bluuebunny/crossref_metadata_2025_split huggingface dataset:
Airway Telomere Length in Lung Transplant Recipients
Authors: Mackintosh John A. , Yerkovich Stephanie T. , Tan Maxine E. , Samson Luke , Hopkins Peter MA , Chambers Daniel C. 
Published: April 2021

IntroductionChronic lung allograft dysfunction (CLAD) represents the major impediment to long term survival following lung transplantation. Donor and recipient telomere length have been shown to associate with lung transplant outcomes, including CLAD. In this study we aimed to measure the telomere lengths of bronchial and bronchiolar airway cells in lung allografts early after transplantation and to investigate associations with CLAD and all-cause mortality.MethodsThis prospective, longitudinal study was performed at The Prince Charles Hospital, Australia. Airway cells were collected via bronchial and bronchiolar airway brushings at post-transplant bronchoscopies. The relative telomere length in airway cells was determined by quantitative PCR based on the T/S ratio. All patients were censored for CLAD and all-cause mortality in August 2020.ResultsIn total 231 bronchoscopies incorporating transbronchial brush and bronchial brush were performed in 120 patients. At the time of censoring, 43% and 35% of patients, respectively, had developed CLAD and had died. Airway bronchiolar and bronchial telomere lengths were strongly correlated (r=0.78, p&lt;0.001), confirming conservation of telomere length with airway branch generation. Both the bronchiolar (r = -0.34, p&lt;0.001) and bronchial (r = -0.31, p&lt;0.001) telomere length decreased with age. Shorter airway telomere length was associated with older donor age and higher donor pack-year smoking history. Neither the bronchiolar nor the bronchial airway telomere length were associated with the development of CLAD (HR 0.39 (0.06-2.3), p=0.30; HR 0.66 (0.2-1.7), p=0.39, respectively) or all-cause mortality (HR 0.92 (0.2-4.5), p=0.92; HR 0.47 (0.1-1.9), p=0.28, respectively).ConclusionsIn this cohort, airway telomere length was associated with donor age and smoking history but was not associated with the future development of CLAD or all-cause mortality.
A Deep Learning Based Framework for Diagnosing Multiple Skin Diseases in a Clinical Environment
Authors: Zhu Chen-Yu , Wang Yu-Kun , Chen Hai-Peng , Gao Kun-Lun , Shu Chang , Wang Jun-Cheng , Yan Li-Feng , Yang Yi-Guang , Xie Feng-Ying , Liu Jie 
Published: April 2021

Background: Numerous studies have attempted to apply artificial intelligence (AI) in the dermatological field, mainly on the classification and segmentation of various dermatoses. However, researches under real clinical settings are scarce.Objectives: This study was aimed to construct a novel framework based on deep learning trained by a dataset that represented the real clinical environment in a tertiary class hospital in China, for better adaptation of the AI application in clinical practice among Asian patients.Methods: Our dataset was composed of 13,603 dermatologist-labeled dermoscopic images, containing 14 categories of diseases, namely lichen planus (LP), rosacea (Rosa), viral warts (VW), acne vulgaris (AV), keloid and hypertrophic scar (KAHS), eczema and dermatitis (EAD), dermatofibroma (DF), seborrheic dermatitis (SD), seborrheic keratosis (SK), melanocytic nevus (MN), hemangioma (Hem), psoriasis (Pso), port wine stain (PWS), and basal cell carcinoma (BCC). In this study, we applied Google's EfficientNet-b4 with pre-trained weights on ImageNet as the backbone of our CNN architecture. The final fully-connected classification layer was replaced with 14 output neurons. We added seven auxiliary classifiers to each of the intermediate layer groups. The modified model was retrained with our dataset and implemented using Pytorch. We constructed saliency maps to visualize our network's attention area of input images for its prediction. To explore the visual characteristics of different clinical classes, we also examined the internal image features learned by the proposed framework using t-SNE (t-distributed Stochastic Neighbor Embedding).Results: Test results showed that the proposed framework achieved a high level of classification performance with an overall accuracy of 0.948, a sensitivity of 0.934 and a specificity of 0.950. We also compared the performance of our algorithm with three most widely used CNN models which showed our model outperformed existing models with the highest area under curve (AUC) of 0.985. We further compared this model with 280 board-certificated dermatologists, and results showed a comparable performance level in an 8-class diagnostic task.Conclusions: The proposed framework retrained by the dataset that represented the real clinical environment in our department could accurately classify most common dermatoses that we encountered during outpatient practice including infectious and inflammatory dermatoses, benign and malignant cutaneous tumors.
Possible Sarcopenia and Impact of Dual-Task Exercise on Gait Speed, Handgrip Strength, Falls, and Perceived Health
Authors: Merchant Reshma Aziz , Chan Yiong Huak , Hui Richard Jor Yeong , Lim Jia Yi , Kwek Sing Cheer , Seetharaman Santhosh K. , Au Lydia Shu Yi , Morley John E. 
Published: April 2021

