bluuebunny/crossref_metadata_2025 huggingface dataset:
It’s Just Conservation: To What Extent Are Marine Protected Areas in the Irish Sea Equitably Governed and Managed?
Authors: Schéré Constance M. , Schreckenberg Kate , Dawson Terence P. , Jones Nikoleta
Published: June 2021

It is not enough to simply designate a protected area. According to the Convention on Biological Diversity’s Aichi Target 11, these sites should be governed and managed effectively and equitably. Equitable (i.e., fair and inclusive) conservation is vital to ensuring effective protection of natural resources while maintaining human well-being. Yet, equity tends to be overlooked in protected area assessments. Three marine protected areas (MPAs) in Great Britain, Northern Ireland, and the Republic of Ireland were selected to assess equitable governance and management in the Irish Sea. This is one of the first studies to assess equity across multiple stakeholder groups in MPAs. The Site-level Assessment for Governance and Equity (SAGE) toolkit, developed by the International Institute for Environment and Development (IIED) to address the gap in equity assessments, was used to evaluate equitable governance and management in these MPAs. Based on the three dimensions of equity (recognition, distribution, and procedure), SAGE contains Likert-scale questions to assess good governance by evaluating how different stakeholder groups perceive their protected area’s management and how included they feel in decision-making. Quantitative data from SAGE is complemented by qualitative data from semi-structured interviews with stakeholders to understand the impact MPA management has on local communities and MPA users. The results of this study reveal a lack of communication between MPA authorities and local stakeholders. They highlight the need for co-management in the form of inclusive partnerships as an alternative to the current top-down governance approach favoed in the United Kingdom and Ireland.
A More Comprehensive Climate Vulnerability Assessment Framework for Fisheries Social-Ecological Systems
Authors: Dudley Peter N. , Rogers Tanya L. , Morales Mark M. , Stoltz Amanda D. , Sheridan Casey J. , Beulke Anne K. , Pomeroy Carrie , Carr Mark H.
Published: June 2021

Understanding and anticipating the effects of climate change on fisheries social-ecological systems (FSESs) is central to proactive fisheries management in a changing global climate. With fisheries management increasingly striving to consider interactions and feedbacks among people, targeted species, and the broader ecological and human communities, fisheries managers and participants need tools to help them assess these complex systems. We developed a new climate vulnerability assessment framework for analyzing the impacts of a climate-induced trend or event on a FSES. The framework divides the FSES into four interrelated and interacting domains: Ecological Community, Fished Species, Fishery, and Human Community. The framework provides a systematic approach to account for indirect as well as direct effects, links among subsystems, and multiple climate change-induced stressors. We demonstrate the framework’s utility by applying it to three case studies: the effects of a marine heatwave on the Dungeness crab FSES, the effects of a marine heatwave on the red sea urchin FSES, and the effects of long-term climate trends on North Pacific albacore. We found that the effects of a climatic trend or event on a FSES are often indirect and can trigger diverse and important feedbacks. These examples also showed that the climatic trend or event may cause changes in the temporal and spatial distribution of fishing effort and fished species that have a more significant impact on the FSES than changes to species abundance per se. Unlike other climate vulnerability assessment frameworks and applications, ours is designed to enable consideration of the range of feedbacks within and among both the ecological and human communities. As such, it is a valuable tool to guide the holistic examination and assessment of potential impacts to FSESs.
Pervasive but Neglected: A Perspective on COVID-19-Associated Pulmonary Mold Infections Among Mechanically Ventilated COVID-19 Patients
Authors: Ghazanfari Mona , Arastehfar Amir , Davoodi Lotfollah , Yazdani Charati Jamshid , Moazeni Maryam , Abastabar Mahdi , Haghani Iman , Mirzakhani Roghayeh , Mayahi Sabah , Fang Wenjie , Liao Wanqing , Nguyen M. Hong , Perlin David S. , Hoenigl Martin , Pan Weihua , Hedayati Mohammad T.
Published: June 2021

Background: Recent studies from multiple countries have shown a high prevalence of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) among severely ill patients. Despite providing valuable insight into the clinical management of CAPA, large-scale prospective studies are limited. Here, we report on one of the largest multicenter epidemiological studies to explore the clinical features and prevalence of COVID-19-associated pulmonary mold infections (CAPMIs) among mechanically ventilated patients.

Methods: Bronchoalveolar lavage (BAL) and serum samples were collected for culture, galactomannan (GM), and β-D-glucan (BDG) testing. Patients were classified as probable CAPMI based on the presence of host factors, radiological findings, and mycological criteria.

Results: During the study period, 302 COVID-19 patients were admitted to intensive care units (ICUs), among whom 105 were mechanically ventilated for ≥4 days. Probable CAPMI was observed among 38% of patients (40/105), among whom BAL culture of 29 patients turned positive for molds, while galactomannan testing on BAL (GM index ≥1) and serum (GM index >0.5) samples were positive for 60% (24/40) and 37.5% (15/39) of patients, respectively. Aspergillus (22/29; 75.8%) and Fusarium (6/29; 20.6%) constituted 96.5% of the molds isolated. Diaporthe foeniculina was isolated from a COVID-19 patient. None of the patients who presented with CAPMI were treated with antifungal drugs.

