bluuebunny/crossref_metadata_2025 huggingface dataset:
CANPT Score: A Tool to Predict Severe COVID-19 on Admission
Authors: Chen Yuanyuan , Zhou Xiaolin , Yan Huadong , Huang Huihong , Li Shengjun , Jiang Zicheng , Zhao Jun , Meng Zhongji
Published: February 2021

Background and Aims: Patients with critical coronavirus disease 2019 (COVID-19) have a mortality rate higher than 50%. The purpose of this study was to establish a model for the prediction of the risk of severe disease and/or death in patients with COVID-19 on admission.

Materials and Methods: Patients diagnosed with COVID-19 in four hospitals in China from January 22, 2020 to April 15, 2020 were retrospectively enrolled. The demographic, laboratory, and clinical data of the patients with COVID-19 were collected. The independent risk factors related to the severity of and death due to COVID-19 were identified with a multivariate logistic regression; a nomogram and prediction model were established. The area under the receiver operating characteristic curve (AUROC) and predictive accuracy were used to evaluate the model's effectiveness.

Results: In total, 582 patients with COVID-19, including 116 patients with severe disease, were enrolled. Their comorbidities, body temperature, neutrophil-to-lymphocyte ratio (NLR), platelet (PLT) count, and levels of total bilirubin (Tbil), creatinine (Cr), creatine kinase (CK), and albumin (Alb) were independent risk factors for severe disease. A nomogram was generated based on these eight variables with a predictive accuracy of 85.9% and an AUROC of 0.858 (95% CI, 0.823–0.893). Based on the nomogram, the CANPT score was established with cut-off values of 12 and 16. The percentages of patients with severe disease in the groups with CANPT scores <12, ≥12, and <16, and ≥16 were 4.15, 27.43, and 69.64%, respectively. Seventeen patients died. NLR, Cr, CK, and Alb were independent risk factors for mortality, and the CAN score was established to predict mortality. With a cut-off value of 15, the predictive accuracy was 97.4%, and the AUROC was 0.903 (95% CI 0.832, 0.974).

Conclusions: The CANPT and CAN scores can predict the risk of severe disease and mortality in COVID-19 patients on admission.
An Open Label Trial to Assess Safety of Losartan for Treating Worsening Respiratory Illness in COVID-19
Authors: Bengtson Charles D. , Montgomery Robert N. , Nazir Usman , Satterwhite Lewis , Kim Michael D. , Bahr Nathan C. , Castro Mario , Baumlin Nathalie , Salathe Matthias
Published: February 2021

Rationale: Coronavirus disease 2019 (COVID-19) can cause disruption of the renin-angiotensin system in the lungs, possibly contributing to pulmonary capillary leakage. Thus, angiotensin receptor blockers (ARBs) may improve respiratory failure.

Objective: Assess safety of losartan for use in respiratory failure related to COVID-19 (NCT04335123).

Methods: Single arm, open label trial of losartan in those hospitalized with respiratory failure related to COVID-19. Oral losartan (25 mg daily for 3 days, then 50 mg) was administered from enrollment until day 14 or hospital discharge. A post-hoc external control group with patients who met all inclusion criteria was matched 1:1 to the treatment group using propensity scores for comparison.

Measures: Primary outcome was cumulative incidence of any adverse events. Secondary, explorative endpoints included measures of respiratory failure, length of stay and vital status.

Results: Of the 34 participants enrolled in the trial, 30 completed the study with a mean age SD of 53.8 ± 17.7 years and 17 males (57%). On losartan, 24/30 (80%) experienced an adverse event as opposed to 29/30 (97%) of controls, with a lower average number of adverse events on losartan relative to control (2.2 vs. 3.3). Using Poisson regression and controlling for age, sex, race, date of enrollment, disease severity at enrollment, and history of high-risk comorbidities, the incidence rate ratio of adverse events on losartan relative to control was 0.69 (95% CI: 0.49–0.97)

Conclusions: Losartan appeared safe for COVID-19-related acute respiratory compromise. To assess true efficacy, randomized trials are needed.
Global Geographic and Temporal Analysis of SARS-CoV-2 Haplotypes Normalized by COVID-19 Cases During the Pandemic
Authors: Justo Arevalo Santiago , Zapata Sifuentes Daniela , Huallpa César J. , Landa Bianchi Gianfranco , Castillo Chávez Adriana , Garavito-Salini Casas Romina , Uceda-Campos Guillermo , Pineda Chavarria Roberto
Published: February 2021

