bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise-Induced Benefits for Alzheimer’s Disease by Stimulating Mitophagy and Improving Mitochondrial Function
Authors: Liang Jiling , Wang Cenyi , Zhang Hu , Huang Jielun , Xie Juying , Chen Ning
Published: October 2021

Neurons are highly specialized post-mitotic cells that are inherently dependent on mitochondria due to their higher bioenergetic demand. Mitochondrial dysfunction is closely associated with a variety of aging-related neurological disorders, such as Alzheimer’s disease (AD), and the accumulation of dysfunctional and superfluous mitochondria has been reported as an early stage that significantly facilitates the progression of AD. Mitochondrial damage causes bioenergetic deficiency, intracellular calcium imbalance and oxidative stress, thereby aggravating β-amyloid (Aβ) accumulation and Tau hyperphosphorylation, and further leading to cognitive decline and memory loss. Although there is an intricate parallel relationship between mitochondrial dysfunction and AD, their triggering factors, such as Aβ aggregation and hyperphosphorylated Tau protein and action time, are still unclear. Moreover, many studies have confirmed abnormal mitochondrial biosynthesis, dynamics and functions will present once the mitochondrial quality control is impaired, thus leading to aggravated AD pathological changes. Accumulating evidence shows beneficial effects of appropriate exercise on improved mitophagy and mitochondrial function to promote mitochondrial plasticity, reduce oxidative stress, enhance cognitive capacity and reduce the risks of cognitive impairment and dementia in later life. Therefore, stimulating mitophagy and optimizing mitochondrial function through exercise may forestall the neurodegenerative process of AD.
Asymmetric Ensemble of Asymmetric U-Net Models for Brain Tumor Segmentation With Uncertainty Estimation
Authors: Rosas-Gonzalez Sarahi , Birgui-Sekou Taibou , Hidane Moncef , Zemmoura Ilyess , Tauber Clovis
Published: October 2021

Accurate brain tumor segmentation is crucial for clinical assessment, follow-up, and subsequent treatment of gliomas. While convolutional neural networks (CNN) have become state of the art in this task, most proposed models either use 2D architectures ignoring 3D contextual information or 3D models requiring large memory capacity and extensive learning databases. In this study, an ensemble of two kinds of U-Net-like models based on both 3D and 2.5D convolutions is proposed to segment multimodal magnetic resonance images (MRI). The 3D model uses concatenated data in a modified U-Net architecture. In contrast, the 2.5D model is based on a multi-input strategy to extract low-level features from each modality independently and on a new 2.5D Multi-View Inception block that aims to merge features from different views of a 3D image aggregating multi-scale features. The Asymmetric Ensemble of Asymmetric U-Net (AE AU-Net) based on both is designed to find a balance between increasing multi-scale and 3D contextual information extraction and keeping memory consumption low. Experiments on 2019 dataset show that our model improves enhancing tumor sub-region segmentation. Overall, performance is comparable with state-of-the-art results, although with less learning data or memory requirements. In addition, we provide voxel-wise and structure-wise uncertainties of the segmentation results, and we have established qualitative and quantitative relationships between uncertainty and prediction errors. Dice similarity coefficient for the whole tumor, tumor core, and tumor enhancing regions on BraTS 2019 validation dataset were 0.902, 0.815, and 0.773. We also applied our method in BraTS 2018 with corresponding Dice score values of 0.908, 0.838, and 0.800.
Association of Circulating T Follicular Helper Cells With Idiopathic Optic Neuritis and Neuromyelitis Optica Spectrum Disorders
Authors: Wu Qian , Yang Binbin , Wang Jiawei
Published: October 2021

Background: T follicular helper cells (Tfh cells) play an important role in activating B lymphocytes and may associate with idiopathic Optic Neuritis (ON) and Neuromyelitis Optica Spectrum Disorders (NMOSD).

Objective: This study aimed to examine the potential role of Tfh cells in pathogenesis of idiopathic ON and NMOSD.

Methods: Circulating CD4+CXCR5+ and CD4+CXCR5+PD-1+ cells in 46 idiopathic ON and 68 NMOSD patients as well as 28 healthy controls were examined by flow cytometry before treatment. Serum AQP4 antibody, Expended Disability Status Scale (EDSS) and Visual Outcome Scale (VOS) were detected before and after treatment.

Results: The percentages of circulating CD4+CXCR5+ and CD4+CXCR5+PD-1+Tfh cells in CD4+ cells (%) were significantly increased in idiopathic ON and NMOSD compared with those of healthy controls (p < 0.01). No significant difference of Tfh cells in blood and cerebral spinal fluid (CSF) was found between ON and NMOSD patients. The percentages of CSF, CD4+, CXCR5+, and CD4+CXCR5+PD-1+ cells in CD4+ cells (%) were positively correlated with those of the blood (r = 0.5781, r = 0.6079, p = 0.0076, and p = 0.0045, respectively). EDSS scores of NMOSD group were higher than those of ON group and the time course of NMOSD patients was longer than that of ON patients (p < 0.01). After methylprednisolone treatment, both EDSS and VOS scores were significantly decreased at discharge compared with before treatment (p < 0.01). There was no significant correlation among Tfh cell percentages in CD4+ cells, CSF leukocytes, CSF protein, annual recurrence rate, EDSS and VOS scores between two groups (p > 0.05).

