bluuebunny/crossref_metadata_2025_split huggingface dataset:
Face and Content Validity of an Automated Vehicle Road Course and a Corresponding Simulation Scenario
Authors: Classen Sherrilene , Wersal James , Mason Justin , Rogers Jason , Sisiopiku Virginia 
Published: January 2021

Introduction: Automated vehicle use is rapidly expanding globally. Florida is one of the leading states for researching, testing, implementing, and operating automated vehicles. Although driving simulators may create an opportunity to assess user behaviors related to automated vehicles, their use in this context is not well-documented.Objectives: This study examined face and content validity of an on-road automated shuttle route and its congruence to a driving simulator scenario representing the on-road route.Methodology: Face validity (i.e., clarity, understandability, congruence) was examined directly by members of the Institute for Mobility, Activity, and Participation. Content validity was assessed via a content validity index (CVI) based on inputs from experts who represented a variety of disciplines. These included computer and information science, engineering, transportation engineering, rehabilitation science, industrial and systems engineering, experimental psychology, and driver rehabilitation science.Findings: Face validity resulted in feedback pertaining to traffic, environment, hazards, fidelity, and “other” recommendations. Six of the recommendations were used to enhance the simulator scenario. For content validity, the CVI scale was equal to 0.83 and was above the acceptable threshold of 0.80. However, on the item level, two items, i.e., traffic flow (I-CVI = 0.57) and seat direction (I-CVI = 0.67), were rated lower than anticipated. The ratings resulted in implementing enhancements to the driving simulator scenario.Conclusion: Automated vehicle on-road routes can be replicated in a driving simulator scenario but require a process of examining the face and content validity and refining the developed scenario as needed to ensure reasonable accuracy.
Investigating Causal Relations Between Sleep-Related Traits and Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study
Authors: Gao Xue , Sun Heli , Zhang Yu , Liu Long , Wang Juping , Wang Tong 
Published: January 2021

ObjectiveExtensive literature put forward the link between sleep and type 2 diabetes mellitus (T2DM), however, little is known about the underlying causality of the associations. Here we aim to assess the causal relationships between five major sleep-related traits and T2DM.Design, Setting, and ParticipantsTwo-sample Mendelian randomization (MR) was utilized to investigate the potential causal relations. Independent genetic variants associated with five sleep-related phenotypes—insomnia, sleep duration, short sleep duration, long sleep duration, and morningness—were chosen as instrumental variables to estimate the causal associations with T2DM. Summary statistics were acquired from the genome-wide association studies of UK Biobank and 23andMe (for sleep-related measures), the DIAbetes Genetics Replication And Meta-analysis and the FinnGen (for T2DM).Main MethodsIndividual Cochran’s Q statistic was applied to remove the pleiotropic instruments, global Q statistics and MR-Egger regression were adopted to test for the global heterogeneity and horizontal pleiotropy of the screened instruments, respectively. Two T2DM cohorts were selected to analyze their associations with sleep traits. A modified inverse variance weighted (IVW) estimate was performed to combine the ratio estimators from each instrument and acquire the causal estimate, alternative methods including IVW with first-order weights, simple and weighted median estimations, and MR-Egger regression were conducted as sensitivity analyses, to ensure the robustness and solidity of the findings.ResultsTwo-sample MR supported findings for an adverse effect of genetically predicted insomnia on T2DM risk (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.09–1.19, p = 1.29E–08) at the Bonferroni-adjusted level of significance (p &lt; 0.005). We further investigated the causal role of T2DM on insomnia but obtained a non-significant estimation. There was also little evidence for the causal effect of other sleep-related measures on T2DM. Results were largely consistent when leveraging two different T2DM cohorts, and were robust among various sensitivity analyses.ConclusionFindings provide significant evidence for an adverse effect of insomnia on T2DM risk. The study extends fundamental knowledge to further understanding of the pathophysiological mechanisms of T2DM, and points out the non-negligible role of insomnia on epidemiologic intervention and clinical therapeutics of T2DM.
Highly Sensitive Flow Cytometric Detection of Residual B-Cells After Rituximab in Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis Patients
Authors: van Dam Laura S. , Oskam Jelle M. , Kamerling Sylvia W. A. , Arends Eline J. , Bredewold O. W. , Berkowska Magdalena A. , van Dongen Jacques J. M. , Rabelink Ton J. , van Kooten Cees , Teng Y. K. Onno 
Published: January 2021

