Search

BackgroundSepsis remains a complex condition with incomplete understanding of its pathogenesis. Further research is needed to identify prognostic factors, risk stratification tools, and effective diagnostic and therapeutic targets.MethodsThree GEO datasets (GSE54514, GSE65682, and GSE95233) were used to explore the potential role of mitochondria-related genes (MiRGs) in sepsis. WGCNA and two machine learning algorithms (RF and LASSO) were used to identify the feature of MiRGs. Consensus clustering was subsequently carried out to determine the molecular subtypes for sepsis. CIBERSORT algorithm was conducted to assess the immune cell infiltration of samples. A nomogram was also established to evaluate the diagnostic ability of feature biomarkers via “rms” package. ResultsThree different expressed MiRGs (DE-MiRGs) were identified as sepsis biomarkers. A significant difference in the immune microenvironment landscape was observed between healthy controls and sepsis patients. Among the DE-MiRGs, NDUFB3 was selected to be a potential therapeutic target and its significant elevated expression level was confirmed in sepsis using in vitro experiments and confocal microscopy, indicating its significant contribution to the mitochondrial quality imbalance in the LPS-simulated sepsis model. ConclusionBy digging the role of these pivotal genes in immune cell infiltration, we gained a better understanding of the molecular immune mechanism in sepsis and identified potential intervention and treatment strategies.

Supple Fig 1, Supple Table 1-8, and Supple Ref. Supplementary Figure S1. 2100 Bioanalyzer spectra of total DNA extracted from CSF samples. Supplementary Table S1. Sample collection information. Supplementary Table S2. Genes/regions included in the LungPlasma panel. Supplementary Table S3. Genes included in the customized SeqCap EZ Choice Library. Supplementary Table S4. List of hotspot mutations and structural rearrangements. Supplementary Table S5. Co-existence of EGFR and PIK3CA mutations as reported in NSCLC patient datasets Supplementary Table S6. Occurrence of somatic protein-changing variants in primary tumor and CSF. Supplementary Table S7. Genes and biological pathways with recurrent somatic protein-changing variants in primary tumor or CSF. Supplementary Table S8. Comparison of EGFR mutation type(s) in CSF cfDNA and pellet DNA as detected by droplet digital PCR (ddPCR).

Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non–small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood.Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM.Results: The status of EGFR-activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development.Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. Clin Cancer Res; 24(1); 209–16. ©2017 AACR.

Additional file 1. SPIRIT checklist.

Background. Cuproptosis, a recently discovered form of cell death, is caused by copper levels exceeding homeostasis thresholds. Although Cu has a potential role in colon adenocarcinoma (COAD), its role in the development of COAD remains unclear. Methods. In this study, 426 patients with COAD were extracted from the Cancer Genome Atlas (TCGA) database. The Pearson correlation algorithm was used to identify cuproptosis-related lncRNAs. Using the univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO) was used to select cuproptosis-related lncRNAs associated with COAD overall survival (OS). A risk model was established based on the multivariate Cox regression analysis. A nomogram model was used to evaluate the prognostic signature based on the risk model. Finally, mutational burden and sensitivity analyses of chemotherapy drugs were performed for COAD patients in the low- and high-risk groups. Result. Ten cuproptosis-related lncRNAs were identified and a novel risk model was constructed. A signature based on ten cuproptosis-related lncRNAs was an independent prognostic predictor for COAD. Mutational burden analysis suggested that patients with high-risk scores had higher mutation frequency and shorter survival. Conclusion. Constructing a risk model based on the ten cuproptosis-related lncRNAs could accurately predict the prognosis of COAD patients, providing a fresh perspective for future research on COAD.

Supplementary Material for Confidence Screening Detector: A New Method for Detecting Test Collusion by Yongze Xu, Ying Cui, Xinyi Wang, and Fang Luo in Applied Psychological Measurement.

Background Methadone is commonly considered an alternative opioid treatment for refractory cancer pain. This study aims to investigate the efficacy, safety, and cost of methadone in the treatment of refractory cancer pain. Methods A retrospective study was conducted in patients who used methadone for refractory cancer pain from April 2016 to December 2020 at a cancer specialized hospital. Pain control, evaluated via pain score and breakthrough pain frequency, and adverse events of methadone were compared with analgesic regimens prior to methadone administration. The factors potentially affecting the switching outcome were analyzed via multivariate analysis. Moreover, the cost of pain control was estimated. Results Ninety patients received methadone for poor pain control (74.4%), intolerable adverse events (10.0%), or both (15.6%) after prior opioid treatments. Sixty-four patients (71.1%) were successfully switched to methadone with median pain score significantly decreased from 4.0 to 2.0 (p Conclusion Methadone is an effective, safe, and cost-saving treatment for patients with refractory cancer pain.