Background: Sarcopenia is defined as a progressive age-related loss in muscle mass and strength affecting physical performance. It is associated with many negative outcomes including falls, disability, cognitive decline, and mortality. Protein enriched diet and resistance training have shown to improve muscle strength and function but there is limited evidence on impact of dual-task exercise in possible sarcopenia.Objective: To evaluate impact of community-based dual-task exercise on muscle strength and physical function in possible sarcopenia defined by either slow gait (SG) or poor handgrip strength (HGS). The secondary aims include effect on cognition, frailty, falls, social isolation, and perceived health.Methods: Community-dwelling older adults ≥60 years old were recruited from screening program intended to identify seniors at risk, and invited to participate in dual-task exercise program called HAPPY (Healthy Aging Promotion Program for You). One hundred and eleven participants with possible sarcopenia completed 3 months follow-up. Questionnaire was administered on demographics, frailty, sarcopenia, falls, perceived health, social network, functional, and cognitive status. Physical performance included assessment of HGS, gait speed, and Short Physical Performance Battery test (SPPB).Results: The mean age of the Exercise group was 75.9 years old and 73.0% were women. The Exercise group had more female (73.0 vs. 47.5%), were older (75.9 vs. 72.5 years old), had higher prevalence of falls (32.4 vs. 15.0%), lower BMI (23.7 vs. 25.8), and education (4.0 vs. 7.2 years). The gait speed of the Exercise group increased significantly with significant reduction in the prevalence of SG and poor HGS. All components of SPPB as well as the total score increased significantly while the prevalence of pre-frailty and falls dropped by half. The risk of social isolation reduced by 25% with significant improvement in perceived health and cognition in the Exercise group. Significant impact on improvement gait speed and SPPB persisted after adjustment for baseline factors.Conclusion: Dual-task exercise program is effective in improving gait speed, SPPB score, and reducing the prevalence of poor HGS with significant improvement in perceived health, cognition, and reduction in falls and frailty. Future prospective randomized control trials are needed to evaluate the effectiveness of dual-task interventions in reversing sarcopenia.
CRISPR/dCas9-Mediated Parkin Inhibition Impairs Mitophagy and Aggravates Apoptosis of Rat Nucleus Pulposus Cells Under Oxidative Stress
Authors: Lan Tao , Zheng Yu-chen , Li Ning-dao , Chen Xiao-sheng , Shen Zhe , Yan Bin 
Published: April 2021

ObjectiveThe aim of this study is to explore the role of Parkin in intervertebral disk degeneration (IDD) and its mitophagy regulation mechanism.Study design and methodsRat nucleus pulposus (NP) cells were stimulated with hydrogen peroxide (H2O2) to a mimic pathological condition. Apoptosis and mitophagy were assessed by Western blot, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and immunofluorescence staining. The CRISPR–dCas9–KRAB system was used to silence the expression of Parkin.ResultIn this study, we found that Parkin was downregulated in rat NP cells under oxidative stress. In addition, treatment with H2O2 resulted in mitochondrial dysfunction, autophagy inhibition, and a significant increase in the rate of apoptosis of NP cells. Meanwhile, mitophagy inhibition enhanced H2O2-induced apoptosis. Furthermore, repression of Parkin significantly attenuated mitophagy and exacerbated apoptosis.ConclusionThese results suggested that Parkin may play a protective role in alleviating the apoptosis of NP cells via mitophagy, and that targeting Parkin may provide a promising therapeutic strategy for the prevention of IDD.
Gender and Socioeconomic Disparities in Global Burden of Epilepsy: An Analysis of Time Trends From 1990 to 2017
Authors: Hu Yin , Shan Yi , Du Qiang , Ding Yao , Shen Chunhong , Wang Shuang , Ding Meiping , Xu Yufeng 
Published: April 2021

