bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling non-linear relationships in epidemiological data: The application and interpretation of spline models
Authors: Schuster Noah A. , Rijnhart Judith J. M. , Twisk Jos W. R. , Heymans Martijn W. 
Published: August 2022

ObjectiveTraditional methods to deal with non-linearity in regression analysis often result in loss of information or compromised interpretability of the results. A recommended but underutilized method for modeling non-linear associations in regression models is spline functions. We explain spline functions in a non-mathematical way and illustrate the application and interpretation to an empirical data example.MethodsUsing data from the Amsterdam Growth and Health Longitudinal Study, we examined the non-linear relationship between the sum of four skinfolds and VO2max, which are measures of body fat and cardiorespiratory fitness, respectively. We compared traditional methods (i.e., quadratic regression and categorization) to spline methods [1- and 3-knot linear spline (LSP) models and a 3-knot restricted cubic spline (RCS) model] in terms of the interpretability of the results and their explained variance (radj2).ResultsThe spline models fitted the data better than the traditional methods. Increasing the number of knots in the LSP model increased the explained variance (from radj2=0.578 for the 1-knot model to radj2=0.582 for the 3-knot model). The RCS model fitted the data best (radj2=0.591), but results in regression coefficients that are harder to interpret.ConclusionSpline functions should be considered more often as they are flexible and can be applied in commonly used regression analysis. RCS regression is generally recommended for prediction research (i.e., to obtain the predicted outcome for a specific exposure value), whereas LSP regression is recommended if one is interested in the effects in a population.
Serum multi-cytokines screening identifies TRAIL and IL-10 as probable new biomarkers for prostate health index diagnostic utility adjustment in grey zone aggressive prostate cancer detection: A single-center data in China
Authors: Chen Haojie , Zhou Jiatong , Luo Jia , Wu Yanyuan , Qian Yuhang , Shi Yuntian , Qu Fajun , Shi Bowen , Ding Jie , Cui Xingang , Yu Yongjiang 
Published: August 2022

ObjectiveTo identify less invasive and easily applicable serum cytokine-derived biomarkers which contribute to the diagnostic utility and risk assessment ability of the prostate health index (PHI) based multivariable model in grey zone aggressive prostate cancer (AG PCa) early detection.MethodsSerum 45 cytokines screening was performed in a small training cohort consisting of 10 sera by Luminex liquid array-based multiplexed immunoassays and identified TRAIL and IL-10 as new biomarkers for PHI diagnostic utility adjustment for further validation with a multivariable predictive model in a cohort including 79 aggressive prostate cancer patients and 209 benign prostatic hyperplasia or indolent PCa patients within the PSA grey zone.ResultsTRAIL and IL-10 were identified as potential serum biomarkers for AG PCa detection by the result of multi-cytokines screening in the univariate analysis, while multivariable logistic regression confirmed the AUC of the full risk predictive model (0.915) including tPSA, fPSA, PHI, TRAIL, and IL-10 was higher than various diagnostic strategies. DCA suggested a superior net benefit and indicated a good discriminative ability of the full risk model consistently with the result of the nomogram.ConclusionWe suggest a significant advantage for the PHI-based multivariate combinations of serum TRAIL and IL-10 comparing to PHI or other serum-derived biomarkers alone in the detection and risk stratification of grey zone AG PCa.
Assessment of disease activity in patients with rheumatoid arthritis using plasma tumour M2-pyruvate kinase test
Authors: Ahn Sung Soo , Kim Hye Min , Park Younhee 
Published: August 2022