Background: Non-adherence to physician-prescribed medications, especially oral medications, is common in children with inflammatory bowel disease (IBD), and medication non-adherence is associated with poorer outcomes in IBD. Therefore, understanding and improving medication adherence in children with IBD is critical for optimizing treatment and improving treatment outcomes. Despite the relatively high prevalence of IBD in children in China, to date, very little is known about medication adherence in these patients.Objective: The aim of this study was to investigate the prevalence of medication non-adherence and its risk factors in children with IBD in China to provide a basis for developing adherence improvement strategies.Methods: A cross-sectional design was employed. Children (aged Results: A total of 119children were included in this study. The results showed that 33 (27.73%) and 86 (72.27%) children had poor and good medication adherence, respectively. Of these, 83 (69.75%) had forgotten to take their medications sometimes, often, or always. On binary logistic regression, we found that the incidence of medication non-adherence in children with IBD course of 3 years and above [OR 4.82 (95%CI: 1.47-15.88); p = 0.01] was significantly higher than that in children with course of 3 months to 1 year, whereas children with higher parental CCKNOW scores [OR 0.77 (95%CI: 0.67-0.88); p = 0.00] had significantly lower incidence of medication non-adherence than those with lower parental CCKNOW scores, and the results of the correlation between parental knowledge scores of the four categories and children’s medication adherence showed that drug knowledge scores (r = 0.36, p < 0.00) and complication knowledge scores (r = 0.24, p = 0.01) were positively correlated with medication adherence.Conclusion: Poor medication adherence in children with IBD in China was common, and forgetting to take medication was the main barrier. Longer disease duration (3 years and above) in children could act as a risk factor for medication adherence, whereas higher level of parental knowledge about IBD could act as a protective factor, and one interesting novel finding was that the level of parental knowledge about drug and complication were significantly correlated with medication adherence in children with IBD. Our results may inform on the design and implementation of medication adherence interventions for children with IBD.

Sceptridium ternatum is a herbaceous plant with significant potential for pharmaceutical and cosmetic applications. In this study, we established a spectrum-effect relationship-based strategy to investigate the bioactive basis and tissue distribution in S. ternatum. First, a phytochemical analysis on the ethanol extracts from roots, stems, and leaves of S. ternatum was performed using the colorimetric method, high-performance liquid chromatography–ultraviolet (HPLC–UV), and high-performance liquid chromatography–electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC–ESI-Q-TOF-MS/MS). Then, radical scavenging assays and the lipopolysaccharide-stimulated RAW 264.7 cell model were used to estimate the antioxidant and anti-inflammatory activities, respectively. Spectrum-effect relationship analysis and molecular docking were further employed to evaluate the correlation between the phytochemical profile and anti-inflammatory activity. Our results demonstrate that S. ternatum leaves contained the most abundant flavonoids and exerted the best biological activities. Their IC50 values for scavenging 2,2ʹ-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) and 1,1-diphenyl-2-picrylhydrazyl radicals were 2.43 ± 0.13 and 5.36 ± 0.54 mg/mL, respectively. In lipopolysaccharide-stimulated RAW 264.7 cells, the leaf extract caused the greatest reduction in nitric oxide production (38.15%) and interleukin-6 release (110.86%). Spectrum-effect relationship analysis and molecular docking indicated that quercetin 3-O-rhamnoside-7-O-glucoside possessed high anti-inflammatory activity by binding with interleukin-6. In conclusion, S. ternatum is a rich source of bioactive flavonoids with potential for exploitation in the prevention and treatment of oxidative stress and inflammation-related pathologies.

Background Sorafenib, the first approved targeted therapy for advanced hepatocellular carcinoma (HCC), is often reported to comprised survival-benefit due to resistance. An underlying mechanism of resistance was proposed using bioinformatics analysis based on differentially expressed genes (DEGs) from microarrays. However, most DEGs were invalidated at both the expression level, and the role in causing resistance. Therefore, we conducted a bioinformatics analysis based on experimentally determined sorafenib-resistance-related genes (SRRGs) to elucidate the mechanism of sorafenib resistance. Methods The SRRGs, which have been experimentally determined to promote or inhibit resistance, were collected from published studies. The Database for Annotation, Visualization and Integrated Discovery (DAVID) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform Gene Ontology (GO) and pathway enrichment analysis, respectively. A corresponding protein-protein interaction network (PPI) was created using the Cytoscape software program, and network hub genes were proposed. Results A total of 145 SRRGs, with 117 promoting and 28 inhibiting resistance, were identified. Cell proliferation, migration, development, response to oxygen levels, epithelial-to-mesenchymal transition (EMT), cell skeleton, protein function, and autophagy were all proposed as crucial gene functions related to resistance. The pathways related to cell proliferation or apoptosis, immune function, endocrine metabolism, stem cell function, and differentiation were identified as key resistance-related pathways. A total of 81 hub genes were proposed, including the following top 10 genes: TP53, AKT1, EGFR, STAT3, VEGFA, JUN, MAPK1, IL6, PTEN, and CTNNB1. Conclusions In conclusion, this study gathered experimentally validated genes that determine sorafenib resistance in HCC, provided an overview of the underlying mechanisms of resistance, and further validated sorafenib resistance in HCC.

With the rapid development and popularity of the Internet, an increasing number of people would like to use online platforms to express themselves and communicate with others. It is inevitable that a large number of online text data are constantly emerging with personal information, which often indicate individual real expression in different conditions and reflect personal inner psychological traits and personality tendency. Applying text mining techniques to analyzing psychological traits behind the online text is not only helpful for individuals to understand themselves, but also useful to avoid the motivation interfere while using traditional methods for psychological assessment. In recent years, the language model named bidirectional encoder representations from transformers (BERT) has greatly improved the performance of both the text classification task and the sentiment analysis task. In this paper, prediction models for psychological traits are constructed based on online text. Comprehensive semantic features and long dependency in the context are obtained by BERT. Considering that distinct algorithm frameworks of classifiers can lead to different classification results, the fully-connected layer of the BERTBASE model and the random forest algorithm are used in the downstream classification task to make comparison. The results show that psychological traits can be effectively predicted from text classification based on BERT, and the average accuracy, average precision and other indicators are more than 97%.