Conclusion: The Circulating T follicular helper cells were increased in both idiopathic ON and NMOSD.
Measuring Patient Safety Climate in Acute Stroke Therapy
Authors: Bohmann Ferdinand O. , Guenther Joachim , Gruber Katharina , Manser Tanja , Steinmetz Helmuth , Pfeilschifter Waltraud
Published: October 2021

Background: Treatment of acute stroke is highly time-dependent and performed by a multiprofessional, interdisciplinary team. Interface problems are expectable and issues relevant to patient safety are omnipresent. The Safety Attitudes Questionnaire (SAQ) is a validated and widely used instrument to measure patient safety climate. The objective of this study was to evaluate the SAQ for the first time in the context of acute stroke care.

Methods: A survey was carried out during the STREAM trial (NCT 032282) at seven university hospitals in Germany from October 2017 to October 2018. The anonymous survey included 33 questions (5-point Likert scale, 1 = disagree to 5 = agree) and addressed the entire multiprofessional stroke team. Statistical analyses were used to examine psychometric properties as well as descriptive findings.

Results: 164 questionnaires were completed yielding a response rate of 66.4%. 67.7% of respondents were physicians and 25.0% were nurses. Confirmatory Factor Analysis revealed that the original 6-factor structure fits the data adequately. The SAQ for acute stroke care showed strong internal consistency (α = 0.88). Exploratory analysis revealed differences in scores on the SAQ dimensions when comparing physicians to nurses and when comparing physicians according to their duration of professional experience.

Conclusion: The SAQ is a helpful and well-applicable tool to measure patient safety in acute stroke care. In comparison to other high-risk fields in medicine, patient safety climate in acute stroke care seems to be on a similar level with the potential for further improvements.

Trial registration:www.ClinicalTrials.gov Identifier: NCT032282.
First Family of MATR3-Related Distal Myopathy From Italy: The Role of Muscle Biopsy in the Diagnosis and Characterization of a Still Poorly Understood Disease
Authors: Cavalli Michele , Cardani Rosanna , Renna Laura Valentina , Toffetti Mauro , Villa Luisa , Meola Giovanni
Published: October 2021

Mutations in the MATR3 gene are associated to distal myopathy with vocal cord and pharyngeal weakness (VCPDM), as well as familiar and sporadic motor neuron disease. To date, 12 VCPDM families from the United States, Germany, Japan, Bulgary, and France have been described in the literature. Here we report an Italian family with a propositus of a 40-year-old woman presenting progressive bilateral foot drop, rhinolalia, and distal muscular atrophy, without clinical signs of motor neuron affection. Her father, deceased some years before, presented a similar distal myopathy phenotype, while her 20-year-old son is asymptomatic. Myopathic changes with vacuolization were observed in muscle biopsy from the propositus. These results, together with the peculiar clinical picture, lead to MATR3 gene sequencing, which revealed a heterozygous p.S85C mutation in the propositus. The same mutation was found in her son. Over a 5-year follow-up, progression is mild in the propositus, while her son remains asymptomatic. Clinical, radiological, and pathological data of our propositus are presented and compared to previously reported cases of VCPDM. VCPDM turns out to be a quite homogenous phenotype of late-onset myopathy associated to p.S85C mutation in MATR3 gene. MATR3-related pathology, encompassing myopathy and motor neuron disease, represents an illustrative example of multisystem proteinopathy (MSP), such as other diseases associated to mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1 genes. The present report contributes to a further characterization of this still poorly understood pathology and points out the diagnostic utility of muscle biopsy in challenging cases.
Quantitative Imaging of Blood-Brain Barrier Permeability Following Repetitive Mild Head Impacts
Authors: Leaston Joshua , Qiao Ju , Harding Ian C. , Kulkarni Praveen , Gharagouzloo Codi , Ebong Eno , Ferris Craig F.
Published: September 2021

This was an exploratory study designed to evaluate the feasibility of a recently established imaging modality, quantitative ultrashort time-to-echo contrast enhanced (QUTE-CE), to follow the early pathology and vulnerability of the blood brain barrier in response to single and repetitive mild head impacts. A closed-head, momentum exchange model was used to produce three consecutive mild head impacts aimed at the forebrain separated by 24 h each. Animals were measured at baseline and within 1 h of impact. Anatomical images were collected to assess the extent of structural damage. QUTE-CE biomarkers for BBB permeability were calculated on 420,000 voxels in the brain and were registered to a bilateral 3D brain atlas providing site-specific information on 118 anatomical regions. Blood brain barrier permeability was confirmed by extravasation of labeled dextran. All head impacts occurred in the absence of any structural brain damage. A single mild head impact had measurable effects on blood brain barrier permeability and was more significant after the second and third impacts. Affected regions included the prefrontal ctx, basal ganglia, hippocampus, amygdala, and brainstem. Our findings support the concerns raised by the healthcare community regarding mild head injuries in participants in organized contact sports and military personnel in basic training and combat.
The Cognitive-Vestibular Compensation Hypothesis: How Cognitive Impairments Might Be the Cost of Coping With Compensation
Authors: Lacroix Emilie , Deggouj Naïma , Edwards Martin Gareth , Van Cutsem Jeroen , Van Puyvelde Martine , Pattyn Nathalie
Published: October 2021

