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Abstract Internal phosphorus loading (IPL), as an important part of lake phosphorus cycle and the key to solve the eutrophication problem, is still an important cause of regional and seasonal algal blooms for some mesotrophic lakes located in plateau areas. We investigated the composition, distribution of P fractions in sediments and suspended particulate matter (SPM) of Erhai Lake, southwest China, and explored the relationships between environmental variables and spatial-temporal variations of P fractions. The total P (TP) in surface sediments ranged from 817 to 1216 mg/kg, with inert Ca-P (32%) and Res-P (24%) predominating, at a moderate level. The comparison of short-term release fluxes (0.08 mg/(m2·d)) and long-term release fluxes (0.09 mg/(m2·d)) reflected that the northern region was recovering slowly from the previous P pollution. Mobile-P (the sum of loosely adsorbed P, iron bound P, and organic P) accounted for 52.3% of the TP in SPM and showed high spatial-temporal variations, which were closely related to the growth of algae throughout the investigation. The results suggested that sediments could make a sustained contribution to IPL, and that the P in SPM was highly active and significantly contributed to eutrophication in Erhai Lake especially at the time of seasonal alternations. Our data provided important theoretical bases for the relationship between internal phosphorus loading and eutrophication in plateau lakes.

Abstract The decrease in sperm count and infertility is a global issue that remains unresolved. By screening environmental bacterial isolates, we have found that a novel lactic acid bacterium, Lactiplantibacillus plantarum SNI3, increased testis size, testosterone levels, sperm count, sexual activity and fertility in mice that have consumed the bacteria for four weeks. The abundance of L. plantarum in the colon microbiome was positively associated with sperm count. Fecal microbiota transplantation (FMT) from L. plantarum SNI3-dosed mice improved testicular functions in microbiome-attenuated recipient animals. To identify mediators that confer pro-reproductive effects on the host, untargeted in situ mass spectrometry metabolomics was performed on testis samples of L. plantarum SNI3-treated and control mice. Enrichment pathway analysis revealed several perturbed metabolic pathways in the testis of treated mice. Within the testis, a dipeptide, glutamyl-glutamate (GluGlu) was the most upregulated metabolite following L. plantarum SNI3 administration. To validate the pro-reproductive feature of GluGlu, systemic and local injections of the dipeptide have been performed. γ-GluGlu increased sperm count but had no effect on testosterone. These findings highlight the role of γ-GluGlu in mediating spermatogenetic effects of L. plantarum on the male mouse host and –following relevant human clinical trials- may provide future tools for treating certain forms of male infertility.

Abstract This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic model (PBPK/PD) of meropenem for critically ill patients. A PBPK model of meropenem in healthy adults was established using PK-Sim software and subsequently extrapolated to critically ill patients based on anatomic and physiological parameters. The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between predicted and observed values of pharmacokinetic parameters Cmax, AUC0-∞, and CL to evaluate the accuracy of the PBPK model. The model was verified using meropenem plasma samples obtained from Intensive Care Unit (ICU) patients, which were determined by HPLC-MS/MS. After that, the PBPK model was combined with a PKPD model, which was developed based on f%T > MIC. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients. The developed PBPK model successfully predicted the meropenem disposition in critically ill patients, wherein the MFE average and GMFE of all predicted PK parameters were within the 1.25-fold error range. The therapeutic drug monitoring (TDM) of meropenem was conducted with 92 blood samples from 31 ICU patients, of which 71 (77.17%) blood samples were consistent with the simulated value. The TDM results showed that meropenem PBPK modeling is well simulated in critically ill patients. Monte Carlo simulations showed that extended infusion and frequent administration were necessary to achieve curative effect for critically ill patients, whereas excessive infusion time (> 4 h) was unnecessary. The PBPK/PD modeling incorporating literature and prospective study data can predict meropenem pharmacokinetics in critically ill patients correctly. Our study provides a reference for dose adjustment in critically ill patients.

Objective To assess the factors that affect the capacity of community pharmacists to deliver pharmacy services (PSs) in Zhengzhou, China.Design An online, cross-sectional survey was conducted.Setting and participants A stratified sampling method was used to select community pharmacists for questionnaires. A total of 124 community pharmacists from various districts of Zhengzhou were included in this study.Results Principal component regression analysis showed that cumulative hours of continuing education (CE), job satisfaction, career prospects, awareness of the need for CE and income had a positive impact on pharmacists’ capacity to deliver PS, with a gradually decreasing degree of influence.Conclusions Most pharmacists felt that their capacity to provide PS met the basic public requirements. Cumulative CE hours had the most significant effect on pharmacists’ capacity to provide PS, while income had the least effect. The government, grassroots community pharmacies, pharmacists and the public should formulate timely and targeted measures to enhance the PS capacity of community pharmacists.

