bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Portrait of GISTs Associated With Clinicopathological Features: A Retrospective Study With Molecular Analysis by a Custom 9-Gene Targeted Next-Generation Sequencing Panel
Authors: Qian Haoran , Yan Na , Hu Xiaotong , Jiang Junchang , Cao Zhengzheng , Shen Dan 
Published: April 2022

Objectives: The study aims to investigate genetic characterization of molecular targets and clinicopathological features with gastrointestinal stromal tumors based on targeted next-generation sequencing.Materials and Methods: We selected 106 patients with GISTs from Sir Run Run Shaw Hospital between July 2019 and March 2021. FFPE samples and paired blood samples were obtained from these patients who underwent excision of the tumor. A customized targeted-NGS panel of nine GIST-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes.Results: In total, 106 patients with a GIST were included in the study which presented with various molecular driver alterations in this study. KIT mutations occurred most often in GISTs (94/106, 95.92%), followed by point mutations in PDGFRA. KIT or PDGFRA mutations were detected to be mutually exclusive in the GIST. A total of eight patients with wide-type KIT/PDGFRA were characterized as WT-GISTs, according to clinical diagnosis which included six quadruple-WT GISTs, 1 BRAF-mutant, and 1 NF1-mutant GIST. In KIT exon 11, the most common mutation type was the codon Mutation (in-frame deletion or indels), whereas the missense mutation was the dominant type in KIT exon 13 and KIT exon 17. All variations in KIT exon 11 observed in this study were concentrated at a certain position of codon 550 to codon 576. Mutation in KIT exon 9 was mostly located at codon 502–503. Two germline pathogenic mutations were detected: NF1-R681* and KRAS-T58I. NF1-L591P was a germline mutation to be identified for the first time and is not recorded in the database. The frequency of driving mutations differed between the primary anatomical site in the GIST (p = 0.0206). KIT exon 11 mutants had a lower proliferation index of Ki67 (68.66%,≤5%), while 50.00% of KIT exon 9 mutants had the Ki67 status greater than 10%.Conclusion: The occurrence and development of a GIST is driven by different molecular variations. Resistance to TKIs arises mainly with resistance mutations in KIT or PDGFRA when they are the primary drivers. Targeted NGS can simultaneously and efficiently detect nine GIST-related gene mutations and provide reference for clinicians’ individualized diagnosis and treatment. Our results have important implications for clinical management.
Efficacy of Bioenergetic Health Index to Predict Delirium After Major Abdominal Surgery in Elderly Patients: A Protocol for a Prospective Observational Cohort Study
Authors: Zhao Yi , Liu Juan , Ou Mengchan , Hao Xuechao 
Published: April 2022

IntroductionPostoperative delirium (POD) is a common disorder following surgery, which seriously threatens the quality of patients’ life, especially the older people. The multifactorial manner of this syndrome has made it hard to define an ideal method to predict individual risk. Mitochondria play a key role in the process of POD, which include inflammatory on the brain caused by surgeries and aging related neurodegeneration. As BHI (Bioenergetic Health Index) could be calculated in cells isolated from an individual’s blood to represent the patient’s composite mitochondrial statue, we hypotheses that HBI of monocytes isolated from individual’s peripheral blood can predict POD after major non-cardiac surgery in elderly patients.Methods and AnalysisThis is a prospective, observational single-blinded study in a single center. 124 patients aged ≥ 65 years and scheduled for major abdominal surgery (&gt;3 h) under general anesthesia will be enrolled. Preoperative and postoperative delirium will be assessed by trained members using Confusion Assessment Method (CAM). For patients unable to speak in the ICU after the surgery, Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) will be used. All patients will undergo venous blood sampling twice to measure BHI (1–2 tubes, 5 ml/tube): before the surgery and 1 day after surgery in wards. After discharge, patients will be contacted by telephone 30 days after surgery to confirm the incidence of post-discharge complications. The severity of complications will be categorized as mild, moderate, severe or fatal using a modified Clavien-Dindo Classification (CDC) scheme.Ethics and DisseminationThe study has been approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University, Sichuan, China (Chairperson Prof Shaolin Deng, No. 2021-502). Study data will be disseminated in manuscripts submitted to peer-reviewed medical journals as well as in abstracts submitted to congresses.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [ChiCTR2100047554].
Regulatory Authority Evaluation of the Effectiveness and Efficiency of the ZaZiBoNa Collaborative Medicines Registration Initiative: The Way Forward
Authors: Sithole Tariro , Mahlangu Gugu , Walker Stuart , Salek Sam 
Published: April 2022

