bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of ex vivo Extracorporeal Membrane Oxygenation Circuits on Sequestration of Antimicrobial Agents
Authors: Zhang Yuan , Hu Hongbin , Zhang Qing , Ou Qing , Zhou Huayou , Sha Tong , Zeng Zhenhua , Wu Jie , Lu Jingrui , Chen Zhongqing
Published: December 2021

Objectives:Ourex vivostudy was designed to determine the sequestration of teicoplanin, tigecycline, micafungin, meropenem, polymyxin B, caspofungin, cefoperazone sulbactam, and voriconazole in extracorporeal membrane oxygenation (ECMO) circuits.

Methods:Simulated closed-loop ECMO circuits were prepared using 2 types of blood-primed ECMO. After the circulation was stabilized, the study drugs were injected into the circuit. Blood samples were collected at 2, 5, 15, 30 min, 1, 3, 6, 12, and 24 h after injection. Drug concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Control groups were stored at 4°C after 3, 6, 12, and 24 h immersing in a water bath at 37°C to observe spontaneous drug degradation.

Results:Twenty-six samples were analyzed. The average drug recoveries from the ECMO circuits and control groups at 24 h relative to baseline were 67 and 89% for teicoplanin, 100 and 145% for tigecycline, 67 and 99% for micafungin, 45 and 75% for meropenem, 62 and 60% for polymyxin B, 83 and 85% for caspofungin, 79 and 98% for cefoperazone, 75 and 87% for sulbactam, and 60 and 101% for voriconazole, respectively. Simple linear regression showed no significant correlation between lipophilicity (r2= 0.008,P= 0.225) or the protein binding rate (r2= 0.168,P= 0.479) of drugs and the extent of drug loss in the ECMO circuits.

Conclusions:In the two ECMO circuits, meropenem and voriconazole were significantly lost, cefoperazone was slightly lost, while tigecycline and caspofungin were not lost. Drugs with high lipophilicity were lost more in the Maquet circuit than in the Sorin circuit. This study needs morein vivostudies with larger samples for further confirmation, and it suggests that therapeutic drug concentration monitoring should be strongly considered during ECMO.
A Computed Tomography Radiomics-Based Prediction Model on Interstitial Lung Disease in Anti-MDA5-Positive Dermatomyositis
Authors: Xu Wenwen , Wu Wanlong , Zheng Yu , Chen Zhiwei , Tao Xinwei , Zhang Danting , Zhao Jiangfeng , Wang Kaiwen , Guo Bingpeng , Luo Qun , Han Qian , Zhou Yan , Ye Shuang
Published: December 2021

Objectives: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5+ DM-ILD) is a life-threatening disease. The current study aimed to quantitatively assess the pulmonary high-resolution computed tomography (HRCT) images of MDA5+ DM-ILD by applying the radiomics approach and establish a multidimensional risk prediction model for the 6-month mortality.

Methods: This retrospective study was conducted in 228 patients from two centers, namely, a derivation cohort and a longitudinal internal validation cohort in Renji Hospital, as well as an external validation cohort in Guangzhou. The derivation cohort was randomly divided into training and testing sets. The primary outcome was 6-month all-cause mortality since the time of admission. Baseline pulmonary HRCT images were quantitatively analyzed by radiomics approach, and a radiomic score (Rad-score) was generated. Clinical predictors selected by univariable Cox regression were further incorporated with the Rad-score, to enhance the prediction performance of the final model (Rad-score plus model). In parallel, an idiopathic pulmonary fibrosis (IPF)-based visual CT score and ILD-GAP score were calculated as comparators.

Results: The Rad-score was significantly associated with the 6-month mortality, outperformed the traditional visual score and ILD-GAP score. The Rad-score plus model was successfully developed to predict the 6-month mortality, with C-index values of 0.88 [95% confidence interval (CI), 0.79–0.96] in the training set (n = 121), 0.88 (95%CI, 0.71–1.0) in the testing set (n = 31), 0.83 (95%CI, 0.68–0.98) in the internal validation cohort (n = 44), and 0.84 (95%CI, 0.64–1.0) in the external validation cohort (n = 32).

Conclusions: The radiomic feature was an independent and reliable prognostic predictor for MDA5+ DM-ILD.
Characteristics Analysis, Clinical Outcome and Risk Factors for Fungal Peritonitis in Peritoneal Dialysis Patients: A 10-Year Case-Control Study
Authors: Li Rongrong , Zhang Difei , He Jingwen , Ou Jianjun , Zhang La , Hu Xiaoxuan , Wu Jianfeng , Liu Hui , Peng Yu , Xu Yuan , Hou Haijing , Liu Xusheng , Lu Fuhua
Published: December 2021

Background: Fungal peritonitis (FP) is a rare but severe complication that can appear in patients receiving peritoneal dialysis (PD). This study aimed to investigate the incidence rate and clinical characteristics of FP, evaluate clinical outcomes between FP and bacterial peritonitis (BP) patients on PD, and especially estimate the risk factors for FP outbreak.

Methods: All episodes of FP diagnosed in our hospital from January 1, 2011, to December 31, 2020, were reviewed in this single-center study. FP cases were analyzed and compared with patients diagnosed with BP in a 1:6 ratio matching for case-control study. Patient information, including clinical information, biochemical analysis, and outcomes, was recorded. Univariate and multivariate logistic regression model were used to analyze the risk factors for FP.