Since the identification of SARS-CoV-2, a large number of genomes have been sequenced with unprecedented speed around the world. This marks a unique opportunity to analyze virus spreading and evolution in a worldwide context. Currently, there is not a useful haplotype description to help to track important and globally scattered mutations. Also, differences in the number of sequenced genomes between countries and/or months make it difficult to identify the emergence of haplotypes in regions where few genomes are sequenced but a large number of cases are reported. We propose an approach based on the normalization by COVID-19 cases of relative frequencies of mutations using all the available data to identify major haplotypes. Furthermore, we can use a similar normalization approach to tracking the temporal and geographic distribution of haplotypes in the world. Using 171,461 genomes, we identify five major haplotypes or operational taxonomic units (OTUs) based on nine high-frequency mutations. OTU_3 characterized by mutations R203K and G204R is currently the most frequent haplotype circulating in four of the six continents analyzed (South America, North America, Europe, Asia, Africa, and Oceania). On the other hand, during almost all months analyzed, OTU_5 characterized by the mutation T85I in nsp2 is the most frequent in North America. Recently (since September), OTU_2 has been established as the most frequent in Europe. OTU_1, the ancestor haplotype, is near to extinction showed by its low number of isolations since May. Also, we analyzed whether age, gender, or patient status is more related to a specific OTU. We did not find OTU’s preference for any age group, gender, or patient status. Finally, we discuss structural and functional hypotheses in the most frequently identified mutations, none of those mutations show a clear effect on the transmissibility or pathogenicity.
Establishment and Application of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry for Detection of Shewanella Genus
Authors: Yu Keyi , Huang Zhenzhou , Li Ying , Fu Qingbo , Lin Lirong , Wu Shiyao , Dai Hang , Cai Hongyan , Xiao Yue , Lan Ruiting , Wang Duochun
Published: February 2021

Shewanella species are widely distributed in the aquatic environment and aquatic organisms. They are opportunistic human pathogens with increasing clinical infections reported in recent years. However, there is a lack of a rapid and accurate method to identify Shewanella species. We evaluated here matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for rapid identification of Shewanella. A peptide mass reference spectra (PMRS) database was constructed for the type strains of 36 Shewanella species. The main spectrum projection (MSP) cluster dendrogram showed that the type strains of Shewanella species can be effectively distinguished according to the different MS fingerprinting. The PMRS database was validated using 125 Shewanella test strains isolated from various sources and periods; 92.8% (n = 116) of the strains were correctly identified at the species level, compared with the results of multilocus sequence analysis (MLSA), which was previously shown to be a method for identifying Shewanella at the species level. The misidentified strains (n = 9) by MALDI-TOF MS involved five species of two groups, i.e., Shewanella algae–Shewanella chilikensis–Shewanella indica and Shewanella seohaensis–Shewanella xiamenensis. We then identified and defined species-specific biomarker peaks of the 36 species using the type strains and validated these selected biomarkers using 125 test strains. Our study demonstrated that MALDI-TOF MS was a reliable and powerful tool for the rapid identification of Shewanella strains at the species level.
Role of the Type VI Secretion System in the Pathogenicity of Pseudomonas syringae pv. actinidiae, the Causative Agent of Kiwifruit Bacterial Canker
Authors: Wang Nana , Han Ning , Tian Runze , Chen Jiliang , Gao Xiaoning , Wu Zhiran , Liu Yuqi , Huang Lili
Published: February 2021

The type VI secretion system (T6SS), a macromolecular machine, plays an important role in the pathogenicity of many Gram-negative bacteria. However, the role of T6SS in the pathogenicity of Pseudomonas syringae pv. actinidiae (Psa), the pathogen of kiwifruit bacterial canker, is yet to be studied. Here, we found a T6SS gene cluster consisting of 13 core genes (A-J) in the genome of Psa M228 based on a genome-wide analysis. To determine whether the T6SS gene cluster affects the pathogenicity of Psa M228, T6SS and its 13 core gene deletion mutants were constructed and their pathogenicity was determined. The deletion mutants showed different degrees of reduction in pathogenicity compared with the wild-type strain M228; in tssM and tssJ mutants, pathogenicity was significantly reduced by 78.7 and 71.3%, respectively. The pathogenicity results were also confirmed by electron microscopy. To further confirm that the reduction in pathogenicity is related to the function of T6SS, we selected the T6SS gene cluster, comprising tssM and tssJ, for further analyses. Western blot results revealed that tssM and tssJ were necessary for hemolytic co-regulatory protein secretion, indicating that they encode a functional T6SS. Further, we explored the mechanism by which T6SS affects the pathogenicity of Psa M228. The ability of bacterial competition, biofilm formation, hydrogen peroxide tolerance, and proteolytic activity were all weakened in the deletion mutants M228ΔT6SS, M228ΔtssM, and M228ΔtssJ. All these properties of the two gene complementation mutants were restored to the same levels as those of the wild-type strain, M228. Quantitative real-time results showed that during the interaction between the deletion mutant M228ΔT6SS and the host, expression levels of T3SS transcriptional regulatory gene hrpR, structural genes hrpZ, hrcC, hopP1, and effector genes hopH1 and hopM1 were down-regulated at different levels. Taken together, our data provide evidence for the first time that the T6SS plays an important role in the pathogenicity of Psa, probably via effects on bacterial competition, biofilm formation, and environmental adaptability. Moreover, a complicated relationship exists between T6SS and T3SS.
Approaches to Investigate Selective Dietary Polysaccharide Utilization by Human Gut Microbiota at a Functional Level
Authors: Klassen Leeann , Xing Xiaohui , Tingley Jeffrey P. , Low Kristin E. , King Marissa L. , Reintjes Greta , Abbott D. Wade
Published: February 2021

