bluuebunny/crossref_metadata_2025_split huggingface dataset:
Striatal fibrinogen extravasation and vascular degeneration correlate with motor dysfunction in an aging mouse model of Alzheimer’s disease
Authors: Berk-Rauch Hanna E. , Choudhury Arnab , Richards Allison T. , Singh Pradeep K. , Chen Zu-Lin , Norris Erin H. , Strickland Sidney , Ahn Hyung Jin 
Published: March 2023

Introduction: Alzheimer’s Disease (AD) patients exhibit signs of motor dysfunction, including gait, locomotion, and balance deficits. Changes in motor function often precede other symptoms of AD as well as correlate with increased severity and mortality. Despite the frequent occurrence of motor dysfunction in AD patients, little is known about the mechanisms by which this behavior is altered.Methods and Results: In the present study, we investigated the relationship between cerebrovascular impairment and motor dysfunction in a mouse model of AD (Tg6799). We found an age-dependent increase of extravasated fibrinogen deposits in the cortex and striatum of AD mice. Interestingly, there was significantly decreased cerebrovascular density in the striatum of the 15-month-old as compared to 7-month-old AD mice. We also found significant demyelination and axonal damage in the striatum of aged AD mice. We analyzed striatum-related motor function and anxiety levels of AD mice at both ages and found that aged AD mice exhibited significant impairment of motor function but not in the younger AD mice.Discussion: Our finding suggests an enticing correlation between extravasated fibrinogen, cerebrovascular damage of the striatum, and motor dysfunction in an AD mouse model, suggesting a possible mechanism underlying motor dysfunction in AD.
Identification of key genes and signaling pathways associated with dementia with Lewy bodies and Parkinson's disease dementia using bioinformatics
Authors: Xu Jing , Li Jia , Sun Ya-juan , Quan Wei , Liu Li , Zhang Qing-hui , Qin Yi-dan , Pei Xiao-chen , Su Hang , Chen Jia-jun 
Published: March 2023

ObjectiveDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are collectively known as Lewy body dementia (LBD). Considering the heterogeneous nature of LBD and the different constellations of symptoms with which patients can present, the exact molecular mechanism underlying the differences between these two isoforms is still unknown. Therefore, this study aimed to explore the biomarkers and potential mechanisms that distinguish between PDD and DLB.MethodsThe mRNA expression profile dataset of GSE150696 was acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between 12 DLB and 12 PDD were identified from Brodmann area 9 of human postmortem brains using GEO2R. A series of bioinformatics methods were applied to identify the potential signaling pathways involved, and a protein–protein interaction (PPI) network was constructed. Weighted gene co-expression network analysis (WGCNA) was used to further investigate the relationship between gene co-expression and different LBD subtypes. Hub genes that are strongly associated with PDD and DLB were obtained from the intersection of DEGs and selected modules by WGCNA.ResultsA total of 1,864 DEGs between PDD and DLB were filtered by the online analysis tool GEO2R. We found that the most significant GO- and KEGG-enriched terms are involved in the establishment of the vesicle localization and pathways of neurodegeneration-multiple diseases. Glycerolipid metabolism and viral myocarditis were enriched in the PDD group. A B-cell receptor signaling pathway and one carbon pool by folate correlated with DLB in the results obtained from the GSEA. We found several clusters of co-expressed genes which we designated by colors in our WGCNA analysis. Furthermore, we identified seven upregulated genes, namely, SNAP25, GRIN2A, GABRG2, GABRA1, GRIA1, SLC17A6, and SYN1, which are significantly correlated with PDD.ConclusionThe seven hub genes and the signaling pathways we identified may be involved in the heterogeneous pathogenesis of PDD and DLB.
Clinical impact of carbapenems in critically ill patients with valproic acid therapy: A propensity-matched analysis
Authors: Hsiao Shu-Chen , Lai Wei-Hung , Chen I-Ling , Shih Fu-Yuan 
Published: March 2023