The combination of valproic acid (VPA) and ibuprofen are common in children with epilepsy. Three case reports investigated that ibuprofen might decrease the plasma concentration of VPA, however, no cohort study was published to evaluate the interaction of ibuprofen on VPA plasma concentration in pediatric patients.Data from patients with measured VPA trough concentrations (C

BackgroundTo identify the diagnostic biomarkers of metabolism-related genes (MRGs), and investigate the association of the MRGs and immune infiltration landscape in diabetic nephropathy (DN).MethodsThe transcriptome matrix was downloaded from the GEO database. R package “limma” was utilized to identify the differential expressed MRGs (DE-MRGs) of HC and DN samples. Genetic Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of DE-MRGs were performed using “clusterProfiler” R package. WGCNA, LASSO, SVM-RFE, and RFE algorithms were employed to select the diagnostic feature biomarkers for DN. The ROC curve was used to evaluate discriminatory ability for diagnostic feature biomarkers. CIBERSORT algorithm was performed to investigate the fraction of the 22-types immune cells in HC and DN group. The correlation of diagnostic feature biomarkers and immune cells were performed via Spearman-rank correlation algorithm.ResultsA total of 449 DE-MRGs were identified in this study. GO and KEGG pathway enrichment analysis indicated that the DE-MRGs were mainly enriched in small molecules catabolic process, purine metabolism, and carbon metabolism. ADI1, PTGS2, DGKH, and POLR2B were identified as diagnostic feature biomarkers for DN via WGCNA, LASSO, SVM-RFE, and RFE algorithms. The result of CIBERSORT algorithm illustrated a remarkable difference of immune cells in HC and DN group, and the diagnostic feature biomarkers were closely associated with immune cells.ConclusionADI1, PTGS2, DGKH, and POLR2B were identified as diagnostic feature biomarkers for DN, and associated with the immune infiltration landscape, providing a novel perspective for the future research and clinical management for DN.

The effect of extended thromboprophylaxis in improving the prognosis of adult patients with coronavirus disease 2019 (COVID-19) after discharge remains debatable. This meta-analysis was aimed to determine the advantages and disadvantages of extended thromboprophylaxis in these patients.Different databases such as PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies that evaluated the effects of extended thromboprophylaxis in post-discharge patients with COVID-19 until 13 June 2022. The primary efficacy outcome was defined by the composite outcome of thromboembolism and all-cause mortality, and the safety outcome was defined by bleeding events. The odds ratios (ORs) and 95 % confidence intervals (CIs) of efficacy and safety outcomes were calculated using fixed- or random-effects model. Interaction analysis was performed to assess and compare observational studies and randomised controlled trials (RCTs). A sensitivity analysis was performed after excluding studies of poor quality.Eight studies involving 10,148 patients were included. The results confirmed that extended thromboprophylaxis, primarily prophylactic use of anticoagulants for35 days, was significantly associated with reduced composite outcome in high-risk post-discharge patients with COVID-19 (OR: 0.52; 95 % CI: 0.41-0.67, P = 0.000). Interaction analysis revealed that the effect estimates were consistent between the RCT and observational studies (PIn post-discharge patients with COVID-19 at high risk of thromboembolism, extended thromboprophylaxis, primarily prophylactic use of anticoagulants for35 days, can significantly reduce the risk of thrombosis and all-cause mortality without increasing the risk of major bleeding events.PROSPERO CRD42022339399.

Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain.A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population.A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events.Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain.ClinicalTrials.gov identifier: NCT03439904.

Objectives Poly (ADP-ribose) polymerase inhibitor (PARPi) have become a mainstay for the treatment of BRCA-mutant malignancies. PARPis are likely to be more effective but also bring an increase in costs. Thus, we aimed at evaluating the cost effectiveness of PARPis in the treatment of malignancies. Methods Studies of cost effectiveness of PARPis were searched from PubMed, Web of Science, and Cochrane Library. Key information was extracted from the identified studies and reviewed. Quality of the included studies was evaluated using Quality of Health Economic Studies (QHES) instrument. Modeling techniques, measurement of parameters and uncertainty analysis were analyzed across studies. Interventions and cost-effectiveness results were reported stratified by patient population. Results Among the 25 studies identified, we included 17 on ovarian cancer, 2 on breast cancer, 3 on pancreatic cancer, and 3 on prostate cancer that involved olaparib, niraparib, rucaparib, and talazoparib. All studies had a QHES score of above 75. In the maintenance therapy of ovarian cancer, additional administration of olaparib was cost-effective for newly diagnosed patients after first-line platinum-based chemotherapy but was not cost-effective for platinum-sensitive recurrent patients in majority studies. However, the economic value of other PARPis in ovarian cancer as well as all PARPis in other tumors remained controversial. Cost-effectiveness of PARPi was primarily impacted by the costs of PARPi, survival time, health utility and discount rate. Moreover, genetic testing improved the cost-effectiveness of PARPi treatment. Conclusions PARPi is potentially cost-effective for patients with ovarian, pancreatic, or prostate cancer. Genetic testing can improve the cost-effectiveness of PARPi.