Objective: The objective of the study is to investigate the gender and socioeconomic disparities in the global burden of epilepsy by prevalence and disability-adjusted life-years (DALYs).Methods: The global, regional, and national gender-specific prevalence and DALYs caused by epilepsy by year and age were extracted from the Global Burden of Disease (GBD) Study 2017. The Gini coefficient and concentration index (CI) were calculated to demonstrate the trends in between-country inequality in the epilepsy burden from 1990 to 2017. Paired Wilcoxon signed rank test, Pearson correlation, and linear regression analyses were performed to analyze the association of gender disparity in epilepsy and socio-demographic index (SDI).Results: The DALYs number of epilepsies increased from 1990 to 2017 by 13.8%, whereas age-standardized DALY rates showed a substantial reduction (16.1%). Men had a higher epilepsy burden than women of the same period. The epilepsy burden appeared to be higher in countries with lower socioeconomic development (CI &lt; 0). The Gini coefficient decreased from 0.273 in 1995 to 0.259 in 2017, representing a decline in the between-country gap. Age-standardized prevalence and DALY rates of men were higher than those of women in each SDI-based country group (p &lt; 0.0001). Male-minus-female difference (r = −0.5100, p &lt; 0.0001) and male-to-female ratio (r = −0.3087, p &lt; 0.0001) of age-standardized DALY rates were negatively correlated with SDI.Conclusion: Although global health care of epilepsy is in progress, the epilepsy burden was concentrated in males and developing countries. Our findings highlight the importance of formulating gender-sensitive health policies and providing more services in developing countries.
Development and Validation of a Clinical Prediction Model for Sleep Disorders in the ICU: A Retrospective Cohort Study
Authors: Li Yun , Zhao Lina , Yang Chenyi , Yu Zhiqiang , Song Jiannan , Zhou Qi , Zhang Xizhe , Gao Jie , Wang Qiang , Wang Haiyun 
Published: April 2021

BackgroundSleep disorders, the serious challenges faced by the intensive care unit (ICU) patients are important issues that need urgent attention. Despite some efforts to reduce sleep disorders with common risk-factor controlling, unidentified risk factors remain.ObjectivesThis study aimed to develop and validate a risk prediction model for sleep disorders in ICU adults.MethodsData were retrieved from the MIMIC-III database. Matching analysis was used to match the patients with and without sleep disorders. A nomogram was developed based on the logistic regression, which was used to identify risk factors for sleep disorders. The calibration and discrimination of the nomogram were evaluated with the 1000 bootstrap resampling and receiver operating characteristic curve (ROC). Besides, the decision curve analysis (DCA) was applied to evaluate the clinical utility of the prediction model.Results2,082 patients were included in the analysis, 80% of whom (n = 1,666) and the remaining 20% (n = 416) were divided into the training and validation sets. After the multivariate analysis, hemoglobin, diastolic blood pressure, respiratory rate, cardiovascular disease, and delirium were the independent risk predictors for sleep disorders. The nomogram showed high sensitivity and specificity of 75.6% and 72.9% in the ROC. The threshold probability of the net benefit was between 55% and 90% in the DCA.ConclusionThe model showed high performance in predicting sleep disorders in ICU adults, the good clinical utility of which may be a useful tool for providing clinical decision support to improve sleep quality in the ICU.
Identifying and Validating Potential Biomarkers of Early Stage Lung Adenocarcinoma Diagnosis and Prognosis
Authors: Chen Yingji , Jin Longyu , Jiang Zhibin , Liu Suo , Feng Wei 
Published: April 2021