Results: A total of 15 FP episodes were observed in 15 PD patients, with an FP rate of 0.0071 episodes per patient-year. Seventeen strains of fungi were isolated and identified. Candida was the most common pathogen (15 strains, 88.2%), followed by Aspergillus fumigatus (2 strains, 11.8%). Between the groups, FP group showed a higher rate of HD transfer and catheter removal, and a lower rate of PD resumption in the short-term outcome (all P < 0.01), while no significant difference in the mortality was noted during the whole study period. The multivariate logistic regression analysis showed that longer PD duration (odds ratio [OR] 1.042, 95% confidence interval [CI] 1.012–1.073, P < 0.01), higher serum potassium (OR 3.373, 95% CI 1.068–10.649, P < 0.05), elevated estimated glomerular filtration rate (eGFR) (OR 1.845, 95% CI 1.151–2.955, P < 0.05), reduced serum albumin level (OR 0.820, 95% CI 0.695–0.968, P < 0.05) and peritoneal effluent polymorphonuclear (PMN) count (OR 0.940, 95%CI 0.900–0.981, P < 0.01) were significantly increased the risk for FP.

Conclusion: These results suggested that FP leads to higher rate of catheter removal and HD transfer, and a lower rate of PD resumption than BP, and that additional attention should be paid to hypoalbuminemia, increased serum potassium, long PD duration, and low peritoneal effluent PMN in PD patients.
COVID-19 Post-acute Sequelae Among Adults: 12 Month Mortality Risk
Authors: Mainous Arch G. , Rooks Benjamin J. , Wu Velyn , Orlando Frank A.
Published: December 2021

Background: There are concerns regarding post-acute sequelae of COVID-19, but it is unclear whether COVID-19 poses a significant downstream mortality risk. The objective was to determine the relationship between COVID-19 infection and 12-month mortality after recovery from the initial episode of COVID-19 in adult patients.

Methods: An analysis of electronic health records (EHR) was performed for a cohort of 13,638 patients, including COVID-19 positive and a comparison group of COVID-19 negative patients, who were followed for 12 months post COVID-19 episode at one health system. Both COVID-19 positive patients and COVID-19 negative patients were PCR validated. COVID-19 positive patients were classified as severe if they were hospitalized within the first 30 days of the date of their initial positive test. The 12-month risk of mortality was assessed in unadjusted Cox regressions and those adjusted for age, sex, race and comorbidities. Separate subgroup analyses were conducted for (a) patients aged 65 and older and (b) those <65 years.

Results: Of the 13,638 patients included in this cohort, 178 had severe COVID-19, 246 had mild/moderate COVID-19, and 13,214 were COVID-19 negative. In the cohort, 2,686 died in the 12-month period. The 12-month adjusted all-cause mortality risk was significantly higher for patients with severe COVID-19 compared to both COVID-19 negative patients (HR 2.50; 95% CI 2.02, 3.09) and mild COVID-19 patients (HR 1.87; 95% CI 1.28, 2.74). The vast majority of deaths (79.5%) were for causes other than respiratory or cardiovascular conditions. Among patients aged <65 years, the pattern was similar but the mortality risk for patients with severe COVID-19 was increased compared to both COVID-19 negative patients (HR 3.33; 95% CI 2.35, 4.73) and mild COVID-19 patients (HR 2.83; 95% CI 1.59, 5.04). Patients aged 65 and older with severe COVID-19 were also at increased 12-month mortality risk compared to COVID-19 negative patients (HR 2.17; 95% CI 1.66, 2.84) but not mild COVID-19 patients (HR 1.41; 95% CI 0.84, 2.34).

Discussion: Patients with a COVID-19 hospitalization were at significantly increased risk for future mortality. In a time when nearly all COVID-19 hospitalizations are preventable this study points to an important and under-investigated sequela of COVID-19 and the corresponding need for prevention.
Combined 5-Fluorouracil and Low Molecular Weight Heparin for the Prevention of Postoperative Proliferative Vitreoretinopathy in Patients With Retinal Detachment: A Meta-Analysis
Authors: Chen Chen , Chen Peng , Liu Xia , Li Hua
Published: December 2021

Background: Postoperative proliferative vitreoretinopathy (PVR) remains a dilemma for retinal surgeons. We performed a literature search and meta-analyses to figure out whether combined 5-fluorouracil (5-FU) and low molecular weight heparin (LMWH) treatment were effective in improving the primary success of vitrectomy and preventing postoperative PVR occurrence in patients with retinal detachment (RD).

Methods: Databases including PubMed, Embase, the Cochrane library, and China National Knowledge Infrastructure (CNKI) were searched from inception to May 2021. Comparative studies approaching the effects of combined 5-FU and LMWH on postoperative PVR were included. Quality assessment was performed using RoB 2 and ROBINS-I tool. Study data were pooled using Review manager 5.4.1. The main outcomes were: the primary success of vitrectomy at 6 months and the postoperative PVR occurrence. The additional outcomes were: number of patients who underwent vitreoretinal reoperations and the number of vitreoretinal reoperations due to postoperative PVR. Subgroup analyses and sensitivity analyses were also performed.

Results: Six clinical trials with a total of 1,208 participants were included. We found that combined 5-FU and LMWH infusion did not improve the primary success of vitrectomy at 6 months (RR = 1.00, 95% CI = 0.95, 1.07, P = 0.89, I2 = 50%). Also, the conjunct therapy had no effect on reducing the number of patients who underwent vitreoretinal reoperations (RR = 1.00, 95% CI = 0.78, 1.28, P = 1.00, I2 = 42%). The overall effect of the treatment on preventing postoperative PVR was negative. However, in patients with PVR grade C (PVRC) before intervention, the 5-FU and LMWH treatment significantly reduced PVR occurrence. Visual acuity was not different between the treatment and control groups. Nevertheless, in one RCT, a significant reduction of VA was observed in the treatment group in macular-sparing patients with RD. No complications were attributed to the conjunct therapy.