Previous research in vestibular cognition has clearly demonstrated a link between the vestibular system and several cognitive and emotional functions. However, the most coherent results supporting this link come from rodent models and healthy human participants artificial stimulation models. Human research with vestibular-damaged patients shows much more variability in the observed results, mostly because of the heterogeneity of vestibular loss (VL), and the interindividual differences in the natural vestibular compensation process. The link between the physiological consequences of VL (such as postural difficulties), and specific cognitive or emotional dysfunction is not clear yet. We suggest that a neuropsychological model, based on Kahneman’s Capacity Model of Attention, could contribute to the understanding of the vestibular compensation process, and partially explain the variability of results observed in vestibular-damaged patients. Several findings in the literature support the idea of a limited quantity of cognitive resources that can be allocated to cognitive tasks during the compensation stages. This basic mechanism of attentional limitations may lead to different compensation profiles in patients, with or without cognitive dysfunction, depending on the compensation stage. We suggest several objective and subjective measures to evaluate this cognitive-vestibular compensation hypothesis.
Changes in Brain Responses to Music and Non-music Sounds Following Creativity Training Within the “Different Hearing” Program
Authors: Arkhipova Anna , Hok Pavel , Valošek Jan , Trnečková Markéta , Všetičková Gabriela , Coufalová Gabriela , Synek Jaromír , Zouhar Vít , Hluštík Petr
Published: October 2021

The “Different Hearing” program (DHP) is an educational activity aimed at stimulating musical creativity of children and adults by group composing in the classroom, alternative to the mainstream model of music education in Czechia. Composing in the classroom in the DHP context does not use traditional musical instruments or notation, instead, the participants use their bodies, sounds originating from common objects as well as environmental sounds as the “elements” for music composition by the participants’ team, with the teacher initiating and then participating and coordinating the creative process, which ends with writing down a graphical score and then performing the composition in front of an audience. The DHP methodology works with a wide definition of musical composition. We hypothesized that the DHP short-term (2 days) intense workshop would induce changes in subjective appreciation of different classes of music and sound (including typical samples of music composed in the DHP course), as well as plastic changes of the brain systems engaged in creative thinking and music perception, in their response to diverse auditory stimuli. In our study, 22 healthy university students participated in the workshop over 2 days and underwent fMRI examinations before and after the workshop, meanwhile 24 students were also scanned twice as a control group. During fMRI, each subject was listening to musical and non-musical sound samples, indicating their esthetic impression with a button press after each sample. As a result, participants’ favorable feelings toward non-musical sound samples were significantly increased only in the active group. fMRI data analyzed using ANOVA with post hoc ROI analysis showed significant group-by-time interaction (opposing trends in the two groups) in the bilateral posterior cingulate cortex/precuneus, which are functional hubs of the default mode network (DMN) and in parts of the executive, motor, and auditory networks. The findings suggest that DHP training modified the behavioral and brain response to diverse sound samples, differentially changing the engagement of functional networks known to be related to creative thinking, namely, increasing DMN activation and decreasing activation of the executive network.
Additively Combining Utilities and Beliefs: Research Gaps and Algorithmic Developments
Authors: Ghambaryan Anush , Gutkin Boris , Klucharev Vasily , Koechlin Etienne
Published: October 2021

Value-based decision making in complex environments, such as those with uncertain and volatile mapping of reward probabilities onto options, may engender computational strategies that are not necessarily optimal in terms of normative frameworks but may ensure effective learning and behavioral flexibility in conditions of limited neural computational resources. In this article, we review a suboptimal strategy – additively combining reward magnitude and reward probability attributes of options for value-based decision making. In addition, we present computational intricacies of a recently developed model (named MIX model) representing an algorithmic implementation of the additive strategy in sequential decision-making with two options. We also discuss its opportunities; and conceptual, inferential, and generalization issues. Furthermore, we suggest future studies that will reveal the potential and serve the further development of the MIX model as a general model of value-based choice making.
Correcting for Superficial Bias in 7T Gradient Echo fMRI
Authors: Huang Pei , Correia Marta M. , Rua Catarina , Rodgers Christopher T. , Henson Richard N. , Carlin Johan D.
Published: October 2021

The arrival of submillimeter ultra high-field fMRI makes it possible to compare activation profiles across cortical layers. However, the blood oxygenation level dependent (BOLD) signal measured by gradient echo (GE) fMRI is biased toward superficial layers of the cortex, which is a serious confound for laminar analysis. Several univariate and multivariate analysis methods have been proposed to correct this bias. We compare these methods using computational simulations of 7T fMRI data from regions of interest (ROI) during a visual attention paradigm. We also tested the methods on a pilot dataset of human 7T fMRI data. The simulations show that two methods–the ratio of ROI means across conditions and a novel application of Deming regression–offer the most robust correction for superficial bias. Deming regression has the additional advantage that it does not require that the conditions differ in their mean activation over voxels within an ROI. When applied to the pilot dataset, we observed strikingly different layer profiles when different attention metrics were used, but were unable to discern any differences in laminar attention across layers when Deming regression or ROI ratio was applied. Our simulations demonstrates that accurate correction of superficial bias is crucial to avoid drawing erroneous conclusions from laminar analyses of GE fMRI data, and this is affirmed by the results from our pilot 7T fMRI data.
Serum Oxytocin Level Correlates With Gut Microbiome Dysbiosis in Children With Autism Spectrum Disorder
Authors: Huang Minshi , Liu Kevin , Wei Zhen , Feng Zhe , Chen Jierong , Yang Jie , Zhong Qin , Wan Guobin , Kong Xue-Jun
Published: October 2021