BackgroundB-cell depletion with rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Nevertheless, relapses are frequent after RTX, often preceded by B-cell repopulation suggesting that residual autoreactive B-cells persist despite therapy. Therefore, this study aimed to identify minimal residual autoimmunity (MRA) in the B-cell compartment of AAV patients treated with RTX.MethodsEuroFlow-based highly-sensitive flow cytometry (HSFC) was employed to study B-cell and plasma cell (PC) subsets in-depth in AAV patients before and after RTX treatment. Additionally, peripheral blood mononuclear cells (PBMCs) of these RTX-treated AAV patients were cultured and in vitro stimulated with CpG, IL-2, and IL-21 to induce antibody-secreting cells (ASC). (ANCA)-IgG was measured in these supernatants by ELISA.ResultsBy employing EuroFlow-based HSFC, we detected circulating CD19+ B-cells at all timepoints after RTX treatment, in contrast to conventional low-sensitive flow cytometry. Pre-germinal center (Pre-GC) B-cells, memory B-cells and CD20+CD138− plasmablasts (PBs) were rapidly and strongly reduced, while CD20−CD138− PrePC and CD20-CD138+ mature (m)PCs were reduced slower and remained detectable. Both memory B-cells and CD20− PCs remained detectable after RTX. Serum ANCA-IgG decreased significantly upon RTX. Changes in ANCA levels strongly correlated with changes in naive, switched CD27+ and CD27− (double-negative) memory B-cells, but not with plasma cells. Lastly, we demonstrated in vitro ANCA production by AAV PBMCs, 24 and 48 weeks after RTX treatment reflecting MRA in the memory compartment of AAV patients.ConclusionWe demonstrated that RTX induced strong reductions in circulating B-cells, but never resulted in complete B-cell depletion. Despite strongly reduced B-cell numbers after RTX, ANCA-specific memory B-cells were still detectable in AAV patients. Thus, MRA is identifiable in AAV and can provide a potential novel approach in personalizing RTX treatment in AAV patients.
DGCR8/miR-106 Axis Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinomas by Downregulating RUNX3
Authors: Zhang Chunlin , Chen Hangqi , Deng Zeyi , Long Dan , Xu Li , Liu Zhaohui 
Published: January 2021

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignant tumor worldwide, and the radiotherapy effect is strongly associated with human papillomavirus (HPV) infection. Therefore, the aim of our study was to analyze the mechanism of HPV E7 and its effects on radiosensitivity in HNSCC cells.Methods: The mRNA expression of DiGeorge syndrome critical region gene 8 (DGCR8), has-miR-106a, and Runt-related transcription factor 3 (RUNX3) was examined by quantitative real-time PCR (RT-qPCR). The protein expression of DGCR8, E7, RUNX3, caspase-3/cleaved caspase-3, poly(ADP-ribose) polymerase (PARP)/cleaved PARP, and γH2AX was measured by Western blot. The expression level of DGCR8 was measured by immunofluorescence assay. Starbase database (http://starbase.sysu.edu.cn/) was used to analyze the correlation between has-miR-106a-5p and DGCR8. TargetScan database (http://www.targetscan.org/vert_72/) was adopted to calculate the prediction of binding sites. Radiosensitivity was evaluated through clone formation assays and Cell Counting Kit-8 (CCK-8) assays.Results: In our study, we found that the mRNA and protein expression levels of HPV E7 and DGCR8 in HPV-positive HNSCC cells were higher than those in HPV-negative cells. The expression of DGCR8 was increased in FaDu and UM-SCC-4 with E7 overexpression, while the expression of DGCR8 was decreased in UM-SCC-47 and UPCI-SCC-090 with E7 silence. The miR-106a expression was increased after DGCR8 overexpression in FaDu and UM-SCC-4. However, the miR-106a expression was decreased in UM-SCC-47 and UPCI-SCC-090 with E7 silence. In radiation conditions, clone formation assays found that less clones formed in FaDu and UM-SCC-4 cells subsequent to silencing DGCR8 or miR-106a than that in the control group, and more clones were formed in UM-SCC-47 and UPCI-SCC-090 cells overexpressing DGCR8 or miR-106a than that in the control group. Luciferase reporter gene assays verified that miR-106a targeted the 3′ untranslated region (UTR) of RUNX3 mRNA. MiR-106a overexpression resulted in a decrease in RUNX3 expression, and miR-106a silence increased RUNX3 expression. Rescue experiments conducted with miR-106a inhibitor restored radiation resistance and reduced DNA damage in radiation condition.Conclusions: Our study indicated that HPV E7 activated DGCR8/miR-106a/RUNX3 axis to enhance radiation sensitivity and provided directions for targeted therapeutic interventions.
The Human Takes It All: Humanlike Synthesized Voices Are Perceived as Less Eerie and More Likable. Evidence From a Subjective Ratings Study
Authors: Kühne Katharina , Fischer Martin H. , Zhou Yuefang 
Published: January 2021