The human diet is temporally and spatially dynamic, and influenced by culture, regional food systems, socioeconomics, and consumer preference. Such factors result in enormous structural diversity of ingested glycans that are refractory to digestion by human enzymes. To convert these glycans into metabolizable nutrients and energy, humans rely upon the catalytic potential encoded within the gut microbiome, a rich collective of microorganisms residing in the gastrointestinal tract. The development of high-throughput sequencing methods has enabled microbial communities to be studied with more coverage and depth, and as a result, cataloging the taxonomic structure of the gut microbiome has become routine. Efforts to unravel the microbial processes governing glycan digestion by the gut microbiome, however, are still in their infancy and will benefit by retooling our approaches to study glycan structure at high resolution and adopting next-generation functional methods. Also, new bioinformatic tools specialized for annotating carbohydrate-active enzymes and predicting their functions with high accuracy will be required for deciphering the catalytic potential of sequence datasets. Furthermore, physiological approaches to enable genotype-phenotype assignments within the gut microbiome, such as fluorescent polysaccharides, has enabled rapid identification of carbohydrate interactions at the single cell level. In this review, we summarize the current state-of-knowledge of these methods and discuss how their continued development will advance our understanding of gut microbiome function.
Proteomic Analysis of Caspofungin-Induced Responses in Planktonic Cells and Biofilms of Candida albicans
Authors: Li Peng , Seneviratne Chaminda J. , Luan Qingxian , Jin Lijian
Published: February 2021

Candida albicans biofilms display markedly increased antifungal resistance, and the underlying mechanisms remain unclear. This study investigated the signature profiles of C. albicans planktonic cells and biofilms in response to caspofungin (CAS) by mass spectrometry-based shotgun proteomics. We found that C. albicans biofilms were twofold more resistant to CAS with reference to planktonic cells. Notably, 9.6% of C. albicans biofilm cells survived the lethal treatment of CAS (128 μg/ml), confirmed by LIVE/DEAD staining, confocal laser scanning microscopy (CLSM) and scanning electron microscopy analyses. The responses of C. albicans planktonic cells and biofilms to CAS treatment at respective minimum inhibitory concentrations (MICs) were assessed by high-throughput proteomics and bioinformatics approaches. There were 148 and 224 proteins with >twofold difference identified from the planktonic cells and biofilms, respectively. CAS treatment downregulated several cell wall- and oxidative stress-related proteins. Whereas, CAS-induced action was compensated by markedly increased expression of many other proteins involved in cell wall integrity and stress response (e.g., heat shock proteins). Moreover, considerable expression changes were identified in metabolism-associated proteins like glycolysis, tricarboxylic acid (TCA) cycle and ATP biosynthesis. Importantly, various key proteins for cell wall integrity, stress response and metabolic regulation (e.g., PIL1, LSP1, HSP90, ICL1, and MLS1) were exclusively enriched and implicated in C. albicans biofilms. This study demonstrates that C. albicans biofilms undergo highly complicated yet complex regulation of multiple cellular pathways in response to CAS. Signature proteins essential for modulating cell wall integrity, stress response and metabolic activities may account for the antifungal resistance of C. albicans biofilms.
Modeling Bacillus cereus Growth and Cereulide Formation in Cereal-, Dairy-, Meat-, Vegetable-Based Food and Culture Medium
Authors: Ellouze Mariem , Buss Da Silva Nathália , Rouzeau-Szynalski Katia , Coisne Laura , Cantergiani Frédérique , Baranyi József
Published: February 2021

This study describes the simultaneousBacillus cereusgrowth and cereulide formation, in culture medium and cereal-, dairy-, meat-, and vegetable-based food matrices. First, bacterial growth experiments were carried out under a wide range of temperatures (from 9 to 45°C), using the emetic reference strain F4810/72, in the above-mentioned matrices. Then, the generated data were put in a modeling framework where the response variable was a vector of two components: the concentration ofB. cereusand that of its toxin, cereulide. Both were considered time-, temperature- and matrix-dependent. The modeling was carried out in a series of steps: the parameters fitted in one step became the response variable of the following step. Using the square root link function, the maximum specific growth rate of the organism and the time to the appearance of quantifiable cereulide were modeled against temperature by cardinal parameters models (CPM), for each matrix. Finally, a validation study was carried out on an independent data set obtained in the same matrices and using variousBacillus cereusstrains. Results showed that both growth and toxin-formation depended on the food matrix and on the environment but not in the same way. Thus, the matrix (culture medium), where the highest growth rate ofB. cereuswas observed, was not the medium where the shortest time to quantifiable cereulide occurred. While the cereal-based matrix generated the smallest growth rates (0.41-times smaller than culture medium did), quantifiable cereulide appeared in it at earlier times compared to the other tested matrices. In fact, three groups of matrices could be distinguished based on their ability to support cereulide formation (1) the cereal-based matrix (highest), (2) the culture medium and the dairy-based matrix (intermediate), and (3) the meat- and vegetable-based matrices (lowest). This ranking between the matrices is quite different from that based on their suitability to the growth of the organism. Our models can be used in HACCP studies, to improve shelf-life predictions and, generally, microbiological food safety assessments of products for whichB. cereusis the main concern.
Ramadan Fasting Leads to Shifts in Human Gut Microbiota Structured by Dietary Composition
Authors: Ali Ikram , Liu Ke , Long Danfeng , Faisal Shah , Hilal Mian Gul , Ali Izhar , Huang Xiaodan , Long Ruijun
Published: February 2021