Linezolid is an oxazolidinone antibacterial drug, and its therapeutic drug monitoring and individualized treatment have been challenged since its approval. With the in-depth clinical research of linezolid, we have changed our attitude toward its therapeutic drug monitoring and our view of individualized treatment. On the basis of summarizing the existing clinical studies, and based on the practical experience of each expert in their respective professional fields, we have formed this expert consensus. Our team of specialists is a multidisciplinary team that includes pharmacotherapists, clinical pharmacology specialists, critical care medicine specialists, respiratory specialists, infectious disease specialists, emergency medicine specialists and more. We are committed to the safe and effective use of linezolid in patients in need, and the promotion of its therapeutic drug monitoring.

Study objectives Vancomycin is a primary antibiotic for the treatment of severe infections in children with malignant hematological disease. However, precise dosing of vancomycin is difficult in children because of high interindividual variability and limited data of pharmacokinetic profiles. The present study aims to develop a population pharmacokinetic (PPK) model for vancomycin in Chinese pediatric patients with hematological malignancies. Design This was a retrospective pharmacokinetic study. Setting The setting for this study was a tertiary-care children's hospital. Patients This study included 92 pediatric patients with hematological malignancies who received vancomycin and experienced therapeutic drug monitoring from February 2017 to December 2018. Measurements and main results A PPK model was generated with a nonlinear mixed effects model. In addition, required doses to achieve target therapeutic concentrations were simulated based on the final model. A one-compartment model with first-order elimination fit the concentration data best. Actual body weight (BW) and glomerular filtration rate (GFR) were the significant influential factors on the clearance (CL) of vancomycin. The final PPK model for CL was CL (L/h) = 4.18 × GFR / 145 0.741 × BW / 25 K , K = BW - 0.856 / BW - 0.856 + 6 . 53 - 0.856 , and the volume of distribution was 22.3 L. The model proved to be robust and reliable. Reference dosing regimens were proposed based on the final model. Conclusions A PPK model of vancomycin was established for Chinese pediatric patients with hematological malignancies using a nonlinear mixed effects model, which provided a reference for the clinical application of vancomycin.

Objective PEGylation is commonly used to optimize pharmacological properties and improve the clinical response of drugs. Due to the inherent toxicity of polyethylene glycol (PEG) and pharmacological changes induced by PEGylation, the safety may be altered and required to be explored. This study explored the adverse events (AEs) associated with PEGylation by comparing pharmacovigilance data of PEGylated and parent drugs. Materials and methods We conducted a disproportionality analysis of spontaneous reports associated with PEGylated and corresponding parent medications from the FDA Adverse Event Reporting System database recorded between the 1st quarter of 2004 and the 4th quarter of 2018 at the level of preferred terms (PTs) and standard MedDRA queries (SMQs), respectively. The AEs probably different in risk due to changed pharmacological effects and inherent toxicity of PEG were analyzed. Results A total of 259,428 cases associated to six drug pairs (filgrastim, asparaginase, interferon α-2a, interferon α-2b,interferon β-1a, and liposomal doxorubicin) were collected. Although 95% of PTs were comparable between the two groups, PTs of deep vein thrombosis, pancreatitis acute, diabetes mellitus, liver disorder, disorientation, aphasia and infection, and SMQ of embolic and thrombotic events were significantly alleviated by PEGylation. No PT was significantly enhanced by PEGylation. Conclusion The pharmacovigilance profiles of PEGylated and non-PEGylated agents were similar. Further clinical assessment is required to validate the pharmacovigilance data.

A superamphiphobic (SAP) surface was fabricated by electrodepositing Cu-Ni micro-nano particles on aluminum substrate and modifying via 1H, 1H, 2H, 2H-perfluorodecyltrimethoxysilane. Scanning electron microscopy, X-ray diffraction, energy-dispersive X-ray spectroscopy, and Fourier-transform infrared spectroscopy were employed to investigate the morphology and chemical composition. The results showed that the SAP surface had three-dimensional micro-nano structures and exhibited a maximum water contact angle of 160.0 \begin{document}$ ^{\circ} $\end{document} , oil contact angle of 151.6 \begin{document}$ ^{\circ} $\end{document} , a minimum water slide angle of 0 \begin{document}$ ^{\circ} $\end{document} and oil slide angle of 9 \begin{document}$ ^{\circ} $\end{document} . The mechanical strength and chemical stability of the SAP surface were tested further. The experimental results showed that the SAP surface presented excellent resistance to wear, prominent acid-resistance and alkali-resistance, self-cleaning and anti-fouling properties.

Cutaneous melanoma (CM) is a malignant tumor with a high incidence rate and poor prognosis. Autophagy plays an essential role in the development of CM; however, the role of autophagy-related long noncoding RNAs (lncRNAs) in this process remains unknown. Human autophagy-related genes were extracted from the Human Autophagy Gene Database and screened for autophagy-related lncRNAs using Pearson correlation. Multivariate Cox regression analysis was implemented to identify ten autophagy-related lncRNAs associated with prognosis, and a risk model was constructed. The Kaplan–Meier survival curve showed that the survival probability of the high-risk group was lower than that of the low-risk group. A novel predictive model was constructed to investigate the independent prognostic value of the risk model. The nomogram results showed that the risk score was an independent prognostic signature that distinguished it from other clinical characteristics. The immune infiltration landscape of the low-risk and high-risk groups was further investigated. The low-risk groups displayed higher immune, stromal, and ESTIMATE scores and lower tumor purity. The CIBERSORT and single sample gene set enrichment analysis (ssGSEA) algorithms indicated a notable gap in immune cells between the low- and high-risk groups. Ten autophagy-related lncRNAs were significantly correlated with immune cells. Finally, Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) results demonstrated that autophagy-related lncRNA-mediated and immune-related signaling pathways are crucial factors in regulating CM. Altogether, these data suggest that constructing a risk model based on ten autophagy-related lncRNAs can accurately predict prognosis and indicate the tumor microenvironment of patients with CM. Thus, our study provides a new perspective for the future clinical treatment of CM.