Conclusions: The combined 5-FU and LMWH treatment neither improved the primary success of vitrectomy at 6 months nor decreased number of patients who underwent vitreoretinal reoperations. Thus, the treatment should not be routinely used in vitrectomy for patients with RD. However, the treatment proved beneficial in reducing postoperative PVR in patients with PVRC before intervention. More high-quality clinical trials are needed to confirm the results.

Systematic Review Registration:https://inplasy.com/inplasy-2021-8-0117/, identifier: INPLASY202180117.
A Natural Antimicrobial Agent: Analysis of Antibacterial Effect and Mechanism of Compound Phenolic Acid on Escherichia coli Based on Tandem Mass Tag Proteomics
Authors: Zhang Geyin , Yang Yunqiao , Memon Fareed Uddin , Hao Kaiyuan , Xu Baichang , Wang Shuaiyang , Wang Ying , Wu Enyun , Chen Xiaogang , Xiong Wenguang , Si Hongbin
Published: December 2021

The objective of this study was to evaluate the antibacterial mechanisms of phenolic acids as natural approaches against multi-drug resistant Escherichia coli (E. coli). For that purpose, five phenolic acids were combined with each other and 31 combinations were obtained in total. To select the most potent and effective combination, all of the obtained combinations were examined for minimum inhibitory concentration (MIC) and it was found that the compound phenolic acid (CPA) 19 (protocatechuic acid, hydrocinnamic acid, and chlorogenic acid at concentrations of 0.833, 0.208, and 1.677 mg/mL, respectively) showed better efficacy against E. coli compared to other combinations. Furthermore, based on tandem mass tag (TMT) proteomics, the treatment of CPA 19 significantly downregulated the proteins associated with resistance (Tsr, Tar, CheA, and CheW), OmpF, and FliC of multidrug-resistant E. coli. At the same time, we proved that CPA 19 improves the sensitivity of E. coli to antibiotics (ceftriaxone sodium, amoxicillin, fosfomycin, sulfamonomethoxine, gatifloxacin, lincomycin, florfenicol, cefotaxime sodium, and rifampicin), causes the flagellum to fall off, breaks the structure of the cell wall and cell membrane, and leads to macromolecules leaks from the cell. This evidence elaborated the potential therapeutic efficacy of CPA 19 and provided a significant contribution to the discovery of antibacterial agents.
Potential Use of CRISPR/Cas13 Machinery in Understanding Virus–Host Interaction
Authors: Bayoumi Mahmoud , Munir Muhammad
Published: December 2021

Prokaryotes have evolutionarily acquired an immune system to fend off invading mobile genetic elements, including viral phages and plasmids. Through recognizing specific sequences of the invading nucleic acid, prokaryotes mediate a subsequent degradation process collectively referred to as the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)–CRISPR-associated (Cas) (CRISPR–Cas) system. The CRISPR–Cas systems are divided into two main classes depending on the structure of the effector Cas proteins. Class I systems have effector modules consisting of multiple proteins, while class II systems have a single multidomain effector. Additionally, the CRISPR–Cas systems can also be categorized into types depending on the spacer acquisition components and their evolutionary features, namely, types I–VI. Among CRISPR/Cas systems, Cas9 is one of the most common multidomain nucleases that identify, degrade, and modulate DNA. Importantly, variants of Cas proteins have recently been found to target RNA, especially the single-effector Cas13 nucleases. The Cas13 has revolutionized our ability to study and perturb RNAs in endogenous microenvironments. The Cas13 effectors offer an excellent candidate for developing novel research tools in virological and biotechnological fields. Herein, in this review, we aim to provide a comprehensive summary of the recent advances of Cas13s for targeting viral RNA for either RNA-mediated degradation or CRISPR–Cas13-based diagnostics. Additionally, we aim to provide an overview of the proposed applications that could revolutionize our understanding of viral–host interactions using Cas13-mediated approaches.
Finafloxacin, a Novel Fluoroquinolone, Reduces the Clinical Signs of Infection and Pathology in a Mouse Model of Q Fever
Authors: Hartley M. Gill , Norville Isobel H. , Richards Mark I. , Barnes Kay B. , Bewley Kevin R. , Vipond Julia , Rayner Emma , Vente Andreas , Armstrong Stuart J. , Harding Sarah V.
Published: December 2021

Finafloxacin is a novel fluoroquinolone with optimal antibacterial activity in low pH environments, therefore offering a therapeutic advantage over some traditional antibiotics, in treating bacterial infections associated with acidic foci. Coxiella burnetii, the causative agent of Q fever, is a bacterium which resides and replicates in acidic intracellular parasitic vacuoles. The efficacy of finafloxacin was evaluated in vivo using the A/J mouse model of inhalational Q fever and was compared to doxycycline, the standard treatment for this infection and ciprofloxacin, a comparator fluoroquinolone. Finafloxacin reduced the severity of the clinical signs of infection and weight loss associated with Q fever, but did not reduce the level of bacterial colonization in tissues compared to doxycycline or ciprofloxacin. However, histopathological analysis suggested that treatment with finafloxacin reduced tissue damage associated with C. burnetii infection. In addition, we report for the first time, the use of viable counts on axenic media to evaluate antibiotic efficacy in vivo.
Sub-Inhibitory Concentrations of Chlorhexidine Induce Resistance to Chlorhexidine and Decrease Antibiotic Susceptibility in Neisseria gonorrhoeae
Authors: Laumen Jolein G. E. , Van Dijck Christophe , Manoharan-Basil Sheeba S. , Abdellati Saïd , De Baetselier Irith , Cuylaerts Vicky , De Block Tessa , Van den Bossche Dorien , Xavier Basil B. , Malhotra-Kumar Surbhi , Kenyon Chris
Published: December 2021