The structure and diversity of human gut microbiota are directly related to diet, though less is known about the influences of ethnicity and diet-related behaviors, such as fasting (intermittent caloric restriction). In this study, we investigated whether fasting for Ramadan altered the microbiota in Chinese and Pakistani individuals. Using high-throughput 16S rRNA gene sequencing and self-reported dietary intake surveys, we determined that both the microbiota and dietary composition were significantly different with little overlap between ethnic groups. Principal Coordinate Analyses (PCoA) comparison of samples collected from both groups before and after fasting showed partial separation of microbiota related to fasting in the Pakistani group, but not in the Chinese group. Measurement of alpha diversity showed that Ramadan fasting significantly altered the coverage and ACE indices among Chinese subjects, but otherwise incurred no changes among either group. Specifically, Prevotella and Faecalibacterium drove predominance of Bacteroidetes and Firmicutes in the Pakistani group, while Bacteroides (phylum Bacteroidetes) were the most prevalent among Chinese participants both before and after fasting. We observed significant enrichment of some specific taxa and depletion of others in individuals of both populations, suggesting that fasting could affect beta diversity. Notably, Dorea, Klebsiella, and Faecalibacterium were more abundant in the Chinese group after fasting, while Sutterella, Parabacteroides, and Alistipes were significantly enriched after fasting in the Pakistani group. Evaluation of the combined groups showed that genera Coprococcus, Clostridium_XlV, and Lachnospiracea were all significantly decreased after fasting. Analysis of food intake and macronutrient energy sources showed that fat-derived energy was positively associated with Oscillibacter and Prevotella, but negatively associated with Bacteroides. In addition, the consumption of sweets was significantly positively correlated with the prevalence of Akkermansia. Our study indicated that diet was the most significant influence on microbiota, and correlated with ethnic groups, while fasting led to enrichment of specific bacterial taxa in some individuals. Given the dearth of understanding about the impacts of fasting on microbiota, our results provide valuable inroads for future study aimed at novel, personalized, behavior-based treatments targeting specific gut microbes for prevention or treatment of digestive disorders.
Cortical Thinning in the Medial Temporal Lobe and Precuneus Is Related to Cognitive Deficits in Patients With Subcortical Ischemic Vascular Disease
Authors: Chen Li , Song Jiarui , Cheng Runtian , Wang Kangcheng , Liu Xiaoshuang , He Miao , Luo Tianyou
Published: February 2021

Subcortical ischemic vascular disease (SIVD) is a major cause of vascular cognitive impairment (CI) and features extensive atrophy in the cerebral cortex. We aimed to test the hypothesis that cognitive deficits in SIVD are linked to decreased cortical thickness in specific brain regions, which may constitute neuroimaging biomarkers of CI. Sixty-seven SIVD patients without (SIVD-NC, n = 35) and with (SIVD-CI, n = 32) CI and a group of healthy controls (HCs, n = 36) underwent structural magnetic resonance imaging (MRI) and cognitive functional assessments. FreeSurfer was used to preprocess structural MRI data and to calculate and compare cortical thickness. The correlation between cortical thickness and cognitive scores was examined in SIVD patients. Significantly altered cortical thickness in the bilateral insula, middle and inferior temporal lobes, precuneus, and medial temporal lobe (MTL) was identified among the three groups (p < 0.05, Monte Carlo simulation corrected). Post hoc results showed significantly decreased thickness in the bilateral insula and temporal lobe in SIVD-NC and SIVD-CI patients compared with HCs. However, the areas with reduced cortical thickness were larger in SIVD-CI than SIVD-NC patients. SIVD-CI patients had significantly reduced thickness in the bilateral precuneus and left MTL (Bonferroni corrected) compared with SIVD-NC patients when we extracted the mean thickness for each region of interest. In SIVD patients, the thicknesses of the left MTL and bilateral precuneus were positively correlated with immediate recall in the memory test. SIVD might lead to extensive cerebral cortical atrophy, while atrophy in the MTL and precuneus might be associated with memory deficits.
Voxel-Mirrored Homotopic Connectivity Associated With Change of Cognitive Function in Chronic Pontine Stroke
Authors: Wu Luobing , Wang Caihong , Liu Jingchun , Guo Jun , Wei Ying , Wang Kaiyu , Miao Peifang , Wang Yingying , Cheng Jingliang
Published: February 2021