Conclusion: Despite being prevalent, the absence of appropriate antifungal treatment highlights that CAPMI is a neglected complication among mechanically ventilated COVID-19 patients admitted to ICUs. CAPMI can be caused by species other than Aspergillus.
The Prognostic Value of Hyponatremia for Predicting Poor Outcome in Patients With COVID-19: A Systematic Review and Meta-Analysis
Authors: Akbar Mohammad Rizki , Pranata Raymond , Wibowo Arief , Irvan  , Sihite Teddy Arnold , Martha Januar Wibawa
Published: June 2021

Background: This meta-analysis aimed to assess the prognostic value of hyponatremia in patients with COVID-19.

Methods: We performed a systematic literature search on PubMed, Scopus, ScienceDirect, and Wiley up until January 26, 2021. The key exposure was hyponatremia, defined as sodium level below the reference level. The outcome of interest was poor outcome, which was a composite of mortality, severe COVID-19, and prolonged hospitalization. Severe COVID-19 was defined severe CAP or needing ICU care or IMV. The pooled effect estimate was odds ratio (OR). Sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), diagnostic OR (DOR), and area under curve (AUC) were generated.

Results: There were 11,493 patients from eight studies included in this systematic review and meta-analysis. The incidence of hyponatremia was 24%, and incidence of poor outcome was 20%. Hyponatremia was associated with poor outcome in COVID-19 (OR 2.65 [1.89, 3.72], p < 0.001; I2: 67.2%). Meta-regression analysis showed that the association between hyponatremia and poor outcome was reduced by age (OR 0.94 [0.90, 0.98], p = 0.006) and hypertension (OR 0.96 [0.93, 0.94], p < 0.001). Hyponatremia has a sensitivity of 0.37 [0.27, 0.48], specificity of 0.82 [0.72, 0.88], PLR of 2.0 [1.5, 2.7], NLR of 0.77 [0.69, 0.87], DOR of 3 [2, 4], and AUC of 0.62 [0.58, 0.66] for predicting poor outcome. In this pooled analysis, hyponatremia has a 33% posttest probability for poor outcome, and absence of hyponatremia confers to a 16% posttest probability.

Conclusion: Hyponatremia was associated with poor outcome in patients with COVID-19.

Systematic Review Registration: PROSPERO, CRD42021233592.
SYmptom-Based STratification of DiabEtes Mellitus by Renal Function Decline (SYSTEM): A Retrospective Cohort Study and Modeling Assessment
Authors: Chan Kam Wa , Chow Tak Yee , Yu Kam Yan , Xu Yulong , Zhang Nevin Lianwen , Wong Vivian Taam , Li Saimei , Tang Sydney Chi Wai
Published: June 2021

Background: Previous UK Biobank studies showed that symptoms and physical measurements had excellent prediction on long-term clinical outcomes in general population. Symptoms and signs could intuitively and non-invasively predict and monitor disease progression, especially for telemedicine, but related research is limited in diabetes and renal medicine.

Methods: This retrospective cohort study aimed to evaluate the predictive power of a symptom-based stratification framework and individual symptoms for diabetes. Three hundred two adult diabetic patients were consecutively sampled from outpatient clinics in Hong Kong for prospective symptom assessment. Demographics and longitudinal measures of biochemical parameters were retrospectively extracted from linked medical records. The association between estimated glomerular filtration rate (GFR) (independent variable) and biochemistry, epidemiological factors, and individual symptoms was assessed by mixed regression analyses. A symptom-based stratification framework of diabetes using symptom clusters was formulated by Delphi consensus method. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were compared between statistical models with different combinations of biochemical, epidemiological, and symptom variables.

Results: In the 4.2-year follow-up period, baseline presentation of edema (−1.8 ml/min/1.73m2, 95%CI: −2.5 to −1.2, p < 0.001), epigastric bloating (−0.8 ml/min/1.73m2, 95%CI: −1.4 to −0.2, p = 0.014) and alternating dry and loose stool (−1.1 ml/min/1.73m2, 95%CI: −1.9 to −0.4, p = 0.004) were independently associated with faster annual GFR decline. Eleven symptom clusters were identified from literature, stratifying diabetes predominantly by gastrointestinal phenotypes. Using symptom clusters synchronized by Delphi consensus as the independent variable in statistical models reduced complexity and improved explanatory power when compared to using individual symptoms. Symptom-biologic-epidemiologic combined model had the lowest AIC (4,478 vs. 5,824 vs. 4,966 vs. 7,926) and BIC (4,597 vs. 5,870 vs. 5,065 vs. 8,026) compared to the symptom, symptom-epidemiologic and biologic-epidemiologic models, respectively. Patients co-presenting with a constellation of fatigue, malaise, dry mouth, and dry throat were independently associated with faster annual GFR decline (−1.1 ml/min/1.73m2, 95%CI: −1.9 to −0.2, p = 0.011).

Conclusions: Add-on symptom-based diagnosis improves the predictive power on renal function decline among diabetic patients based on key biochemical and epidemiological factors. Dynamic change of symptoms should be considered in clinical practice and research design.
Can Clinical Symptoms and Laboratory Results Predict CT Abnormality? Initial Findings Using Novel Machine Learning Techniques in Children With COVID-19 Infections
Authors: Ma Huijing , Ye Qinghao , Ding Weiping , Jiang Yinghui , Wang Minhao , Niu Zhangming , Zhou Xi , Gao Yuan , Wang Chengjia , Menpes-Smith Wade , Fang Evandro Fei , Shao Jianbo , Xia Jun , Yang Guang
Published: June 2021