BackgroundPyruvate kinase M2 (PKM2) is an enzyme that regulates the final process of glycolysis and exists in tetrameric and dimeric forms. The dimeric form of PKM2, also known as tumour M2-PK, increases when aerobic glycolysis is augmented, a feature observed in rheumatoid arthritis (RA). We investigated whether plasma tumour M2-PK is elevated in patients with RA and whether its levels correlate with disease activity.MethodsPlasma levels of tumour M2-PK were measured for patients with RA (n=151), those with osteoarthritis (OA) (n=37), and controls (n=37). We evaluated the association between plasma tumour M2-PK and continuous variables using Pearson’s correlation analysis, and multivariate logistic regression analysis to determine the association between plasma tumour M2-PK and disease activity status. Knee synovial tissue blocks from patients with RA and OA were subjected to real-time quantitative PCR (qPCR) using two different primers for PKM2 and tumour M2-PK immunohistochemical (IHC) staining.ResultsThe tumour M2-PK level significantly correlated with the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) (r=0.546, p&lt;0.001) and DAS28-C-reactive protein (CRP) (r=0.589, p&lt;0.001). Moreover, repeat testing of tumour M2-PK levels in 20 patients revealed a significant decline in tumour M2-PK levels after reduction in inflammation (p&lt;0.001). Area under the receiver operating characteristic curve (AUROC) analysis demonstrated that upon incorporation of tumour M2-PK, ESR, and CRP, the area under the curve was 0.962 for distinguishing moderate/high from remission/low disease activity. Adjusted logistic regression also revealed that a tumour M2-PK &gt;43.9 U/mL (OR 3.672, p=0.042) independently predicted moderate/high disease activity status. Furthermore, tumour M2-PK levels in patients with RA were significantly higher than in those with OA and controls (all p&lt;0.001). However, no differences were found in PKM2 expression in RA and OA synovial tissues as assessed by qPCR, and IHC analysis revealed negligible tumour M2-PK expression in the synovial tissues.ConclusionCirculating plasma tumour M2-PK levels may be a clinically useful indicator for evaluating disease activity and RA diagnosis.
Macrophage polarization regulates intervertebral disc degeneration by modulating cell proliferation, inflammation mediator secretion, and extracellular matrix metabolism
Authors: Li Xiao-Chuan , Luo Shao-Jian , Fan Wu , Zhou Tian-Li , Tan Dan-Qin , Tan Rong-Xiong , Xian Qun-Ze , Li Jian , Huang Chun-Ming , Wang Mao-Sheng 
Published: August 2022

Macrophage infiltration and polarization have been increasingly observed in intervertebral disc (IVD) degeneration (IDD). However, their biological roles in IDD are still unrevealed. We harvested conditioned media (CM) derived from a spectrum of macrophages induced from THP-1 cells, and examined how they affect nucleus pulposus cells (NPCs) in vitro, by studying cell proliferation, extracellular matrix (ECM) synthesis, and pro-inflammation expression; and in vivo by injection CM in a rat IDD model. Then, high-throughput sequencing was used to detect differentially expressed genes (DEGs). Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) networks were used to further analysis. Higher CCR7+ (M1 marker) and CD206+ (M2 marker) cell counts were found in the degenerated human IVD tissues as compared with the control. Furthermore, the cell co-culture model showed M1CM attenuated NPC proliferation, downregulated the expression of ECM anabolic genes encoding aggrecan and collagen IIα1, upregulated the expression of ECM catabolic genes encoding MMP-13, and inflammation-related genes encoding IL-1β, IL-6, and IL-12, while M2CM showed contrasting trends. In IDD model, higher histological scores and lower disc height index were found following M1CM treatment, while M2CM exhibited opposite results. M1CM injection decreased ECM anabolic and increased ECM catabolic, as well as the upregulation of inflammation-related genes after 8 weeks treatment, while M2CM slowed down these trends. Finally, a total of 637 upregulated and 655 downregulated genes were detected in M1CM treated NPCs, and 975 upregulated genes and 930 downregulated genes in the M2CM groups. The top 30 GO terms were shown and the most significant KEGG pathway was cell cycle in both groups. Based on the PPI analysis, the five most significant hub genes were PLK1, KIF20A, RRM2, CDC20, and UBE2C in the M1CM groups and RRM2, CCNB1, CDC20, PLK1, and UBE2C in the M2CM groups. In conclusion, macrophage polarization exhibited diverse roles in IDD progression, with M1CM exacerbating cell proliferation suppression and IVD degeneration, while M2CM attenuated IDD development. These findings may facilitate the further elucidation of the role of macrophage polarization in IDD, and provide novel insights into the therapeutic potential of macrophages.
A tumor microenvironment-related risk model for predicting the prognosis and tumor immunity of breast cancer patients
Authors: Geng Shengkai , Fu Yipeng , Fu Shaomei , Wu Kejin 
Published: August 2022