IntroductionZaZiBoNa, the work-sharing initiative in the Southern African Development Community (SADC) that has been in operation for 8 years has successfully assessed over 300 dossiers/applications, with an overall median time to recommendation of 12 months. All 16 SADC countries participate in the initiative as either active or non-active members. While the successes of ZaZiBoNa are evident, some challenges still exist. The aim of this study was to solicit the views of the participating authorities on the effectiveness and efficiency of the current operating model of the ZaZiBoNa initiative.MethodsData were collected in 2021 using the Process, Effectiveness and Efficiency Rating (PEER) questionnaire developed by the authors. The questionnaire was completed by the focal person in each country and approved by the head of the authority.ResultsZaZiBoNa serves as a platform for work sharing, information exchange, capacity building and harmonisation of registration requirements. One of the benefits to regulators has been the improvement in the capacity to conduct assessments. Manufacturers have benefited from compiling one package (modules 2–5) for the initial submission as well as a single response package to the consolidated list of questions, which saves time and resources. Respondents were of the view that patients have benefited as the ZaZiBoNa has contributed to an improved availability and accessibility to quality-assured medicines. Some of the challenges identified were the inadequacy of resources and differences in time to the implementation of ZaZiBoNa recommendations by the individual countries. The establishment of a regional unit hosted in one of the member countries to enable centralised submission and coordination was identified as the best strategy to improve the effectiveness and efficiency of the initiative in the interim, with the long-term goal being the establishment of a regional medicines authority.ConclusionThe study identified the strengths of the ZaZiBoNa initiative as well as the opportunities for improvement. The recommendations made would further strengthen this initiative.
Structural Basis for Allostery in PLP-dependent Enzymes
Authors: Tran Jenny U. , Brown Breann L. 
Published: April 2022

Pyridoxal 5′-phosphate (PLP)-dependent enzymes are found ubiquitously in nature and are involved in a variety of biological pathways, from natural product synthesis to amino acid and glucose metabolism. The first structure of a PLP-dependent enzyme was reported over 40 years ago, and since that time, there is a steady wealth of structural and functional information revealed for a wide array of these enzymes. A functional mechanism that is gaining more appreciation due to its relevance in drug design is that of protein allostery, where binding of a protein or ligand at a distal site influences the structure, organization, and function at the active site. Here, we present a review of current structure-based mechanisms of allostery for select members of each PLP-dependent enzyme family. Knowledge of these mechanisms may have a larger potential for identifying key similarities and differences among enzyme families that can eventually be exploited for therapeutic development.
Effects of Repetitive Transcranial Magnetic Stimulation on Cerebellar Metabolism in Patients With Spinocerebellar Ataxia Type 3
Authors: Chen Xin-Yuan , Lian Yan-Hua , Liu Xia-Hua , Sikandar Arif , Li Meng-Cheng , Xu Hao-Ling , Hu Jian-Ping , Chen Qun-Lin , Gan Shi-Rui 
Published: April 2022

BackgroundSpinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant hereditary ataxia, and, thus far, effective treatment remains low. Repetitive transcranial magnetic stimulation (rTMS) can improve the symptoms of spinal cerebellar ataxia, but the mechanism is unclear; in addition, whether any improvement in the symptoms is related to cerebellar metabolism has not yet been investigated. Therefore, the purpose of this study was to investigate the effects of low-frequency rTMS on local cerebellar metabolism in patients with SCA3 and the relationship between the improvement in the symptoms and cerebellar metabolism.MethodsA double-blind, prospective, randomized, sham-controlled trial was carried out among 18 SCA3 patients. The participants were randomly assigned to the real stimulation group (n = 9) or sham stimulation group (n = 9). Each participant in both the groups underwent 30 min of 1 Hz rTMS stimulation (a total of 900 pulses), differing only in terms of stimulator placement, for 15 consecutive days. To separately compare pre- and post-stimulation data (magnetic resonance spectroscopy (MRS) data and the International Cooperative Ataxia Rating Scale (ICARS) score) in the real and sham groups, paired-sample t-tests and Wilcoxon’s signed-rank tests were used in the analyses. The differences in the ICARS and MRS data between the two groups were analyzed with independent t-tests and covariance. To explore the association between the changes in the concentration of cerebellar metabolism and ICARS, we applied Pearson’s correlation analysis.ResultsAfter 15 days of treatment, the ICARS scores significantly decreased in both the groups, while the decrease was more significant in the real stimulation group compared to the sham stimulation group (p &lt; 0.001). The analysis of covariance further confirmed that the total ICARS scores decreased more dramatically in the real stimulation group after treatment compared to the sham stimulation group (F = 31.239, p &lt; 0.001). The values of NAA/Cr and Cho/Cr in the cerebellar vermis, bilateral dentate nucleus, and bilateral cerebellar hemisphere increased significantly in the real stimulation group (p &lt; 0.05), but no significant differences were found in the sham stimulation group (p &gt; 0.05). The analysis of covariance also confirmed the greater change in the real stimulation group. This study also demonstrated that there was a negative correlation between NAA/Cr in the right cerebellar hemisphere and ICARS in the real stimulation group (r = − 0.831, p = 0.02).ConclusionThe treatment with rTMS over the cerebellum was found to induce changes in the cerebellar local metabolism and microenvironment in the SCA3 patients. The alterations may contribute to the improvement of the symptoms of ataxia in SCA3 patients.
Assessment of Anxiety in Patients With Epilepsy: A Literature Review
Authors: Rauh Raphael , Schulze-Bonhage Andreas , Metternich Birgitta 
Published: April 2022

ObjectiveApproximately 20% of people with epilepsy (PWE) suffer from anxiety. These fears are quite diverse and may manifest periictally or interictally, be part of the seizure's semiology, or an expression of reactive psychological distress from seizures themselves. Our review addresses the question of what screening tools are used in clinical care and epileptological research to capture the complexity of epilepsy-specific anxieties.MethodOn 2021/11/11, we entered a search string in PubMed that covered our research interest as completely as possible. We also screened the bibliographies of our findings and followed PubMed's recommendations. From the assessments we found in the included studies, we extracted domains that represent the range of manifestations of anxiety, in order to compare the tools and to discuss to what extent they are suitable for assessing epilepsy-specific anxieties.ResultsWe screened 1,621 abstracts. In total, we identified 24 different anxiety assessments. In addition to the psychiatric assessments in use, we found 7 tools that were designed to assess epilepsy-specific anxieties. The latter focus on different aspects of epilepsy-specific anxieties. In some cases, the conceptual frameworks are not sufficiently transparent or divergent.ConclusionBecause a diagnosis of epilepsy can result in, or seizures may appear as, anxiety, it is important to better understand this psychological burden and address it therapeutically, if necessary. There is a need for screening tools that integrate specific points of a variety of assessments, so as to cover the broad range of epilepsy-specific fears. None of the assessments we found meets this integrative perspective. At the same time, the appropriate design of such a required tool presupposes a conceptual framework of what should be considered as epilepsy-specific anxiety.
Fundus Changes Evaluated by OCTA in Patients With Cerebral Small Vessel Disease and Their Correlations: A Cross-Sectional Study
Authors: Fu Wang , Zhou Xiaoyu , Wang Minli , Li Ping , Hou Jingjing , Gao Peng , Wang Jue 
Published: April 2022