Background:The increasing involvement of social robots in human lives raises the question as to how humans perceive social robots. Little is known about human perception of synthesized voices.Aim:To investigate which synthesized voice parameters predict the speaker's eeriness and voice likability; to determine if individual listener characteristics (e.g., personality, attitude toward robots, age) influence synthesized voice evaluations; and to explore which paralinguistic features subjectively distinguish humans from robots/artificial agents.Methods:95 adults (62 females) listened to randomly presented audio-clips of three categories: synthesized (Watson, IBM), humanoid (robotSophia, Hanson Robotics), and human voices (five clips/category). Voices were rated on intelligibility, prosody, trustworthiness, confidence, enthusiasm, pleasantness, human-likeness, likability, and naturalness. Speakers were rated on appeal, credibility, human-likeness, and eeriness. Participants' personality traits, attitudes to robots, and demographics were obtained.Results:The human voice and human speaker characteristics received reliably higher scores on all dimensions except for eeriness. Synthesized voice ratings were positively related to participants' agreeableness and neuroticism. Females rated synthesized voices more positively on most dimensions. Surprisingly, interest in social robots and attitudes toward robots played almost no role in voice evaluation. Contrary to the expectations of an uncanny valley, when the ratings of human-likeness for both the voice and the speaker characteristics were higher, they seemed less eerie to the participants. Moreover, when the speaker's voice was more humanlike, it was more liked by the participants. This latter point was only applicable to one of the synthesized voices. Finally, pleasantness and trustworthiness of the synthesized voice predicted the likability of the speaker's voice. Qualitative content analysis identified intonation, sound, emotion, and imageability/embodiment as diagnostic features.Discussion:Humans clearly prefer human voices, but manipulating diagnostic speech features might increase acceptance of synthesized voices and thereby support human-robot interaction. There is limited evidence that human-likeness of a voice is negatively linked to the perceived eeriness of the speaker.
Deep Learning-Based Screening Test for Cognitive Impairment Using Basic Blood Test Data for Health Examination
Authors: Sakatani Kaoru , Oyama Katsunori , Hu Lizhen 
Published: January 2021