Recent neuroimaging studies have shown the possibility of cognitive impairment after pontine stroke. In this study, we aimed to use voxel-mirrored homotopic connectivity (VMHC) to investigate changes in the cognitive function in chronic pontine stroke. Functional MRI (fMRI) and behavioral assessments of cognitive function were obtained from 56 patients with chronic pontine ischemic stroke [28 patients with left-sided pontine stroke (LP) and 28 patients with right-sided pontine stroke (RP)] and 35 matched healthy controls (HC). The one-way ANOVA test was performed for the three groups after the VMHC analysis. Results showed that there were significant decreases in the bilateral lingual gyrus (Lingual_L and Lingual_R) and the left precuneus (Precuneus_L) in patients with chronic pontine ischemic stroke compared to HCs. However, in a post-hoc multiple comparison test, this difference remained only between the HC and RP groups. Moreover, we explored the relationship between the decreased z-values in VMHC and the behavior-task scores using a Pearson's correlation test and found that both scores of short-term memory and long-term memory in the Rey Auditory Verbal Learning Test were positively correlated with z-values of the left lingual gyrus (Lingual_L), the right lingual gyrus (Lingual_R), and the left precuneus (Precuneus_L) in VMHC. Besides that, the z-values of Precuneus_L in VMHC were also negatively correlated with the reaction time for correct responses in the Flanker task and the spatial memory task. In conclusion, first, the lingual gyrus played an important role in verbal memory. Second, the precuneus influenced the working memory, both auditory-verbal memory and visual memory. Third, the right-sided stroke played a greater role in the results of this study. This study provides a basis for further elucidation of the characteristics and mechanisms of cognitive impairment after pontine stroke.
Age-Related EEG Power Reductions Cannot Be Explained by Changes of the Conductivity Distribution in the Head Due to Brain Atrophy
Authors: He Mingjian , Liu Feng , Nummenmaa Aapo , Hämäläinen Matti , Dickerson Bradford C. , Purdon Patrick L.
Published: February 2021

Electroencephalogram (EEG) power reductions in the aging brain have been described by numerous previous studies. However, the underlying mechanism for the observed brain signal power reduction remains unclear. One possible cause for reduced EEG signals in elderly subjects might be the increased distance from the primary neural electrical currents on the cortex to the scalp electrodes as the result of cortical atrophies. While brain shrinkage itself reflects age-related neurological changes, the effects of changes in the distribution of electrical conductivity are often not distinguished from altered neural activity when interpreting EEG power reductions. To address this ambiguity, we employed EEG forward models to investigate whether brain shrinkage is a major factor for the signal attenuation in the aging brain. We simulated brain shrinkage in spherical and realistic brain models and found that changes in the conductor geometry cannot fully account for the EEG power reductions even when the brain was shrunk to unrealistic sizes. Our results quantify the extent of power reductions from brain shrinkage and pave the way for more accurate inferences about deficient neural activity and circuit integrity based on EEG power reductions in the aging population.
Melamine Disrupts Acetylcholine-Mediated Neural Information Flow in the Hippocampal CA3–CA1 Pathway
Authors: Sun Wei , Liu Peidong , Tang Chunzhi , An Lei
Published: February 2021

Considering the cognitive and synaptic deficits following intragastric administration of melamine, the aim of the current investigation was to test whether the hippocampal oscillations were affected. The local field potential (LFP) was recorded in the hippocampal CA3–CA1 pathway of Wistar rats during a spatial-dependent Y-maze task. The general partial directed coherence (gPDC) method was used to assess the directionality of neural information flow (NIF) between the CA3 and CA1 regions. The levels of acetylcholine (ACh) and its esterolytic protease, acetylcholinesterase (AChE), were detected in the hippocampus (HPC) following the behavioral test. The values of phase synchronization between the CA3 and CA1 regions in delta, low theta, and high theta oscillations were reduced significantly in the melamine-treated group. Moreover, the coupling directional index and the strength of CA3 driving CA1 were critically decreased in the above three frequency bands as well. Meanwhile, a reduction in ACh expression and an enhancement in AChE activity were found in the HPC of melamine-treated rats. Intrahippocampal infusion with ACh could mitigate the weakened neural coupling and directional NIF in parallel with spatial learning improvements. However, infusion of scopolamine, an acetylcholine receptor antagonist, could block the mitigative effects of ACh treatment in melamine rats. These findings provide first evidence that ACh-mediated neuronal coupling and NIF in the CA3–CA1 pathway are involved in spatial learning deficits induced by chronic melamine exposure.
The Human ApoE4 Variant Reduces Functional Recovery and Neuronal Sprouting After Incomplete Spinal Cord Injury in Male Mice
Authors: Toro Carlos A. , Hansen Jens , Siddiq Mustafa M. , Johnson Kaitlin , Zhao Wei , Azulai Daniella , Das Dibash K. , Bauman William , Sebra Robert , Cai Dongming , Iyengar Ravi , Cardozo Christopher P.
Published: February 2021

Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two apolipoprotein E (ApoE)4 alleles show worse functional outcomes and longer hospital stays after SCI, but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.
Repeated Low-Level Blast Acutely Alters Brain Cytokines, Neurovascular Proteins, Mechanotransduction, and Neurodegenerative Markers in a Rat Model
Authors: Heyburn Lanier , Abutarboush Rania , Goodrich Samantha , Urioste Rodrigo , Batuure Andrew , Wheel Jaimena , Wilder Donna M. , Arun Peethambaran , Ahlers Stephen T. , Long Joseph B. , Sajja Venkatasivasai Sujith
Published: February 2021