Abstract Objective Nowadays, there has been limited Mendelian randomization (MR) research focusing on the causal relationship between estradiol and vaginitis. Therefore, this study conducted a two-way MR study to clarify the causal effect and related influencing factors between them. Methods All genetic datasets were obtained using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. MR analysis was performed using MR-Egger, weighted median (WM) and inverse variance weighted (IVW) methods to assess the causal relationship between exposure and outcome and to validate the findings by comprehensively evaluating the effects of pleiotropic effects and outliers. Results MR analysis revealed no significant causal relationship between estradiol and vaginitis risk. There was a negative correlation between estradiol and age at menarche (IVW, OR: 0.9996, 95% CI: 0.9992–1.0000, P = 0.0295; WM, OR: 0.9995, 95% CI: 0.9993–0.9998, P = 0.0003), and there was a positive correlation between age at menarche and vaginitis (IVW, OR: 1.5108, 95% CI: 1.1474–2.0930, P = 0.0043; MR-Egger, OR: 2.5575, 95% CI: 1.7664–9.6580, P = 0.0013). Estradiol was negatively correlated with age at menopause (IVW, OR: 0.9872, 95% CI: 0.9786–0.9959, P = 0.0041). However, there was no causal relationship between age at menopause and vaginitis (P > 0.05). In addition, HPV E7 Type 16, HPV E7 Type 18, and Lactobacillus had no direct causal effects on estradiol and vaginitis (P > 0.05). Sensitivity analyses revealed no heterogeneity and horizontal pleiotropy. Conclusion When estrogen levels drop, it will lead to a later age of menarche, and a later age of menarche may increase the risk of vaginitis, highlighting that the longer the female reproductive tract receives estrogen stimulation, the stronger the defense ability is formed, and the prevalence of vaginitis is reduced. In conclusion, this study indirectly supports an association between reduced level of estrogen or short time of estrogen stimulation and increased risk of vaginitis.

Introduction Missed fractures are the most frequent diagnostic error attributed to clinicians in UK emergency departments and a significant cause of patient morbidity. Recently, advances in computer vision have led to artificial intelligence (AI)-enhanced model developments, which can support clinicians in the detection of fractures. Previous research has shown these models to have promising effects on diagnostic performance, but their impact on the diagnostic accuracy of clinicians in the National Health Service (NHS) setting has not yet been fully evaluated.Methods and analysis A dataset of 500 plain radiographs derived from Oxford University Hospitals (OUH) NHS Foundation Trust will be collated to include all bones except the skull, facial bones and cervical spine. The dataset will be split evenly between radiographs showing one or more fractures and those without. The reference ground truth for each image will be established through independent review by two senior musculoskeletal radiologists. A third senior radiologist will resolve disagreements between two primary radiologists. The dataset will be analysed by a commercially available AI tool, BoneView (Gleamer, Paris, France), and its accuracy for detecting fractures will be determined with reference to the ground truth diagnosis. We will undertake a multiple case multiple reader study in which clinicians interpret all images without AI support, then repeat the process with access to AI algorithm output following a 4-week washout. 18 clinicians will be recruited as readers from four hospitals in England, from six distinct clinical groups, each with three levels of seniority (early-stage, mid-stage and later-stage career). Changes in the accuracy, confidence and speed of reporting will be compared with and without AI support. Readers will use a secure web-based DICOM (Digital Imaging and Communications in Medicine) viewer (www.raiqc.com), allowing radiograph viewing and abnormality identification. Pooled analyses will be reported for overall reader performance as well as for subgroups including clinical role, level of seniority, pathological finding and difficulty of image.Ethics and dissemination The study has been approved by the UK Healthcare Research Authority (IRAS 310995, approved on 13 December 2022). The use of anonymised retrospective radiographs has been authorised by OUH NHS Foundation Trust. The results will be presented at relevant conferences and published in a peer-reviewed journal.Trial registration numbers This study is registered with ISRCTN (ISRCTN19562541) and ClinicalTrials.gov (NCT06130397). The paper reports the results of a substudy of STEDI2 (Simulation Training for Emergency Department Imaging Phase 2).

Involving addition of chemical groups or protein units to specific residues of the target protein, post-translational modifications (PTMs) alter the charge, hydrophobicity, and conformation of a protein, which in turn influences protein function, protein–protein interaction, and protein aggregation. These alterations, which include phosphorylation, glycosylation, ubiquitination, methylation, acetylation, lipidation, and lactylation, are significant biological events in the development of cancer, and play vital roles in numerous biological processes. The processes behind essential functions, the screening of clinical illness signs, and the identification of therapeutic targets all depend heavily on further research into the PTMs. This review outlines the influence of several PTM types on prostate cancer (PCa) diagnosis, therapy, and prognosis in an effort to shed fresh light on the molecular causes and progression of the disease.

Background Anaemia is a severe and common complication in patients with aneurysmal subarachnoid haemorrhage (aSAH). Early intervention for at-risk patients before anaemia occurs is indicated as potentially beneficial, but no validated method synthesises patients’ complicated clinical features into an instrument. The purpose of the current study was to develop and externally validate a nomogram that predicted postacute phase anaemia after aSAH.Methods We developed a novel nomogram for aSAH patients to predict postacute phase anaemia (3 days after occurrence of aSAH, prior to discharge) on the basis of demographic information, imaging, type of treatment, aneurysm features, blood tests and clinical characteristics. We designed the model from a development cohort and tested the nomogram in external and prospective validation cohorts. We included 456 aSAH patients from The First Affiliated Hospital for the development, 220 from Sanmen People’s Hospital for external validation and a prospective validation cohort that included 13 patients from Hangzhou Red Cross Hospital. We assessed the performance of the nomogram via concordance statistics and evaluated the calibration of predicted anaemia outcome with observed anaemia occurrence.Results Variables included in the nomogram were age, treatment method (open surgery or endovascular therapy), baseline haemoglobin level, fasting blood glucose level, systemic inflammatory response syndrome score on admission, Glasgow Coma Scale score, aneurysm size, prothrombin time and heart rate. In the validation cohort, the model for prediction of postacute phase anaemia had a c-statistic of 0.910, with satisfactory calibration (judged by eye) for the predicted and reported anaemia outcome. Among forward-looking forecasts, our predictive model achieved an 84% success rate, which showed that it has some clinical practicability.Conclusions The developed and validated nomogram can be used to calculate individualised anaemia risk and has the potential to serve as a practical tool for clinicians in devising improved treatment strategies for aSAH.