The rapid spread of coronavirus 2019 disease (COVID-19) has manifested a global public health crisis, and chest CT has been proven to be a powerful tool for screening, triage, evaluation and prognosis in COVID-19 patients. However, CT is not only costly but also associated with an increased incidence of cancer, in particular for children. This study will question whether clinical symptoms and laboratory results can predict the CT outcomes for the pediatric patients with positive RT-PCR testing results in order to determine the necessity of CT for such a vulnerable group. Clinical data were collected from 244 consecutive pediatric patients (16 years of age and under) treated at Wuhan Children's Hospital with positive RT-PCR testing, and the chest CT were performed within 3 days of clinical data collection, from January 21 to March 8, 2020. This study was approved by the local ethics committee of Wuhan Children's Hospital. Advanced decision tree based machine learning models were developed for the prediction of CT outcomes. Results have shown that age, lymphocyte, neutrophils, ferritin and C-reactive protein are the most related clinical indicators for predicting CT outcomes for pediatric patients with positive RT-PCR testing. Our decision support system has managed to achieve an AUC of 0.84 with 0.82 accuracy and 0.84 sensitivity for predicting CT outcomes. Our model can effectively predict CT outcomes, and our findings have indicated that the use of CT should be reconsidered for pediatric patients, as it may not be indispensable.
Skin Immune Response of Immunocompetent and Immunosuppressed C57BL/6 Mice After Experimental Subcutaneous Infection Caused by Purpureocillium lilacinum
Authors: Corrêa-Moreira Danielly , dos Santos Arethuza , Menezes Rodrigo C. , Morgado Fernanda N. , Borba Cintia M. , Oliveira-Ferreira Joseli
Published: June 2021

Hyalohyphomycosis is a fungal infection characterized by the presence of a hyaline mycelium in the host. It is caused by several agents, such asPurpureocillium lilacinum. Our study aimed to evaluate some cell subsets and inflammatory markers involved in thein situimmune response to subcutaneous hyalohyphomycosis byP. lilacinumin C57BL/6 murine models. The fungal isolate was inoculated in mice randomly distributed in immunocompetent/infected (CI) and immunosuppressed/infected (SI) groups. Mice were evaluated on days 1, 3, 5, and 7 after inoculation. Histopathological studies showed several lesions in the site of infection as well as the formation of multifocal and mixed inflammatory infiltrates, which differed between the CI and SI groups. This analysis also revealed conidia and hypha-like structures in subcutaneous tissues of mice of both groups. The immunohistochemical analysis showed lower percentages of macrophages and neutrophils in the SI group compared to those in the CI group. Moreover, the intensity of interleukin (IL)-1β and nitric oxide synthase 2 production by cells of immunosuppressed mice was discreet, compared to immunocompetent mice that ranged from moderate to intense over time. The quantitative interference of dexamethasone in the response to the fungus was also demonstrated. We concluded that our results can be useful not only to broaden the knowledge onP. lilacinumbut also, based on this host–parasite relationship, to contribute to the understanding of the mechanisms of infection.
Genomic Analysis of Enterococcus spp. Isolated From a Wastewater Treatment Plant and Its Associated Waters in Umgungundlovu District, South Africa
Authors: Mbanga Joshua , Amoako Daniel G. , Abia Akebe L. K. , Allam Mushal , Ismail Arshad , Essack Sabiha Y.
Published: June 2021

We investigated the antibiotic resistome, mobilome, virulome, and phylogenomic lineages of Enterococcus spp. obtained from a wastewater treatment plant and its associated waters using whole-genome sequencing (WGS) and bioinformatics tools. The whole genomes of Enterococcus isolates including Enterococcus faecalis (n = 4), Enterococcus faecium (n = 5), Enterococcus hirae (n = 2), and Enterococcus durans (n = 1) with similar resistance patterns from different sampling sites and time points were sequenced on an Illumina MiSeq machine. Multilocus sequence typing (MLST) analysis revealed two E. faecalis isolates that had a common sequence type ST179; the rest had unique sequence types ST841, and ST300. The E. faecium genomes belonged to 3 sequence types, ST94 (n = 2), ST361 (n = 2), and ST1096 (n = 1). Detected resistance genes included those encoding tetracycline [tet(S), tet(M), and tet(L)], and macrolides [msr(C), msr(D), erm(B), and mef(A)] resistance. Antibiotic resistance genes were associated with insertion sequences (IS6, ISL3, and IS982), and transposons (Tn3 and Tn6000). The tet(M) resistance gene was consistently found associated with a conjugative transposon protein (TcpC). A total of 20 different virulence genes were identified in E. faecalis and E. faecium including those encoding for sex pheromones (cCF10, cOB1, cad, and came), adhesion (ace, SrtA, ebpA, ebpC, and efaAfs), and cell invasion (hylA and hylB). Several virulence genes were associated with the insertion sequence IS256. No virulence genes were detected in E. hirae and E. durans. Phylogenetic analysis revealed that all Enterococcus spp. isolates were more closely related to animal and environmental isolates than clinical isolates. Enterococcus spp. with a diverse range of resistance and virulence genes as well as associated mobile genetic elements (MGEs) exist in the wastewater environment in South Africa.
Diversity of Marine Macro-Algicolous Endophytic Fungi and Cytotoxic Potential of Biscogniauxia petrensis Metabolites Against Cancer Cell Lines
Authors: Sahoo Subhadarsini , Subban Kamalraj , Chelliah Jayabaskaran
Published: June 2021