BackgroundThis study aimed to construct a tumor microenvironment (TME)-related risk model to predict the overall survival (OS) of patients with breast cancer.MethodsGene expression data from The Cancer Genome Atlas was used as the training set. Differentially expressed gene analysis, prognosis analysis, weighted gene co-expression network analysis, Least Absolute Shrinkage and Selection Operator regression analysis, and Wald stepwise Cox regression were performed to screen for the TME-related risk model. Three Gene Expression Omnibus databases were used to validate the predictive efficiency of the prognostic model. The TME-risk-related biological function was investigated using the gene set enrichment analysis (GSEA) method. Tumor immune and mutation signatures were analyzed between low- and high-TME-risk groups. The patients’ response to chemotherapy and immunotherapy were evaluated by the tumor immune dysfunction and exclusion (TIDE) score and immunophenscore (IPS).ResultsFive TME-related genes were screened for constructing a prognostic signature. Higher TME risk scores were significantly associated with worse clinical outcomes in the training set and the validation set. Correlation and stratification analyses also confirmed the predictive efficiency of the TME risk model in different subtypes and stages of breast cancer. Furthermore, immune checkpoint expression and immune cell infiltration were found to be upregulated in the low-TME-risk group. Biological processes related to immune response functions were proved to be enriched in the low-TME-risk group through GSEA analysis. Tumor mutation analysis and TIDE and IPS analyses showed that the high-TME-risk group had more tumor mutation burden and responded better to immunotherapy.ConclusionThe novel and robust TME-related risk model had a strong implication for breast cancer patients in OS, immune response, and therapeutic efficiency.
Exosomal miRNAs in the plasma of Cynoglossus semilaevis infected with Vibrio harveyi: Pleiotropic regulators and potential biomarkers involved in inflammatory and immune responses
Authors: Zhu Tengfei , Kong Ming , Li Chen , Shao Changwei 
Published: August 2022

Exosomes are a class of extracellular vesicles with diameters ranging from ~50 to 150 nm. Incorporating diverse biological substances and being present extensively in biofluids, exosomes are involved in intracellular communication in various physiological and pathological processes and emerging as promising biomarkers for the prognosis and diagnosis of many diseases. Accumulating evidence shows that exosomes also play important roles in the inflammatory and immune responses to bacterial infection. However, the study of exosomes in teleost fish remains scarce. In the present study, we focused on the exosomal microRNAs (miRNAs) in the plasma of Chinese tongue sole (Cynoglossus semilaevis) in response to Vibrio harveyi infection. After bacterial challenge, the plasma was sampled at both the early (6 and 16 h) and late stages. (48, 72, and 96 h) of infection, followed by exosome isolation and exosomal miRNA sequencing. Results showed that the expression profile of 85 exosomal miRNAs was significantly different among the control, early-, and late-infection groups. The predictive genes targeted by exosomal miRNAs were extensively involved in various inflammatory and immune processes by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, suggesting that a series of processes were regulated by exosomal miRNAs in the plasma, including the pathogen invasion and recognition and the activation and regulation of signaling pathways related to cytokine production. Moreover, the spleen was found to be a preference for exosome enrichment and the underlying mechanism of interleukin-6 production regulated by ZC3H12A, ARID5A, and exosomal ssa-miR-146a-5p were probably present in Chinese tongue sole. Additionally, the enhanced levels of ssa-miR-146a-5p and nbr-miR-731 in plasma exosomes and the spleen of the infection groups were identified, indicating their application as biomarkers in favor of the prognosis and diagnosis of V. harveyi infection in Chinese tongue sole. Therefore, the collective results in the present study indicated the pleiotropic roles of exosomal miRNAs in the regulation of inflammatory and immune responses and their potential utilization as biomarkers in teleost fish.
Thrombocytopenia in the first trimester predicts adverse pregnancy outcomes in obstetric antiphospholipid syndrome
Authors: Jin Jiayang , Xu Xue , Hou Lei , Hou Yuke , Li Jing , Liang Meiying , Li Chun 
Published: August 2022

