bluuebunny/crossref_metadata_2025_split huggingface dataset:
Off-label use of antimicrobials among hospitalized children: a retrospective study of 3,406 patients
Authors: Tang Lin , Zhao Kai , Hou Ning 
Published: May 2023

IntroductionOff-label drug use is a global problem for which many countries and regions have issued legal provisions or reached an expert consensus. Off-label use is sometimes a necessity, especially since antibacterial drugs have become one of the most widely used drugs in pediatric settings and the issue of causing antimicrobial resistance has increasingly become unavoidable. It also poses additional risks, such as adverse drug reactions.MethodsOur study analyzed the antimicrobial prescriptions of pediatric inpatients in a large Chinese hospital in the first half of 2021. This retrospective investigation included 6,829 prescriptions, including 2,294 off-label prescriptions. We performed descriptive analyses of prescription antimicrobial agents among pediatric populations and reported the percentages and frequencies.Results It was found that off-label use of antibiotics was present in many children (n = 1,665, 48.9%) and was most common in newborns (n  = 328, 82.8%). Among the commonly used antibiotics in pediatric patients, cephalosporins (n  = 2,778, 40.7%) accounted for a relatively low proportion of offlabel use (n  = 360, 15.7%), while macrolides (n  = 628, 27.4%) and penicillins (n  = 610, 26.6%) accounted for a higher proportion. The off-label type mainly referred to the appropriate population (46.5%) and dosage (dose, 10.0%; frequency of administration, 48.3%).DiscussionOff-label use was due to imperfect labels, improper medications, or medication errors. Only a few consensuses could apply to pediatric patients. More clinical trials are required to update the consensus, and drug labels must be continuously improved. The prescription behavior of doctors is also needed to be regulated. Rational use of drugs, especially antimicrobials, is the responsibility of all people, including the states, medical institutions, and individuals.
Venetoclax is a potent hepsin inhibitor that reduces the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells
Authors: Rodenas Maria Carmen , Peñas-Martínez Julia , Pardo-Sánchez Irene , Zaragoza-Huesca David , Ortega-Sabater Carmen , Peña-García Jorge , Espín Salvador , Ricote Guillermo , Montenegro Sofía , Ayala-De La Peña Francisco , Luengo-Gil Ginés , Nieto Andrés , García-Molina Francisco , Vicente Vicente , Bernardi Francesco , Lozano María Luisa , Mulero Victoriano , Pérez-Sánchez Horacio , Carmona-Bayonas Alberto , Martínez-Martínez Irene 
Published: May 2023

Introduction: Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. This study aims to explore the molecular role of hepsin in colorectal cancer.Methods: Hepsin levels in plasma from resected and metastatic colorectal cancer patients were analyzed by ELISA. The effect of hepsin levels on cell migration, invasion, and proliferation, as well as on the activation of crucial cancer signaling pathways, was performed in vitro using colorectal cancer cells. A thrombin generation assay determined the procoagulant function of hepsin from these cells. A virtual screening of a database containing more than 2000 FDA-approved compounds was performed to screen hepsin inhibitors, and selected compounds were tested in vitro for their ability to suppress hepsin effects in colorectal cancer cells. Xenotransplantation assays were done in zebrafish larvae to study the impact of venetoclax on invasion promoted by hepsin.Results: Our results showed higher plasma hepsin levels in metastatic patients, among which, hepsin was higher in those suffering thrombosis. Hepsin overexpression increased colorectal cancer cell invasion, Erk1/2 and STAT3 phosphorylation, and thrombin generation in plasma. In addition, we identified venetoclax as a potent hepsin inhibitor that reduced the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells. Interestingly, pretreatment with Venetoclax of cells overexpressing hepsin reduced their invasiveness in vivo.Discussion: Our results demonstrate that hepsin overexpression correlates with a more aggressive and prothrombotic tumor phenotype. Likewise, they demonstrate the antitumor role of venetoclax as a hepsin inhibitor, laying the groundwork for molecular-targeted therapy for colorectal cancer.
Exercise program to reduce the risk of cognitive decline and physical frailty in older adults: study protocol for an open label double-arm clinical trial
Authors: Noguchi-Shinohara Moeko , Yokoyama Kunihiko , Komatsu Junji , Masuda Kazumi , Kouno Mitsunobu , Yoshita Mitsuhiro , Ono Kenjiro 
Published: May 2023