To investigate the levels of serum oxytocin (OT) in children with autism spectrum disorder (ASD) and explore the association between OT levels and gut microbiota relative abundances, we recruited 39 children with ASD children–mother dyads and 44 healthy controls. Serum OT levels were determined via enzyme-linked immunosorbent assay and gut microbiota abundances were determined by 16S rRNA sequencing. We found that the OT level of ASD was lower than the healthy control group overall (P < 0.05). Furthermore, we present preliminary evidence of gut microbiome dysbiosis observed among children with ASD to lower levels of OT based on correlational analysis between serum OT and specific gut microbiota abundances (P < 0.05). We also found sex-related differences in serum OT levels and GIS index (P < 0.05). However, the generalizability of findings relevant to females with ASD require further validation in future studies involving larger sample sizes and balanced sex distributions due to the small number of females involved in this study. Nonetheless, these new findings further our understanding of the effects of low serum OT levels among individuals with ASD, which provides preliminary evidence in hopes of guiding future study design or mechanistic studies. The findings of the present study may be suggestive of potential ASD subtypes based on ASD severity and gut microbiome composition that may facilitate the prediction of the therapeutic responses of OT among those with ASD.
Mid-Air Tactile Sensations Evoked by Laser-Induced Plasma: A Neurophysiological Study
Authors: Kim Hyung-Sik , Kim Kyu Beom , Lee Je-Hyeop , Jung Jin-Ju , Kim Ye-Jin , Kim Sung-Phil , Choi Mi-Hyun , Yi Jeong-Han , Chung Soon-Cheol
Published: October 2021

This study demonstrates the feasibility of a mid-air means of haptic stimulation at a long distance using the plasma effect induced by laser. We hypothesize that the stress wave generated by laser-induced plasma in the air can propagate through the air to reach the nearby human skin and evoke tactile sensation. To validate this hypothesis, we investigated somatosensory responses in the human brain to laser plasma stimuli by analyzing electroencephalography (EEG) in 14 participants. Three types of stimuli were provided to the index finger: a plasma stimulus induced from the laser, a mechanical stimulus transferred through Styrofoam stick, and a sham stimulus providing only the sound of the plasma and mechanical stimuli at the same time. The event-related desynchronization/synchronization (ERD/S) of sensorimotor rhythms (SMRs) in EEG was analyzed. Every participant verbally reported that they could feel a soft tap on the finger in response to the laser stimulus, but not to the sham stimulus. The spectrogram of EEG evoked by laser stimulation was similar to that evoked by mechanical stimulation; alpha ERD and beta ERS were present over the sensorimotor area in response to laser as well as mechanical stimuli. A decoding analysis revealed that classification error increased when discriminating ERD/S patterns between laser and mechanical stimuli, compared to the case of discriminating between laser and sham, or mechanical and sham stimuli. Our neurophysiological results confirm that tactile sensation can be evoked by the plasma effect induced by laser in the air, which may provide a mid-air haptic stimulation method.
Presenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome
Authors: Vázquez-Costa Juan Francisco , Payá-Montes María , Martínez-Molina Marina , Jaijo Teresa , Szymanski Jazek , Mazón Miguel , Sopena-Novales Pablo ,   ENoD Consortium, Pérez-Tur Jordi , Sevilla Teresa
Published: October 2021

Background and Purpose

Primary lateral sclerosis (PLS) is a progressive upper motor neuron (UMN) disorder. It is debated whether PLS is part of the amyotrophic lateral sclerosis (ALS) spectrum, or a syndrome encompassing different neurodegenerative diseases. Recently, new diagnostic criteria for PLS have been proposed. We describe four patients of two pedigrees, meeting definite PLS criteria and harboring two different mutations in presenilin 1 (PSEN1).

Methods

Patients underwent neurological and neuropsychological examination, MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid-related biomarkers, and next-generation sequencing (NGS) testing.

Results

Four patients, aged 25–45 years old, presented with a progressive UMN syndrome meeting clinical criteria of definite PLS. Cognitive symptoms and signs were mild or absent during the first year of the disease but appeared or progressed later in the disease course. Brain MRI showed microbleeds in two siblings, but iron-related hypointensities in the motor cortex were absent. Brain FDG-PET showed variable areas of hypometabolism, including the motor cortex and frontotemporal lobes. Amyloid deposition was confirmed with either cerebrospinal fluid (CSF) or imaging biomarkers. Two heterozygous likely pathogenic mutations inPSEN1(p.Pro88Leu and p.Leu166Pro) were found in the NGS testing.

Conclusion

Clinically defined PLS is a syndrome encompassing different neurodegenerative diseases. The NGS testing should be part of the diagnostic workup in patients with PLS, at least in those with red flags, such as early-onset, cognitive impairment, and/or family history of neurodegenerative diseases.
NUDT21 Promotes Tumor Growth and Metastasis Through Modulating SGPP2 in Human Gastric Cancer
Authors: Zhu Yong , Zhang Rumeng , Zhang Ying , Cheng Xiao , Li Lin , Wu Zhengsheng , Ding Keshuo
Published: October 2021