Objectives: Chlorhexidine digluconate (chlorhexidine) and Listerine® mouthwashes are being promoted as alternative treatment options to prevent the emergence of antimicrobial resistance in Neisseria gonorrhoeae. We performed in vitro challenge experiments to assess induction and evolution of resistance to these two mouthwashes and potential cross-resistance to other antimicrobials.

Methods: A customized morbidostat was used to subject N. gonorrhoeae reference strain WHO-F to dynamically sustained Listerine® or chlorhexidine pressure for 18 days and 40 days, respectively. Cultures were sampled twice a week and minimal inhibitory concentrations (MICs) of Listerine®, chlorhexidine, ceftriaxone, ciprofloxacin, cefixime and azithromycin were determined using the agar dilution method. Isolates with an increased MIC for Listerine® or chlorhexidine were subjected to whole genome sequencing to track the evolution of resistance.

Results: We were unable to increase MICs for Listerine®. Three out of five cultures developed a 10-fold increase in chlorhexidine MIC within 40 days compared to baseline (from 2 to 20 mg/L). Increases in chlorhexidine MIC were positively associated with increases in the MICs of azithromycin and ciprofloxacin. Low-to-higher-level chlorhexidine resistance (2–20 mg/L) was associated with mutations in NorM. Higher-level resistance (20 mg/L) was temporally associated with mutations upstream of the MtrCDE efflux pump repressor (mtrR) and the mlaA gene, part of the maintenance of lipid asymmetry (Mla) system.

Conclusion: Exposure to sub-lethal chlorhexidine concentrations may not only enhance resistance to chlorhexidine itself but also cross-resistance to other antibiotics in N. gonorrhoeae. This raises concern regarding the widespread use of chlorhexidine as an oral antiseptic, for example in the field of dentistry.
Modified Models for Predicting Malignancy Using Ultrasound Characters Have High Accuracy in Thyroid Nodules With Small Size
Authors: Jiang Shan , Xie Qingji , Li Nan , Chen Haizhen , Chen Xi
Published: December 2021

To assess the malignancy risk of thyroid nodules, ten ultrasound characteristics are suggested as key diagnostic markers. The European Thyroid Association Guidelines (EU-TIRADS) and 2015 American Thyroid Association Management Guidelines (2015ATA) are mainly used for ultrasound malignancy risk stratification, but both are less accurate and do not appropriatetly classify high risk patients in clinical examination. Previous studies focus on papillary thyroid carcinoma (PTC), but follicular thyroid carcinoma (FTC) and medullary thyroid carcinoma (MTC) remained to be characterized. Thus, this study aimed to determine the diagnostic accuracy and establish models using all ultrasound features including the nodule size for predicting the malignancy of thyroid nodules (PTC, FTC, and MTC) in China. We applied logistic regression to the data of 1,500 patients who received medical treatment in Shanghai and Fujian. Ultrasound features including taller-than-wide shape and invasion of the thyroid capsule showed high odds ratio (OR 19.329 and 4.672) for PTC in this dataset. Invasion of the thyroid also showed the highest odds ratio (OR = 8.10) for MTC. For FTC, the halo sign has the highest odds ratio (OR = 13.40). Four ultrasound features revealed distinct OR in PTC nodule groups with different sizes. In this study, we constructed a logistic model with accuracy up to 80%. In addition, this model revealed more accuracy than TIRADS in 4b and 4c category nodules. Hence, this model could well predict malignancy in small nodules and classify high-risk patients.
Scatterometry Measurements With Scattered Light Imaging Enable New Insights Into the Nerve Fiber Architecture of the Brain
Authors: Menzel Miriam , Ritzkowski Marouan , Reuter Jan A. , Gräßel David , Amunts Katrin , Axer Markus
Published: December 2021

The correct reconstruction of individual (crossing) nerve fibers is a prerequisite when constructing a detailed network model of the brain. The recently developed technique Scattered Light Imaging (SLI) allows the reconstruction of crossing nerve fiber pathways in whole brain tissue samples with micrometer resolution: the individual fiber orientations are determined by illuminating unstained histological brain sections from different directions, measuring the transmitted scattered light under normal incidence, and studying the light intensity profiles of each pixel in the resulting image series. So far, SLI measurements were performed with a fixed polar angle of illumination and a small number of illumination directions, providing only an estimate of the nerve fiber directions and limited information about the underlying tissue structure. Here, we use a display with individually controllable light-emitting diodes to measure the full distribution of scattered light behind the sample (scattering pattern) for each image pixel at once, enabling scatterometry measurements of whole brain tissue samples. We compare our results to coherent Fourier scatterometry (raster-scanning the sample with a non-focused laser beam) and previous SLI measurements with fixed polar angle of illumination, using sections from a vervet monkey brain and human optic tracts. Finally, we present SLI scatterometry measurements of a human brain section with 3 μm in-plane resolution, demonstrating that the technique is a powerful approach to gain new insights into the nerve fiber architecture of the human brain.
Corticotropin Releasing Factor Binding Protein as a Novel Target to Restore Brain Homeostasis: Lessons Learned From Alcohol Use Disorder Research
Authors: Curley Dallece E. , Webb Ashley E. , Sheffler Douglas J. , Haass-Koffler Carolina L.
Published: December 2021

