJECTIVES: This study aimed to estimate the prevalence and mortality rates of HHD in mainland China and Taiwan Province using data from the Global Burden of Disease Study 2019 (GBD 2019), and forecast the development trend of HHD from 2020 to 2024. METHODS: We obtained data on number of cases, deaths, crude prevalence rate, crude death rate, age-standardized prevalence rate (ASPR), and age-standardized death rate (ASDR) for mainland China and Taiwan Province from 1990 to 2019 from the GBD 2019. Joinpoint software was used to estimate average annual percentage change (AAPC) with 95% confidence intervals, and the number of HHD cases in China from 2022 to 2024 was predicted by the exponential smoothing method. RESULTS: Between 1990 and 2019, HHD cases and deaths increased in mainland China, but the ASPR and ASDR decreased by 5.96% and 48.72%, respectively. In Taiwan Province, ASPR and ASDR decreased by 7.66% and 52.14%, respectively. The number of HHD cases and death rates varied by region, age, and sex, with a higher number of cases in mainland China than in Taiwan Province. By 2024, the number of HHD cases in mainland China was projected to be over 9.6 million cases, and in Taiwan Province, it was projected to surpass 120,000 cases. CONCLUSION: The differences in HHD cases between mainland China and Taiwan Province in terms of age and sex indicated the need for effective prevention and control measures, especially targeting the elderly population. These findings can inform policymakers and health professionals in the development of targeted prevention and treatment strategies and resource allocation for HHD in China.

Assessment of lung deformation in patients with idiopathic pulmonary fibrosis with elastic registration technique on pulmonary three-dimensional ultrashort echo time MRI.

OBJECTIVE: To assess lung deformation in patients with idiopathic pulmonary fibrosis (IPF) using with elastic registration algorithm applied to three-dimensional ultrashort echo time (3D-UTE) MRI and analyze relationship of lung deformation with the severity of IPF. METHODS: Seventy-six patients with IPF (mean age: 62 ± 6 years) and 62 age- and gender-matched healthy controls (mean age: 58 ± 4 years) were prospectively enrolled. End-inspiration and end-expiration images acquired with a single breath-hold 3D-UTE sequence were registered using elastic registration algorithm. Jacobian determinants were calculated from deformation fields and represented on color maps. Jac-mean (absolute value of the log means of Jacobian determinants) and the Dice similarity coefficient (Dice) were compared between different groups. RESULTS: Compared with healthy controls, the Jac-mean of IPF patients significantly decreased (0.21 ± 0.08 vs. 0.27 ± 0. 07, p < 0.001). Furthermore, the Jac-mean and Dice correlated with the metrics of pulmonary function tests and the composite physiological index. The lung deformation in IPF patients with dyspnea Medical Research Council (MRC) ≥ 3 (Jac-mean: 0.16 ± 0.03; Dice: 0.06 ± 0.02) was significantly lower than MRC1 (Jac-mean: 0. 25 ± 0.03, p < 0.001; Dice: 0.10 ± 0.01, p < 0.001) and MRC 2 (Jac-mean: 0.22 ± 0.11, p = 0.001; Dice: 0.08 ± 0.03, p = 0.006). Meanwhile, Jac-mean and Dice correlated with health-related quality of life, 6 min-walk distance, and the extent of pulmonary fibrosis. Jac-mean correlated with pulmonary vascular-related indexes on high-resolution CT. CONCLUSION: The decreased lung deformation in IPF patients correlated with the clinical severity of IPF patients. Elastic registration of inspiratory-to-expiratory 3D UTE MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. CRITICAL RELEVANCE STATEMENT: This prospective study demonstrated that lung deformation decreased in idiopathic pulmonary fibrosis (IPF) patients and correlated with the severity of IPF. Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. KEY POINTS: • Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI could evaluate lung deformation. • Lung deformation significantly decreased in idiopathic pulmonary fibrosis (IPF) patients, compared with the healthy controls. • Reduced lung deformation of IPF patients correlated with worsened pulmonary function and the composite physiological index (CPI).

Digital economy and high-quality development of the healthcare industry.

The high-quality development of the healthcare industry is of great significance for improving people's health and promoting the construction of a harmonious society. This paper focuses on the relationship between the development of China's digital economy and the high-quality development of the healthcare industry. Based on the panel data of 30 provinces in China from 2011 to 2020, this paper empirically studies whether the development of the digital economy promotes the high-quality development of the healthcare industry. This study finds that the development of digital economy has significantly promoted the high-quality development of the medical and health industry. The results of this study are still valid after a series of robustness tests including variable substitution, sample adjustment, and endogenous problem mitigation. Heterogeneity analysis shows that the effect of this policy is more significant in the eastern region and southern areas. The results of spatial econometric analysis show that the development of digital economy has obvious spatial spillover effect. The research in this paper can provide reference for developing countries to enhance the development level of digital health industry and improve people's lives.