BackgroundValproic acid (VPA) is one of the most widely used broad-spectrum antiepileptic drugs, and carbapenems (CBPs) remain the drug of choice for severe infection caused by multidrug-resistant bacteria in critically ill patients. The interaction between VPA and CBPs can lead to a rapid depletion of serum VPA level. This may then cause status epilepticus (SE), which is associated with significant mortality. However, the prognostic impact of drug interactions in critically ill patients remains an under-investigated issue.ObjectiveThe aim of this study was to compare the prognosis of critically ill patients treated with VPA and concomitant CBPs or other broad-spectrum antibiotics.MethodsAdult patients admitted to a medical center intensive care unit between January 2007 and December 2017 who concomitantly received VPA and antibiotics were enrolled. The risk of reduced VPA serum concentration, seizures and SE, mortality rate, length of hospital stay (LOS), and healthcare expenditure after concomitant administration were analyzed after propensity score matching.ResultsA total of 1,277 patients were included in the study, of whom 264 (20.7%) concomitantly received VPA and CBPs. After matching, the patients who received CBPs were associated with lower VPA serum concentration (15.8 vs. 60.8 mg/L; p &lt; 0.0001), a higher risk of seizures (51.2 vs. 32.4%; adjusted odds ratio [aOR], 2.19; 95% CI, 1.48–3.24; p &lt; 0.0001), higher risk of SE (13.6 vs. 4.7%; aOR, 3.20; 95% CI, 1.51–6.74; p = 0.0014), higher in-hospital mortality rate (33.8 vs. 24.9%; aOR, 1.57; 95% CI, 1.03–2.20; p = 0.036), longer LOS after concomitant therapy (41 vs. 30 days; p &lt; 0.001), and increased healthcare expenditure (US$20,970 vs. US$12,848; p &lt; 0.0001) than those who received other broad-spectrum antibiotics.ConclusionThe administration of CBPs in epileptic patients under VPA therapy was associated with lower VAP serum concentration, a higher risk of seizures and SE, mortality, longer LOS, and significant utilization of healthcare resources. Healthcare professionals should pay attention to the concomitant use of VPA and CBPs when treating patients with epilepsy. Further studies are warranted to investigate the reason for the poor outcomes and whether avoiding the co-administration of VPA and CBP can improve the outcomes of epileptic patients.
DBS of the ANT for refractory epilepsy: A single center experience of seizure reduction, side effects and neuropsychological outcomes
Authors: Olaciregui Dague Karmele , Witt Juri-Alexander , von Wrede Randi , Helmstaedter Christoph , Surges Rainer 
Published: March 2023

ObjectiveEvaluation of the antiseizure efficacy, side effects and neuropsychological effects of Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT). ANT-DBS is a treatment option for patients with difficult-to-treat epilepsy. Though several works outline the cognitive and/or mood effects of ANT-DBS for the treatment of epilepsy, data on the intersection between antiseizure efficacy, cognitive and undesired effects are scarce.MethodsWe retrospectively analyzed the data of our cohort of 13 patients. Post-implantation seizure frequencies were measured at 6 months, 12 months and last follow-up, as well as averaged throughout follow-up. These values were then compared with mean seizure frequencies in the 6 months before implantation. To address acute cognitive effects of DBS a baseline assessment was performed after implantation and before stimulation, and a follow-up assessment was conducted under DBS. The long-term effects of DBS on cognition were assessed by comparing the preoperative neuropsychological profile with a long-term follow-up under DBS.ResultsIn the entire cohort, 54.5% of patients were responders, with an average seizure reduction of 73.6%. One of these patients achieved temporary seizure freedom and near-total seizure reduction during the entire follow-up. Seizure reduction of &lt;50% was achieved in 3 patients. Non-responders suffered an average seizure increase of 27.3%. Eight of twenty-two active electrodes (36,4%) were off-target. Two of our patients had both electrodes implanted off-target. When removing these two patients from the analysis and averaging seizure frequency during the entire follow-up period, four patients (44.4%) were responders and three experienced a seizure reduction of &lt;50%. Intolerable side effects arose in 5 patients, mostly psychiatric. Regarding acute cognitive effects of DBS, only one patient showed a significant decline in executive functions. Long-term neuropsychological effects included significant intraindividual changes in verbal learning and memory. Figural memory, attention and executive functions, confrontative naming and mental rotation were mostly unchanged, and improved in few cases.SignificanceIn our cohort, more than half of patients were responders. Psychiatric side effects seem to have been more prevalent compared to other published cohorts. This may be partially explained by a relatively high occurrence of off-target electrodes.
Bioactive nutraceuticals oligo-lactic acid and fermented soy extract alleviate cognitive decline in mice in part via anti-neuroinflammation and modulation of gut microbiota
Authors: Abdolmaleky Hamid M. , Sheng Yin , Zhou Jin-Rong 
Published: March 2023