Exposure to the repeated low-level blast overpressure (BOP) periodically experienced by military personnel in operational and training environments can lead to deficits in behavior and cognition. While these low-intensity blasts do not cause overt changes acutely, repeated exposures may lead to cumulative effects in the brain that include acute inflammation, vascular disruption, and other molecular changes, which may eventually contribute to neurodegenerative processes. To identify these acute changes in the brain following repeated BOP, an advanced blast simulator was used to expose rats to 8.5 or 10 psi BOP once per day for 14 days. At 24 h after the final BOP, brain tissue was collected and analyzed for inflammatory markers, astrogliosis (GFAP), tight junction proteins (claudin-5 and occludin), and neurodegeneration-related proteins (Aβ40/42, pTau, TDP-43). After repeated exposure to 8.5 psi BOP, the change in cytokine profile was relatively modest compared to the changes observed following 10 psi BOP, which included a significant reduction in several inflammatory markers. Reduction in the tight junction protein occludin was observed in both groups when compared to controls, suggesting cerebrovascular disruption. While repeated exposure to 8.5 psi BOP led to a reduction in the Alzheimer’s disease (AD)-related proteins amyloid-β (Aβ)40 and Aβ42, these changes were not observed in the 10 psi group, which had a significant reduction in phosphorylated tau. Finally, repeated 10 psi BOP exposures led to an increase in GFAP, indicating alterations in astrocytes, and an increase in the mechanosensitive ion channel receptor protein, Piezo2, which may increase brain sensitivity to injury from pressure changes from BOP exposure. Overall, cumulative effects of repeated low-level BOP may increase the vulnerability to injury of the brain by disrupting neurovascular architecture, which may lead to downstream deleterious effects on behavior and cognition.
Bilateral Repetitive Transcranial Magnetic Stimulation With the H-Coil in Parkinson's Disease: A Randomized, Sham-Controlled Study
Authors: Spagnolo Francesca , Fichera Mario , Chieffo Raffaella , Dalla Costa Gloria , Pisa Marco , Volonté Maria Antonietta , Falautano Monica , Zangen Abraham , Comi Giancarlo , Leocani Letizia
Published: February 2021

Background: Pilot open-label application of high-frequency repetitive transcranial magnetic stimulation (rTMS) with H-coil in Parkinson's Disease (PD) have shown promising results.

Objective: To evaluate safety and efficacy of high-frequency rTMS with H-coil in PD in a double-blind, placebo-controlled, randomized study.

Methods: Sixty patients with PD were randomized into 3 groups: M1-PFC (real stimulation on primary motor-M1 and pre-frontal cortices-PFC), M1 (real rTMS on M1, sham on PFC), Sham (apparent stimulation). Primary outcome was baseline-normalized percent improvement in UPDRS part III OFF-therapy at the end of treatment (12 rTMS sessions, 4 weeks). Secondary outcomes were improvement in UPDRS part III sub-scores, timed tests, and neuropsychological tests. Statistical analysis compared improvement following real and sham stimulation at the end of the protocol using either a t-test or a Mann-Whitney test.

Results: All patients tolerated the treatment and concluded the study. One patient from M1-PFC group was excluded from the analysis due to newly discovered uncontrolled diabetes mellitus. No serious adverse effect was recorded. At the end of treatment, patients receiving real rTMS (M1-PFC and M1 combined) showed significantly greater improvement compared to sham in UPDRS part III total score (p = 0.007), tremor subscore (p = 0.011), and lateralized sub-scores (p = 0.042 for the more affected side; p = 0.012 for the less affected side). No significant differences have been oserved in safety and efficacy outcomes between the two real rTMS groups. Notably, mild, not-distressing and transient dyskinesias occurred in 3 patients after real rTMS in OFF state.

Conclusions: The present findings suggest that high-frequency rTMS with H-coil is a safe and potentially effective procedure and prompt larger studies for validation as add-on treatment in PD.
Scoring Model to Predict Functional Outcome in Poor-Grade Aneurysmal Subarachnoid Hemorrhage
Authors: Shen Jie , Yu Jianbo , Huang Sicong , Mungur Rajneesh , Huang Kaiyuan , Pan Xinfa , Yu Guofeng , Xie Zhikai , Zhou Lihui , Liu Zongchi , Cheng Dexin , Pan Jianwei , Zhan Renya
Published: February 2021

Background: Patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH), defined as World Federation of Neurosurgical Societies (WFNS) grades IV–V have high rates of disability and mortality. The objective of this study was to accurately prognosticate the outcomes of patients with poor-grade aSAH by developing a new scoring model.

Methods: A total of 147 poor-grade aSAH patients in our center were enrolled. Risk variables identified by multivariate logistic regression analysis were used to devise a scoring model (total score, 0–9 points). The scores were estimated on the basis of β coefficients. A cohort of 68 patients from another institute was used to validate the model.

Results: Multivariate logistic regression analysis revealed that modified Fisher grade >2 [odds ratio [OR], 2.972; P = 0.034], age ≥65 years (OR, 3.534; P = 0.006), conservative treatment (OR, 5.078; P = 0.019), WFNS grade V (OR, 2.638; P = 0.029), delayed cerebral ischemia (OR, 3.170; P = 0.016), shunt-dependent hydrocephalus (OR, 3.202; P = 0.032), and cerebral herniation (OR, 7.337; P < 0.001) were significant predictors for poor prognosis [modified Rankin Scale [mRS] ≥3]. A scoring system was constructed by the integration of these factors and divided the poor-grade aSAH patients into three categories: low risk (0–1 points), intermediate risk (2–3 points), and high risk (4–9 points), with predicted risks of poor prognosis of 11, 52, and 87%, respectively (P < 0.001). The area under the curve in the derivation cohort was 0.844 (95% CI, 0.778–0.909). The AUC in the validation cohort was 0.831 (95% CI, 0.732–0.929).