Spatial and temporal analysis of China's healthcare resource allocation measurements based on provincial data: 2010-2021.

Background: With the development of society, industrialization, urbanization, aging, lifestyle and social transformation, environmental degradation, global warming and other factors have had a great impact on the health of the population, and there is an urgent need to take a series of practical actions to promote the improvement of national health. Among them, healthcare resource allocation plays a key role in advancing the level of national health, treatment of chronic diseases, and leisure and healthcare. Methods: This article collected panel data on healthcare resource allocation in all provinces of China from 2010 to 2021, and comprehensively applied Analytic Hierarchy Process, comprehensive scoring method, regional difference analysis and spatial autocorrelation analysis to reveal regional differences, spatial-temporal patterns and development characteristics of healthcare resource allocation in China. Results: In terms of regional differences, intra-regional differences in healthcare resource allocation tend to narrow and inter-regional differences tend to widen. In terms of spatial pattern, the western provinces on the left side of the Hu Huanyong line generally have higher scores, while the central and eastern provinces on the right side of the Hu Huanyong line have lower scores, and healthcare resource allocation in the provinces on the left side of the Hu Huanyong line, such as Tibet, Xinjiang, Qinghai, Ningxia, Gansu, Inner Mongolia, Sichuan, have the spatial characteristics of HH clusters in terms of geographic location, while the southeast coastal provinces, such as Zhejiang, Fujian, Guangdong, Hainan, have the spatial characteristics of LL clusters in terms of geographic location. From the quadrant analysis, the 2010-2021 healthcare resource allocation in the first quadrant concentrates most of the provinces in the western and northeastern regions, while the third quadrant concentrates most of the provinces in the eastern region. Conclusion: The allocation of healthcare resources in China's four major zones has undergone a process of change from "unbalanced quantity to relatively balanced quantity," but high-quality healthcare resources are highly concentrated in the eastern part of the country, and the problem of contradiction between people and doctors is prominent. It is recommended that Internet plus healthcare technology be used to reshape the regional allocation of high-quality healthcare resources.

Multi-parametric MRI assessment of melatonin regulating the polarization of microglia in rats after cerebral ischemia/reperfusion injury.

OBJECTIVES: Multi-parametric magnetic resonance imaging (MRI) can provide comprehensive and valuable information for precise diagnosis and treatment evaluation of a number of diseases. In this study, the neuroprotective effects of melatonin (Mel) on a rat model of cerebral ischemia/reperfusion injury (CIRI) were assessed by multi-parametric MRI combined with histopathological techniques for longitudinal monitoring of the lesion microenvironment. METHODS: Sixty Sprague Dawley (SD) rats were randomly divided into three groups: the Sham, CIRI and CIRI + Mel groups. At multiple time points after ischemia, MRI scanning was performed on a 7.0 Tesla MRI scanner. Multi-parametric MRI includes T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), and chemical exchange saturation transfer (CEST)-MRI. CEST effects were calculated by the Lorentzian difference method, 3.5 ppm indicates amide protons of mobile proteins/peptide (Amide-CEST) and 2.0 ppm indicates amine protons (Guan-CEST). Multiple histopathological techniques were used to examine the histopathological changes and explore the therapeutic effects of Mel. RESULTS: T2WI and DWI-MRI could localize the infarct foci and areas in CIRI rats, which was further validated by staining, 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) staining. After Mel treatment, T2WI and DWI-MRI showed smaller infarct volume, and neurons displayed improved morphology with less apoptosis rates. Notably, Amide-CEST and Guan-CEST signal decreased as early as 2 h after CIRI (all P <0.001), reflecting the change of pH after ischemia. After Mel treatment, both Amide-CEST and Guan-CEST signal increased in ischemic cortex and striatum compared with control group (all P < 0.001). The immunofluorescence staining and western blotting analysis suggested the expression of M2 microglia increased after Mel treatment; While，after Mel treatment the inflammatory factor interleukin-1ß (IL-1ß) decreased compared with control CIRI rats. CONCLUSIONS: Multi-parametric MRI was shown to be an effective method to monitor the brain damage in a rat model of CIRI and assess the therapeutic effects of Mel treatment. Amide-CEST and Guan-CEST were especially sensitive to the changes in brain microenvironment during the early stage after CIRI. Furthermore, the neuroprotective effect of Mel treatment is associated with its promotion of the microglia polarized to M2 type in CIRI rats.