ObjectiveIt is a big problem that many older adults are physically inactive. Well-known benefits of physical exercise include a decrease in the risk of cognitive decline and physical frailty. Therefore, this study aims to examine whether our proposed exercise program can prevent cognitive decline and improve physical function in the elderly.MethodsThis study will include nondemented older adults (n = 103) without regular exercise habits. The trial will include a physical exercise training program (once a week) and nutritional lectures (once a month) over 5 months and follow-up for ≥1 year. The primary endpoint is the program’s efficacy in preventing cognitive decline, as assessed by changes in the memory performance index of the mild cognitive impairment (MCI) screen; the secondary endpoints are the incidence of MCI and dementia, physical testing, and frailty proportion. In the exploratory phase of the study, we will elucidate the underlying diseases causing MCI in community-dwelling older adults by neuroimaging.DiscussionThis double-arm trial that aims to assess the impact of physical exercise on nondemented older adults’ cognitive and physical function. Furthermore, our newly developed exercise program will be easy for older adults to undertake.Clinical Trial Registration: https://clinicaltrials.gov/, identifier [jRCT 1040220140].
Association between handgrip strength asymmetry and cognitive function across ethnicity in rural China: a cross-sectional study
Authors: Feng Wenjing , Ma Mingfeng , Gao Hanshu , Yuan Wei , Li Ruixue , Guo Hui , Gu Cuiying , Sun Zhaoqing , Zhang Yao , Zheng Liqiang 
Published: May 2023

BackgroundRecently, the association between handgrip strength (HGS) asymmetry and cognition has been revealed, but evidences are still scarce. Particularly, the association between asymmetric HGS and cognitive performance in various cognitive domains is unclear and whether this association is stable across ethnic groups is unknown.MethodThe population was from a longitudinal study in rural areas of Fuxin, Liaoning, China. The Chinese version of Montreal Cognitive Assessment-Basic (MOCA-BC) was used to evaluate the cognitive function. The HGS ratio was calculated as maximal non-dominant HGS divided by maximal dominant HGS. HGS ratio &lt;0.9 or &gt;1.1 was classified as asymmetric dominant/non-dominant HGS, respectively. Generalized linear models were used to analyze the relationship between asymmetric HGS and cognitive function adjusted for HGS, handedness, wave, age, sex, education, ethnicity, smoking, drinking, physical labor level, BMI, hypertension, diabetes and dyslipidemia.ResultA total of 2,969 participants ≥50 years were included in this study. Adjusted for HGS and other confunding variables, there was an inverted U-shaped association between HGS ratio and MoCA-BC scores (Pnon–linear = 0.004). The association between HGS ratio and MoCA-BC scores was inconsistent among ethnic groups (Pinteraction = 0.048). In Han, only asymmetric non-dominant HGS was associated with lower cognitive scores [β = −0.67, 95% confidence interval (CI): −1.26 ∼−0.08, P = 0.027]; in Mongolians, asymmetric dominant HGS(β = −0.60, 95% CI: −1.35 ∼ 0.15, P = 0.115) and asymmetric non-dominant HGS (β = −0.56, 95% CI: −1.42 ∼ 0.31, P = 0.206) were all associated with lower cognitive scores, although no statistical significance was found. Asymmetric non-dominant HGS and lower HGS, but not asymmetric dominant HGS were all independently associated with impairment of Delayed Recall (OR = 1.35, 95% CI: 1.05 ∼ 1.74; OR per 5 kg decrease = 1.10, 95% CI: 1.01 ∼ 1.21) and Fluency (OR = 1.43, 95% CI: 1.15 ∼ 1.78; OR per 5 kg decrease = 1.10, 95% CI: 1.02 ∼ 1.19). Both asymmetric dominant HGS (OR = 1.34, 95% CI: 1.07 ∼ 1.67) and lower HGS (OR per 5 kg decrease = 1.21, 95% CI: 1.10 ∼ 1.32) were associated with impairment of visuoperception.ConclusionHGS and HGS asymmetry were all independently related to lower global cognitive performance. The association between HGS asymmetry and cognitive function varies among ethnic groups.
Extreme prematurity and perinatal risk factors related to extremely preterm birth are associated with complex patterns of regional brain volume alterations at 10 years of age: a voxel-based morphometry study
Authors: Kvanta Hedvig , Bolk Jenny , Broström Lina , Fernández de Gamarra-Oca Lexuri , Padilla Nelly , Ådén Ulrika 
Published: May 2023