Background: In order to develop a new screening test of cognitive impairment, we studied whether cognitive function can be estimated from basic blood test data by applying deep learning models. This model was constructed based on the effects of systemic metabolic disorders on cognitive function.Methods: We employed a deep neural network (DNN) to predict cognitive function based on subject's age and blood test items (23 items). We included 202 patients (73.48 ± 13.1 years) with various systemic metabolic disorders for training of the DNN model, and the following groups for validation of the model: (1) Patient group, 65 patients (73.6 ± 11.0 years) who were hospitalized for rehabilitation after stroke; (2) Healthy group, 37 subjects (62.0 ± 8.6 years); (3) Health examination group, 165 subjects (54.0 ± 8.6 years) admitted for a health examination. The subjects underwent the Mini-Mental State Examination (MMSE).Results: There were significant positive correlations between the predicted MMSE scores and ground truth scores in the Patient and Healthy groups (r = 0.66, p &lt; 0.001). There were no significant differences between the predicted MMSE scores and ground truth scores in the Patient group (p &gt; 0.05); however, in the Healthy group, the predicted MMSE scores were slightly, but significantly, lower than the ground truth scores (p &lt; 0.05). In the Health examination group, the DNN model classified 94 subjects as normal (MMSE = 27–30), 67 subjects as having mild cognitive impairment (24–26), and four subjects as having dementia (≤ 23). In 37 subjects in the Health examination group, the predicted MMSE scores were slightly lower than the ground truth MMSE (p &lt; 0.05). In contrast, in the subjects with neurological disorders, such as subarachnoid hemorrhage, the ground truth MMSE scores were lower than the predicted scores.Conclusions: The DNN model could predict cognitive function accurately. The predicted MMSE scores were significantly lower than the ground truth scores in the Healthy and Health examination groups, while there was no significant difference in the Patient group. We suggest that the difference between the predicted and ground truth MMSE scores was caused by changes in atherosclerosis with aging, and that applying the DNN model to younger subjects may predict future cognitive impairment after the onset of atherosclerosis.
Anodal Transcranial Direct Current Stimulation of Anterior Cingulate Cortex Modulates Subcortical Brain Regions Resulting in Cognitive Enhancement
Authors: Khan Ahsan , Wang Xin , Ti Chun Hang Eden , Tse Chun-Yu , Tong Kai-Yu 
Published: January 2021

Transcranial direct current stimulation (tDCS) has been widely utilized in research settings and modulates brain activity. The application of anodal tDCS on the prefrontal cortex has indicated improvement in cognitive functioning. The cingulate cortex, situated in the medial aspect of the prefrontal cortex, has been identified as a core region performing cognitive functions. Most of the previous studies investigating the impact of stimulation on the prefrontal cortex stimulated the dorsolateral prefrontal cortex (DLPFC), however, the impact of stimulation on cingulate has not been explored. The current study investigates the effect of stimulation on the resting-state functional connectivity of the anterior cingulate cortex with other regions of the brain and changes in behavioral results in a color-word Stroop task, which has repeatedly elicited activation in different regions of the cingulate. Twenty subjects were randomly assigned to the experimental and sham group, and their medial prefrontal area was stimulated using MRI compatible tDCS. Resting-state functional magnetic resonance imaging (rs-fMRI) and cognitive Stroop task were monitored before, during, and after the stimulation. Neuroimaging results indicated a significant decrease in resting-state functional connectivity in the experimental group during and after stimulation as compared to before stimulation in two clusters including right insular cortex, right central operculum cortex, right frontal operculum cortex and right planum polare with the left anterior cingulate cortex (L-ACC) selected as the seed. The behavioral results indicated a significant decrease in reaction time (RT) following stimulation in the experimental group compared to the sham group. Moreover, the change in functional connectivity in subcortical regions with L-ACC as the seed and change in RT was positively correlated. The results demonstrated that ACC has a close functional relationship with the subcortical regions, and stimulation of ACC can modulate these connections, which subsequently improves behavioral performance, thus, providing another potential target of stimulation for cognitive enhancement.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04318522.
Holly (Ilex latifolia Thunb.) Polyphenols Extracts Alleviate Hepatic Damage by Regulating Ferroptosis Following Diquat Challenge in a Piglet Model
Authors: He Pengwei , Hua Hongwei , Tian Wei , Zhu Huiling , Liu Yulan , Xu Xiao 
Published: January 2021

Background: Holly (Ilex latifolia Thunb.) polyphenols extracts (HPE) contain high amounts of polyphenols, including phenolic acids, triterpenoids, tannic acids, and so on, which have strong antioxidant function. This experiment was aimed to explore the protective effect and mechanism of HPE against hepatic injury induced by diquat.Methods: Thirty-two weaned piglets were allotted by a 2 × 2 factorial experiment design with diet type (basal diet vs. HPE diet) and diquat challenge (saline vs. diquat). On the 21st day, piglets were injected with diquat or saline. One week later, blood samples were collected. Then all piglets were slaughtered and hepatic samples were collected.Results: Dietary HPE supplementation improves hepatic morphology, the activities of plasma aspartate aminotransferase, alanine aminotransferase, and glutamyl transpeptidase, and enhances hepatic anti-oxidative capacity, while it regulates the expression of ferroptosis mediators (transferrin receptor protein 1, heat shock protein beta 1, solute carrier family 7 member 11, and glutathione peroxidase 4) in diquat-challenged piglets.Conclusion: These results indicate that dietary HPE supplementation enhances hepatic morphology and function, which is involved in modulating antioxidant capacity and ferroptosis.
Global, Regional, and National Burden of Chronic Myeloid Leukemia, 1990–2017: A Systematic Analysis for the Global Burden of Disease Study 2017
Authors: Lin Qingqing , Mao Liping , Shao Li , Zhu Li , Han Qingmei , Zhu Honghu , Jin Jie , You Liangshun 
Published: January 2021