BACKGROUND: Total parenteral nutrition (TPN) is an essential treatment for patients who undergo abdominal surgery. Due to the gap of knowledge background between clinicians and pharmacists, the participation of the latter may improve TPN standardization. However, the impact on clinical outcome is unknown. In this study, we evaluated the impact of appropriacy and efficacy of TPN prescription, after a pharmacist-led TPN standardization program introduced. METHODS: A pharmacist-led TPN standardization program was introduced in the Zhejiang Cancer Hospital and the clinical outcomes were assessed. The TPN standardization program includes a pre-established standard multidisciplinary evaluation standard, a computerized TPN management system and regular evaluations of TPN prescription performed by pharmacists. Any concerns were identified and improved via discussed with doctors. To evaluate the effect of pharmacists’ intervention in nutritional status and postoperative complications, an observational before-and-after cohort study was performed. All patients admitted in hospital with colorectal cancer (CRC) and receiving abdominal surgery in June 2019 (pre-intervention cohort) and June 2020 (post-intervention cohort) were retrospectively analyzed. Nutritional status of patients was evaluated using the levels of postoperative serum albumin, prealbumin, total protein, and their decrease extent. Surgical or TPN-related complications and recovery time were collated as the clinical outcomes. RESULTS: There were no significant differences in the basic clinical information of the two cohorts, suggesting that the two groups are comparable. The average postoperative prealbumin levels were elevated in 2020 compared to 2019 (192.3±5.5 mg/L for 2019 and 229.5±4.8 mg/L for 2020, P

Additional file 1. Table S1 showing the parameters of measured climatic variables of each FIT plot among three sample regions.

In this experiment, in order to study the formation mechanism of the lamb fur of Tan sheep, skin samples were collected from Tan sheep at the newborn and er-mao stages. Then, the phosphorylated proteomes of the skin samples of Tan sheep at the two different stages were compared and analyzed using a TMT labeled quantitative phosphorylation proteomic technique. A total of 2806 phosphorylated proteins were identified, including 8184 phosphorylation sites. The results of this study’s quantitative analysis showed that when compared with the skin samples at the er-mao stage, the phosphorylation levels of 171 sites had been upregulated in the skin samples at newborn stage. Meanwhile, 125 sites had been downregulated at the same stage. As shown by the results of the functional enrichment analysis of the differentially phosphorylated proteins, they had been mainly enriched in the cysteine and methionine metabolism. In addition, the phosphorylation levels of KAP4.7 and KAP13.1 had also varied during the different skin stages. These results indicated that the cysteine metabolism pathways, as well as the phosphorylation modifications of the keratin associated proteins in the skin, played important roles in the formation of the er-mao stage fur of the Tan sheep. Therefore, the findings of this study provided a new angle for interpreting the formation mechanism of er-mao stage fur properties. Supplementary Information The online version contains supplementary material available at 10.1007/s11250-021-02899-6.

Schistosoma japonicum, prevalent in East and Southeast Asia, is a zoonotic parasite that causes human schistosomiasis. The evolutionary history and local adaptation of S. japonicum are poorly known due to the lack of high-quality whole-genome data. We assembled a chromosome-level genome of S. japonicum and analyzed the genomes of 72 S. japonicum collected from six populations covering its entire endemic region. We studied a zoophilic lineage from Taiwan that was primarily separated from other zoonotic populations at ~45 Kya. This is consistent with the divergent history of their intermediate hosts. A severe population bottleneck was detected in S. japonicum during the Last Glacial Maximum, that coincided with demographic history of the modern humans in Asia. We identified several genomic regions likely underlying positive selection. For example, GATAD2A showed substantial differentiation between the zoophilic and zoonotic populations. RNAi knockdown suggested that it is associated with parasite development and infection establishment in definitive hosts. Another example was Lmln, a protein-coding gene associated with the specificity of the intermediate hosts, that showed divergent adaptation between mountain and lake areas. These findings provide a comprehensive set of population-genomic data and a genomic resource for further functional and medical studies.