ObjectiveTo detect fundus changes in patients with cerebral small vessel disease (CSVD) using optical coherence tomography angiography (OCTA) and to investigate the correlations between CSVD and fundus changes.MethodsFrom January 2019 to January 2020, patients diagnosed with CSVD by magnetic resonance imaging (MRI) were enrolled in our study and received fundus examinations using OCTA. CSVD was defined as white matter hyperintensities, enlarged perivascular spaces, lacunes, or microbleeds on MRI. OCTA parameters included foveal avascular zone areas, retinal nerve fiber layer thickness, and capillary densities of the superficial retinal capillary plexuses, deep retinal capillary plexuses, and the radial peripapillary capillary network of the disc. Univariate and multivariate logistic regression analyses were performed to explore the correlation between CSVD and fundus changes.ResultsA total of 115 patients (40% male) were enrolled and analyzed, and the mean age was 65.11 ± 11.23 years. After multivariate logistic regression analysis, the radial peripapillary capillary network density was negatively correlated with severity of deep white matter lesions (OR: 0.909; 95% CI: 0.828–0.998; p = 0.046) and perivascular spaces (OR: 0.881; 95% CI: 0.779–0.995; p = 0.041). Parafoveal vessel densities of the superficial retinal capillary plexuses were independently correlated with lacunes (OR: 0.889; 95% CI: 0.817–0.967; p = 0.006).ConclusionOCTA parameters were correlated with CSVD, indicating that OCTA is a potential method for CSVD screening.
An Optimal Animal Model of Ischemic Stroke Established by Digital Subtraction Angiography-Guided Autologous Thrombi in Cynomolgus Monkeys
Authors: Ye Juan , Shang Hailong , Du Hongdi , Cao Ying , Hua Lei , Zhu Feng , Liu Wei , Wang Ying , Chen Siyu , Qiu Zhifu , Shen Hailin 
Published: April 2022

ObjectiveIschemic stroke seriously threatens human health, characterized by the high rates of incidence, disability, and death. Developing a reliable animal model that mimics most of the features of stroke is critical for pathological studies and clinical research. In this study, we aimed to establish and examine a model of middle cerebral artery occlusion (MCAO) guided by digital subtraction angiography (DSA) in cynomolgus monkeys.Materials and MethodsIn this study, 15 adult male cynomolgus monkeys were enrolled. Under the guidance of DSA, a MCAO model was established by injecting an autologous venous clot into the middle cerebral artery (MCA) via femoral artery catheter. Thrombolytic therapy with alteplase (rt-PA) was given to eight of these monkeys at 3 h after the occlusion. Blood test and imaging examination, such as computed tomography angiography (CTA), CT perfusion (CTP), brain magnetic resonance imaging (MRI), and brain magnetic resonance angiography (MRA), were performed after the operation to identify the post-infarction changes. The behavioral performance of cynomolgus monkeys was continuously observed for 7 days after operation. The animals were eunthanized on the 8th day after operation, and then the brain tissues of monkeys were taken for triphenyltetrazolium chloride (TTC) staining.ResultsAmong the 15 cynomolgus monkeys, 12 of them were successfully modeled, as confirmed by the imaging findings and staining assessment. One monkey died of brain hernia resulted from intracranial hemorrhage confirmed by necropsy. DSA, CTA, and MRA indicated the presence of an arterial occlusion. CTP and MRI showed acute focal cerebral ischemia. TTC staining revealed infarct lesions formed in the brain tissues.ConclusionOur study may provide an optimal non-human primate model for an in-depth study of the pathogenesis and treatment of focal cerebral ischemia.
The Complex Relationship Between Cooling Parameters and Neuroprotection in a Model of Selective Hypothermia
Authors: Mattingly Thomas K. , McDavid Andrew , Wolf Amparo , Lieber Glen , Solar Ronald , Lee Donald , Lownie Stephen P. 
Published: April 2022