Abstract This study examines a collaborative framework that utilizes an intelligent deep Q-network to regulate the formation of leader–follower Unmanned Aerial Vehicles (UAVs). The aim is to tackle the challenges posed by the highly dynamic and uncertain flight environment of UAVs. In the context of UAVs, we have developed a dynamic model that captures the collective state of the system. This model encompasses variables like as the relative positions, heading angle, rolling angle, and velocity of different nodes in the formation. In the subsequent section, we elucidate the operational procedure of UAVs in a collaborative manner, employing the conceptual framework of Markov Decision Process (MDP). Furthermore, we employ the Reinforcement Learning (RL) to facilitate this process. In light of this premise, a fundamental framework is presented for addressing the control problem of UAVs utilizing the DQN scheme. This framework encompasses a technique for action selection known as $$\varepsilon$$ ε -imitation, as well as algorithmic specifics. Finally, the efficacy and portability of the DQN-based approach are substantiated by numerical simulation validation. The average reward curve demonstrates a satisfactory level of convergence, and kinematic link between the nodes inside the formation satisfies the essential requirements for the creation of a controller.

Introduction Radiographic bone age (BA) assessment is widely used to evaluate children’s growth disorders and predict their future height. Moreover, children are more sensitive and vulnerable to X-ray radiation exposure than adults. The purpose of this study is to develop a new, safer, radiation-free BA assessment method for children by using three-dimensional ultrasound (3D-US) and artificial intelligence (AI), and to test the diagnostic accuracy and reliability of this method.Methods and analysis This is a prospective, observational study. All participants will be recruited through Paediatric Growth and Development Clinic. All participants will receive left hand 3D-US and X-ray examination at the Shanghai Sixth People’s Hospital on the same day, all images will be recorded. These image related data will be collected and randomly divided into training set (80% of all) and test set (20% of all). The training set will be used to establish a cascade network of 3D-US skeletal image segmentation and BA prediction model to achieve end-to-end prediction of image to BA. The test set will be used to evaluate the accuracy of AI BA model of 3D-US. We have developed a new ultrasonic scanning device, which can be proposed to automatic 3D-US scanning of hands. AI algorithms, such as convolutional neural network, will be used to identify and segment the skeletal structures in the hand 3D-US images. We will achieve automatic segmentation of hand skeletal 3D-US images, establish BA prediction model of 3D-US, and test the accuracy of the prediction model.Ethics and dissemination The Ethics Committee of Shanghai Sixth People’s Hospital approved this study. The approval number is 2022-019. A written informed consent will be obtained from their parent or guardian of each participant. Final results will be published in peer-reviewed journals and presented at national and international conferences.Trial registration number ChiCTR2200057236.

Objectives To identify the most significantly differentially expressed circular RNAs (circRNAs) in colorectal cancer (CRC) tissues in terms of their expression levels and circularity, and to analyze the relationship between their expression levels and the clinical characteristics of patients. Methods circRNA RNA-seq technology was used to screen differentially expressed circRNAs in CRC. Sanger sequencing was used to identify circRNA back-splice junction sites. The relative expression levels of hsa_circ_0003761 (circMSH3) in CRC tissues and cell lines were detected by quantitative real-time fluorescence PCR technology. An RNA-protein pull-down assay was used to detect protein binding to circRNAs. Dual-luciferase reporter gene vectors were constructed to verify that circRNAs bind to microRNAs. Results Four hundred twenty circRNAs were found to be upregulated, and 616 circRNAs were downregulated. circMSH3 was derived from the MutS homolog 3 (MSH3) gene and was formed by a loop of exons 9, 10, 11, and 12. In 110 pairs of CRC and adjacent tissues, circMSH3 expression was 4.487-fold higher in CRC tissues. circMSH3 was also highly expressed in the HT-29 and LOVO CRC cell lines. The expression level of circMSH3 was associated with distant metastasis in CRC patients (P = 0.043); the area under the curve (AUC) of circMSH3 for CRC diagnosis was 0.75, with a sensitivity and specificity of 70.9% and 66.4%, respectively. circMSH3 could bind to a variety of proteins, mainly those involved in RNA transcription, splicing, cell cycle, and cell junctions. Furthermore, circMSH3 could bind to miR-1276, miR-942-5p, and miR-409-3p. Conclusion circMSH3 is a potential biomarker for the diagnosis of CRC and affects the distant metastasis of CRC. Multiple RNA-binding protein binds to circMSH3, and circMSH3 binds to miR-1276, miR-942-5p, and miR-409-3p, thereby affecting the expression of circMSH3.

Spatially resolved metabolomics enables the investigation of tumoral metabolites in situ. Inter- and intratumor heterogeneity are key factors associated with patient outcomes. Adrenocortical carcinoma (ACC) is an exceedingly rare tumor associated with poor survival. Its clinical prognosis is highly variable, but the contributions of tumor metabolic heterogeneity have not been investigated thus far to our knowledge. An in-depth understanding of tumor heterogeneity requires molecular feature-based identification of tumor subpopulations associated with tumor aggressiveness. Here, using spatial metabolomics by high–mass resolution MALDI Fourier transform ion cyclotron resonance mass spectrometry imaging, we assessed metabolic heterogeneity by de novo discovery of metabolic subpopulations and Simpson’s diversity index. After identification of tumor subpopulations in 72 patients with ACC, we additionally performed a comparison with 25 tissue sections of normal adrenal cortex to identify their common and unique metabolic subpopulations. We observed variability of ACC tumor heterogeneity and correlation of high metabolic heterogeneity with worse clinical outcome. Moreover, we identified tumor subpopulations that served as independent prognostic factors and, furthermore, discovered 4 associated anticancer drug action pathways. Our research may facilitate comprehensive understanding of the biological implications of tumor subpopulations in ACC and showed that metabolic heterogeneity might impact chemotherapy.