At present, there is no ideal method for the treatment of trigeminal neuralgia (TN). The need for an easy, safe, non- or micro-neurodestructive, repeatable treatment, with a fairly satisfactory rate of pain relief, is paramount. Pulsed radiofrequency (PRF) as a minimally invasive and microdestructive technique has been reported to be an option for TN; however, no study has reported the long-term outcome of TN in a large case series.We aimed to investigate the efficacy, safety, and the long-term outcomes of PRF treatment for patients with TN.This was a long-term, large case series, retrospective study.The study was conducted at Tiantan hospital,Beijing.We retrospectively analyzed medical databases and follow-up data of 149 patients with TN from January 2008 through March 2021, who underwent PRF treatment, with a median follow-up time of 71.0 months (interquartile range, 20.0 months to 112.0 months). Baseline characteristics and intraoperative data of patients were retrospectively extracted; data about complications and side effects were also collected. The follow-up data were composed of the postoperative Barrow Neurological Institute Pain Intensity Score pain intensity at a different time, the onset time of PRF treatment, and the time when pain was recurrent.The initial pain relief rate was 75.17% after the procedure. The cumulative recurrence-free survival after the procedure was 75.00% at one month; 72.87% at 6 months; 70.59% at 12 months; 65.39% at 24 months; 61.63% 48 months; 56.73% at 96 months; and 49.64% at 144 months. The median recurrence-free time was 118 months according to the Kaplan-Meier estimator. Nineteen patients had pain recurrence with a median time of 15 months (range, 1.0 months to 96.0 months), among whom, 12 underwent a second PRF procedure and 9 patients experienced satisfactory pain relief. No serious complications or side effects occurred after the procedure.This was a single-center, retrospective study. Our study failed to conduct a stratified analysis on the effect of PRF treatment for classic and idiopathic TN. The most efficacious parameters of PRF applied for TN and studies trying to identify positive predictive factors of pain relief before PRF treatment have yet to be investigated.The results of this study show the promising long-term effect of PRF on primary TN. The safety and repeatability might be more easily accepted by patients with TN and should be considered a preferred treatment option before choosing neurodestructive or more invasive methods.

BACKGROUND: Despite the vital role of blood perfusion in tumor progression, the prognostic value of typical blood perfusion markers, such as microvessel density (MVD) or microvessel area (MVA), in patients with non-small cell lung cancer (NSCLC) is still unclear. This study established a modified MVD (mMVD) measurement based on perfusion distance and determined its prognostic value in patients with NSCLC. METHODS: A total of 100 patients with NSCLC were enrolled in this retrospective study. The intratumor microvessels of NSCLC patients were visualized using immunohistochemical staining for CD31. The blood perfusion distance was evaluated as the distance from each vessel to its nearest cancer cell (D(mvcc)), and the cutoff value for prognosis was determined. Apart from the total MVD (tMVD), microvessels near cancer cells within the cutoff-D(mvcc) were counted as mMVD. Predictive values for mortality and recurrence were evaluated and compared. RESULTS: The D(mvcc) ranged from 1.6 to 269.8 µm (median, 13.1 µm). The mMVD (range: 2–70; median 23) was counted from tMVD according to the cutoff-D(mvcc) (~20 µm). Compared with tMVD, a larger fraction of mMVD (80% vs. 2.9%) played a significant role in overall survival, with an improved area under the receiver operating characteristic (ROC) curve (AUC) (0.74 vs. 0.56). A high mMVD was an independent positive indicator of overall survival (OS) and progression-free survival (PFS). In contrast, tMVD was only related to PFS at the optimal cutoff. CONCLUSIONS: Perfusion-distance-based mMVD is a promising prognostic factor for NSCLC patients with superior sensitivity, specificity, and clinical applicability compared to tMVD. This study provides novel insights into the prognostic role of tumor vessel perfusion in patients with NSCLC.

Objectives: To estimate the frequency of manipulations of all tablets and capsules prescribed for children in a teaching and tertiary children's hospital in China over the course of 1 month. Moreover, hypothetical reduction of manipulation according to the availability of low-strength tablets/capsules licensed by the Chinese National Medical Products Administration (CNMPA) was evaluated.Methods: Information on all tablets and capsules prescribed in the hospital from March 17 to April 16, 2019 was collected. It was assumed that tablets or capsules were manipulated if the prescribed dose would have required only a proportion of the intact dose form. Manipulation typically includes splitting or crushing tablets, opening capsules and dispersing in water, or combinations of these method. Moreover, we defined an “avoidable manipulation,” when the dose could be rounded and/or when alternative products with a reduced strength or in liquid formulation were available in the hospital, and a “inappropriate manipulation,” which involved manipulated medications with a direct contraindication for any manipulation, such as those with a narrow therapeutic index or hazardous ingredients, or modified release dosage-forms. The frequencies of total, avoidable, and inappropriate manipulation were estimated, along with the hypothetical reduction of manipulation according to the availability of CNMPA-approved drug doses.Results: A total of 17,123 prescriptions for 142 medications were identified to have required a manipulation among 78,366 prescriptions administered during the study period, with 43 different proportions of subdivisions, ranging from a 19/20 to 1/180 product strength reduction. Half, quarter, and trisection were the most common subdivisions administered. Overall, 19% of the manipulated prescriptions were determined to be avoidable, and 19% of the manipulations involved medications with a clear recommendation to not manipulate. In addition, 21% of the manipulated prescriptions could have been potentially avoided if all of the approved preparations with the lowest strength would have been available at the hospital. Any manipulations undertaken were carried out by pharmacists and family care givers.Conclusions: More than 20% of tablets and capsules prescriptions need manipulated, included a high incidence of avoidable and inappropriate manipulation.