ObjectiveStructural brain volumetric differences have been investigated previously in very preterm children. However, children born extremely preterm, at the border of viability, have been studied to a lesser degree. Our group previously analyzed children born extremely preterm at term using voxel-based morphometry. In this study, we aimed to examine regional gray and white matter differences for children born extremely preterm derived from the same cohort during childhood. We also aimed to explore the effect of perinatal risk factors on brain volumes in the same group.MethodsAt 10 years of age, 51 children born extremely preterm (before 27 weeks and 0 days) and 38 term-born controls with high-quality 3.0 Tesla magnetic resonance images were included. Statistical analyses using voxel-based morphometry were conducted on images that were normalized using age-specific templates, modulated, and smoothed. Analyses were also performed in stratified groups of children born extremely preterm in the absence or presence of perinatal risk factors that have previously been shown to be associated with volumetric differences at term.ResultsWe found volumetric decreases in gray and white matter in the temporal lobes, gray matter decreases in the precuneus gyri, and white matter decreases in the anterior cingulum for children born extremely preterm (all p &lt; 0.001, and pfwe &lt; 0.05). Gray and white matter increases were predominantly observed in the right posterior cingulum and occipital lobe (all p &lt; 0.001, and pfwe &lt; 0.05). Of the examined perinatal risk factors, intraventricular hemorrhage grades I-II compared with no intraventricular hemorrhage and patent ductus arteriosus ligation compared with no treated patent ductus arteriosus or patent ductus arteriosus treated with ibuprofen led to volumetric differences at 10 years of age (all p &lt; 0.001, and pfwe &lt; 0.05).ConclusionsChildren born extremely preterm exhibit volumetric alterations in a pattern overlapping that previously found at term, where many regions with differences are the main hubs of higher order networks. Some, but not all, risk factors known to be associated with structural alterations at term were associated with alterations at 10 years of age.
An online survival predictor in glioma patients using machine learning based on WHO CNS5 data
Authors: Ye Liguo , Gu Lingui , Zheng Zhiyao , Zhang Xin , Xing Hao , Guo Xiaopeng , Chen Wenlin , Wang Yaning , Wang Yuekun , Liang Tingyu , Wang Hai , Li Yilin , Jin Shanmu , Shi Yixin , Liu Delin , Yang Tianrui , Liu Qianshu , Deng Congcong , Wang Yu , Ma Wenbin 
Published: May 2023

BackgroundThe World Health Organization (WHO) CNS5 classification system highlights the significance of molecular biomarkers in providing meaningful prognostic and therapeutic information for gliomas. However, predicting individual patient survival remains challenging due to the lack of integrated quantitative assessment tools. In this study, we aimed to design a WHO CNS5-related risk signature to predict the overall survival (OS) rate of glioma patients using machine learning algorithms.MethodsWe extracted data from patients who underwent an operation for histopathologically confirmed glioma from our hospital database (2011–2022) and split them into a training and hold-out test set in a 7/3 ratio. We used biological markers related to WHO CNS5, clinical data (age, sex, and WHO grade), and prognosis follow-up information to identify prognostic factors and construct a predictive dynamic nomograph to predict the survival rate of glioma patients using 4 kinds machine learning algorithms (RF, SVM, XGB, and GLM).ResultsA total of 198 patients with complete WHO5 molecular data and follow-up information were included in the study. The median OS time of all patients was 29.77 [95% confidence interval (CI): 21.19–38.34] months. Age, FGFR2, IDH1, CDK4, CDK6, KIT, and CDKN2A were considered vital indicators related to the prognosis and OS time of glioma. To better predict the prognosis of glioma patients, we constructed a WHO5-related risk signature and nomogram. The AUC values of the ROC curves of the nomogram for predicting the 1, 3, and 5-year OS were 0.849, 0.835, and 0.821 in training set, and, 0.844, 0.943, and 0.959 in validation set. The calibration plot confirmed the reliability of the nomogram, and the c-index was 0.742 in training set and 0.775 in validation set. Additionally, our nomogram showed a superior net benefit across a broader scale of threshold probabilities in decision curve analysis. Therefore, we selected it as the backend for the online survival prediction tool (Glioma Survival Calculator, https://who5pumch.shinyapps.io/DynNomapp/), which can calculate the survival probability for a specific time of the patients.ConclusionAn online prognosis predictor based on WHO5-related biomarkers was constructed. This therapeutically promising tool may increase the precision of forecast therapy outcomes and assess prognosis.
Developmental patterning of peptide transcription in the central circadian clock in both sexes
Authors: Carmona-Alcocer Vania , Brown Lindsey S. , Anchan Aiesha , Rohr Kayla E. , Evans Jennifer A. 
Published: May 2023