Abstract RNA modifications play a major role in tumorigenicity and progression, but the expression and function in glioblastoma (GBM) have not been well described. In this study, we developed a GBM score based on the differentially expressed genes (DEGs) between groups showing RNA modification patterns. We assessed the association between the GBM score and tumor microenvironment (TME) characteristics. Based on the gene expression of these regulators, we identified two clusters with distinct RNA modification patterns. Kaplan–Meier survival curves showed that patients in cluster 1 had worse survival than those in cluster 2. Kaplan–Meier and multivariate Cox regression analyses showed that GBM scores (based on DEGs between RNA modification patterns) are an independent predictive biomarker for patient prognosis. Besides, we found that samples with high scores were significantly associated with epithelial-to-mesenchymal transition and immune checkpoints, while samples with low scores were associated with cell cycle regulation. Importantly, GBM-score markedly positively correlated drug resistance, while negatively correlated with drug sensitive. The responders of anti-PD-1/PD-L1 immunotherapy tend to have a lower GBM score than non-responders. In conclusion, our comprehensive analysis of multiple RNA modifications in GBM revealed that RNA modification regulators were closely correlated with TME.

Abstract We investigated cross-sectional associations between children’s neurodevelopment and their gut microbiota composition. Study children (36 months of age) lived in rural China (n = 46). Neurodevelopment was assessed using the Bayley Scales of Infant Development, 2nd Edition, yielding the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI). Children's gut microbiota was assessed using 16S rRNA gene profiling. Microbial diversity was characterized using alpha diversity patterns. Additionally, 3 coabundance factors were determined for the 25 most abundant taxa. Multivariable linear regression models were constructed to examine the relationships between Bayley scores (MDI and PDI) and children's gut microbiota. In adjusted models, MDI and PDI scores were not associated with alpha diversity indices. However, in adjusted models, MDI and PDI scores were positively associated with the first coabundance factor, which captured positive loadings for the genera Faecalibacterium, Sutterella, and Clostridium cluster XIVa. For an interquartile range increase in the first coabundance factor, MDI scores increased by 3.9 points [95% confidence interval (CI): 0, 7.7], while PDI scores increased by 8.6 points (95% CI 3.1, 14). Our results highlight the potential for gut microbial compositional characteristics to be important correlates of children's Bayley Scales performance at 36 months of age.

Abstract The presence of a new lumbar swelling or pain in the postoperative period following laparoscopic surgery should raise the suspicion of a lumbar hernia. Cross‐sectional imaging can be used to establish an early diagnosis to enable successful management.

Abstract Pancreatic cancer will gradually become the second leading cause of cancer death due to its poor suitability for surgical treatment, frequent recurrence and metastasis, and insensitivity to radiotherapy and chemotherapy. Strategies for precise early detection and effective targeted treatment of pancreatic cancer are urgently needed. Because of its unique advantages, molecular targeted contrast-enhanced ultrasound imaging (CEUI) has generated new opportunities to overcome this challenge. The aim of this study was to explore multifunctional nanobubbles named IR780-NBs-DTX as novel ultrasound contrast agents (UCAs) for dual-mode targeted imaging and photothermal ablation combined with chemotherapy for pancreatic cancer. An optimized “film hydration method” was used to prepare IR780-NBs-DTX in this research. The characteristics and ability of the new UCAs were detected via in vitro, in vivo and ex vivo experiments. The initial dose of 0.15 mg IR-780 iodide/1.0 mg DTX was considered to be the best formula for IR780-NBs-DTX, and the concentration of 6 ×106 bubbles/mL was best for CEUI. The excellent characteristics of IR780-NBs-DTX, including a uniform nanoscale particle size (349.8± 159.1 nm, n= 3), good performance in dual-mode imaging, high stability and reliable biocompatibility, were also proven. In the in vitro cell experiments, IR780-NBs-DTX targeted more pancreatic cancer cells than the control treatments, and the targeting rate was approximately 95.6± 1.7%. Under irradiation with an 808 nm laser, most cells died. Furthermore, the in vivo study demonstrated that IR780-NBs-DTX could precisely detect pancreatic cancer through near infrared fluorescence (NIRF) imaging and CEUI, and the tumor almost disappeared at 18 days after combined treatment. In ex vivo experiments, immunohistochemistry (IHC) and immunofluorescence (IF) showed that the expression of HSP70 increased and that of PCNA decreased, and many apoptotic tumor cells were observed by TUNEL staining in the IR780-NBs-DTX group. The newly prepared IR780-NBs-DTX are novel nanosized UCAs with high efficiency for dual-mode molecular targeted imaging and combined therapy, and they may have future potential applications in the precise detection and effective targeted therapy of small and metastatic lesions in the early stage of pancreatic cancer.