In the design and operation scenarios driven by Digital Twins, large computer-aided design (CAD) models of production line equipment can limit the real-time performance and fidelity of the interaction between digital and physical entities. Digital CAD models often consist of combined parts with characteristics of discrete folded corner planes. CAD models simplified to a lower resolution by current mainstream mesh simplification algorithms might suffer from significant feature loss and mesh breakage, and the interfaces between the different parts cannot be well identified and simplified. A lightweight approach for common CAD assembly models of Digital Twins is proposed. Based on quadric error metrics, constraints of discrete folded corner plane characteristics of Digital Twin CAD models are added. The triangular regularity in the neighborhood of the contraction target vertices is used as the penalty function, and edge contraction is performed based on the cost. Finally, a segmentation algorithm is employed to identify and remove the interfaces between the two CAD assembly models. The proposed approach is verified through common stereoscopic warehouse, robot base, and shelf models. In addition, a scenario of a smart phone production line is applied. The experimental results indicate that the geometric error of the simplified mesh is reduced, the frame rate is improved, and the integrity of the geometric features and triangular facets is effectively preserved.

Background: Gestational Trophoblastic Neoplasia (GTN) is a spectrum of pregnancy-associated tumours emerging from placental tissue. Generally, GTN patients are considered to have a high rate of recovery. However, almost 25 per cent of GTN tumours resist, or have a high probability of relapsing following the first line of chemo treatment. Thus, tumours that resist or relapse requires salvage chemotherapy, sometimes accompanied by surgery. Globally, clinicians utilize a range of salvage regimens. Currently, ongoing debates are centred around choosing the best regimens in terms of safety and efficacy. Therefore, the current research aims to appraise the success and level of safeness using chemotherapy to treat patients with resistant or recurrent GTN. Methods: The authors will conduct a methodological exploration in online-based databases to find Randomized Controlled Trials related to the adoption of chemotherapy agents as treatment for resistant or recurrent GTN patients. The databases are as follows: EMBASE, PubMed, Cochrane Database Central, UpToDate, Chinese National Knowledge Infrastructure, Web of Science, and WanFang Database. The search will be limited to articles published in either English or Chinese. Moreover, the authors will also perform a search for ongoing trials on online-based clinical trial registries. Two independent authors will screen and select articles for review. A similar process will be followed by two independent authors to complete the extraction of data and evaluate the bias risk. In relevant cases, the authors will contract trial investigators to obtain related, unpublished data. The authors will use the random-effects model for pooling data in RevMan software (v5.3). Results: The present systematic review aims to evaluate the efficacy and level of safeness associated with using chemotherapy for resistant or recurrent GTN patients. Conclusion: The results of the proposed systematic analysis could summarize the most recent evidence for the use of chemotherapy agents on GTN patients. Ethics and dissemination: Since the proposed study uses pre-published data, an ethical approval is not required. Review registration number: Aug 25, 2021.osf.io/rgzbn. (https://osf.io/rgzbn/).

Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life.Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035).In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522).Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain.ClinicalTrials.gov, NCT03455023.

We aimed to propose a cell cycle-related multi/mRNA signature (CCS) for prognosis prediction and uncover new tumor-driver genes for hepatocellular carcinoma (HCC). Cell cycle-related gene sets and HCC samples with mRNA-Seq data were retrieved from public sources. The genes differentially expressed in HCCs relative to normal peritumoral tissues were extracted through statistical analysis. The CCS was constructed by Cox regression analyses. Predictive capacity and clinical practicality of the signature were evaluated and validated. The expression of the function-unknown genes in the CCS was determined by RT-qPCR. Candidate gene TICRR was selected for subsequent validation through functional experiments. A cell cycle-related 13-mRNA signature was generated from the exploratory cohort [The Cancer Genome Atlas (TCGA), n = 371)]. HCC cases were classified as high- vs. low-risk groups per overall survival (OS) [hazard ratio (HR) = 2.699]. Significantly, the CCS exhibited great predictive value for prognosis in three independent cohorts, particularly in GSE76427 cohort [area under the curve (AUC) = 0.835/0.822/0.808/0.821/0.826 at 1/2/3/4/5 years]. The nomogram constructed by integrating clinicopathological features with the CCS indicated high accuracy and practicability. Significant enrichment of tumorigenesis-associated pathways was observed in the high-risk patients by Gene Set Enrichment Analysis (GSEA). RT-qPCR revealed that TICRR was overexpressed in HCC samples. Increased TICRR expression implied poor prognosis in HCC patients. Furthermore, depletion of TICRR in HCC cells decreased cell proliferation and the G1/S transition. In conclusion, the established 13-CCS had efficacy in prognostic prediction of HCC patients. Additionally, TICRR was demonstrated as a tumor-driver gene for this deadly disease.

Tetracycline may cause tooth discoloration when used in young children during tooth development. Whether tigecycline, a tetracycline derivative, has either a similar adverse event or not remains unclear. We assessed the discoloration of the permanent teeth of patients

Partial discharge (PD) issue of high voltage power module packaging insulation is increasingly critical due to the development of high voltage wide bandgap power modules towards high power density, which leads to smaller packages and higher operating voltages. However, existing standards for high voltage power modules focus on PD measurement under the sinusoidal waveform rather than actual DC or square waveform that poses actual electric stress on packaging insulation, and thus cannot fully represent the PD phenomenon in power electronics systems. To bridge this gap, this paper introduces a PD testing platform trimmed for high voltage power electronics systems, including a high-voltage (10 kV) square wave generator using supercascode structure with off-shelf SiC devices, and a contactless PD monitor using Super High Frequency (SHF) signatures from the PD event. The challenges in the design of this platform include the development of a PD-free high voltage square wave generator, and SHF PD signature separation from EMI noises induced by high dV/dt switching actions. Experiment validation is included in the last section of this paper.