Stress is well-known to contribute to the development of many psychiatric illnesses including alcohol and substance use disorder (AUD and SUD). The deleterious effects of stress have also been implicated in the acceleration of biological age, and age-related neurodegenerative disease. The physio-pathology of stress is regulated by the corticotropin-releasing factor (CRF) system, the upstream component of the hypothalamic-pituitary-adrenal (HPA) axis. Extensive literature has shown that dysregulation of the CRF neuroendocrine system contributes to escalation of alcohol consumption and, similarly, chronic alcohol consumption contributes to disruption of the stress system. The CRF system also represents the central switchboard for regulating homeostasis, and more recent studies have found that stress and aberrations in the CRF pathway are implicated in accelerated aging and age-related neurodegenerative disease. Corticotropin releasing factor binding protein (CRFBP) is a secreted glycoprotein distributed in peripheral tissues and in specific brain regions. It neutralizes the effects of CRF by sequestering free CRF, but may also possess excitatory function by interacting with CRF receptors. CRFBP’s dual role in influencing CRF bioavailability and CRF receptor signaling has been shown to have a major part in the HPA axis response. Therefore, CRFBP may represent a valuable target to treat stress-related illness, including: development of novel medications to treat AUD and restore homeostasis in the aging brain. This narrative review focuses on molecular mechanisms related to the role of CRFBP in the progression of addictive and psychiatric disorders, biological aging, and age-related neurodegenerative disease. We provide an overview of recent studies investigating modulation of this pathway as a potential therapeutic target for AUD and age-related neurodegenerative disease.
Short Circuit Recognition for Metal Electrorefining Using an Improved Faster R-CNN With Synthetic Infrared Images
Authors: Li Xin , Li Yonggang , Wu Renchao , Zhou Can , Zhu Hongqiu
Published: December 2021

This paper is concerned with the problem of short circuit detection in infrared image for metal electrorefining with an improved Faster Region-based Convolutional Neural Network (Faster R-CNN). To address the problem of insufficient label data, a framework for automatically generating labeled infrared images is proposed. After discussing factors that affect sample diversity, background, object shape, and gray scale distribution are established as three key variables for synthesis. Raw infrared images without fault are used as backgrounds. By simulating the other two key variables on the background, different classes of objects are synthesized. To improve the detection rate of small scale targets, an attention module is introduced in the network to fuse the semantic segment results of U-Net and the synthetic dataset. In this way, the Faster R-CNN can obtain rich representation ability about small scale object on the infrared images. Strategies of parameter tuning and transfer learning are also applied to improve the detection precision. The detection system trains on only synthetic dataset and tests on actual images. Extensive experiments on different infrared datasets demonstrate the effectiveness of the synthetic methods. The synthetically trained network obtains a mAP of 0.826, and the recall rate of small latent short circuit is superior to that of Faster R-CNN and U-Net, effectively avoiding short-circuit missed detection.
The Selective Loss of Purkinje Cells Induces Specific Peripheral Immune Alterations
Authors: del Pilar Carlos , Lebrón-Galán Rafael , Pérez-Martín Ester , Pérez-Revuelta Laura , Ávila-Zarza Carmelo Antonio , Alonso José Ramón , Clemente Diego , Weruaga Eduardo , Díaz David
Published: December 2021

The progression of neurodegenerative diseases is reciprocally associated with impairments in peripheral immune responses. We investigated different contexts of selective neurodegeneration to identify specific alterations of peripheral immune cells and, at the same time, discover potential biomarkers associated to this pathological condition. Consequently, a model of human cerebellar degeneration and ataxia -the Purkinje Cell Degeneration (PCD) mouse- has been employed, as it allows the study of different processes of selective neuronal death in the same animal, i.e., Purkinje cells in the cerebellum and mitral cells in the olfactory bulb. Infiltrated leukocytes were studied in both brain areas and compared with those from other standardized neuroinflammatory models obtained by administering either gamma radiation or lipopolysaccharide. Moreover, both myeloid and lymphoid splenic populations were analyzed by flow cytometry, focusing on markers of functional maturity and antigen presentation. The severity and type of neural damage and inflammation affected immune cell infiltration. Leukocytes were more numerous in the cerebellum of PCD mice, being located predominantly within those cerebellar layers mostly affected by neurodegeneration, in a completely different manner than the typical models of induced neuroinflammation. Furthermore, the milder degeneration of the olfactory bulb did not foster leukocyte attraction. Concerning the splenic analysis, in PCD mice we found: (1) a decreased percentage of several myeloid cell subsets, and (2) a reduced mean fluorescence intensity in those myeloid markers related to both antigen presentation and functional maturity. In conclusion, the selective degeneration of Purkinje cells triggers a specific effect on peripheral immune cells, fostering both attraction and functional changes. This fact endorses the employment of peripheral immune cell populations as concrete biomarkers for monitoring different neuronal death processes.
Innovative Therapeutic Approaches for Huntington’s Disease: From Nucleic Acids to GPCR-Targeting Small Molecules
Authors: Komatsu Hidetoshi
Published: December 2021