Conclusions: The new scoring model can improve prognostication and help decision-making for subsequent complementary treatment in patients with aSAH.
Clinical Implication of Corrective Saccades in the Video Head Impulse Test for the Diagnosis of Posterior Inferior Cerebellar Artery Infarction
Authors: Nam Gi-Sung , Shin Hyun-June , Kang Jin-Ju , Lee Na-Ri , Oh Sun-Young
Published: February 2021

Objective: In the present study, we characterized the vestibulo-ocular reflex (VOR) gain and properties of corrective saccades (CS) in patients with posterior inferior cerebellar artery (PICA) stroke and determined the best parameter to differentiate PICA stroke from benign peripheral vestibular neuritis (VN). In particular, we studied CS amplitude and asymmetry in video head impulse tests (vHITs) to discriminate these two less-studied disease conditions.

Methods: The vHITs were performed within 1 week from symptom onset in patients with PICA stroke (n = 17), patients with VN (n = 17), and healthy subjects (HS, n = 17).

Results: PICA stroke patients had bilaterally reduced VOR gains in the horizontal semicircular canal (HC) and the posterior semicircular canal (PC) compared with HSs. When compared with VN patients, PICA stroke patients showed preserved gains in the HC and anterior semicircular canal (AC) bilaterally (i.e., symmetric VOR gain). Similar to VOR gain, smaller but bilaterally symmetric CS in the HC and AC were observed in PICA stroke patients compared with VN patients; the mean amplitude of CS for the ipsilesional HC was reduced (p < 0.001, Mann–Whitney U-test), but the mean amplitude of CS for the contralesional HC was increased (p < 0.03, Mann–Whitney U-test) in PICA stroke compared with VN. The receiver operating characteristic (ROC) curve showed that CS amplitude asymmetry (CSs) and VOR gain asymmetry (Gs) of HC are excellent parameters to distinguish PICA stroke from VN.

Conclusion: In the current study, we quantitatively investigated the VOR gain and CS using vHITs for three semicircular canals in PICA stroke and VN patients. In addition to VOR gain, quantitative assessments of CS using vHITs can provide sensitive and objective parameters to distinguish between peripheral and central vestibulopathies.
Experiences of Patients With Auditory Processing Disorder in Getting Support in Health, Education, and Work Settings: Findings From an Online Survey
Authors: Agrawal Deepashri , Dritsakis Giorgos , Mahon Merle , Mountjoy Alyson , Bamiou Doris E.
Published: February 2021

Objective: To explore the views and experiences of individuals with Auditory Processing Disorder (APD) and/or their families in getting support from services and to receive their suggestions for improvement.

Design: Cross-sectional random sample survey with descriptive analysis.

Settings: Online survey.

Participants: One hundred and fifty six individuals with APD and/or their family members from the APD Support UK patient support organization and four associated APD Facebook groups.

Main Outcome Measure: A 16-item questionnaire on negative and positive experiences in getting a referral for diagnosis, funding for the FM system, and overall support for APD.

Results: The key findings that emerged included reports of difficulty in getting a referral for diagnosis (54%), obtaining funding for an FM system (45%), getting support for APD (61%), and poor recognition and awareness of APD (63%) in Education, Health or Work settings. The positive experiences reported were ease in getting a referral for diagnosis (46%), in obtaining an FM system (20%), and with diagnosis leading to help at school or to a better understanding of the condition and the required adjustments. The recommended improvement areas were raising awareness of APD and related management in Education (30%), the Health sector (25%), and the public (18%).

Conclusions: Individuals and families of individuals with APD overwhelmingly report a lack of awareness of APD across health, education, and work sectors, and difficulties in getting access to diagnosis and support. This information may provide an initial understanding of the patients' needs for clinical services for APD, identify research priorities, and influence longer-term public health decisions toward improved care.
Skeletal Muscle in Cerebral Palsy: From Belly to Myofibril
Authors: Howard Jason J. , Herzog Walter
Published: February 2021

This review will provide a comprehensive, up-to-date review of the current knowledge regarding the pathophysiology of muscle contractures in cerebral palsy. Although much has been known about the clinical manifestations of both dynamic and static muscle contractures, until recently, little was known about the underlying mechanisms for the development of such contractures. In particular, recent basic science and imaging studies have reported an upregulation of collagen content associated with muscle stiffness. Paradoxically, contractile elements such as myofibrils have been found to be highly elastic, possibly an adaptation to a muscle that is under significantin vivotension. Sarcomeres have also been reported to be excessively long, likely responsible for the poor force generating capacity and underlying weakness seen in children with cerebral palsy (CP). Overall muscle volume and length have been found to be decreased in CP, likely secondary to abnormalities in sarcomerogenesis. Recent animal and clinical work has suggested that the use of botulinum toxin for spasticity management has been shown to increase muscle atrophy and fibrofatty content in the CP muscle. Given that the CP muscle is short and small already, this calls into question the use of such agents for spasticity management given the functional and histological cost of such interventions. Recent theories involving muscle homeostasis, epigenetic mechanisms, and inflammatory mediators of regulation have added to our emerging understanding of this complicated area.
Phonological Underspecification: An Explanation for How a Rake Can Become Awake
Authors: Cummings Alycia E. , Wu Ying C. , Ogiela Diane A.
Published: February 2021