Hypersaline environments are known to support diverse fungal species from various orders. The production of secondary metabolites is one of the strategies that fungi adopt to thrive under such extreme environments, bringing up the stress tolerance response. Some such unique secondary metabolites also exhibit clinical significance. The increasing prevalence of drug resistance in cancer therapy demands further exploration of these novel bioactive compounds as cancer therapeutics. In the present study, a total of 31 endophytic fungi harboring inside red, green, and brown marine algae have been isolated and identified. The maximum likelihood analysis and diversity indices of fungal endophytes revealed the phylogenetic relationship and species richness. The genus Aspergillus was found to be the dominating fungus, followed by Cladosporium spp. All the isolated endophytic fungal extracts were tested for their cytotoxicity against HeLa and A431 cancer cell lines. Nine isolates were further analyzed for their cytotoxic activity from the culture filtrate and mycelia extract. Among these isolates, Biscogniauxia petrensis showed potential cytotoxicity with CC50 values of 18.04 and 24.85 μg/ml against HeLa and A431 cells, respectively. Furthermore, the media and solvent extraction optimization revealed the highest cytotoxic active compounds in ethyl acetate extract from the potato dextrose yeast extract broth medium. The compound-induced cell death via apoptosis was 50–60 and 45% when assayed using propidium iodide-live/dead and loss of mitochondrial membrane potential assay, respectively, in HeLa cells. Four bioactive fractions (bioassay-based) were obtained and analyzed using chromatography and spectroscopy. This study reports, for the first time, the cytotoxic activity of an endophytic fungal community that was isolated from marine macro-algae in the Rameswaram coastal region of Tamil Nadu, India. In addition, B. petrensis is a prominent apoptotic agent, which can be used in pharmaceutical applications as a therapeutic.
Host Adaptive Evolution of Avian-Origin H3N2 Canine Influenza Virus
Authors: Guo Fucheng , Roy Ayan , Wang Ruichen , Yang Jinjin , Zhang Zhipeng , Luo Wen , Shen Xuejuan , Chen Rui-Ai , Irwin David M. , Shen Yongyi
Published: June 2021

Since its first isolation in around 2007, the avian-origin H3N2 canine influenza virus (CIV) has become established and continues to circulate in dog populations. This virus serves as a useful model for deciphering the complex evolutionary process of interspecies transmission of influenza A virus (IAV) from one species to its subsequent circulation in another mammalian host. The present investigation is a comprehensive effort to identify and characterize genetic changes that accumulated in the avian-origin H3N2 CIV during its circulation in the dog. We revealed that H3N2 CIV experiences greater selection pressure with extremely high global non-synonymous to synonymous substitution ratios per codon (dN/dS ratio) for each gene compared to the avian reservoir viruses. A total of 54 amino acid substitutions were observed to have accumulated and become fixed in the H3N2 CIV population based on our comprehensive codon-based frequency diagram analysis. Of these substitutions, 11 sites also display high prevalence in H3N8 CIV, indicating that convergent evolution has occurred on different lineages of CIV. Notably, six substitutions, including HA-G146S, M1-V15I, NS1-E227K, PA-C241Y, PB2-K251R, and PB2-G590S, have been reported to play imperative roles in facilitating the transmission and spillover of IAVs across species barriers. Most of these substitutions were found to have become fixed in around 2015, which might have been a favorable factor that facilitating the spread of these CIV lineages from South Asia to North America and subsequent further circulation in these areas. We also detected 12 sites in six viral genes with evidence for positive selection by comparing the rates of non-synonymous and synonymous substitutions at each site. Besides, our study reports trends of enhanced ongoing adaptation of H3N2 CIV to their respective host cellular systems, based on the codon adaptation index analysis, which points toward increasing fitness for efficient viral replication. In addition, a reduction in the abundance of the CpG motif, as evident from an analysis of relative dinucleotide abundance, may contribute to the successful evasion of host immune recognition. The present study provides key insights into the adaptive changes that have accumulated in the avian-origin H3N2 viral genomes during its establishment and circulation into dog populations.
Shifted Dynamics of Glucose Metabolism in the Hippocampus During Aging
Authors: Ge Ivan , Kirschen Gregory Wohl , Wang Xinxing
Published: June 2021

Aging is a process that adversely affects brain functions such as cognition. Brain activity is highly energy consuming, with glucose serving as the main energy source under normal circumstances. Whether the dynamics of glucose metabolism change with aging is not well understood. This study sought to investigate the activity-dependent changes in glucose metabolism of the mouse hippocampus during aging. In brief, after 1 h of contextual exploration in an enriched environmental condition or 1 h in a familiar home cage condition, metabolites were measured from the hippocampus of both young adult and aged mice with metabolomic profiling. Compared to the home cage context, the enriched contextual exploration condition resulted in changes in the concentration of 11 glucose metabolism-related metabolites in the young adult hippocampus. In contrast, glucose metabolism-related metabolite changes were more apparent in the aged group altered by contextual exploration when compared to those in the home cage condition. Importantly, in the aged groups, several key metabolites involved in glycolysis, the TCA cycle, and ketone body metabolism accumulated, suggesting the less efficient metabolization of glucose-based energy resources. Altogether, the analyses revealed that in the aged mice altered by enriched contextual exploration, the glucose resource seems to be unable to provide enough energy for hippocampal function.
Reaction–Diffusion Model-Based Research on Formation Mechanism of Neuron Dendritic Spine Patterns
Authors: Jia Yiqing , Zhao Qili , Yin Hongqiang , Guo Shan , Sun Mingzhu , Yang Zhuo , Zhao Xin
Published: June 2021