IntroductionNeuropeptide signaling modulates the function of central clock neurons in the suprachiasmatic nucleus (SCN) during development and adulthood. Arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) are expressed early in SCN development, but the precise timing of transcriptional onset has been difficult to establish due to age-related changes in the rhythmic expression of each peptide.MethodsTo provide insight into spatial patterning of peptide transcription during SCN development, we used a transgenic approach to define the onset of Avp and Vip transcription. Avp-Cre or Vip-Cre males were crossed to Ai9+/+ females, producing offspring in which the fluorescent protein tdTomato (tdT) is expressed at the onset of Avp or Vip transcription. Spatial patterning of Avp-tdT and Vip-tdT expression was examined at critical developmental time points spanning mid-embryonic age to adulthood in both sexes.ResultsWe find that Avp-tdT and Vip-tdT expression is initiated at different developmental time points in spatial subclusters of SCN neurons, with developmental patterning that differs by sex.ConclusionsThese data suggest that SCN neurons can be distinguished into further subtypes based on the developmental patterning of neuropeptide expression, which may contribute to regional and/or sex differences in cellular function in adulthood.
Deciphering the mechanism of jujube vinegar on hyperlipoidemia through gut microbiome based on 16S rRNA, BugBase analysis, and the stamp analysis of KEEG
Authors: Duan Guofeng , Li Lijuan 
Published: May 2023

BackgroundGrowing data indicate that the gut microbiome may contribute to the rising incidence of hyperlipoidemia. Jujube vinegar lowers lipids, protects the liver, and reduces oxidant capacity, however, it is unknown whether this is due to the gut flora. To further research the role of the gut microbiome in treating hyperlipidemia with jujube vinegar, we looked into whether the action of jujube vinegar is related to the regulation of the gut microbiome.MethodThirty male ICR mice were used. The control group (CON), the high-fat diet (HFD) group, and the vinegar group (VIN) each consisted of ten female ICR mice fed consistently for eight weeks. For each treatment, we kept track of body mass, liver index, blood lipid levels, and oxidative stress state. We also analyzed mouse feces using high-throughput 16srRNA sequencing to examine the relationship between jujube vinegar’s hypolipidemic effect and antioxidant activity and how it affects the gut microbiome.ResultsJujube vinegar reduced body weight by 19.92%, serum TC, TG, and LDL-C by 25.09%, 26.83%, and 11.66%, and increased HDL-C by 1.44 times, serum AST and ALT decreased by 26.36% and 34.87% respectively, the blood levels of SOD and GSH-Px increased 1.35-fold and 1.60-fold, respectively. While blood MDA decreased 33.21%, the liver’s SOD and GSH-Px increased 1.32-fold and 1.60-fold, respectively, and the liver’s MDA decreased 48.96% in HFD mice. The gut microbiome analysis revealed that jujube vinegar increased the intestinal microbial ASV count by 13.46%, and the F/B (Firmicutes/Bacteroidota) ratio by 2.08-fold in high-fat diet mice, and the proportion was significantly inversely correlated with TC, TG, and LDL-C and positively correlated with HDL-C. Biomarker bacteria in the vinegar group included Lactobacillaceae and Lactobacillus, which correlated favorably with HDL-C, SOD, and GSH-Px and negatively with LDL-C, TC, and TG. Jujube vinegar increased the abundance of the Aerobic, Contains Mobile Elements, and Facultative Aerobic by 2.84 times, 1.45 times, and 2.40 times, while decreased the abundance of Potential pathogens by 44.72%, according to the BugBase study. The KEGG analysis showed that jujube vinegar was predominantly reflected in the biological process of gene function and related to signal transduction pathways, including glucagon signaling system, HIF-1 signaling pathway, adipocytokine signaling pathway, amino sugar, and nucleotide sugar metabolism, and so forth.ConclusionBased on these findings, jujube vinegar may reduce hyperlipoidemia by controlling the gut microbiome and enhancing antioxidant capacity.
Ubiquitination-related biomarkers in metastatic melanoma patients and their roles in tumor microenvironment
Authors: Zhang Li , Shi Zhehao , Zhang Fan , Chen Bin , Qiu Wei , Cai Lei , Lin Xiaohua 
Published: May 2023