Objectives: To present a case series of modified transjugular intrahepatic portosystemic shunts (TIPS) and percutaneous transhepatic intrahepatic portosystemic shunts (PTIPS) in cirrhotic patients with variceal bleeding (VB). In addition, the scientific literature pertaining to PTIPS was reviewed. Methods: This retrospective clinical case series included six cirrhotic patients with VB who were treated with PTIPS after the failure of endoscopic band ligation or endoscopic injection sclerotherapy combined with vasoactive drugs. The treatment was conducted between January 2017 and June 2019 at a single institution. Three patients suffered from severe atrophy of the right or left lobar of the liver as well as the main right or left branch of the portal vein. The remaining three patients showed severe atrophy of the whole liver and portal vein, resulting in widening of the liver fissure. A paired t-test was used to compare the changes in portal pressure gradient between before and after the PTIPS operation. The rebleeding rate, treatment efficacy, complications, and technical success rate were all assessed during follow-up. Results: All six PTIPS procedures were performed successfully, with no severe procedural-related complications observed. None of the patients experienced VB during a mean follow-up of 22.8 (range, 18.0–28.0) months. The mean portosystemic pressure gradient decreased from 28.3 ​± ​4.3 ​mmHg pre-procedure to 12.3 ​± ​2.6 ​mmHg immediately post-procedure (P ​

Purpose: We aimed to compare treatment efficacy, safety and material cost between tissue gel and coil regarding variceal embolization during transjugular intrahepatic portosystemic shunt (TIPS).Materials & Methods: This retrospective study including cirrhotic patients with variceal bleeding treated with TIPS combined with variceal embolization between January 2016 and August 2017. Patients were divided into three groups according to embolic agents used in variceal embolization: tissue gel group (Group A), combination group (Group B), and coil group (Group C). The primary endpoint was 1-year rebleeding rate after TIPS creation. The secondary endpoints included shunt dysfunction, overt hepatic encephalopathy, liver function, and embolic agents-related expense. Results: A total of 60 patients (30, 10, and 20 in Group A, B, and C) were included. Variceal rebleeding occurred in 3 (10%), 0 (0%), and 4 (20%) patients within one year after TIPS creation in Group A, B, and C, respectively. Stent dysfunction occurred in 2 (3.3%) patients and 9 (15.0%) patients experienced overt hepatic encephalopathy. No significant differences were observed between three groups regarding primary and secondary endpoints except embolic agents-related expense, with a significantly lower cost in Group A when compared to the other two groups. Stent dysfunction occurred in two patients, with one patient in Group A developed acute occlusion caused by thrombus and another patient in Group C underwent stent stenosis during follow-up. Conclusions: Compares to coil alone or combines with coil, tissue gel has similar treatment efficacy and safety, but with significantly lower cost for variceal bleeding during TIPS.

Phosphorus (P) is an essential element for crop production and a key source of nonpoint pollution in agroecosystems. In this study, we sought to analyze P levels and the factors affecting soil P availability, via P adsorption, in a typical field system that is characterized by the year-round cultivation of vegetables. A total of 190 sites were sampled from vegetable fields in Guangdong Province, South China. Within the research area, average concentrations of 124.49 mg P kg-1 and 1.55 g P kg-1 were recorded for available P (AP) and total P (TP), respectively, which are 8.53- and 1.78-fold higher, respectively, than the corresponding values recorded in 1980. The determined P adsorption maximum (Qm) averaged at 488.38 mg kg-1, which represents a reduction of 16% compared to the values obtained four decades ago. Accumulations of both TP and AP were found to be negatively correlated with the soil’s maximum adsorption buffering capacity (MBC), although no significant correlations with the soil binding energies (k) and Qm, were seen. However, soil pH was found to be significantly correlated with k and Qm. Furthermore, both free Mn oxides (Mnd) and silt concentrations in the soil were found to contribute to explaining the variations in Qm. Collectively, the findings of this study provide evidence to indicate that there has been an excessive accumulation of P in the perennial vegetable fields of Guangdong Province over the past four decades, which may have had negative effects on the P supply potential of the soil by reducing the maximum adsorption buffering capacity.

Abstract Ehlers‐Danlos syndrome, specifically EDS4, can be a dangerous condition. Clinicians should be aware of this when referring such patients for any interventional procedure. An MDT approach should be adopted to help plan perioperative treatment and care.

Introduction Childhood overweight and obesity (OWO) is a primary global health challenge. Childhood OWO prevention is now a public health priority in China. The Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI), one of four trials being undertaken by the international HeLTI consortium, aims to evaluate the effectiveness of a multifaceted, community-family-mother-child intervention on childhood OWO and non-communicable diseases risk.Methods and analysis This is a multicentre, cluster-randomised, controlled trial conducted in Shanghai, China. The unit of randomisation is the service area of Maternal Child Health Units (N=36). We will recruit 4500 women/partners/families in maternity and district level hospitals. Participants in the intervention group will receive a multifaceted, integrated package of health promotion interventions beginning in preconception or in the first trimester of pregnancy, continuing into infancy and early childhood. The intervention, which is centred on a modified motivational interviewing approach, will target early-life maternal and child risk factors for adiposity. Through the development of a biological specimen bank, we will study potential mechanisms underlying the effects of the intervention. The primary outcome for the trial is childhood OWO (body mass index for age ≥85th percentile) at 5 years of age, based on WHO sex-specific standards. The study has a power of 0.8 (α=0.05) to detect a 30% risk reduction in the proportion of children with OWO at 5 years of age, from 24.4% in the control group to 17% in the intervention group. Recruitment was launched on 30 August 2018 for the pilot study and 10 January 2019 for the formal study.Ethics and dissemination The study has been approved by the Medical Research Ethics Committee of the International Peace Maternity and Child Health Hospital in Shanghai, China, and the Research Ethics Board of the Centre Intégré Universitaire de Santé et Services Sociaux de l’Estrie–CHUS in Sherbrooke, Canada. Data sharing policies are consistent with the governance policy of the HeLTI consortium and government legislation.Trial registration number ChiCTR1800017773.Protocol version November 11, 2020 (Version #5).