Cost-effectiveness analysis of dinutuximab ß for the treatment of high-risk neuroblastoma in China.

BACKGROUND: Dinutuximab ß can be used to treat children with high-risk neuroblastoma (NB). Due to its high price, whether dinutuximab ß is cost-effective for the treatment of high-risk NB remains uncertain. Therefore, assessing the cost-effectiveness of dinutuximab ß in children with high-risk NB is of high importance. METHODS: The health utilities and economic outcomes in children with high-risk NB were projected using a partitioned survival model. The individual patient data (IPD) of add-on treatment with dinutuximab ß (GD2 group) were derived from the literature, while the IPD of traditional therapy (TT group) were obtained from retrospective data of Shanghai Children's Medical Center. Treatment costs included drugs, adverse event-related expenses, and medical resource use. Utility values were obtained from the literature. Costs and quality-adjusted life-years (QALYs) were measured over a 10-year time horizon. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also conducted. RESULTS: Compared with the TT group, QALY increased in the GD2 group by 0.72 with an increased cost of $171,269.70, leading to an incremental cost-effectiveness ratio of 236,462.75$/QALY. DSA showed that the price of dinutuximab ß was the main factor on the results than other parameters. Compared with the TT group, the GD2 group could not be cost-effective in the PSA at the $37,920/QALY threshold. CONCLUSION: Results found that dinutuximab ß is not a cost-effective treatment option for children with high-risk NB unless its price is significantly reduced.

Multimodal Assessment of Schizophrenia Symptom Severity From Linguistic, Acoustic and Visual Cues.

Assessing the condition of every schizophrenia patient correctly normally requires lengthy and frequent interviews with professionally trained doctors. To alleviate the time and manual burden on those mental health professionals, this paper proposes a multimodal assessment model that predicts the severity level of each symptom defined in Scale for the Assessment of Thought, Language, and Communication (TLC) and Positive and Negative Syndrome Scale (PANSS) based on the patient's linguistic, acoustic, and visual behavior. The proposed deep-learning model consists of a multimodal fusion framework and four unimodal transformer-based backbone networks. The second-stage pre-training is introduced to make each off-the-shelf pre-trained model learn the pattern of schizophrenia data more effectively. It learns to extract the desired features from the view of its modality. Next, the pre-trained parameters are frozen, and the light-weight trainable unimodal modules are inserted and fine-tuned to keep the number of parameters low while maintaining the superb performance simultaneously. Finally, the four adapted unimodal modules are fused into a final multimodal assessment model through the proposed multimodal fusion framework. For the purpose of validation, we train and evaluate the proposed model on schizophrenia patients recruited from National Taiwan University Hospital, whose performance achieves 0.534/0.685 in MAE/MSE, outperforming the related works in the literature. Through the experimental results and ablation studies, as well as the comparison with other related multimodal assessment works, our approach not only demonstrates the superiority of our performance but also the effectiveness of our approach to extract and integrate information from multiple modalities.

Risk assessment of venous thromboembolism in head and neck cancer patients and its establishment of a prediction model.

IMPORTANCE: Venous thromboembolism (VTE) is closely relevant to head and neck cancer (HNC) prognosis, but little data exist on the risk prediction of VTE in patients with HNC. OBJECTIVE: To study the risk factors regarding VTE in HNC patients and construct a nomogram model for its prediction. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional retrospective study was implemented to comparatively analyze 220 HNC patients from January 2018 to December 2021. The Lasso algorithm was used to optimize the selection of variables. A nomogram model for predicting HNC-associated VTE was established using multivariate logistic regression analysis. Internal validation of the model was performed by bootstrap resampling (1000 times). Calibration plot and decision curve analysis (DCA) were applied to evaluate the calibration capability of the prediction model. MAIN OUTCOME AND MEASURE: The demographics, medical history, blood biochemical indicators, and modalities of treatment were included for analysis. RESULTS: The incidence of HNC-associated VTE was 2.8% (55/1967) in authors' affiliation. Five variables of risk factors, including surgery, radiochemotherapy, D-dimer, aspartate transaminase, and globulin, were screened and selected as predictors by Lasso algorithm. A prediction model that incorporated these independent predictors was developed and presented as the nomogram. The model showed good discrimination with a C-index of 0.972 (95% CI: 0.934-0.997), and had an area under the receiver operating characteristic curve value of 0.981 (p < 0.001, 95% CI: 0.964-0.998). The calibration curve displayed good agreement of the predicted probability with the actual observed probability for HNC-associated VTE. The DCA plot showed that the application of this nomogram was associated with net benefit gains in clinical practice. CONCLUSIONS AND RELEVANCE: The high-performance nomogram model developed in this study may help early diagnose the risk of VTE in HNC patients and to guide individualized decision-making on thromboprophylaxis.