BackgroundSkin cutaneous melanoma (SKCM) is the deadliest type of cutaneous malignancy. Ubiquitination is a process of protein sorting and degradation that exhibits multiple functions in the progression of various tumors. This study aimed to characterize a set of genes for ubiquitination in SKCM.MethodsThe expression patterns of ubiquitin-associated genes (URGs) and the corresponding clinical information in SKCM tissues were comprehensively analyzed based on The Cancer Genome Atlas (TCGA) database. We performed univariate and multivariate Cox proportional regression models to characterize the risk scores and identify four critical genes related to prognostic ubiquitination (HCLS1, CORO1A, NCF1 and CCRL2), which were used to construct the prognostic signatures. We also studied the effects of HCLS1, CORO1A and CCRL2 on tumor metastasis-related indicators at the cellular level through in vitro experiments.ResultsSKCM patients in the low-risk group showing a longer survival than those in the high-risk group. Characteristic risk scores correlated with several clinicopathological variables and reflected the infiltration of multiple immune cells. In addition, the knockdown of CLS1, CORO1A and CCRL2 affected cellular malignant biological behavior through the EMT signaling pathway.ConclusionThis study provides a novel and prospective strategy to improve the clinical survival of SKCM patients.
Urine-Derived Stem Cells Express 571 Neuromuscular Disorders Causing Genes, Making Them a Potential in vitro Model for Rare Genetic Diseases
Authors: Falzarano Maria Sofia , Rossi Rachele , Grilli Andrea , Fang Mingyan , Osman Hana , Sabatelli Patrizia , Antoniel Manuela , Lu Zhiyuan , Li Wenyan , Selvatici Rita , Al-Khalili Cristina , Gualandi Francesca , Bicciato Silvio , Torelli Silvia , Ferlini Alessandra 
Published: May 2023

Background: Neuromuscular disorders (NMDs) are a heterogeneous group of genetic diseases, caused by mutations in genes involved in spinal cord, peripheral nerve, neuromuscular junction, and muscle functions. To advance the knowledge of the pathological mechanisms underlying NMDs and to eventually identify new potential drugs paving the way for personalized medicine, limitations regarding the availability of neuromuscular disease-related biological samples, rarely accessible from patients, are a major challenge.Aim: We characterized urinary stem cells (USCs) by in-depth transcriptome and protein profiling to evaluate whether this easily accessible source of patient-derived cells is suitable to study neuromuscular genetic diseases, focusing especially on those currently involved in clinical trials.Methods: The global transcriptomics of either native or MyoD transformed USCs obtained from control individuals was performed by RNA-seq. The expression of 610 genes belonging to 16 groups of disorders (http://www.musclegenetable.fr/) whose mutations cause neuromuscular diseases, was investigated on the RNA-seq output. In addition, protein expression of 11 genes related to NMDs including COL6A, EMD, LMNA, SMN, UBA1, DYNC1H1, SOD1, C9orf72, DYSF, DAG1, and HTT was analyzed in native USCs by immunofluorescence and/or Western blot (WB).Results: RNA-seq profile of control USCs shows that 571 out of 610 genes known to be involved in NMDs, are expressed in USCs. Interestingly, the expression levels of the majority of NMD genes remain unmodified following USCs MyoD transformation. Most genes involved in the pathogenesis of all 16 groups of NMDs are well represented except for channelopathies and malignant hyperthermia related genes. All tested proteins showed high expression values, suggesting consistency between transcription and protein representation in USCs.Conclusion: Our data suggest that USCs are human cells, obtainable by non-invasive means, which might be used as a patient-specific cell model to study neuromuscular disease-causing genes and that they can be likely adopted for a variety of in vitro functional studies such as mutation characterization, pathway identification, and drug screening.