BackgroundWith the advent of tyrosine kinase inhibitors (TKIs), the prognosis of chronic myeloid leukemia (CML) seems to have dramatically improved over the last two decades. Accurate information of the global burden of CML is critical for direct health policy and healthcare resource allocation in the era of high-cost TKI therapy.ObjectiveThis study aimed to evaluate the health burden of CML at global, regional, and national levels from 1990 to 2017.MethodsWe collected data of CML between 1990 and 2017 from the Global Burden of Disease (GBD) study 2017 including, annual incidence, disease-related mortality, and disability-adjusted life-years (DALY), and the corresponding age-standardized rates (ASRs). To summarize the results, countries were categorized by sociodemographic index (SDI) quintiles and 21 GBD regions.ResultsIn 2017, an estimated 34,179 [95% Uncertainty Interval (UI), 31,516–36,714) incident cases of CML were recorded, and 24,054 (95%UI, 22,233–26,072) CML-related deaths were reported worldwide. Both, the age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) steadily decreased from 1990 to 2017, with estimated annual percentage changes (EAPCs) of −2.39 (95%UI, −8.13–3.71) and −2.74 (95%UI, −9.31–4.31), respectively. The global incidence and mortality of CML in males were higher than that in females. The ASRs varied substantially across regions, with the highest burden in Andean Latin America, Central Sub-Saharan Africa, and Southeast Asia. Besides, the ASRs decreased most obviously in the high-SDI regions compared to non-high-SDI regions. Moreover, the lower the SDI, the higher was the proportion of deaths in the younger age groups.ConclusionDespite the decreasing trends of ASRs of CML from 1990 to 2017, the health-related burden of CML remains a challenge for the low-SDI regions. These findings highlight that appropriate strategies should be adopted in low-SDI countries to reduce the ASRs of CML.
A Targeted Gene Panel for Circulating Tumor DNA Sequencing in Neuroblastoma
Authors: Cimmino Flora , Lasorsa Vito Alessandro , Vetrella Simona , Iolascon Achille , Capasso Mario 
Published: January 2021

BackgroundLiquid biopsies do not reflect the complete mutation profile of the tumor but have the potential to identify actionable mutations when tumor biopsies are not available as well as variants with low allele frequency. Most retrospective studies conducted in small cohorts of pediatric cancers have illustrated that the technology yield substantial potential in neuroblastoma.AimThe molecular landscape of neuroblastoma harbors potentially actionable genomic alterations. We aimed to study the utility of liquid biopsy to characterize the mutational landscape of primary neuroblastoma using a custom gene panel for ctDNA targeted sequencing.MethodsTargeted next-generation sequencing (NGS) was performed on ctDNA of 11 patients with primary neuroblastoma stage 4. To avoid the detection of false variants, we used UMIs (unique molecular identifiers) for the library construction, increased the sequencing depth and developed ad hoc bioinformatic analyses including the hard filtering of the variant calls.ResultsWe identified 9/11 (81.8%) patients who carry at least one pathogenic variation. The most frequently mutated genes were KMT2C (five cases), NOTCH1/2 (four cases), CREBBP (three cases), ARID1A/B (three cases), ALK (two cases), FGFR1 (two cases), FAT4 (two cases) and CARD11 (two cases).ConclusionsWe developed a targeted NGS approach to identify tumor-specific alterations in ctDNA of neuroblastoma patients. Our results show the reliability of our approach to generate genomic information which can be integrated with clinical and pathological data at diagnosis.