BackgroundThrombocytopenia is a common manifestation of antiphospholipid syndrome (APS), and is a main concern for bleeding on the standard treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) in obstetric APS (OAPS).ObjectiveThis study assesses the possible relationship between thrombocytopenia during the first trimester and adverse pregnancy outcomes (APOs) in OAPS patients.MethodsA case-control study was conducted at Peking University People’s Hospital, Beijing, China. The clinical, immunologic, and pregnancy outcomes of the OAPS patients were collected. Univariate and multivariate logistic regression analyses were applied to assess the relationship between APOs and thrombocytopenia in the first trimester.ResultsA total of 115 participants were included in the analysis. There were no difference on antepartum and postpartum hemorrhage between the two groups. The gestational age in the thrombocytopenia group was less than that in the control group (34.12 ± 8.44 vs. 37.44 ± 3.81 weeks, p = 0.002). Hypocomplementemia, double aPL positive, and high titers of anti-β2 glycoprotein I were more frequent in APS patients with thrombocytopenia (p &lt; 0.05). Compared to the control group, thrombocytopenia in the first trimester was correlated with SGA (12.12% vs. 31.25%, p = 0.043), premature birth &lt;37 weeks (16.16% vs 43.75%, p = 0.010) and intrauterine fetal death (2.02% vs 12.50%, p = 0.033). Thrombocytopenia in first-trimester independently increased the risk of preterm birth &lt;37 weeks (OR = 5.40, 95% CI: 1.35-21.53, p = 0.02) after adjusting for demographic and laboratory factors. After adding medication adjustments, these factors above become insignificant (p &gt; 0.05). Of note, the number of platelets increased after delivery in 14 thrombocytopenia patients with live fetuses (p = 0.03).ConclusionThis study demonstrates that thrombocytopenia in the first trimester increases the risks of preterm birth in women with APS. The effective OAPS treatments may improve pregnancy outcomes and not increase the risk of antepartum and postpartum hemorrhage.
Identification of individual bottlenose dolphins (Tursiops truncatus) emitters using a cheap wearable acoustic tag
Authors: Gallo Alessandro , Thieffry Aglaé , Boye Martin , Monmasson Kyra , Hausberger Martine , Lemasson Alban 
Published: August 2022

Study of animal communication and its potential social role implies associating signals to an emitter. This has been a major limitation in the study of cetacean communication as they produce sounds underwater with no distinctive behavioral signs. Different techniques have been used to identify callers, but all proved to have ethical or practical limitations. Bio-logging technology has recently provided new hopes, but tags developed so far are costly and do not allow sufficiently reliable discrimination between calls made by the tagged individual and those made by the surrounding individuals. We propose a new device developed at reasonable cost while providing reliable recordings. We tested caller identification through recordings of vocal production of a group of captive bottlenose dolphins under controlled and spontaneous contexts. Our device proved to identify callers through visual examination of sonograms and quantitative measures of amplitudes, even if tagged emitters are 0.4 m apart (regardless of body orientations). Although this device is not able to identify emitters in an entire group when all individuals are not equipped, it enables efficient exclusion of individuals who were not the caller, suggesting that identification of a caller would be reliable if all the individuals were equipped. This is to our knowledge the first description of a promising low-cost safe recording device allowing individual identification of emitters for captive dolphins. With some improvements, this device could become an interesting tool to increase our knowledge of dolphin acoustic communication.
The multi-domain exercise intervention for memory and brain function in late middle-aged and older adults at risk for Alzheimer's disease: A protocol for Western–Eastern Brain Fitness Integration Training trial
Authors: Chang Yu-Kai , Erickson Kirk I. , Aghjayan Sarah L. , Chen Feng-Tzu , Li Ruei-Hong , Shih Jia-Ru , Chang Shao-Hsi , Huang Chih-Mao , Chu Chien-Heng 
Published: August 2022