The pattern abnormalities of dendritic spine, tiny protrusions on neuron dendrites, have been found related to multiple nervous system diseases, such as Parkinson's disease and schizophrenia. The determination of the factors affecting spine patterns is of vital importance to explore the pathogenesis of these diseases, and further, search the treatment method for them. Although the study of dendritic spines is a hot topic in neuroscience in recent years, there is still a lack of systematic study on the formation mechanism of its pattern. This paper provided a reinterpretation of reaction-diffusion model to simulate the formation process of dendritic spine, and further, study the factors affecting spine patterns. First, all four classic shapes of spines, mushroom-type, stubby-type, thin-type, and branched-type were reproduced using the model. We found that the consumption rate of substrates by the cytoskeleton is a key factor to regulate spine shape. Moreover, we found that the density of spines can be regulated by the amount of an exogenous activator and inhibitor, which is in accordance with the anatomical results found in hippocampal CA1 in SD rats with glioma. Further, we analyzed the inner mechanism of the above model parameters regulating the dendritic spine pattern through Turing instability analysis and drew a conclusion that an exogenous inhibitor and activator changes Turing wavelength through which to regulate spine densities. Finally, we discussed the deep regulation mechanisms of several reported regulators of dendritic spine shape and densities based on our simulation results. Our work might evoke attention to the mathematic model-based pathogenesis research for neuron diseases which are related to the dendritic spine pattern abnormalities and spark inspiration in the treatment research for these diseases.
A Clustering Algorithm for Multi-Modal Heterogeneous Big Data With Abnormal Data
Authors: Yan An , Wang Wei , Ren Yi , Geng HongWei
Published: June 2021

The problems of data abnormalities and missing data are puzzling the traditional multi-modal heterogeneous big data clustering. In order to solve this issue, a multi-view heterogeneous big data clustering algorithm based on improved Kmeans clustering is established in this paper. At first, for the big data which involve heterogeneous data, based on multi view data analyzing, we propose an advanced Kmeans algorithm on the base of multi view heterogeneous system to determine the similarity detection metrics. Then, a BP neural network method is used to predict the missing attribute values, complete the missing data and restore the big data structure in heterogeneous state. Last, we ulteriorly propose a data denoising algorithm to denoise the abnormal data. Based on the above methods, we construct a framework namely BPK-means to resolve the problems of data abnormalities and missing data. Our solution approach is evaluated through rigorous performance evaluation study. Compared with the original algorithm, both theoretical verification and experimental results show that the accuracy of the proposed method is greatly improved.
Modulatory Effects of Monoamines and Perineuronal Nets on Output of Cerebellar Purkinje Cells
Authors: Hirono Moritoshi , Karube Fuyuki , Yanagawa Yuchio
Published: June 2021

Classically, the cerebellum has been thought to play a significant role in motor coordination. However, a growing body of evidence for novel neural connections between the cerebellum and various brain regions indicates that the cerebellum also contributes to other brain functions implicated in reward, language, and social behavior. Cerebellar Purkinje cells (PCs) make inhibitory GABAergic synapses with their target neurons: other PCs and Lugaro/globular cells via PC axon collaterals, and neurons in the deep cerebellar nuclei (DCN) via PC primary axons. PC-Lugaro/globular cell connections form a cerebellar cortical microcircuit, which is driven by serotonin and noradrenaline. PCs’ primary outputs control not only firing but also synaptic plasticity of DCN neurons following the integration of excitatory and inhibitory inputs in the cerebellar cortex. Thus, strong PC-mediated inhibition is involved in cerebellar functions as a key regulator of cerebellar neural networks. In this review, we focus on physiological characteristics of GABAergic transmission from PCs. First, we introduce monoaminergic modulation of GABAergic transmission at synapses of PC-Lugaro/globular cell as well as PC-large glutamatergic DCN neuron, and a Lugaro/globular cell-incorporated microcircuit. Second, we review the physiological roles of perineuronal nets (PNNs), which are organized components of the extracellular matrix and enwrap the cell bodies and proximal processes, in GABA release from PCs to large glutamatergic DCN neurons and in cerebellar motor learning. Recent evidence suggests that alterations in PNN density in the DCN can regulate cerebellar functions.
Oxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors
Authors: Lefevre Arthur , Benusiglio Diego , Tang Yan , Krabichler Quirin , Charlet Alexandre , Grinevich Valery
Published: June 2021

Oxytocin (OT) is a neuropeptide produced by hypothalamic neurons and is known to modulate social behavior among other functions. Several experiments have shown that OT modulates neuronal activity in many brain areas, including sensory cortices. OT neurons thus project axons to various cortical and subcortical structures and activate neuronal subpopulations to increase the signal-to-noise ratio, and in turn, increases the saliency of social stimuli. Less is known about the origin of inputs to OT neurons, but recent studies show that cells projecting to OT neurons are often located in regions where the OT receptor (OTR) is expressed. Thus, we propose the existence of reciprocal connectivity between OT neurons and extrahypothalamic OTR neurons to tune OT neuron activity depending on the behavioral context. Furthermore, the latest studies have shown that OTR-expressing neurons located in social brain regions also project to other social brain regions containing OTR-expressing neurons. We hypothesize that OTR-expressing neurons across the brain constitute a common network coordinated by OT.
Cortical Electrical Stimulation Ameliorates Traumatic Brain Injury-Induced Sensorimotor and Cognitive Deficits in Rats
Authors: Kuo Chi-Wei , Chang Ming-Yuan , Liu Hui-Hua , He Xiao-Kuo , Chan Shu-Yen , Huang Ying-Zu , Peng Chih-Wei , Chang Pi-Kai , Pan Chien-Yuan , Hsieh Tsung-Hsun
Published: June 2021

Objective: Individuals with different severities of traumatic brain injury (TBI) often suffer long-lasting motor, sensory, neurological, or cognitive disturbances. To date, no neuromodulation-based therapies have been used to manage the functional deficits associated with TBI. Cortical electrical stimulation (CES) has been increasingly developed for modulating brain plasticity and is considered to have therapeutic potential in TBI. However, the therapeutic value of such a technique for TBI is still unclear. Accordingly, an animal model of this disease would be helpful for mechanistic insight into using CES as a novel treatment approach in TBI. The current study aims to apply a novel CES scheme with a theta-burst stimulation (TBS) protocol to identify the therapeutic potential of CES in a weight drop-induced rat model of TBI.