Gastric cancer is one of the major malignancies with poor survival outcome. In this study, we reported that NUDT21 promoted cell proliferation, colony formation, cell migration and invasion in gastric cancer cells. The expression levels of NUDT21 were found to be much higher in human gastric cancer tissues compared with normal gastric tissues. NUDT21 expression was positively correlated with tumor size, lymph node metastasis and clinical stage in gastric cancer patients. High level of NUDT21 was associated with poor overall survival (OS) rates in gastric cancer patients. The expression levels of NUDT21 were also much higher in gastric cancer tissues from patients with distant metastasis compared with those of patients without distant metastasis. Moreover, forced expression of NUDT21 in gastric cancer cells promoted tumor growth and cell proliferation in xenograft nude mice, and depletion of NUDT21 in gastric cancer cells restrained lung metastasis in vivo. Through high throughput RNA-sequencing, SGPP2 was identified to be positively regulated by NUDT21 and mediated the tumor promoting role of NUDT21 in gastric cancer cells. Therefore, NUDT21 played an oncogenic role in human gastric cancer cells. NUDT21 could be considered as a novel potential target for gastric cancer therapy.
MRI-Based Grading of Clear Cell Renal Cell Carcinoma Using a Machine Learning Classifier
Authors: Chen Xin-Yuan , Zhang Yu , Chen Yu-Xing , Huang Zi-Qiang , Xia Xiao-Yue , Yan Yi-Xin , Xu Mo-Ping , Chen Wen , Wang Xian-long , Chen Qun-Lin
Published: October 2021

Objective

To develop a machine learning (ML)-based classifier for discriminating between low-grade (ISUP I-II) and high-grade (ISUP III-IV) clear cell renal cell carcinomas (ccRCCs) using MRI textures.

Materials and Methods

We retrospectively evaluated a total of 99 patients (with 61 low-grade and 38 high-grade ccRCCs), who were randomly divided into a training set (n = 70) and a validation set (n = 29). Regions of interest (ROIs) of all tumors were manually drawn three times by a radiologist at the maximum lesion level of the cross-sectional CMP sequence images. The quantitative texture analysis software, MaZda, was used to extract texture features, including histograms, co-occurrence matrixes, run-length matrixes, gradient models, and autoregressive models. Reproducibility of the texture features was assessed with the intra-class correlation coefficient (ICC). Features were chosen based on their importance coefficients in a random forest model, while the multi-layer perceptron algorithm was used to build a classifier on the training set, which was later evaluated with the validation set.

Results

The ICCs of 257 texture features were equal to or higher than 0.80 (0.828–0.998. Six features, namely Kurtosis, 135dr_RLNonUni, Horzl_GLevNonU, 135dr_GLevNonU, S(4,4)Entropy, and S(0,5)SumEntrp, were chosen to develop the multi-layer perceptron classifier. A three-layer perceptron model, which has 229 nodes in the hidden layer, was trained on the training set. The accuracy of the model was 95.7% with the training set and 86.2% with the validation set. The areas under the receiver operating curves were 0.997 and 0.758 for the training and validation sets, respectively.

Conclusions

A machine learning-based grading model was developed that can aid in the clinical diagnosis of clear cell renal cell carcinoma using MRI images.
The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer
Authors: Pan Yue , Deng Chao , Qiu Zhenhua , Cao Chenghui , Wu Fang
Published: October 2021

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance.
Factors That Improve Chest Computed Tomography-Defined Sarcopenia Prognosis in Advanced Non-Small Cell Lung Cancer
Authors: Yang Ming , Tan Lingling , Xie Lingling , Hu Song , Liu Dan , Wang Jing , Li Weimin
Published: October 2021

Background

Whether muscle strength and physical performance should be components of sarcopenia remains controversial. This study evaluated the skeletal muscle index derived from computed tomography images at the 12th thoracic vertebra level (T12 SMI), handgrip strength, performance status, and their combination for predicting overall survival in patients with advanced non-small cell lung cancer.

Methods

Chest computed tomography, handgrip strength measurement, and bioelectrical impedance analysis were performed. Sarcopenia was defined based on the T12 SMI alone or the T12 SMI, handgrip, and/or physical performance (i.e. Asian Working Group for Sarcopenia [AWGS]-defined sarcopenia or severe sarcopenia).

Results

Overall, 639 participants were included; 488 (76.4%) died. At baseline, 160 (25.0%), 141 (22.1%), and 42 (6.6%) patients had computed tomography-defined sarcopenia, AWGS-defined sarcopenia, and AWGS-defined severe sarcopenia, respectively. Chest computed tomography-defined sarcopenia (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.65-2.43), AWGS-defined sarcopenia (HR, 2.00; 95% CI, 1.59-2.49), and AWGS-defined severe sarcopenia (HR, 3.01; 95% CI, 2.21-4.09) were more strongly associated with poor prognosis than a performance status score ≥2 (HR, 1.37; 95% CI, 1.10-1.73).

Conclusions

Adding handgrip strength and the performance status score to chest computed tomography-defined sarcopenia improved its prognostic ability. Oncological sarcopenia research should focus on muscle mass, strength, and function.
COVID-19-Associated Case Fatality Rate in Subjects Under 18 Years Old in Mexico, up to December 31, 2020
Authors: Navarro-Olivos Efraín , Padilla-Raygoza Nicolás , Flores-Vargas Gilberto , Gallardo-Luna María de Jesús , León-Verdín Ma Guadalupe , Lara-Lona Elia , Magos-Vázquez Francisco J. , Díaz-Martínez Daniel Alberto
Published: October 2021

Background: The emergence of the SARS-CoV-2 and the COVID-19 have become a global health crisis. The infection has been present in all the social sectors. Subjects under 18 years are one of them. The objective was to analyze the case fatality ratio of COVID-19 cases in the Mexican population under 18 years of age registered in the National Epidemiological Surveillance System from March 2020 to December 31, 2020.