Sexual function assessment in patients with SAPHO syndrome: a cross-sectional study.

INTRODUCTION: SAPHO syndrome is a group of special syndromes characterized by synovitis, acne, pustulosis, hyperostosis and osteitis. Skin lesions and joint damage are the main clinical manifestations. Among them, females mostly present with palm toe pustulosis, while males have severe acne as the main external manifestation. The bone and joint damage characterized by bone hypertrophy and osteitis is the core manifestation of SAPHO and affects all parts of the body. SAPHO syndrome causes great physical and mental suffering to patients, and it also brings a huge financial burden to the family. The purpose of this study is to explore the impact of SAPHO on the quality of sexual life of patients. METHODS: We screened and included 249 SAPHO patients (169 women and 80 men) from Peking Union Medical College Hospital (Beijing, China). First, we recorded the basic situation of the patient through questionnaires (including gender, age, SAPHO duration, BMI, smoking, drinking, marital status, educational level, occupational status and work status.). Then, the patient needed to fill in the Short Form-36 quality of life questionnaire (SF-36 QoL) to record the quality of life. For Sexual dysfunction (SD), female patients needed to fill in the Female Sexual Function Index (FSFI) to assess the quality of sexual life; while the International Index of Erectile Function (IIEF) was used to assess the SD of male patients. At the same time, we used self-esteem and relationship questionnaire (SEAR) to analyze the psychological state of SAPHO patients. Finally, we performed statistical analysis on the data obtained, and then explored the connection between SAPHO and SD. RESULTS: In this cross-sectional study, a total of 249 patients completed the questionnaire and constituted the study population. We found that among 169 female patients, 124 patients had FSD (73.4%); while 45 patients did not have FSD (26.6%); and among 80 male patients, 45 (56.3%) had ED; However, 35 patients did not have ED (43.7%). The results of the quality of life and mental state assessment showed that female patients with SD showed lower scores in terms of mental state. Among all male participants, we found no significant difference in quality of life and mental state among participants with or without SD. In addition, there was no significant difference in the duration of SAPHO between female and male participants with or without SD. CONCLUSION: This study is the first to evaluate the SD of SAPHO patients. The incidence of SD in female SAPHO patients is higher than that in male patients; the cause of female SD may be mainly psychological factors. These results prove that it is particularly important to focus on regulating their psychological state while diagnosing and treating SAPHO patients in clinical practice.

Harnessing microbial phylum-specific molecular markers for assessment of environmental estrogen degradation.

Steroidal estrogens are ubiquitous contaminants that have garnered attention worldwide due to their endocrine-disrupting and carcinogenic activities at sub-nanomolar concentrations. Microbial degradation is one of the main mechanisms through which estrogens can be removed from the environment. Numerous bacteria have been isolated and identified as estrogen degraders; however, little is known about their contribution to environmental estrogen removal. Here, our global metagenomic analysis indicated that estrogen degradation genes are widely distributed among bacteria, especially among aquatic actinobacterial and proteobacterial species. Thus, by using the Rhodococcus sp. strain B50 as the model organism, we identified three actinobacteria-specific estrogen degradation genes, namely aedGHJ, by performing gene disruption experiments and metabolite profile analysis. Among these genes, the product of aedJ was discovered to mediate the conjugation of coenzyme A with a unique actinobacterial C17 estrogenic metabolite, 5-oxo-4-norestrogenic acid. However, proteobacteria were found to exclusively adopt an α-oxoacid ferredoxin oxidoreductase (i.e., the product of edcC) to degrade a proteobacterial C18 estrogenic metabolite, namely 3-oxo-4,5-seco-estrogenic acid. We employed actinobacterial aedJ and proteobacterial edcC as specific biomarkers for quantitative polymerase chain reaction (qPCR) to elucidate the potential of microbes for estrogen biodegradation in contaminated ecosystems. The results indicated that aedJ was more abundant than edcC in most environmental samples. Our results greatly expand the understanding of environmental estrogen degradation. Moreover, our study suggests that qPCR-based functional assays are a simple, cost-effective, and rapid approach for holistically evaluating estrogen biodegradation in the environment.