Methods: TBI rats were divided into the sham CES treatment group and CES treatment group. Following early and long-term CES intervention (starting 24 h after TBI, 1 session/day, 5 days/week) in awake TBI animals for a total of 4 weeks, the effects of CES on the modified neurological severity score (mNSS), sensorimotor and cognitive behaviors and neuroinflammatory changes were identified.

Results: We found that the 4-week CES intervention significantly alleviated the TBI-induced neurological, sensorimotor, and cognitive deficits in locomotor activity, sensory and recognition memory. Immunohistochemically, we found that CES mitigated the glial fibrillary acidic protein (GFAP) activation in the hippocampus.

Conclusion: These findings suggest that CES has significant benefits in alleviating TBI-related symptoms and represents a promising treatment for TBI.
A Systematic Review of the Potential Implication of Infectious Agents in Myasthenia Gravis
Authors: Leopardi Victoria , Chang Yu-Mei , Pham Andrew , Luo Jie , Garden Oliver A.
Published: June 2021

Background: Myasthenia gravis (MG) is an autoimmune disorder of unknown etiology in most patients, in which autoantibodies target components of neuromuscular junctions and impair nerve to muscle transmission.

Objective: To provide a synthesis of the evidence examining infectious agents associated with the onset of MG.

Hypothesis: We hypothesized that microbes play a pathogenic role in the initiation of MG. For clinical cases, the onset of clinical signs is used as a proxy for the true onset of autoimmunity.

Methods: We searched PubMed and Web of Science. Papers captured through database searching (n = 827) were assessed, yielding a total of 42 publications meeting the inclusion and exclusion criteria. An additional 6 papers were retrieved from the reference lists of relevant articles. For each pathogen, an integrated metric of evidence (IME) value, from minus 8 to plus 8, was computed based on study design, quality of data, confidence of infectious disease diagnosis, likelihood of a causal link between the pathogen and MG, confidence of MG diagnosis, and the number of infected patients. Negative IME values corresponded to studies providing evidence against a role for microbes as triggers of MG.

Results: One hundred and sixty-nine myasthenic patients infected with 21 different pathogens were documented. Epstein-Barr virus (median = 4.71), human papillomavirus (median = 4.35), and poliovirus (median = 4.29) demonstrated the highest IME values. The total median IME was 2.63 (mean = 2.53; range −3.79–5.25), suggesting a general lack of evidence for a causal link.

Conclusions: There was a notable absence of mechanistic studies designed to answer this question directly. The question of the pathogenic contribution of microbes to MG remains open.
Can Spectral Power Be Used as a Candidate Seizure Marker of the Periodic Discharges Pattern?
Authors: Chen Jianhua , Zhou Xiangqin , Jin Liri , Lu Qiang , Sun Heyang , Liu Qing , Huang Yan
Published: June 2021

Introduction: It remains controversial whether the periodic discharges (PDs) pattern is an ictal or interictal phenomenon. The aims of the study are to apply time-frequency and power spectrum analysis to study the PDs pattern and prediction of seizures.

Methods: We retrospectively searched continuous electroencephalography (cEEG) recordings to identify patients exhibiting the PDs pattern. Artifact-free cEEG segments demonstrating the PDs pattern with stable baselines were chosen for time-frequency and power spectrum analysis.

Results: In total, 72 patients (1.3%) exhibited the PDs pattern, with a mean age 36.0 ± 20.7 years (range, 8–76 years). The median spectral power of PDs with a length of 60 s was 70.94 μV2 and that of PDs with a length of 20 s was 195.80 μV2. During follow-up, patients with spectral power of PDs of length 60 and 20 s lower than 28.65 and 36.09 μV2, respectively, exhibited no seizure. For predicting seizures, when the spectral power for PDs of 60 and 20 s equaled to 17.26 and 21.40 μV2, respectively, the diagnostic sensitivity was 100% and specificity was 86%. The locations of maximal spectral power of PDs, crude seizure onset zone (SOZ) judged from scalp EEG, and the most prominent regions of hyper- or hypo-metabolism on FDG-PET were congruent.

Conclusions: Spectral power might be a candidate seizure marker of the PDs pattern. High spectral power predicted a high risk of seizures, and low spectral power was associated with a low risk of seizures.
SENSE-Cog Asia: A Feasibility Study of a Hearing Intervention to Improve Outcomes in People With Dementia
Authors: Sheikh Saima , Tofique Sehrish , Zehra Nosheen , Amjad Rabia , Rasheed Maham , Usman Maria , Lal Shanker , Hooper Emma , Miah Jahanara , Husain Nusrat , Jafri Hussain , Chaudhry Nasim , Leroi Iracema
Published: June 2021

Background: There are few evidence-based non-pharmacological interventions adapted for people with dementia (PwD) in lower- and middle-income countries (LMIC). Thus, there is value in culturally adapting existing interventions from other settings. One such intervention for PwD involves hearing rehabilitation, which may improve dementia-related outcomes.