Background: Canagliflozin (CANA) administration increases the risk of lower limb amputation in the clinic. The present study aimed to investigate whether and how CANA interferes with the intracellular physiological processes of bone marrow derived mesenchymal stem cells (BM-MSCs) and its contribution to ischaemic lower limb. Methods: The in vivo blood flow recovery in ischaemic lower limbs following CANA treatment was evaluated. The cellular function of BM-MSCs after CANA treatment were also assessed in vitro. In silico docking analysis and mutant substitution assay were conducted to confirm the interaction of CANA with glutamate dehydrogenase 1 (GDH1). Findings: Following CANA treatment, attenuated angiogenesis and hampered blood flow recovery in the ischaemic region were detected in diabetic and non-diabetic mice, and inhibition of the proliferation and migration of BM-MSCs were also observed. CANA was involved in mitochondrial respiratory malfunction in BM-MSCs and the inhibition of ATP production, cytochrome c release and vessel endothelial growth factor A (VEGFA) secretion, which may contribute to reductions in the tissue repair capacity of BM-MSCs. The detrimental effects of CANA on MSCs result from the inhibition of GDH1 by CANA (evidenced by in silico docking analysis and H199A-GDH1/N392A-GDH1 mutant substitution). Interpretation: Our work highlights that the inhibition of GDH1 activity by CANA interferes with the metabolic activity of the mitochondria, and this interference deteriorates the retention of and VEGFA secretion by MSCs. Funding: National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province and Wenzhou Science and Technology Bureau Foundation. Keywords: Canagliflozin, Mesenchymal Stem Cells, Mitochondria, Glutamate dehydrogenase, Ischaemia

ObjectivesHyperkyphosis is associated with restricted pulmonary function and posture, potentially contributing to poor sleep. A previous study reported older women with hyperkyphosis had worse self-reported sleep quality, but it is less clear if this association exists in men. We examined the association between hyperkyphosis and subjective and objective sleep quality in a cohort of older men.DesignLongitudinal analysis of data from large cohort of older men participating in the Osteoporotic Fractures in Men Study (MrOS).SettingCommunity.ParticipantsWe studied 754 men participants in MrOS who had kyphosis measured during the 3rd clinic visit (2007-2009) and future subjective and objective sleep quality assessed between 2009-2012 (an average of 2.9 years later).InterventionN/A.MeasurementsTo measure kyphosis, 1.7 cm thick wooden blocks were placed under the participant's head to achieve a neutral spine position while lying supine on a DXA table. We collected data on both subjective (Pittsburgh Sleep Quality Index [PSQI], and Epworth Sleepiness Scale [ESS]) and objective (wrist actigraphy: Total Sleep Time [TST], Wake After Sleep Onset [WASO], Sleep Efficiency [SE], Sleep Onset Latency [SOL]; and polysomnography: Apnea Hypopnea Index [AHI]) sleep measurements. Those who required >3 blocks were considered hyperkyphotic (n = 145 or 19.2%).ResultsIn unadjusted and multivariable analyses, men with hyperkyphosis did not report having worse self-reported sleep characteristics based on PSQI and ESS. Similarly, there were no significant associations between hyperkyphosis and objective sleep measures. When examined as a continuous predictor (blocks ranging from 0-8), results were no different.ConclusionsAlthough we hypothesized that poor posture in those with hyperkyphosis would interfere with sleep, in this sample of older men, worse kyphosis was not associated with self-reported or objectively measured poor sleep quality.

The presence of Alternaria toxins (ATs) in fruit purees may cause potential harm to the life and health of consumers. As time passes, ATs have become the key detection objects in this kind of food. Based on this, a novel and rapid method was established in this paper for the simultaneous detection of seven ATS (tenuazonic acid, alternariol, alternariol monomethyl ether, altenuene, tentoxin, altenusin, and altertoxin I) in mixed fruit purees using ultra-high performance liquid chromatography-tandem mass spectrometry. The sample was prepared using the modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method to complete the extraction and clean-up steps in one procedure. In this QuEChERS method, sample was extracted with water and acetonitrile (1.5% formic acid), then salted out with NaCl, separated on an ACQUITY UPLC BEH C18 with gradient elution by using acetonitrile and 0.1% formic acid aqueous as eluent, and detected by UPLC-MS/MS under positive (ESI+) and negative (ESI−) electrospray ionization and MRM models. Results showed that the seven ATs exhibited a good linearity in the concentration range of 0.5–200 ng/mL with R2 > 0.9925, and the limits of detection (LODs) of the instrument were in the range of 0.18–0.53 μg/kg. The average recoveries ranged from 79.5% to 106.7%, with the relative standard deviations (RSDs) no more than 9.78% at spiked levels of 5, 10, and 20 μg/kg for seven ATs. The established method was applied to the determination and analysis of the seven ATs in 80 mixed fruit puree samples. The results showed that ATs were detected in 31 of the 80 samples, and the content of ATs ranged from 1.32 μg/kg to 54.89 μg/kg. Moreover, the content of TeA was the highest in the detected samples (23.32–54.89 μg/kg), while the detection rate of Ten (24/31 samples) was higher than the other ATs. Furthermore, the other five ATs had similar and lower levels of contamination. The method established in this paper is accurate, rapid, simple, sensitive, repeatable, and stable, and can be used for the practical determination of seven ATs in fruit puree or other similar samples. Moreover, this method could provide theory foundation for the establishment of limit standard of ATs and provide a reference for the development of similar detection standard methods in the future.