IntroductionCognition decline is associated with aging and certain diseases, such as neurodegenerative or neuropsychiatric disorders, diabetes and chronic kidney disease. Inflammation/neuroinflammation is considered an important causal factor, and experimental evidence suggests that anti-inflammatory natural compounds may effectively prevent cognitive decline. The goal of this study was to evaluate the effects of two natural bioactive agents, oligo-lactic acid (LAP) and fermented soy extract (ImmunBalance, IMB), on cognition in an adenine-induced cognitive impairment mouse model and to investigate the modulation of related biomarkers.MethodsMale C57 black mice were randomly assigned into the following experimental groups and received the corresponding treatments for 2 weeks before the use of adenine for model development: (1) negative control; (2) model control: injection of adenine at 50 mg/kg daily for 4 weeks; (3, 4) IMB groups: adenine injection and IMB oral gavage at 250 and 1,000 mg/kg BW, respectively; and (5) LAP group: adenine injection and LAP oral gavage at 1,000 mg/kg BW. One week after the model was developed, mice were evaluated for cognitive performances by using Y maze test, novel object recognition test, open field test, and Barnes maze tests. At the end of the experiment, brain tissues and cecum fecal samples were collected for analysis of gene expression and gut microbiota.ResultsMice treated with LAP or IMB had significantly improved spatial working memory, spatial recognition memory (LAP only), novel object recognition, and spatial learning and memory, compared with those in the model group. Gene expression analysis showed that, among a panel of cognition related genes, six of them (ELOVL2, GLUT4, Nestein, SNCA, TGFB1, and TGFB2) were significantly altered in the model group. LAP treatment significantly reversed expression levels of inflammatory/neuroinflammatory genes (SNCA, TGFB1), and IMB significantly reversed expression levels of genes related to inflammation/neuroinflammation, neurogenesis, and energy metabolism (ELOVL2, GLUT4, Nestin, TGFB1, and TGFB2). The altered microbiome was attenuated only by IMB.DiscussionIn conclusion, our data showed that LAP improved cognition associated with regulating biomarkers related to neuroinflammation and energy metabolism, whereas IMB improved cognition associated with regulating biomarkers related to neuroinflammation, energy metabolism, and neurogenesis, and modulating gut microbiota. Our results suggest that LAP and IMB may improve cognitive performance in mice via distinct mechanisms of action.
Global human obesity and global social index: Relationship and clustering
Authors: Munir Mubbasher , Zakaria Zahrahtul Amani , Nisar Haseeb , Ahmed Zahoor , Korma Sameh A. , Esatbeyoglu Tuba 
Published: March 2023