Objective: To culturally adapt and evaluate the feasibility and acceptability of a multi-faceted hearing support intervention to enhance quality of life in PwD for a LMIC setting, Pakistan.

Design: This was a study in three phases: (1) training and capacity building to deliver the study, including Patient and Public Involvement (PPI); (2) cultural adaptation of the intervention; and (3) delivery of a single-group feasibility study with a pre-test post-test design.

Setting: Home-based intervention, in two cities of Pakistan.

Participants: Adults aged ≥ 60 with mild-moderate dementia and uncorrected or partially corrected hearing impairment, and their study partners (n = 14).

Intervention: An adapted hearing support intervention (HSI) comprising a full assessment of hearing function, fitting of hearing aids, and home-based support from a “hearing support practitioner.”

Outcomes: Ratings of the feasibility of the study procedures, and acceptability/tolerability of the adapted intervention were ascertained through questionnaires, participant diaries, therapist logbooks and semi-structured interviews. A signal of effectiveness of the intervention was also explored using a battery of dementia-related outcome measures.

Results: Following cultural adaptation and capacity building for study conduct and delivery, we successfully implemented all intervention components in most participants, which were well-received and enacted by participant dyads. Acceptability (i.e., understanding, motivation, sense of achievement) and tolerability (i.e., effort, fatigue) ratings and safety of the intervention were within a priori target ranges. Recruitment and retention targets required improvement, due to the COVID-19 pandemic outbreak, as well as the lack of a clear clinical diagnostic pathway for dementia in both sites. Areas for future modification were clearly identified, including: the assessment/delivery logistics circuit; procedures for arranging visits; communication among referring clinicians and the study team.

Conclusion: This is the first study in a LMIC of sensory enhancement to improve dementia outcomes. Positive feasibility, acceptability and tolerability findings suggest that a full-scale effectiveness trial, with certain modifications is warranted.
Comparison of Neurite Orientation Dispersion and Density Imaging and Two-Compartment Spherical Mean Technique Parameter Maps in Multiple Sclerosis
Authors: Johnson Daniel , Ricciardi Antonio , Brownlee Wallace , Kanber Baris , Prados Ferran , Collorone Sara , Kaden Enrico , Toosy Ahmed , Alexander Daniel C. , Gandini Wheeler-Kingshott Claudia A. M. , Ciccarelli Olga , Grussu Francesco
Published: June 2021

Background: Neurite orientation dispersion and density imaging (NODDI) and the spherical mean technique (SMT) are diffusion MRI methods providing metrics with sensitivity to similar characteristics of white matter microstructure. There has been limited comparison of changes in NODDI and SMT parameters due to multiple sclerosis (MS) pathology in clinical settings.

Purpose: To compare group-wise differences between healthy controls and MS patients in NODDI and SMT metrics, investigating associations with disability and correlations with diffusion tensor imaging (DTI) metrics.

Methods: Sixty three relapsing-remitting MS patients were compared to 28 healthy controls. NODDI and SMT metrics corresponding to intracellular volume fraction (vin), orientation dispersion (ODI and ODE), diffusivity (D) (SMT only) and isotropic volume fraction (viso) (NODDI only) were calculated from diffusion MRI data, alongside DTI metrics (fractional anisotropy, FA; axial/mean/radial diffusivity, AD/MD/RD). Correlations between all pairs of MRI metrics were calculated in normal-appearing white matter (NAWM). Associations with expanded disability status scale (EDSS), controlling for age and gender, were evaluated. Patient-control differences were assessed voxel-by-voxel in MNI space controlling for age and gender at the 5% significance level, correcting for multiple comparisons. Spatial overlap of areas showing significant differences were compared using Dice coefficients.

Results: NODDI and SMT show significant associations with EDSS (standardised beta coefficient −0.34 in NAWM and −0.37 in lesions for NODDI vin; 0.38 and −0.31 for SMT ODE and vin in lesions; p < 0.05). Significant correlations in NAWM are observed between DTI and NODDI/SMT metrics. NODDI vin and SMT vin strongly correlated (r = 0.72, p < 0.05), likewise NODDI ODI and SMT ODE (r = −0.80, p < 0.05). All DTI, NODDI and SMT metrics detect widespread differences between patients and controls in NAWM (12.57% and 11.90% of MNI brain mask for SMT and NODDI vin, Dice overlap of 0.42).

Data Conclusion: SMT and NODDI detect significant differences in white matter microstructure between MS patients and controls, concurring on the direction of these changes, providing consistent descriptors of tissue microstructure that correlate with disability and show alterations beyond focal damage. Our study suggests that NODDI and SMT may play a role in monitoring MS in clinical trials and practice.
Transcranial Auricular Vagus Nerve Stimulation (taVNS) and Ear-EEG: Potential for Closed-Loop Portable Non-invasive Brain Stimulation
Authors: Ruhnau Philipp , Zaehle Tino
Published: June 2021