Material and Methods: The design is cross-sectional, quantitative, and analytical. All the suspected cases of respiratory viral disease, with a real-time polymerase chain reaction (RT-PCR) test result, aged from 0 to 17 years, were included. Descriptive statistics are presented for all the variables. Epidemiological curves were designed. The chi-squared test and its P-values were obtained to show the relationship between comorbidities and death. The case fatality ratio was computed for each comorbidity, sex, and age group. Multivariable logistic regression models were fitted to study the effect between comorbidities with the fatality of cases, adjusting for sex and age group as potential confounders. The alpha value was fixed to 0.05 to assess significance.

Results: The number of records for this study was 167,856. Among them, 48,505 were from SARS-CoV-2-positive patients (28.90%), and 119,351 (71.10%) were negative. Of those who died, males (55.29%) (P < 0.05) and those under 2 years of age (50.35%) (P < 0.05) predominated. Unlike in older populations, from the comorbidities considered risk factors for death by COVID-19, only immunosuppression showed a statistically significant effect on the fatality of cases after adjustment by the other related variables. Sex and age group were not confounders for the models in those under 18 years old. Pneumonia, being younger than 5 years, and immunosuppression are related to death.

Conclusion: The case fatality ratio in those under 18 years old is low. Special attention must be paid to those children under 5 years. The development of pneumonia is a warning indicator while treating them. On the other hand, having an open database of cases allows the researchers to analyze the impact of COVID-19 in different population sectors, which has clear benefits for public health.
Correlation Analysis of Anti-Cardiolipin Antibody/D Dimer/C-Reactive Protein and Coronary Artery Lesions/Multiple-Organ Damage in Children With Kawasaki Disease
Authors: Xu Yun-ming , Chu Yan-qiu , Wang Hong
Published: October 2021

Aim: Kawasaki disease (KD) is a systemic vasculitis with unknown etiology. In addition to cardiovascular system involvement, it can also have other multiple organs involved. This study is aimed at investigating the correlation between anti-cardiolipin antibody (ACA)/D dimer/C reactive protein (CRP) and coronary artery lesions (CAL)/multiple-organ lesions in children with KD.

Methods: Retrospective analysis was performed in 284 KD/IKD patients from May 2015 to April 2016. Among them, 175 were males (61.6%), with average age of 2 years and 5 months old. Patients were divided into ACA+ group and ACA- group, elevated D dimer group (DDE) and normal D dimer group (DDN), and coronary artery injury (CAL) group and non-coronary artery injury (NCAL) group.

Results: ACA was most likely tested positive in younger KD children (p < 0.05). ACA+ and hypoproteinemia were correlated with CAL, thrombocytosis, and granulocytopenia (p < 0.05–0.01). Levels of cTnI and CK in the CAL group were significantly higher than those in the NCAL group (p < 0.05). CAL was more frequently detected in younger patients and patients with prolonged fever, later IVIG treatment, and elevated CRP over 100 mg/l, but there was no statistically significant difference (all p > 0.05). In the KD with DDE group, the incidence of granulopenia, thrombocytosis, myocardial damage, cholestasis, hypoproteinemia, and aseptic urethritis was significantly higher than that in the KD with DDN group (p < 0.05–0.01). However, elevated D dimer was not associated with CAL. CRP elevation was highly correlated with D dimer, but not with CAL.

Conclusion: Higher incidence of CAL and myocardial damage occurred in KD patients with positive ACA and hypoproteinemia. In the current study, ACA was only tested for positive and negative, which is a limitation to this study. To further elucidate the association, ACA titers would establish its significance in drawing a conclusion for the significance of ACA in CAL and myocardial damages. In addition, higher incidence of CAL occurred in younger patients. The higher D dimer was associated with increased multiple-organ damage (MOD). CRP was closely correlated with D dimer, but not correlated with ACA and CAL.
Immunogenicity and Complications of the Pentavalent Vaccine in Iranian Children
Authors: Ekrami Noghabi Mina , Saffar Mohammad Jafar , Rezai Shaghayegh , Saffar Hana , Saffar Hiva , Hosseinzadeh Fatemeh , Nadi Ghara Aliasghar , Rezai Mohammad Sadegh
Published: October 2021

Objective: Vaccination is one of the most convenient and safe preventive care measures available for children. The Pentavalent vaccine which protects against five major infections including diphtheria, tetanus, pertussis, hepatitis B(HepB) and Haemophilus influenzae type b(Hib) was added to the Iranian national immunization program in November 2014. This study aimed to determine the Pentavalent vaccine adverse events and immunogenicity in an Iranian children population in Sari, northern Iran.

Method: In this descriptive-analytical study, children who were vaccinated with three doses of the Pentavalent vaccine were studied. Two venous blood samples were obtained before the first dose and 4 weeks following the last booster dose. Possible local and systemic complications of the vaccine were recorded until 7 days following vaccination. Antibody titers were measured by quantitative ELISA kits and geometric mean titer(GMT) was calculated for each vaccine component before and after 3 doses of vaccine. Statistical analysis was performed by SPSS 20.0 software and Chi-square and Fisher's exact tests were used for analysis.

Results: Immunogenicity of the Pentavalent vaccine for tetanus was 100%(GMT:2.52 Eu/mL, 95%CI: 2.22–2.88), Hib 98.7%(GMT:2.44 Eu/mL, 95%CI: 2.06–2.89), HepB 98.7%(GMT:153.54 Eu/mL, 95%CI: 133.73–176.29), diphtheria 93.1%(GMT:0.43 Eu/mL, 95%CI:0.37–0.51) and pertussis were 63.7% (GMT:19.44 Eu/mL, 95%CI:16.42–23.03). The most common systemic complication after vaccination was fever. Also, one infant cried for more than 3 hours after the second dose. Other serious side effects were not observed.