BackgroundLung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. At present, most patients with LUAD are diagnosed at an advanced stage, and the prognosis of advanced LUAD is poor. Hence, we aimed to identify novel biomarkers for the diagnosis and treatment of early stage LUAD and to explore their predictive value.MethodsThe microarray datasets GSE63459, GSE27262, and GSE33532 were searched, and the differentially expressed genes (DEGs) were obtained using GEO2R. The DEGs were subjected to gene ontology (GO) and pathway enrichment analyses using METASCAPE. A protein–protein interaction (PPI) network was plotted with STRING and visualized by Cytoscape. Module analysis of the PPI network was performed using MCODE. Overall survival (OS) analysis and analysis of the mRNA expression levels of genes identified by MCODE were performed with UALCAN. Western blot analysis of hub genes in LUAD patients, MTS assays, and clonogenic assays were performed to test the effects of the hub genes on cell proliferation in vitro.ResultsA total of 341 DEGs were obtained, which were mainly enriched in terms related to blood vessel development, growth factor binding, and extracellular matrix organization. A PPI network consisting of 300 nodes and 1140 edges was constructed, and a significant module including 15 genes was identified. Elevated expression of ASPM, CCNB2, CDCA5, PRC1, KIAA0101, and UBE2T was associated with poor OS in LUAD patients. In the protein level, the hub gene was overexpressed in LUAD patients. In vitro experiments showed that knockdown of the hub genes in the LUAD cell lines could promote cell proliferation.ConclusionsDEGs are potential biomarkers for early stage lung adenocarcinoma and could have utility for the diagnosis and predicting treatment efficacy.
Comprehensive RNA-Seq Analysis of Potential Therapeutic Targets of Gan–Dou–Fu–Mu Decoction for Treatment of Wilson Disease Using a Toxic Milk Mouse Model
Authors: Wei Taohua , Hao Wenjie , Tang Lulu , Wu Huan , Huang Shi , Yang Yue , Qian Nannan , Liu Jie , Yang Wenming , Duan Xianchun 
Published: April 2021

Background: Gan–Dou–Fu–Mu decoction (GDFMD) improves liver fibrosis in experimental and clinical studies including those on toxic mouse model of Wilson disease (Model). However, the mechanisms underlying the effect of GDFMD have not been characterized. Herein, we deciphered the potential therapeutic targets of GDFMD using transcriptome analysis.Methods: We constructed a tx-j Wilson disease (WD) mouse model, and assessed the effect of GDFMD on the liver of model mice by hematoxylin and eosin, Masson, and immunohistochemical staining. Subsequently, we identified differentially expressed genes (DEGs) that were upregulated in the Model (Model vs. control) and those that were downregulated upon GDFMD treatment (compared to the Model) using RNA-sequencing (RNA-Seq). Biological functions and signaling pathways in which the DEGs were involved were determined by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses. A protein–protein interaction (PPI) network was constructed using the STRING database, and the modules were identified using MCODE plugin with the Cytoscape software. Several genes identified in the RNA-Seq analysis were validated by real-time quantitative PCR.Results: Total of 2124 DEGs were screened through the Model vs. control and Model vs. GDFMD comparisons, and dozens of GO and KEGG pathway terms modulated by GDFMD were identified. Dozens of pathways involved in metabolism (including metabolic processes for organic acids, carboxylic acids, monocarboxylic acids, lipids, fatty acids, cellular lipids, steroids, alcohols, eicosanoids, long-chain fatty acids), immune and inflammatory response (such as complement and coagulation cascades, cytokine–cytokine receptor interaction, inflammatory mediator regulation of TRP channels, antigen processing and presentation, T-cell receptor signaling pathway), liver fibrosis (such as ECM-receptor interactions), and cell death (PI3K-Akt signaling pathway, apoptosis, TGF-beta signaling pathway, etc.) were identified as potential targets of GDFMD in the Model. Some hub genes and four modules were identified in the PPI network. The results of real-time quantitative PCR analysis were consistent with those of RNA-Seq analysis.Conclusions: We performed gene expression profiling of GDFMD-treated WD model mice using RNA-Seq analysis and found the genes, pathways, and processes effected by the treatment. Our study provides a theoretical basis to prevent liver fibrosis resulting from WD using GDFMD.
MicroRNA-223 Suppresses IL-1β and TNF-α Production in Gouty Inflammation by Targeting the NLRP3 Inflammasome
Authors: Zhang Quan-Bo , Zhu Dan , Dai Fei , Huang Yu-Qin , Zheng Jian-Xiong , Tang Yi-Ping , Dong Zeng-Rong , Liao Xia , Qing Yu-Feng 
Published: April 2021