No matter how hard we concentrate, our attention fluctuates – a fact that greatly affects our success in completing a current task. Here, we review work from two methods that, in a closed-loop manner, have the potential to ameliorate these fluctuations. Ear-EEG can measure electric brain activity from areas in or around the ear, using small and thus portable hardware. It has been shown to capture the state of attention with high temporal resolution. Transcutaneous auricular vagus nerve stimulation (taVNS) comes with the same advantages (small and light) and critically current research suggests that it is possible to influence ongoing brain activity that has been linked to attention. Following the review of current work on ear-EEG and taVNS we suggest that a combination of the two methods in a closed-loop system could serve as a potential application to modulate attention.
Comparison of Visual Neuroadaptations After Multifocal and Monofocal Intraocular Lens Implantation
Authors: Zhang Li , Lin Duoru , Wang Yong , Chen Wan , Xiao Wei , Xiang Yi , Zhu Yi , Chen Chuan , Dong Xiying , Liu Yizhi , Chen Weirong , Lin Haotian
Published: June 2021

Visual neuroadaptation is believed to play an important role in determining the final visual outcomes following intraocular lens (IOL) implantation. To investigate visual neuroadaptation in patients with age-related cataracts (ARCs) after phacoemulsification with multifocal and monofocal IOL implantation, we conducted a prospective, controlled clinical trial in Zhongshan Ophthalmology Center. This study included 22 patients with bilateral ARCs: 11 patients underwent phacoemulsification and multifocal IOL (Mu-IOL) implantation, and 11 patients underwent phacoemulsification and monofocal IOL (Mo-IOL) implantation. Visual disturbances (glare and halos), visual function (including visual acuity, retinal straylight, contrast sensitivity, and visual evoked potentials) and visual cortical function (fractional amplitude of low-frequency fluctuations, fALFF) in Bowman’s areas 17–19 as the region of interest were assessed before and after surgeries. The results showed that the fALFF values of the visual cortex in the Mu-IOL group decreased at 1 week postoperatively and recovered to baseline at 3 months and then improved at 6 months, compared with preoperative levels (at a whole-brain threshold of P < 0.05, AlphaSim-corrected, voxels > 228, repeated measures analysis of variance). Significantly increased fALFF values in the visual cortex were detected 1 week after surgery in the Mo-IOL group and decreased to baseline at 3 and 6 months. The fALFF of the lingual gyrus was negatively correlated with visual disturbances (P < 0.05). To conclude, early postoperative visual neuroadaptation was detected in the Mu-IOL group by resting-state fMRI analysis. The different changing trends of postoperative fALFF values in the two groups indicated distinct neuroadaptations patterns after Mu-IOL and Mo-IOL implantation.
Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer’s Disease
Authors: Le Douce Juliette , Delétage Nathalie , Bourdès Valérie , Lemarchant Sighild , Godfrin Yann
Published: June 2021

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of older people worldwide and is characterized by a progressive deterioration of cognitive functions, including learning and memory. There are currently very few approved treatments (i.e., acetylcholinesterase inhibitors such as donepezil), all of which are limited to the symptomatic control of AD and are associated with side effects that may result in discontinuation of treatment. Therefore, there is an urgent need to develop disease-modifying treatments to prevent AD-induced cognitive deficits. Subcommissural organ (SCO)-spondin is a brain-specific glycoprotein produced during embryogenesis and has a substantial impact on neuronal development. In the current study, we sought to evaluate the protective effects of the linear (NX210) and cyclized (NX210c) forms of a SCO-spondin-derived peptide on learning and memory in a mouse model of AD. Mice received an intracerebroventricular injection of Aβ25–35 oligomers and were subsequently treated with intraperitoneal injections of vehicle, NX210 or NX210c of different doses (ranging from 0.1 to 30 mg/kg) and therapy paradigms (early or late stand-alone treatments, combination with donepezil or second-line treatment). Cognitive function was evaluated using Y-Maze, step-through latency passive avoidance (STPA) and Morris water maze (MWM) tests for up to 4 months. Early stage daily treatment with NX210 and NX210c decreased the levels of common pathological markers and features of AD, including Aβ1–42, phosphorylated-tau, inflammation, astrogliosis and lipid peroxidation. Meanwhile, use of these drugs increased the levels of synaptophysin and postsynaptic density protein 95. Regardless of the experimental paradigm used, NX210 and NX210c prevented Aβ25–35-induced decrease in spontaneous alternations (Y-Maze) and step-through latency into the dark compartment (STPA), and Aβ25–35-induced increase in time needed to locate the immersed platform during the learning phase and decrease in time spent in the target quadrant during the retention phase (MWM). Interestingly, this study provides the novel evidence that the native and oxidized cyclic forms of the SCO-spondin-derived peptide reduce pathological factors associated with AD and restore learning and memory at both early and late disease stages. Overall, this study sheds light on the therapeutic potential of this innovative disease-modifying peptide to restore memory function in patients with AD.
Directions of Deep Brain Stimulation for Epilepsy and Parkinson’s Disease
Authors: Wu Ying-Chang , Liao Ying-Siou , Yeh Wen-Hsiu , Liang Sheng-Fu , Shaw Fu-Zen
Published: June 2021

Background

Deep brain stimulation (DBS) is an effective treatment for movement disorders and neurological/psychiatric disorders. DBS has been approved for the control of Parkinson disease (PD) and epilepsy.

Objectives

A systematic review and possible future direction of DBS system studies is performed in the open loop and closed-loop configuration on PD and epilepsy.

Methods

We searched Google Scholar database for DBS system and development. DBS search results were categorized into clinical device and research system from the open-loop and closed-loop perspectives.

Results

We performed literature review for DBS on PD and epilepsy in terms of system development by the open loop and closed-loop configuration. This study described development and trends for DBS in terms of electrode, recording, stimulation, and signal processing. The closed-loop DBS system raised a more attention in recent researches.

Conclusion

We overviewed development and progress of DBS. Our results suggest that the closed-loop DBS is important for PD and epilepsy.