Conclusion: The Pentavalent vaccine used in Iran can cause adequate antibody response against diphtheria, tetanus, pertussis, Hib and hepatitis B in most cases with minimal side effects. The immunogenicity of this vaccine is significantly lower for pertussis. In this study, no severe complication leading to contraindication to subsequent injections was reported. So, the present policy in replacing triple DTP vaccine with Pentavalent vaccine should be continued in Iran.
Encephalopathy in Preterm Infants: Advances in Neuroprotection With Caffeine
Authors: Yang Liu , Yu Xuefei , Zhang Yajun , Liu Na , Xue Xindong , Fu Jianhua
Published: October 2021

With the improvement in neonatal rescue technology, the survival rate of critically ill preterm infants has substantially increased; however, the incidence of brain injury and sequelae in surviving preterm infants has concomitantly increased. Although the etiology and pathogenesis of preterm brain injury, and its prevention and treatment have been investigated in recent years, powerful and effective neuroprotective strategies are lacking. Caffeine is an emerging neuroprotective drug, and its benefits have been widely recognized; however, its effects depend on the dose of caffeine administered, the neurodevelopmental stage at the time of administration, and the duration of exposure. The main mechanisms of caffeine involve adenosine receptor antagonism, phosphodiesterase inhibition, calcium ion activation, and γ-aminobutyric acid receptor antagonism. Studies have shown that there are both direct and indirect beneficial effects of caffeine on the immature brain. Accordingly, this article briefly reviews the pharmacological characteristics of caffeine, its mechanism of action in the context of encephalopathy in premature infants, and its use in the neuroprotection of encephalopathy in this patient population.
Kikuchi-Fujimoto Disease With Encephalopathy in Children: Case Reports and Literature Review
Authors: Pan Yu-Ting , Cao Li-Ming , Xu Yan , Fan Zhi-Dan , Yu Hai-Guo
Published: October 2021

Background: Kikuchi-Fujimoto disease (KFD) is a benign and self-limiting disease characterized by regional lymphadenitis and low-grade fever. Encephalopathy may present in children with KFD. We present three cases of KFD with encephalopathy in children and a literature review.

Methods: Literature published between 2010 and 2020 was reviewed to understand the clinical features, laboratory findings, and treatments for encephalopathy occurring in children with KFD.

Results: The interval between KFD and onset of neurological symptoms was 10 days to 3 months. Laboratory results were normal, except for high protein levels in cerebrospinal fluid findings. Brain magnetic resonance imaging (MRI) findings include hyperintense T2 and FLAIR signal in the supratentorial white matter, deep gray matter, brain stem, cerebellum, temporal lobes, pons, and basal ganglia. Glucocorticoids and immunoglobulin could be effective for treating KFD with encephalopathy.

Conclusion: The early clinical manifestations of KFD with encephalopathy in children lack specificity, and the diagnosis is mainly based on CSF analysis and brain MRI findings. Early and timely immunomodulatory therapy is effective and can improve the prognosis of patients with KFD with encephalopathy.
Novel Pyrazolo[3,4-b] Pyridine Derivative (HLQ2g) Attenuates Hypoxic Pulmonary Hypertension via Restoring cGKI Expression and BMP Signaling Pathway
Authors: Li Lijun , Yin Minghui , Hu Liqing , Tian Xiaoting , He Xiangrong , Zhao Congke , Li Ying , Li Qianbin , Li Xiaohui
Published: October 2021

Pulmonary hypertension (PH) is an extremely serious cardiopulmonary disease, finally leading to progressive right ventricular failure and death. Our previous studies have nominated HLQ2g, a pyrazolo[3,4-b] pyridine derivative stimulating soluble guanylate cyclase (sGC), as a new candidate for the treatment of PH, but the specific mechanism is still not clear. The PH model induced by hypoxia was established in rats. Right ventricular systolic pressure (RVSP) was assessed by jugular vein catheterization. RV weight was the index to evaluate RV hypertrophy. The protein levels of cGMP-dependent protein kinase type I (cGKI), bone morphogenetic protein receptor 2 (BMPR2), phosphorylated Smad1/5/8 (p-Smad1/5/8), and inhibitor of differention 1 (Id1) in pulmonary artery and human pulmonary artery smooth muscle cells (HPASMCs) were determined by western blotting. Cell proliferation and migration were evaluated. In the whole experiment, the first clinically available sGC stimulator Riociguat was used as the reference. In hypoxic PH rat model, elevated RVSP and RV hypertrophy were significantly reduced by HLQ2g treatment. Both Riociguat and HLQ2g attenuated vascular remodeling accompanied with up-regulated cGKI expression and BMP signaling pathway, which was characterized by elevated expression of BMPR2, p-Smad1/5/8, and Id1 in HPH rats. In addition, HLQ2g inhibited proliferation and migration of HPASMCs induced by hypoxia and platelet-derived growth factor (PDGF), restored BMPR2 signaling, which was recalled by Rp-8-Br-PET-cGMPS, the inhibitor of cGKI. In summary, the novel pyrazolo[3,4-b] pyridine derivative HLQ2g can alleviate HPH progression by up-regulating cGKI protein and BMP signaling pathway.
Single-Cell Transcriptomic Analysis of Peripheral Blood Reveals a Novel B-Cell Subset in Renal Allograft Recipients With Accommodation
Authors: Zhuang Quan , Li Hao , Peng Bo , Liu Yang , Zhang Ying , Cai Haozheng , Liu Shu , Ming Yingzi
Published: September 2021

Background: Kidney transplantation (KTx) is a preeminent treatment for end-stage renal disease (ESRD). After the application of immunosuppressants (IS), renal allograft recipients could reach a state called accommodation which means they are neither rejected nor infected. This study aimed to describe the details of this immune accommodation and reveal a novel mechanism of IS on immune cell subpopulations.