Huntington’s disease (HD) is a fatal neurodegenerative disorder due to an extraordinarily expanded CAG repeat in the huntingtin gene that confers a gain-of-toxic function in the mutant protein. There is currently no effective cure that attenuates progression and severity of the disease. Since HD is an inherited monogenic disorder, lowering the mutant huntingtin (mHTT) represents a promising therapeutic strategy. Huntingtin lowering strategies mostly focus on nucleic acid approaches, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). While these approaches seem to be effective, the drug delivery to the brain poses a great challenge and requires direct injection into the central nervous system (CNS) that results in substantial burden for patients. This review discusses the topics on Huntingtin lowering strategies with clinical trials in patients already underway and introduce an innovative approach that has the potential to deter the disease progression through the inhibition of GPR52, a striatal-enriched class A orphan G protein-coupled receptor (GPCR) that represents a promising therapeutic target for psychiatric disorders. Chemically simple, potent, and selective GPR52 antagonists have been discovered through high-throughput screening and subsequent structure-activity relationship studies. These small molecule antagonists not only diminish both soluble and aggregated mHTT in the striatum, but also ameliorate HD-like defects in HD mice. This therapeutic approach offers great promise as a novel strategy for HD therapy, while nucleic acid delivery still faces considerable challenges.
Oxidized Albumin and Cartilage Acidic Protein-1 as Blood Biomarkers to Predict Ischemic Stroke Outcomes
Authors: Kuwashiro Takahiro , Tanabe Kazuhiro , Hayashi Chihiro , Mizoguchi Tadataka , Mori Kota , Jinnouchi Juro , Yasaka Masahiro , Okada Yasushi
Published: December 2021

Background:There is high demand for blood biomarkers that reflect the therapeutic response or predict the outcomes of patients with acute ischemic stroke (AIS); however, few biomarkers have been evidentially verified to date. This study evaluated two proteins, oxidized albumin (OxHSA) and cartilage acidic protein-1 (CRTAC1), as potential prognostic markers of AIS.

Methods:The ratio of OxHSA to normal albumin (%OxHSA) and the level of CRTAC1 in the sera of 74 AIS patients were analyzed on admission (day 0), and at 1 and 7 days after admission. AIS patients were divided into two groups according to their modified Rankin Scale (mRS) at 3 months after discharge: the low-mRS (mRS < 2) group included 48 patients and the high-mRS (mRS ≥ 2) group included 26 patients. The differences in %OxHSA and CRTAC1 between the two groups on days 0, 1, and 7 were evaluated.

Results:The mean %OxHSA values of the high-mRS group on days 0, 1, and 7 were significantly higher than those of the low-mRS group (p< 0.05). The CRTAC1 levels continuously increased from day 0 to day 7, and those of the high-mRS group were significantly higher than those of the low-mRS group on day 7 (p< 0.05).

Conclusions:These results suggest that higher %OxHSA and CRTAC1 are associated with poor outcomes in AIS patients. An index that combines %OxHSA and CRTAC1 can accurately predict the outcomes of AIS patients.
Predictive Factors for the Need of Tracheostomy in Patients With Large Vessel Occlusion Stroke Being Treated With Mechanical Thrombectomy
Authors: Maier Ilko L. , Schramm Katarina , Bähr Mathias , Behme Daniel , Psychogios Marios-Nikos , Liman Jan
Published: December 2021

Background: Patients with large vessel occlusion stroke (LVOS) eligible for mechanical thrombectomy (MT) are at risk for stroke- and non-stroke-related complications resulting in the need for tracheostomy (TS). Risk factors for TS have not yet been systematically investigated in this subgroup of stroke patients.

Methods: Prospectively derived data from patients with LVOS and MT being treated in a large, academic neurological ICU (neuro-ICU) between 2014 and 2019 were analyzed in this single-center study. Predictive value of peri- and post-interventional factors, stroke imaging, and pre-stroke medical history were investigated for their potential to predict tracheostomy during ICU stay using logistic regression models.

Results: From 635 LVOS-patients treated with MT, 40 (6.3%) underwent tracheostomy during their neuro-ICU stay. Patients receiving tracheostomy were younger [71 (62–75) vs. 77 (66–83), p < 0.001], had a higher National Institute of Health Stroke Scale (NIHSS) at baseline [18 (15–20) vs. 15 (10–19), p = 0.009] as well as higher rates of hospital acquired pneumonia (HAP) [39 (97.5%) vs. 224 (37.6%), p < 0.001], failed extubation [15 (37.5%) vs. 19 (3.2%), p < 0.001], sepsis [11 (27.5%) vs. 16 (2.7%), p < 0.001], symptomatic intracerebral hemorrhage [5 (12.5%) vs. 22 (3.9%), p = 0.026] and decompressive hemicraniectomy (DH) [19 (51.4%) vs. 21 (3.8%), p < 0.001]. In multivariate logistic regression analysis, HAP (OR 21.26 (CI 2.76–163.56), p = 0.003], Sepsis [OR 5.39 (1.71–16.91), p = 0.004], failed extubation [OR 8.41 (3.09–22.93), p < 0.001] and DH [OR 9.94 (3.92–25.21), p < 0.001] remained as strongest predictors for TS. Patients with longer periods from admission to TS had longer ICU length of stay (r = 0.384, p = 0.03). There was no association between the time from admission to TS and clinical outcome (NIHSS at discharge: r = 0.125, p = 0.461; mRS at 90 days: r = −0.179, p = 0.403).