[This corrects the article DOI: 10.1371/journal.pone.0178887.].

Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader–Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. Research in context: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

The majority of Countdown countries did not reach the fourth Millennium Development Goal (MDG 4) on reducing child mortality, despite the fact that donor funding to the health sector has drastically increased. When tracking aid invested in child survival, previous studies have exclusively focused on aid targeting reproductive, maternal, newborn, and child health (RMNCH). We take a multi-sectoral approach and extend the estimation to the four sectors that determine child survival: health (RMNCH and non-RMNCH), education, water and sanitation, and food and humanitarian assistance (Food/HA).Using donor reported data, obtained mainly from the OECD Creditor Reporting System and Development Assistance Committee, we tracked the level and trends of aid (in grants or loans) disbursed to each of the four sectors at the global, regional, and country levels. We performed detailed analyses on missing data and conducted imputation with various methods. To identify aid projects for RMNCH, we developed an identification strategy that combined keyword searches and manual coding. To quantify aid for RMNCH in projects with multiple purposes, we adopted an integrated approach and produced the lower and upper bounds of estimates for RMNCH, so as to avoid making assumptions or using weak evidence for allocation. We checked the sensitivity of trends to the estimation methods and compared our estimates to that produced by other studies. Our study yielded time-series and recipient-specific annual estimates of aid disbursed to each sector, as well as their lower- and upper-bounds in 134 countries between 2000 and 2014, with a specific focus on Countdown countries. We found that the upper-bound estimates of total aid disbursed to the four sectors in 134 countries rose from US$ 22.62 billion in 2000 to US$ 59.29 billion in 2014, with the increase occurring in all income groups and regions with sub-Saharan Africa receiving the largest sum. Aid to RMNCH has experienced the fastest growth (12.4%), followed by aid to Food/HA (9.4%), education (5.1%), and water and sanitation (5.0%). With the exception of RMNCH, the average per capita aid disbursed to each sector in the 74 Countdown countries was smaller than in non-Countdown countries. While countries with a large number of child deaths tend to receive the largest amount of disbursements, non-Countdown countries with small populations usually received the highest level of per capita aid for child survival among all 134 countries. Compared to other Countdown countries, those that met MDG 4 with a high reliance on health aid received much higher per capita aid across all sectors. These findings are robust to estimation methods.The study suggests that to improve child survival, better targeted investments should be made in the four sectors, and aid to non-health sectors could be a possible contributor to child mortality reduction. We recommend that future studies on tracking aid for child survival go beyond the health sector and include other sectors that directly affect child survival. Investigation should also be made about the link between aid to each of the four sectors and child mortality reduction.

Traffic identification of the target category is currently a significant challenge for network monitoring and management. To identify the target category with pertinence, a feature extraction algorithm based on the subset with highest proportion is presented in this paper. The method is proposed to be applied to the identification of any category that is assigned as the target one, but not restricted to certain specific category. We divide the process of feature extraction into two stages. In the stage of primary feature extraction, the feature subset is extracted from the dataset which has the highest proportion of the target category. In the stage of secondary feature extraction, the features that can distinguish the target and interfering categories are added to the feature subset. Our theoretical analysis and experimental observations reveal that the proposed algorithm is able to extract fewer features with greater identification ability of the target category. Moreover, the universality of the proposed algorithm proves to be available with the experiment that every category is set to be the target one.

Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) has a potential immunoregulatory role dependent on Toll-like receptors (TLRs). TLR2, associated with deleterious systemic inflammation, cardiac dysfunction, and acute kidney injury, acts synergistically in sepsis. The role of MFHAS1 in targeting TLR2 involved in sepsis has not been examined thus far. This study aimed to examine the relationship of MFHAS1 and sepsis, and the effect of MFHAS1 on the TLR2 signaling pathway. Blood samples were collected from eight sepsis patients after surgery and eight patients undergoing selective surgery to determine blood MFHAS1 levels. HEK 293 cells, RAW 264.7 macrophages and THP-1 monocytes were used to confirm the effect of MFHAS1 on TLR2 signaling pathway. Our study showed that blood MFHAS1 was significantly elevated in septic patients, and MFHAS1 was more increased in mononuclear cells from septic patients. Pam3CSK4 (TLR2 ligand) was found to induce MFHAS1 production in RAW 264.7 murine macrophages and THP-1 human monocytes in a time-dependent manner. MFHAS1 has dual effects on TLR2 signaling pathway and inflammation, i.e., inhibitory effect at 6 hours, and then stimulatory effect after 24 hours through the activation of TLR2/NF-κB signaling pathway, and MFHAS1 induced the phosphorylation of JNK and p38 after TLR2 stimulation.