Neural markers, such as the mismatch negativity (MMN), have been used to examine the phonological underspecification of English feature contrasts using the Featurally Underspecified Lexicon (FUL) model. However, neural indices have not been examined within the approximant phoneme class, even though there is evidence suggesting processing asymmetries between liquid (e.g., /ɹ/) and glide (e.g., /w/) phonemes. The goal of this study was to determine whether glide phonemes elicit electrophysiological asymmetries related to [consonantal] underspecification when contrasted with liquid phonemes in adult English speakers. Specifically, /ɹɑ/ is categorized as [+consonantal] while /wɑ/ is not specified [i.e., (–consonantal)]. Following the FUL framework, if /w/ is less specified than /ɹ/, the former phoneme should elicit a larger MMN response than the latter phoneme. Fifteen English-speaking adults were presented with two syllables, /ɹɑ/ and /wɑ/, in an event-related potential (ERP) oddball paradigm in which both syllables served as the standard and deviant stimulus in opposite stimulus sets. Three types of analyses were used: (1) traditional mean amplitude measurements; (2) cluster-based permutation analyses; and (3) event-related spectral perturbation (ERSP) analyses. The less specified /wɑ/ elicited a large MMN, while a much smaller MMN was elicited by the more specified /ɹɑ/. In the standard and deviant ERP waveforms, /wɑ/ elicited a significantly larger negative response than did /ɹɑ/. Theta activity elicited by /ɹɑ/ was significantly greater than that elicited by /wɑ/ in the 100–300 ms time window. Also, low gamma activation was significantly lower for /ɹɑ/ vs. /wɑ/ deviants over the left hemisphere, as compared to the right, in the 100–150 ms window. These outcomes suggest that the [consonantal] feature follows the underspecification predictions of FUL previously tested with the place of articulation and voicing features. Thus, this study provides new evidence for phonological underspecification. Moreover, as neural oscillation patterns have not previously been discussed in the underspecification literature, the ERSP analyses identified potential new indices of phonological underspecification.
Neuronal Actions of Transspinal Stimulation on Locomotor Networks and Reflex Excitability During Walking in Humans With and Without Spinal Cord Injury
Authors: Islam Md. Anamul , Pulverenti Timothy S. , Knikou Maria
Published: February 2021

This study investigated the neuromodulatory effects of transspinal stimulation on soleus H-reflex excitability and electromyographic (EMG) activity during stepping in humans with and without spinal cord injury (SCI). Thirteen able-bodied adults and 5 individuals with SCI participated in the study. EMG activity from both legs was determined for steps without, during, and after a single-pulse or pulse train transspinal stimulation delivered during stepping randomly at different phases of the step cycle. The soleus H-reflex was recorded in both subject groups under control conditions and following single-pulse transspinal stimulation at an individualized exactly similar positive and negative conditioning-test interval. The EMG activity was decreased in both subject groups at the steps during transspinal stimulation, while intralimb and interlimb coordination were altered only in SCI subjects. At the steps immediately after transspinal stimulation, the physiological phase-dependent EMG modulation pattern remained unaffected in able-bodied subjects. The conditioned soleus H-reflex was depressed throughout the step cycle in both subject groups. Transspinal stimulation modulated depolarization of motoneurons over multiple segments, limb coordination, and soleus H-reflex excitability during assisted stepping. The soleus H-reflex depression may be the result of complex spinal inhibitory interneuronal circuits activated by transspinal stimulation and collision between orthodromic and antidromic volleys in the peripheral mixed nerve. The soleus H-reflex depression by transspinal stimulation suggests a potential application for normalization of spinal reflex excitability after SCI.
Neural Signatures of Performance Feedback in the Paced Auditory Serial Addition Task (PASAT): An ERP Study
Authors: Sommer Anja , Ecker Lukas , Plewnia Christian
Published: February 2021

Research on cognitive control has sparked increasing interest in recent years, as it is an important prerequisite for goal oriented human behavior. The paced auditory serial addition task (PASAT) has been used to test and train cognitive control functions. This adaptive, challenging task includes continuous performance feedback. Therefore, additional cognitive control capacities are required to process this information along with the already high task-load. The underlying neural mechanisms, however, are still unclear. To explore the neural signatures of the PASAT and particularly the processing of distractive feedback information, feedback locked event-related potentials were derived from 24 healthy participants during an adaptive 2-back version of the PASAT. Larger neural activation after negative feedback was found for feedback related negativity (FRN), P300, and late positive potential (LPP). In early stages of feedback processing (i.e., FRN), a larger difference between positive and negative feedback responses was associated with poorer overall performance. This association was inverted in later stages (i.e., P300 and LPP). Together, our findings indicate stage-dependent associations between neural activation after negative information and cognitive functioning. Conceivably, increased early responses to negative feedback signify distraction, whereas higher activity at later stages reflects cognitive control processes to preserve ongoing performance.