BackgroundHypothermia remains the best studied neuroprotectant. Despite extensive positive large and small animal data, side effects continue to limit human applications. Selective hypothermia is an efficient way of applying neuroprotection to the brain without the systemic complications of global hypothermia. However, optimal depth and duration of therapeutic hypothermia are still unknown. We analyzed a large animal cohort study of selective hypothermia for statistical relationships between depth or duration of hypothermia and the final stroke volume.MethodsA cohort of 30 swine stroke subjects provided the dataset for normothermic and selective hypothermic animals. Hypothermic parameters including duration, temperature nadir, and an Area Under the Curve measurement for 34 and 30°C were correlated with the final infarct volumes measured by MRI and histology.ResultsBetween group comparisons continue to demonstrate a reduction in infarct volume with selective hypothermia. Histologically-derived infarct volumes were 1.2 mm3 smaller in hypothermia-treated pigs (P = 0.04) and showed a similar, but non-significant reduction in MRI (P = 0.15). However, within the selective hypothermia group, more intense cooling, as measured through increased AUC 34 and decreased temperature nadir was associated with larger infarct proportions by MRI [Pearson's r = 0.48 (p = 0.05) and r = −0.59 (p = 0.01), respectively]. Reevaluation of the entire cohort with quadratic regression demonstrated a U-shaped pattern, wherein the average infarct proportion was minimized at 515 degree-minutes (AUC34) of cooling, and increased thereafter. In a single case of direct brain tissue oxygen monitoring during selective hypothermia, brain tissue oxygen strongly correlated with brain temperature reduction over the course of selective hypothermia to 23°C.ConclusionsIn a large animal model of selective hypothermia applied to focal ischemia, there is a non-monotone relationship between duration and depth of hypothermia and stroke volume reduction. This suggests a limit to depth or duration of selective hypothermia for optimal neuroprotection. Further research is required to delineate more precise depth and duration limits for selective hypothermia.
Impulsivity Moderates the Effect of Neurofeedback Training on the Contingent Negative Variation in Autism Spectrum Disorder
Authors: Prillinger Karin , Radev Stefan T. , Doganay Kamer , Poustka Luise , Konicar Lilian 
Published: April 2022

BackgroundThe contingent negative variation (CNV) is a well-studied indicator of attention- and expectancy-related processes in the human brain. An abnormal CNV amplitude has been found in diverse neurodevelopmental psychiatric disorders. However, its role as a potential biomarker of successful clinical interventions in autism spectrum disorder (ASD) remains unclear.MethodsIn this randomized controlled trial, we investigated how the CNV changes following an intensive neurofeedback training. Therefore, twenty-one adolescents with ASD underwent 24 sessions of slow cortical potential (SCP) neurofeedback training. Twenty additional adolescents with ASD formed a control group and received treatment as usual. CNV waveforms were obtained from a continuous performance test (CPT), which all adolescents performed before and after the corresponding 3-month long training period. In order to utilize all available neural time series, trial-based area under the curve values for all four electroencephalogram (EEG) channels were analyzed with a hierarchical Bayesian model. In addition, the model included impulsivity, inattention, and hyperactivity as potential moderators of change in CNV.ResultsOur model implies that impulsivity moderates the effects of neurofeedback training on CNV depending on group. In the control group, the average CNV amplitude decreased or did not change after treatment as usual. In the experimental group, the CNV changed depending on the severity of comorbid impulsivity symptoms. The average CNV amplitude of participants with low impulsivity scores decreased markedly, whereas the average CNV amplitude of participants with high impulsivity increased.ConclusionThe degree of impulsivity seems to play a crucial role in the changeability of the CNV following an intensive neurofeedback training. Therefore, comorbid symptomatology should be recorded and analyzed in future EEG-based brain training interventions.Clinical Trial Registrationhttps://www.drks.de, identifier DRKS00012339.