BackgroundAging is associated with cognitive decline, increased risk for dementia, and deterioration of brain function. Modifiable lifestyle factors (e.g., exercise, meditation, and social interaction) have been proposed to benefit memory and brain function. However, previous studies have focused on a single exercise modality or a single lifestyle factor. Consequently, the effect of a more comprehensive exercise program that combines multiple exercise modalities and lifestyle factors, as well as examines potential mediators and moderators, on cognitive function and brain health in late middle-aged and older adults remains understudied. This study's primary aim is to examine the effect of a multi-domain exercise intervention on memory and brain function in cognitively healthy late middle-aged and older adults. In addition, we will examine whether apolipoprotein E (ApoE) genotypes, physical fitness (i.e., cardiovascular fitness, body composition, muscular fitness, flexibility, balance, and power), and brain-derived neurotrophic factor (BDNF) moderate and mediate the exercise intervention effects on memory and brain function.MethodsThe Western-Eastern Brain Fitness Integration Training (WE-BFit) is a single-blinded, double-arm, 6-month randomized controlled trial. One hundred cognitively healthy adults, aged 45–70 years, with different risks for Alzheimer's disease (i.e., ApoE genotype) will be recruited and randomized into either a multi-domain exercise group or an online educational course control group. The exercise intervention consists of one 90-min on-site and several online sessions up to 60 min per week for 6 months. Working memory, episodic memory, physical fitness, and BDNF will be assessed before and after the 6-month intervention. The effects of the WE-BFit on memory and brain function will be described and analyzed. We will further examine how ApoE genotype and changes in physical fitness and BDNF affect the effects of the intervention.DiscussionWE-BFit is designed to improve memory and brain function using a multi-domain exercise intervention. The results will provide insight into the implementation of an exercise intervention with multiple domains to preserve memory and brain function in adults with genetic risk levels for Alzheimer's disease.Clinical trial registrationClinicalTrials.gov, identifier: NCT05068271.
Efficacy of acupuncture in animal models of vascular dementia: A systematic review and network meta-analysis
Authors: Li Guangyao , Shi Yuling , Zhang Lu , Yang Chuanghui , Wan Ting , Lv Hang , Jian Wenxuan , Li Jinghu , Li Min 
Published: August 2022

Background and purposeAcupuncture is widely used in clinical practice for the treatment of vascular diseases. However, the protocol, efficacy, and mechanism of acupuncture in animal models of vascular dementia are still controversial. Based on the above problems, we initiated this comprehensive study.MethodsTo analyze the literatures included in this study, 4 databases were searched and the SYRCLE's Risk of bias tool was employed. To perform the subgroup analysis of different acupuncture methods and the Review Manager 5.3 was applied. Meanwhile, the pairwise and network meta-analysis were conducted using Addis 1.16.8. The outcomes included escape latency, number of crossings, time spent in the target quadrant, and swimming speed.ResultsForty-two studies with a total of 1,486 animals were included in this meta-analysis. According to the results from subgroup analysis, GV20 + ST36 (Baihui + bilateral Zusanli) combined with 14-day manual acupuncture can obtain best improvement of the rats cognitive function among all acupuncture regimens (MD: −23.41; 95%CI: −26.66, −20.15; I2 = 0%; P &lt; 0.001). The heterogeneity of other acupuncture treatments was significantly higher than that of GV20 + ST36, because the treatment courses were not uniform. Pair-wise and network comparisons are highly consistent. The major results of the network meta-analysis were as follows, In comparison to the impaired group, the acupuncture group showed significantly reduced escape latency (MD: −25.87; 95%CI: −30.75, −21.12), increased number of original platform crossings (MD: 2.63; 95%CI: 1.94, 3.34) and time spent in the target quadrant (MD: 7.88; 95%CI: 4.25, 11.44). The overall results of the network meta-analysis are as follows: the normal and sham-operated groups performed the best, followed by medicine and acupuncture, while no effect was found in the impaired group treated with non-acupoint and palliative.ConclusionsAcupuncture significantly improves cognitive function in rats with vascular dementia. Compared to other acupuncture plans, (GV20 + ST36, MA) and 14 -day manual acupuncture can be used to obtain better results. The main mechanism of acupuncture in the treatment of vascular dementia is reduced oxidative stress, neuronal inflammation, and apoptosis, as well as the increased synaptic plasticity and neurotransmitters.Systematic review registrationhttps://inplasy.com/inplasy-2021-11-0036/, identifier: INPLASY2021110036.