Offshore Wind Energy and Marine Biodiversity in the North Sea: Life Cycle Impact Assessment for Benthic Communities.

Large-scale offshore wind energy developments represent a major player in the energy transition but are likely to have (negative or positive) impacts on marine biodiversity. Wind turbine foundations and sour protection often replace soft sediment with hard substrates, creating artificial reefs for sessile dwellers. Offshore wind farm (OWF) furthermore leads to a decrease in (and even a cessation of) bottom trawling, as this activity is prohibited in many OWFs. The long-term cumulative impacts of these changes on marine biodiversity remain largely unknown. This study integrates such impacts into characterization factors for life cycle assessment based on the North Sea and illustrates its application. Our results suggest that there are no net adverse impacts during OWF operation on benthic communities inhabiting the original sand bottom within OWFs. Artificial reefs could lead to a doubling of species richness and a two-order-of-magnitude increase of species abundance. Seabed occupation will also incur in minor biodiversity losses in the soft sediment. Our results were not conclusive concerning the trawling avoidance benefits. The developed characterization factors quantifying biodiversity-related impacts from OWF operation provide a stepping stone toward a better representation of biodiversity in life cycle assessment.

Low-cost, portable, on-site fluorescent detection of As(III) by a paper-based microfluidic device based on aptamer and smartphone imaging.

A turn-on fluorescent aptasensor based on a paper-based microfluidic chip was developed to detect arsenite via aptamer competition strategy and smartphone imaging. The chip was prepared by wax-printing hydrophilic channels on filter paper. It is portable, low-cost, and environmentally friendly. Double-stranded DNA consisting of aptamer and fluorescence-labeled complementary strands was immobilized on the reaction zone of the paper chip. Due to the specific strong binding between aptamer and arsenite, the fluorescent complementary strand was squeezed out and driven by capillary force to the detection area of the paper chip, so that the fluorescent signal arose in the detection area under the excitation wavelength of 488 nm. Arsenite can be quantified by using smartphone imaging and RGB image analysis. Under the optimal conditions, the paper-based microfluidic aptasensor exhibited excellent linear response over a wide range of 1 to 1000 nM, with a detection limit as low as 0.96 nM (3σ).

Effects of osseous structure based on three-dimensional reconstructive imaging evaluation in the assessment of temporomandibular joint disc position.

OBJECTIVES: This pilot morphological study aimed to investigate the association between anterior disc displacement (ADD) and the status of the mandibular condyle and articular fossa. MATERIALS AND METHODS: Thirty-four patients were divided into a normal articular disc position group and an ADD with and without reduction group. Images reconstructed were used to determine multiple group comparisons of these three different types of disc position, and the diagnostic efficacy for the morphological parameters with significant group difference was analyzed to assess. RESULTS: The condylar volume (CV), condylar superficial area (CSA), superior joint space (SJS), and medial joint space (MJS) all exhibited obvious changes (P < 0.05). Additionally, they all had a reliable diagnostic accuracy in differentiating between normal disc position and ADD with an AUC value from 0.723 to 0.858. Among them, the CV, SJS, and MJS (P < 0.05) had a significantly positive impact on the groups by analysis of multivariate logistic ordinal regression model. CONCLUSIONS: The CV, CSA, SJS, and MJS are significantly associated with different disc displacement types. The condyle in ADD exhibited altered dimensions. These could be promising biometric markers for assessing ADD. CLINICAL RELEVANCE: The morphological changes of mandibular condyle and glenoid fossa were significantly influenced by the status of disc displacement, and condyles with disc displacement had three-dimensionally altered condylar dimensions, irrespective of age and sex.

Biosimilarity Assessment of the Biosimilar Teriparatide Candidate and the Reference Drug in Healthy Subjects.