IntroductionObesity, a complex, multifactorial disease, is considered a global disease burden widely affecting the quality of life across different populations. Factors involved in obesity involve genetics, behavior and socioeconomic and environmental origins, each contributing to the risk of debilitating morbidity and mortality. However, the trends across the world vary due to various globalization parameters.MethodsThis article tends to identify the global social indicators, compiled into a global index, and develop a correlation between the global social index created by using the human development index, social and political globalization, the global happiness index, and the quality of infrastructure, institutions, and individuals using the internet factors and its effect on global obesity.Results and DiscussionOur results identified a positive correlation between medium human development levels with obesity compared to low and very high human development levels. Economic stability due to rapid industrialization has increased the buying capacity and changed the global food system, which seems to be the major driver of the rise of global obesity.ConclusionThe results decipher that global social indicators and overall social index have positively affected global obesity, which will help policymakers and governmental organizations monitor the obesity patterns across their regions by a significant contribution from globally influenced social factors.
Fully automated bladder tumor segmentation from T2 MRI images using 3D U-Net algorithm
Authors: Coroamă Diana Mihaela , Dioșan Laura , Telecan Teodora , Andras Iulia , Crișan Nicolae , Medan Paul , Andreica Anca , Caraiani Cosmin , Lebovici Andrei , Boca Bianca , Bálint Zoltán 
Published: March 2023

IntroductionBladder magnetic resonance imaging (MRI) has been recently integrated in the diagnosis pathway of bladder cancer. However, automatic recognition of suspicious lesions is still challenging. Thus, development of a solution for proper delimitation of the tumor and its separation from the healthy tissue is of primordial importance. As a solution to this unmet medical need, we aimed to develop an artificial intelligence-based decision support system, which automatically segments the bladder wall and the tumor as well as any suspect area from the 3D MRI images.MaterialsWe retrospectively assessed all patients diagnosed with bladder cancer, who underwent MRI at our department (n=33). All examinations were performed using a 1.5 Tesla MRI scanner. All images were reviewed by two radiologists, who performed manual segmentation of the bladder wall and all lesions. First, the performance of our fully automated end-to-end segmentation model based on a 3D U-Net architecture (by considering various depths of 4, 5 or 6 blocks) trained in two data augmentation scenarios (on 5 and 10 augmentation datasets per original data, respectively) was tested. Second, two learning setups were analyzed by training the segmentation algorithm with 7 and 14 MRI original volumes, respectively.ResultsWe obtained a Dice-based performance over 0.878 for automatic segmentation of bladder wall and tumors, as compared to manual segmentation. A larger training dataset using 10 augmentations for 7 patients could further improve the results of the U-Net-5 model (0.902 Dice coefficient at image level). This model performed best in terms of automated segmentation of bladder, as compared to U-Net-4 and U-Net-6. However, in this case increased time for learning was needed as compared to U-Net-4. We observed that an extended dataset for training led to significantly improved segmentation of the bladder wall, but not of the tumor.ConclusionWe developed an intelligent system for bladder tumors automated diagnostic, that uses a deep learning model to segment both the bladder wall and the tumor. As a conclusion, low complexity networks, with less than five-layers U-Net architecture are feasible and show good performance for automatic 3D MRI image segmentation in patients with bladder tumors.
An inflammation-related gene landscape predicts prognosis and response to immunotherapy in virus-associated hepatocellular carcinoma
Authors: Gao Ying-jie , Li Shi-rong , Huang Yuan 
Published: March 2023