Methods: We analyzed multiple cell subgroups and their gene expression of peripheral T, B, myeloid, and NK cells from renal allograft recipients with accommodation and healthy control (HC) by single-cell transcriptomics sequencing (scRNA-seq) and flow cytometry.

Results: A total of 8,272 cells were isolated and sequenced from three individuals, including 2,758 cells from HC, 2,550 cells from ESRD patient, and 2,964 cells from KTx patient, as well as 396 immune response–related genes were detected during sequencing. 5 T-cell, 4 NK-cell, 5 myeloid, and 4 B-cell clusters were defined. Among them, a B-cell subset (CD19+IGLC3lowIGKChighTCL1A-CD127+) of renal transplant recipients with accommodation was significantly lower than that of HC and verified by flow cytometry, and this B-cell subset showed an activated potential because of its high expression of CD127. Furthermore, we found that IL32 might be the key cytokine to induce the differentiation of this B-cell cluster.

Conclusion: We found a novel B-cell subset (CD19+IGLC3lowIGKChighTCL1A-CD127+) which was inhibited and decreased in renal allograft recipients with accommodation. This study might reveal the effect of commonly used IS in clinical practice on B-cell subsets and related mechanism.
Network Pharmacology-Based Strategy for the Investigation of the Anti-Osteoporosis Effects and Underlying Mechanism of Zhuangguguanjie Formulation
Authors: Gong Wang , Chen Xingren , Shi Tianshu , Shao Xiaoyan , An Xueying , Qin Jianghui , Chen Xiang , Jiang Qing , Guo Baosheng
Published: October 2021

As the society is aging, the increasing prevalence of osteoporosis has generated huge social and economic impact, while the drug therapy for osteoporosis is limited due to multiple targets involved in this disease. Zhuangguguanjie formulation (ZG) is extensively used in the clinical treatment of bone and joint diseases, but the underlying mechanism has not been fully described. This study aimed to examine the therapeutic effect and potential mechanism of ZG on postmenopausal osteoporosis. The ovariectomized (OVX) mice were treated with normal saline or ZG for 4 weeks after ovariectomy following a series of analyses. The bone mass density (BMD) and trabecular parameters were examined by micro-CT. Bone remodeling was evaluated by the bone histomorphometry analysis and ELISA assay of bone turnover biomarkers in serum. The possible drug–disease common targets were analyzed by network pharmacology. To predict the potential biological processes and related pathways, GO/KEGG enrichment analysis was performed. The effects of ZG on the differentiation phenotype of osteoclasts and osteoblasts and the predicted pathway were verified in vitro. The results showed that ZG significantly improved the bone mass and micro-trabecular architecture in OVX mice compared with untreated OVX mice. ZG could promote bone formation and inhibit bone resorption to ameliorate ovariectomy-induced osteoporosis as evidenced by increased number of osteoblast (N.Ob/Tb.Pm) and decreased number of osteoclast (N.Oc/Tb.Pm) in treated group compared with untreated OVX mice. After identifying potential drug–disease common targets by network pharmacology, GO enrichment analysis predicted that ZG might affect various biological processes including osteoblastic differentiation and osteoclast differentiation. The KEGG enrichment analysis suggested that PI3K/Akt and mTOR signaling pathways could be the possible pathways. Furthermore, the experiments in vitro validated our findings. ZG significantly down-regulated the expression of osteoclast differentiation markers, reduced osteoclastic resorption, and inhibited the phosphorylation of PI3K/Akt, while ZG obviously up-regulated the expression of osteogenic biomarkers, promoted the formation of calcium nodules, and hampered the phosphorylation of 70S6K1/mTOR, which can be reversed by the corresponding pathway activator. Thus, our study suggested that ZG could inhibit the PI3K/Akt signaling pathway to reduce osteoclastic bone resorption as well as hamper the mTORC1/S6K1 signaling pathway to promote osteoblastic bone formation.
Edible Bird’s Nest: Recent Updates and Industry Insights Based On Laboratory Findings
Authors: Chok Kian Chung , Ng Ming Guan , Ng Khuen Yen , Koh Rhun Yian , Tiong Yee Lian , Chye Soi Moi
Published: October 2021

Edible bird’s nest (EBN) is a traditional Chinese delicacy made of the saliva of swiftlets found in Southeast Asia. With increasing demands for EBN, quality control of EBN products is important for safe consumption. The processing steps are particularly important for efficient extraction of bioactive compounds. Geographical location, collection place, and harvesting season contribute to differences in nutritional contents in EBN. Concerns regarding presence of adulterant, chemical, and microbial contaminants in EBN as well as authentication and chemical composition measuring methods are discussed in this review. Recent discoveries of beneficial health functions of EBN in antimicrobial and antiviral actions, immunomodulation, cancer prevention and treatment, tissue regeneration, cardiometabolic maintenance, antioxidant action and neuroprotection are also reviewed. Our review provides an update on the recent research on EBN.