SAL001, a recombinant form of parathyroid hormone, is a biosimilar drug to teriparatide and is planned to be used in osteoporosis treatment. A single-dose, randomized, open-label, 2-way crossover trial was conducted in healthy subjects to compare the pharmacokinetics (PK) and safety between SAL001 and the reference drug. Sixty-four subjects were enrolled in the study, and 61 subjects completed the study. In each period, 20 µg of the test or reference formulation was administered subcutaneously. SAL001 was administered by autoinjector pen, whereas the reference drug was administered by a self-matched injection pen. Serial blood samples were obtained for the analyses of PK and serum calcium concentration. Geometric mean ratios with 90%CIs for the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were estimated. The safety of these 2 formulations was also evaluated. Overall, the 90%CIs for the geometric mean ratios of Cmax , AUC from time 0 to the last quantifiable time point, and AUC from time 0 extrapolated to infinity of the test or reference product were within 80.0%-125.0% of biosimilarity criteria. Other PK parameters, serum calcium concentration, and safety profiles had no significant differences between the 2 formulations. SAL001 demonstrated PK similarity to the reference drug, and the serum calcium concentration and safety profiles of SAL001 were also considered comparable to the reference drug.

Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.

BACKGROUND: The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. METHODS: A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. RESULTS: In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10-8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. CONCLUSIONS: In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

Life cycle assessment of material footprint in recycling: A case of concrete recycling.

Meeting the current demand for concrete requires not only mining tons of gravel and sand, but also burning large amounts of fossil fuel resources in cement kilning. Consequently, concrete recycling is crucial to achieving a material-efficient society, especially with the application of various categories of concrete and the goal of phasing out fossil fuels. A comparative life cycle assessment (LCA) is used to assess the engineering material footprint (EMF) and the fossil fuel material footprint (FMF) in closed-loop recycling of three types of concrete: siliceous concrete, limestone concrete, and lightweight aggregate concrete. This study aims to investigate the impact of (i) concrete categories, (ii) methods to model recycling, and (iii) using renewable energy sources on the material footprint in concrete recycling. The results highlight that the concrete recycling system can reduce 99% of the EMF and 66-93% of the FMF compared with the baseline system, in which concrete waste is landfilled. All three recycling modeling approaches indicate that concrete recycling can considerably reduce EMF and FMF compared with the baseline system, primarily resulting from the displacement of virgin raw materials. Using alternative diesels is more sensitive than adopting renewable electricity in reduction of the FMF in concrete recycling. Replacing diesel with electrolysis- and coal-based synthetic diesel for concrete recycling could even increase the FMF, while using biodiesel made from rapeseed and wood-based synthetic diesel can reduce 47-51% and 84-89% of the FMF, respectively, compared to the virgin diesel-based recycling system. Finally, we discussed the multifunctionality and rebound effects of recycling, and double-counting risk in material and energy accounting.

Magnetic Resonance Imaging Combined with Histological Techniques for Dynamic Assessment of Cytotoxic Edema after Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: Reperfusion therapy after ischemic cerebral stroke may cause cerebral ischemia-reperfusion injury (CIRI), and cerebral edema is an important factor that may aggravate CIRI. Our study aimed to dynamically monitor the development of early cytotoxic edema after CIRI by magnetic resonance imaging (MRI) and to validate it using multiple histological imaging methods. METHODS: Male Sprague Dawley rats were divided into sham and CIRI groups. T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI)-MRI scans were performed in the sham and CIRI groups after reperfusion. Relative apparent diffusion coefficient (rADC) values were calculated and the midline shift (MLS) was measured. A series of histological detection techniques were performed to observe changes in the cerebral cortex and striatum of CIRI rats. Correlation analysis of rADC values with aquaporin-4 (AQP4) and sodium-potassium-chloride cotransport protein 1 (Na+-K+-2Cl-- cotransporter 1; NKCC1) was performed. RESULTS: rADC values began to increase and reached a relatively low value in the cerebral cortex and striatum at 24 h after reperfusion, and the MLS reached relatively high values at 24 h after reperfusion (all p < 0.05). Hematoxylin-eosin (HE) staining showed that the nerve cells in the cortex and striatum of the sham group were regular in morphology and neatly arranged, and in the CIRI-24 h group were irregular, disorganized, and loosely structured. Using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, the number of TUNEL+ cells in the ischemic cortex and striatum in CIRI-24 h group was shown to increase significantly compared with the sham group (p < 0.05). Transmission electron microscopy showed that the perivascular astrocytic foot processes were swollen in the cortex and striatum of the CIRI-24 h group. Pearson correlation analysis demonstrated that rADC values were negatively correlated with the number of anti-glial fibrillary acidic protein (GFAP)+AQP4+ and GFAP+NKCC1+ cells of the CIRI rats. CONCLUSIONS: MRI combined with histological techniques can dynamically assess cytotoxic edema after CIRI, in a manner that is clear and intuitive for scientific researchers and clinicians, and provides a scientific basis for the application of MRI techniques for monitoring the dynamic progress of CIRI.