Conclusions: Patients with LVOS undergoing MT are at high risk to require TS if extubation after the intervention fails, DH is needed, and severe infectious complications occur in the acute phase after ischemic stroke. These factors are likely to be useful for the indication and timing of TS to reduce overall sedation and shorten ICU length of stay.
Motor and Non-motor Symptoms Associated With Exercise Behavior in Parkinson's Disease Patients: Factors Differ Between Patients With and Without Postural Instability
Authors: Song Joomee , Youn Jinyoung , Huh Young Eun , Mun Jun Kyu , Ahn Jong Hyeon , Lee Dongyeong , Shin Woo Young , Cho Jin Whan
Published: December 2021

Background: Exercise is an important treatment for Parkinson's disease (PD). Therefore, recognizing determinants of exercise behavior for PD based on disease stage is essential. We sought to find whether the determinants differ based on presence of postural instability (PI), which is indicative of disease stage in PD.

Methods: We enrolled patients at Samsung Medical Center from September 2019 to November 2020, who had the ability to perform exercise [modified Hoehn and Yahr (HY) stage ≤ 3]. All the motor and non-motor symptoms were investigated. The exercise of the PD patients was evaluated using the Physical Activity Scale of the Elderly (PASE)-leisure score. We classified patients into PD without PI (HY stage 1 – 2) and PD with PI (HY stage 2.5 – 3) groups. Multivariate linear regression was performed using backward elimination in each group to determine factors associated with PASE-leisure score.

Results: A total of 233 patients were enrolled. In the PD without PI group (n = 177), the positive determinant of exercise was Activities-Specific Balance Confidence (ABC) score (β = 0.142, p = 0.032), and the negative determinants were fatigue score (β = −0.228, p = 0.018), female (β = −6.900, p = 0.016) and currently employed status (β = −6.072, p = 0.046). In the PD with PI group (n = 56), the positive determinant was non-motor symptom scale (NMSS) score (β = 0.221, p = 0.017) and disease duration (β = 1.001, p = 0.036), while the negative determinants were UPDRS part 3 score (β = −0.974, p < 0.001), UPDRS part 4 score (β = −2.192, p = 0.002), and age (β = −1.052, p < 0.001).

Conclusion: Different motor and non-motor symptoms were associated with the exercise in PD patients with and without PI. When encouraging PD patients to exercise, personalized and different strategies should be applied based on the presence of PI.
Dissecting Motor and Cognitive Component Processes of a Finger-Tapping Task With Hybrid Dopamine Positron Emission Tomography and Functional Magnetic Resonance Imaging
Authors: Grill Filip , Johansson Jarkko , Axelsson Jan , Brynolfsson Patrik , Nyberg Lars , Rieckmann Anna
Published: December 2021

Striatal dopamine is involved in facilitation of motor action as well as various cognitive and emotional functions. Positron emission tomography (PET) is the primary imaging method used to investigate dopamine function in humans. Previous PET studies have shown striatal dopamine release during simple finger tapping in both the putamen and the caudate. It is likely that dopamine release in the putamen is related to motor processes while dopamine release in the caudate could signal sustained cognitive component processes of the task, but the poor temporal resolution of PET has hindered firm conclusions. In this study we simultaneously collected [11C]Raclopride PET and functional Magnetic Resonance Imaging (fMRI) data while participants performed finger tapping, with fMRI being able to isolate activations related to individual tapping events. The results revealed fMRI-PET overlap in the bilateral putamen, which is consistent with a motor component process. Selective PET responses in the caudate, ventral striatum, and right posterior putamen, were also observed but did not overlap with fMRI responses to tapping events, suggesting that these reflect non-motor component processes of finger tapping. Our findings suggest an interplay between motor and non-motor-related dopamine release during simple finger tapping and illustrate the potential of hybrid PET-fMRI in revealing distinct component processes of cognitive functions.
Artificial Intelligence Algorithms in Visual Evoked Potential-Based Brain-Computer Interfaces for Motor Rehabilitation Applications: Systematic Review and Future Directions
Authors: Gutierrez-Martinez Josefina , Mercado-Gutierrez Jorge A. , Carvajal-Gámez Blanca E. , Rosas-Trigueros Jorge L. , Contreras-Martinez Adrian E.
Published: December 2021

Brain-Computer Interface (BCI) is a technology that uses electroencephalographic (EEG) signals to control external devices, such as Functional Electrical Stimulation (FES). Visual BCI paradigms based on P300 and Steady State Visually Evoked potentials (SSVEP) have shown high potential for clinical purposes. Numerous studies have been published on P300- and SSVEP-based non-invasive BCIs, but many of them present two shortcomings: (1) they are not aimed for motor rehabilitation applications, and (2) they do not report in detail the artificial intelligence (AI) methods used for classification, or their performance metrics. To address this gap, in this paper the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology was applied to prepare a systematic literature review (SLR). Papers older than 10 years, repeated or not related to a motor rehabilitation application, were excluded. Of all the studies, 51.02% referred to theoretical analysis of classification algorithms. Of the remaining, 28.48% were for spelling, 12.73% for diverse applications (control of wheelchair or home appliances), and only 7.77% were focused on motor rehabilitation. After the inclusion and exclusion criteria were applied and quality screening was performed, 34 articles were selected. Of them, 26.47% used the P300 and 55.8% the SSVEP signal. Five applications categories were established: Rehabilitation Systems (17.64%), Virtual Reality environments (23.52%), FES (17.64%), Orthosis (29.41%), and Prosthesis (11.76%). Of all the works, only four performed tests with patients. The most reported machine learning (ML) algorithms used for classification were linear discriminant analysis (LDA) (48.64%) and support vector machine (16.21%), while only one study used a deep learning algorithm: a Convolutional Neural Network (CNN). The reported accuracy ranged from 38.02 to 100%, and the Information Transfer Rate from 1.55 to 49.25 bits per minute. While LDA is still the most used AI algorithm, CNN has shown promising results, but due to their high technical implementation requirements, many researchers do not justify its implementation as worthwile. To achieve quick and accurate online BCIs for motor rehabilitation applications, future works on SSVEP-, P300-based and hybrid BCIs should focus on optimizing the visual stimulation module and the training stage of ML and DL algorithms.
Cortical Activation During Finger Tapping Task Performance in Parkinson's Disease Is Influenced by Priming Conditions: An ALE Meta-Analysis
Authors: Li Jingjing , Liu Zheng , Du Zhongquan , Zhu Ningning , Qiu Xueqing , Xu Xia
Published: December 2021