Introduction: MicroRNA-223 (MiR-223) serves as an important regulator of inflammatory and immune responses and is implicated in several auto-inflammatory disorders. Here, we measured miR-223 expression in acute and intercritical gout patients, after which we used RAW264.7 macrophages transfected with a miR-223 mimic/inhibitor to determine the function of miR-223 in monosodium urate (MSU)-induced gouty inflammation.Methods and Results: MiR-223 was detected among 122 acute gout patients (AG), 118 intercritical gout patients (IG), and 125 healthy subjects (HC). RAW264.7 macrophages were cultured and treated with MSU. Over-expression or under-expression of miR-223 was inducted in RAW264.7 macrophages to investigate the function of miR-223. Real-time quantitative PCR, ELISA and western blotting were used to determine the expression levels of miR-223, cytokines and the NLRP3 inflammasome (NLRP3, ASC, and caspase-1). MiR-223 expression was significantly decreased in the AG group in comparison with the IG and HC groups (p &lt; 0.001, respectively). Up-regulated expression of miR-223 was observed after acute gout remission in comparison with that observed during gout flares in 30 paired cases (p &lt; 0.001). The abundance of the NLRP3 inflammasome and cytokines was significantly increased after RAW264.7 macrophages were treated with MSU (p &lt; 0.01, respectively), while that of miR-223 was significantly reduced (p &lt; 0.01). Up-regulation of miR-223 decreased the concentrations of IL-1β and TNF-α, as well as the NLRP3 inflammasome expression (p &lt; 0.01, respectively), while IL-37 and TGF-β1 levels were unchanged (p &gt; 0.05, respectively). Under-expression of miR-223 increased the concentrations of IL-1β and TNF-α, as well as NLRP3 inflammasome expression (p &lt; 0.01, respectively), while IL-37 and TGF-β1 levels were not influenced (p &gt; 0.05, respectively).Conclusion: These findings suggest that miR-223 provides negative feedback regulation of the development of gouty inflammation by suppressing production of IL-1β and TNF-α, but not by regulating IL-37 and TGF-β1. Moreover, miR-223 regulates cytokine production by targeting the NLRP3 inflammasome.
Monobenzone, a Novel and Potent KDM1A Inhibitor, Suppresses Migration of Gastric Cancer Cells
Authors: Ma Peizhi , Jia Gang , Song Zhiyu 
Published: April 2021

Lysine-specific demethylase1 (KDM1A) is generally highly expressed in various cancer tissues, and promotes the initiation and development of cancers via diverse cellular signaling pathways. Therefore, KDM1A is a promising drug target in many cancers, and it is crucial to find effective KDM1A inhibitors, while none of them has entered into market. With the help of compound library, monobenzone, a local depigmentor using as a treating over-pigmentation in clinic, was characterized as an effective KDM1A inhibitor (IC50 = 0.4507 μM), which may competitively inhibit KDM1A reversibly. Further cellular study confirmed that monobenzone could inhibit the proliferation of gastric cancer cell lines MGC-803 and BGC-823 with IC50 as 7.82 ± 0.55 μM and 6.99 ± 0.51 μM, respectively, and erase the substrate of KDM1A, H3K4me1/2 and H3K9 me2, and inhibit the migration of gastric cancer cell by reversing epithelial–mesenchymal transition (EMT). As the structure of monobenzone is very simple and small, this study provides a novel backbone for the further optimization of KDM1A inhibitor and gives monobenzone potential new application.
Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia
Authors: Willcocks Isabella R. , Legge Sophie E. , Nalmpanti Mariana , Mazzeo Lucy , King Adrian , Jansen John , Helthuis Marinka , Owen Michael J. , O’Donovan Michael C. , Walters James T. R. , Pardiñas Antonio F. 
Published: April 2021

Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.