BackgroundDue to the viral infection, chronic inflammation significantly increases the likelihood of hepatocellular carcinoma (HCC) development. Nevertheless, an inflammation-based signature aimed to predict the prognosis and therapeutic effect in virus-related HCC has rarely been established.MethodBased on the integrated analysis, inflammation-associated genes (IRGs) were systematically assessed. We comprehensively investigated the correlation between inflammation and transcriptional profiles, prognosis, and immune cell infiltration. Then, an inflammation-related risk model (IRM) to predict the overall survival (OS) and response to treatment for virus-related HCC patients was constructed and verified. Also, the potential association between IRGs and tumor microenvironment (TME) was investigated. Ultimately, hub genes were validated in plasma samples and cell lines via qRT-PCR. After transfection with shCCL20 combined with overSLC7A2, morphological change of SMMC7721 and huh7 cells was observed. Tumorigenicity model in nude mouse was established.ResultsAn inflammatory response-related gene signature model, containing MEP1A, CCL20, ADORA2B, TNFSF9, ICAM4, and SLC7A2, was constructed by conjoint analysis of least absolute shrinkage and selection operator (LASSO) Cox regression and gaussian finite mixture model (GMM). Besides, survival analysis attested that higher IRG scores were positively relevant to worse survival outcomes in virus-related HCC patients, which was testified by external validation cohorts (the ICGC cohort and GSE84337 dataset). Univariate and multivariate Cox regression analyses commonly proved that the IRG was an independent prognostic factor for virus-related HCC patients. Thus, a nomogram with clinical factors and IRG was also constructed to superiorly predict the prognosis of patients. Featured with microsatellite instability-high, mutation burden, and immune activation, lower IRG score verified a superior OS for sufferers. Additionally, IRG score was remarkedly correlated with the cancer stem cell index and drug susceptibility. The measurement of plasma samples further validated that CCL20 upexpression and SLC7A2 downexpression were positively related with virus-related HCC patients, which was in accord with the results in cell lines. Furthermore, CCL20 knockdown combined with SLC7A2 overexpression availably weakened the tumor growth in vivo.ConclusionsCollectively, IRG score, serving as a potential candidate, accurately and stably predicted the prognosis and response to immunotherapy in virus-related HCC patients, which could guide individualized treatment decision-making for the sufferers.
Adjuvant transarterial chemoembolization timing after radical resection is an independent prognostic factor for patients with hepatocellular carcinoma
Authors: Sun Hongfa , Wang Hanlin , Wang Youpeng , Zhong Wenqing , Meng Yushan , Lv Ziqiang , Guo Weidong , Han Bing 
Published: March 2023

BackgroundIt has been reported that postoperative adjuvant TACE (PA-TACE) treatment decreases recurrence and significantly improves the survival of patients who undergo radical resection of hepatocellular carcinoma (HCC) with high-risk recurrence factors. However, when to perform PA-TACE has not been fully studied.MethodsWe retrospectively collected the clinicopathologic characteristics of the patients with HCC between October 2013 and June 2020. The optimal cutoff value for PA-TACE time was determined based on the R package “maxstat”. Logistic regression and Cox regression analysis were used to determine the effect of the choice of PA-TACE timing on prognosis.ResultsThe analysis was performed on 789 patients with HCC, and 484 patients were finally involved and were divided into training cohort (378) and validation cohort (106). The PA-TACE timing was found to be associated with survival outcomes. Multivariate logistic analysis found independent predictors of the PA-TACE timing, including gender and history of HBV. Multivariate Cox analysis showed that Ki-67, tumor size, MVI and the PA-TACE timing were independent prognostic factors for RFS in HCC patients.ConclusionsBased on this study, HCC patients with high-risk recurrence factors can receive personalized assistance in undergoing PA-TACE treatment and improve their survival outcomes.
Therapeutic drug monitoring guided dosing versus standard dosing of alectinib in advanced ALK positive non-small cell lung cancer patients: Study protocol for an international, multicenter phase IV randomized controlled trial (ADAPT ALEC)
Authors: Meertens Marinda , Muntinghe-Wagenaar M. Benthe , Sikkema Barend J. , Lopez-Yurda Marta , Retèl Valesca P. , Paats Marthe S. , Ter Heine Rob , Schuuring Ed , Timens Wim , Touw Daan J. , van Boven Job F. M. , de Langen Adrianus. J. , Hashemi Sayed M. S. , Hendriks Lizza E. L. , Croes Sander , van den Heuvel Michel M. , Dingemans Anne-Marie C. , Mathijssen Ron H. J. , Smit Egbert F. , Huitema Alwin D. R. , Steeghs Neeltje , van der Wekken Anthonie J. 
Published: March 2023

BackgroundAlectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (Cmin,SS) were below 435 ng/mL. This may suggest that patients should have an alectinib Cmin,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM.MethodsADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib Cmin,SS &lt; 435 ng/mL, arm A will receive increased doses of alectinib till Cmin,SS ≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition.DiscussionThe ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib.Clinical trial registrationClinicalTrials.gov, identifier NCT05525338.