The finger tapping task (FTT) is commonly used in the evaluation of dyskinesia among patients with Parkinson's disease (PD). Past research has indicated that cortical activation during FTT is different between self-priming and cue-priming conditions. To evaluate how priming conditions affect the distribution of brain activation and the reorganization of brain function, and to investigate the differences in brain activation areas during FTT between PD patients and healthy control (HC) participants, we conducted an activation likelihood estimation (ALE) meta-analysis on the existing literature. Analyses were based on data from 15 independent samples that included 181 participants with PD and 164 HC participants. We found that there was significantly more activation in the middle frontal gyrus, precentral gyrus, post-central gyrus, superior parietal lobe, inferior parietal lobule, cerebellum, and basal ganglia during FTT in PD patients than in HCs. In self-priming conditions, PD patients had less activation in the parietal lobe and insular cortex but more activation in the cerebellum than the HCs. In cue-priming conditions, the PD patients showed less activation in the cerebellum and frontal-parietal areas and more activation in the superior frontal gyrus and superior temporal gyrus than the HCs. Our study illustrates that cue-priming manipulations affect the distribution of activity in brain regions involved in motor control and motor performance in PD patients. In cue-priming conditions, brain activity in regions associated with perceptual processing and inhibitory control was enhanced, while sensory motor areas associated with attention and motor control were impaired.
A Data-Based Approach for Selecting Pre- and Intra-Operative Language Mapping Tasks
Authors: Ekert Justyna O. , Kirkman Matthew A. , Seghier Mohamed L. , Green David W. , Price Cathy J.
Published: December 2021

Background: Pre- and intra-operative language mapping in neurosurgery patients frequently involves an object naming task. The choice of the optimal object naming paradigm remains challenging due to lack of normative data and standardization in mapping practices. The aim of this study was to identify object naming paradigms that robustly and consistently activate classical language regions and could therefore be used to improve the sensitivity of language mapping in brain tumor and epilepsy patients.

Methods: Functional magnetic resonance imaging (fMRI) data from two independent groups of healthy controls (total = 79) were used to generate threshold-weighted voxel-based consistency maps. This novel approach allowed us to compare inter-subject consistency of activation for naming single objects in the visual and auditory modality and naming two objects in a phrase or a sentence.

Results: We found that the consistency of activation in language regions was greater for naming two objects per picture than one object per picture, even when controlling for the number of names produced in 5 s.

Conclusion: More consistent activation in language areas for naming two objects compared to one object suggests that two-object naming tasks may be more suitable for delimiting language eloquent regions with pre- and intra-operative language testing. More broadly, we propose that the functional specificity of brain mapping paradigms for a whole range of different linguistic and non-linguistic functions could be enhanced by referring to databased models of inter-subject consistency and variability in typical and atypical brain responses.
Microstructural Tissue Changes in a Rat Model of Mild Traumatic Brain Injury
Authors: Chary Karthik , Narvaez Omar , Salo Raimo A. , San Martín Molina Isabel , Tohka Jussi , Aggarwal Manisha , Gröhn Olli , Sierra Alejandra
Published: December 2021

Our study investigates the potential of diffusion MRI (dMRI), including diffusion tensor imaging (DTI), fixel-based analysis (FBA) and neurite orientation dispersion and density imaging (NODDI), to detect microstructural tissue abnormalities in rats after mild traumatic brain injury (mTBI). The brains of sham-operated and mTBI rats 35 days after lateral fluid percussion injury were imaged ex vivo in a 11.7-T scanner. Voxel-based analyses of DTI-, fixel- and NODDI-based metrics detected extensive tissue changes in directly affected brain areas close to the primary injury, and more importantly, also in distal areas connected to primary injury and indirectly affected by the secondary injury mechanisms. Histology revealed ongoing axonal abnormalities and inflammation, 35 days after the injury, in the brain areas highlighted in the group analyses. Fractional anisotropy (FA), fiber density (FD) and fiber density and fiber bundle cross-section (FDC) showed similar pattern of significant areas throughout the brain; however, FA showed more significant voxels in gray matter areas, while FD and FDC in white matter areas, and orientation dispersion index (ODI) in areas most damage based on histology. Region-of-interest (ROI)-based analyses on dMRI maps and histology in selected brain regions revealed that the changes in MRI parameters could be attributed to both alterations in myelinated fiber bundles and increased cellularity. This study demonstrates that the combination of dMRI methods can provide a more complete insight into the microstructural alterations in white and gray matter after mTBI, which may aid diagnosis and prognosis following a mild brain injury.