In this paper, we introduce a challenging global large-scale ship database (called GLSD), designed specifically for ship detection tasks. The designed GLSD database includes a total of 212,357 annotated instances from 152,576 images. Based on the collected images, we propose 13 ship categories that widely exist in international routes. These categories include Sailing boat, Fishing boat, Passenger ship, Warship, General cargo ship, Container ship, Bulk cargo carrier, Barge, Ore carrier, Speed boat, Canoe, Oil carrier, and Tug. The motivations of developing GLSD include the following: 1) providing a refine and extensive ship detection database that benefits the object detection community, 2) establishing a database with exhaustive labels (bounding boxes and ship class categories) in a uniform classification scheme, and 3) providing a large-scale ship database with geographic information (covering more than 3000 ports and 33 routes) that benefits multi-modal analysis. In addition, we discuss the evaluation protocols corresponding to image characteristics in GLSD and analyze the performance of selected state-of-the-art object detection algorithms on GSLD, aiming to establish baselines for future studies. More information regarding the designed GLSD can be found at https://github.com/jiaming-wang/GLSD., 11 pages, 7 figures

Background The toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness. However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC). Methods Cell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative real-time PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules. Results MD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing. Conclusions Our findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.

Aim: To evaluate the impact of CYP3A4*1G, CYP3A5*3 and ABCB1-C3435T polymorphisms on tacrolimus concentrations, efficacy and tolerance in pediatric primary nephrotic syndrome. Methods: Dose-adjusted concentrations (C0/D), daily dose, frequency and time to relapse, cumulative remission days, and adverse reactions in 65 Chinese patients with various genotypes were retrospectively collected and compared. Results: C0/D increased in CYP3A4*1/*1, CYP3A5*3/*3 and CYP3A4*1/*1-3A5*3/*3 diplotype carriers by 38.4, 69.7 and 40.9% compared with CYP3A4*1/*1G, CYP3A5*1/*3 and noncarriers, respectively. Recurrence risks were decreased in CYP3A4*1/*1 (0.43 of hazard ratio to *1/*1G) and CYP3A5*3/*3 carriers (0.43 of hazard ratio to *1/*3). None of polymorphisms was linked to adverse reactions. Conclusion: The genotypes of CYP3A4*1G and CYP3A5*3 rather than ABCB1-C3435T potentially predicted tacrolimus exposure and clinical response in pediatric primary nephrotic syndrome.

Background: An integral and well-functioning vascular system is essential for tumor progression and chemotherapy infusion. However, the lumen integrity of the microvessels and its significance in prognosis has not been studied. In this study, we found that the proportion of collapsed microvessels is suggested to be a novel biomarker for predicting prognosis in patients with non-small cell lung cancer (NSCLC). Methods: In this study, immunohistochemical CD31 staining was performed to identify the microvessels in tumor specimens. Proportions of collapsed vessels were estimated in CD31-stained tumor specimens from 100 patients with NSCLC. The correlation between collapsed microvessel proportion and survival time were evaluated by univariate and multivariate analysis. Results: Data from 99 patients were analyzed and a wide range of collapse–microvessel fraction was observed in 96 patients (1.4%–70%). Elevated collapse proportion (⩾6.5%) indicated poor overall survival in both univariate analysis ( p = 0.042) and multivariate analysis ( p = 0.014). Conclusions: Elevated proportion of collapsed microvessels indicted poor survival outcome in patients with NSCLC.

Background: Sustained tumor growth and metastasis require sufficient blood supply, and microvessel area (MVA) has been reported that is related to prognosis of cancer patients. However, tumor cells may not be nourished enough by blood vessels when the cells are separated from vessels by thick stroma. Therefore we investigated whether stroma-area normalized MVA (SnMVA) is a more important prognostic factor than MVA. Materials and Methods: 100 NSCLC patients who underwent resection between July 2011 and October 2012 were randomly selected. We determined the MVA of the tumor tissues by anti-CD31 immunostaining of microvessels. Stroma-area normalized MVA (SnMVA) was a ratio of MVA to stromal area. Correlation of MVA and SnMVA with overall survival (OS) or progression-free survival (PFS) was assessed using multivariate analysis. Results: Median MVA was 0.0228 (range, 0.00393 to 0.172), and median SnMVA was 0.0441 × 10-6 (range, 0.00393 × 10-6 to 0.259 × 10-6). There was no significant difference in OS between groups of different MVA (HR 0.58, 95%CI 0.28 to 1.19, p = 0.148). In contrast, the risk of death was significantly decreased in high SnMVA group (at or below the median) than in group with low SnMVA (HR 0.47, 95%CI 0.23 to 0.97, p = 0.046). Furthermore, in multivariate analysis, high SnMVA, but not MVA, was an independent prognostic factor after adjusting for age, sex, tumor stage and other factors. OS was significantly associated with SnMVA in six of seven subgroup analysis, but with MVA in only three. Conclusions: Our study showed that the NSCLC patients with high SnMVA had higher OS. And SnMVA is a prognostic factor with greater accuracy than MVA. Since stroma exists widely in a variety of cancer tissues, we infer that SnMVA may also predict the prognostic of other types of cancers.