In the present study, trehalose was utilized to improve primary culture of mouse epididymal epithelial cells in vitro, and to enhance naked DNA delivery in epididymis in vivo. During the six-day culture, the proliferation activity of the cells in the medium with addition of trehalose was higher than that of those cells cultured in absence of trehalose (p

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is critical in modulating platelet functions. In the present study, we evaluated the effect of S14161, a recently identified pan-class I PI3K inhibitor, on platelet activation and thrombus formation. Results showed that S14161 inhibited human platelet aggregation induced by collagen, thrombin, U46619, and ADP in a dose-dependent manner. Flow cytometric studies showed that S14161 inhibited convulxin- or thrombin-induced P-selectin expression and fibrinogen binding of single platelet. S14161 also inhibited platelet spreading on fibrinogen and clot retraction, processes mediated by outside-in signaling. Using a microfluidic chamber we demonstrated that S14161 decreased platelet adhesion on collagen-coated surface by about 80%. Western blot showed that S14161 inhibited phosphorylation of Akt at both Ser473 and Thr308 sites, and GSK3β at Ser9 in response to collagen, thrombin, or U46619. Comparable studies showed that S14161 has a higher potential bioavailability than LY294002, a prototypical inhibitor of pan-class I PI3K. Finally, the effects of S14161 on thrombus formation in vivo were measured using a ferric chloride-induced carotid artery injury model in mice. The intraperitoneal injection of S14161 (2 mg/kg) to male C57BL/6 mice significantly extended the first occlusion time (5.05 ± 0.99 min, n = 9) compared to the vehicle controls (3.72 ± 0.95 min, n = 8) (P0.05). Taken together, our data showed that S14161 inhibits platelet activation and thrombus formation without significant bleeding tendency and toxicity, and considering its potential higher bioavailability, it may be developed as a novel therapeutic agent for the prevention of thrombotic disorders.

Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR). Heme oxygenase-1 (HO-1) is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC). The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy.RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II). The HO-1/extracellular signal-related kinase (ERK)/p38/mitogen-activated protein kinase (MAPK) pathway was detected in an autophagy model and mineral oil-induced IR in vitro.In liver IR, the expression of LC3-II peaked 12-24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI) in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA.RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.

While genome-wide association studies (GWAS) and candidate gene approaches have identified many genetic variants that contribute to disease risk as main effects, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. To explore the importance of GxE interactions for diabetes-related traits, a tool for Genome-wide Complex Trait Analysis (GCTA) was used to examine GxE variance contribution of 15 macronutrients and lifestyle to the total phenotypic variance of diabetes-related traits at the genome-wide level in a European American population. GCTA identified two key environmental factors making significant contributions to the GxE variance for diabetes-related traits: carbohydrate for fasting insulin (25.1% of total variance, P-nominal = 0.032) and homeostasis model assessment of insulin resistance (HOMA-IR) (24.2% of total variance, P-nominal = 0.035), n-6 polyunsaturated fatty acid (PUFA) for HOMA-β-cell-function (39.0% of total variance, P-nominal = 0.005). To demonstrate and support the results from GCTA, a GxE GWAS was conducted with each of the significant dietary factors and a control E factor (dietary protein), which contributed a non-significant GxE variance. We observed that GxE GWAS for the environmental factor contributing a significant GxE variance yielded more significant SNPs than the control factor. For each trait, we selected all significant SNPs produced from GxE GWAS, and conducted anew the GCTA to estimate the variance they contributed. We noted the variance contributed by these SNPs is higher than that of the control. In conclusion, we utilized a novel method that demonstrates the importance of genome-wide GxE interactions in explaining the variance of diabetes-related traits.

BACKGROUND: Cholangiocarcinoma (CC) is an intractable cancer, arising from biliary epithelial cells, which has a poor prognosis and is increasing in incidence. Early diagnosis of CC is essential as surgical resection remains the only effective therapy. The purpose of this study was to identify improved biomarkers to facilitate early diagnosis and prognostication in CC. METHODS: A comparative expression profile of human bile samples from patients with cholangitis and CC was constructed using a classic 2D/MS/MS strategy and the expression of selected proteins was confirmed by Western blotting. Immunohistochemistry was performed to determine the expression levels of selected candidate biomarkers in CC and matched normal tissues. Finally, spermatogenesis associated 20 (SSP411; also named SPATA20) was quantified in serum samples using an ELISA. RESULTS: We identified 97 differentially expressed protein spots, corresponding to 49 different genes, of which 38 were upregulated in bile from CC patients. Western blotting confirmed that phosphoglycerate mutase 1 (brain) (PGAM-1), protein disulfide isomerase family A, member 3 (PDIA3), heat shock 60 kDa protein 1 (chaperonin) (HSPD1) and SSP411 were significantly upregulated in individual bile samples from CC patients. Immunohistochemistry demonstrated these proteins were also overexpressed in CC, relative to normal tissues. SSP411 displayed value as a potential serum diagnostic biomarker for CC, with a sensitivity of 90.0% and specificity of 83.3% at a cutoff value of 0.63. CONCLUSIONS: We successfully constructed a proteomic profile of CC bile proteins, providing a valuable pool novel of candidate biomarkers. SSP411 has potential as a biomarker for the diagnosis of CC.

Abstract This study uses a 2D high-resolution thermo-mechanical coupled model to investigate the dynamic processes of deep plate hydration, dehydration, and subsequent magmatic activity in ocean-continent subduction zones. We reveal the pathways and temporal evolution of water transport to the deep mantle during the subduction process. Plate dehydration plays a critical role in triggering partial melting of the deep mantle and related magmatic activity. Our study shows significant differences in the volumes of melt produced at different depths, with dehydration reactions in deeper regions being weaker compared to shallower ones. It takes a longer time to reach the suitable P-T conditions for hydrous melting in the deep mantle. The results highlight the geophysical significance of water transport in deep subduction zones and its role in magmatic processes, particularly in the formation of magma chambers beneath continental plates.