bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Unresectable Hepatocellular Carcinoma: Efficacy and Systemic Immune Response
Authors: Yang Fei , Xu Gui-Li , Huang Jin-Tao , Yin Yu , Xiang Wei , Zhong Bin-Yan , Li Wan-Ci , Shen Jian , Zhang Shuai , Yang Jun , Sun Hong Peng , Wang Wan-Sheng , Zhu Xiao-Li 
Published: February 2022

BackgroundLocoregional therapy combined with systemic therapy can further improve the prognoses for HCC. However, the efficacy of TACE combined with ICIs and TKIs for HCC and whether this triple therapy can activate systemic immune response are still unknown.PurposeTo identify the efficacy of TACE+ICIs+TKIs for unresectable hepatocellular carcinoma (uHCC) and its effect on systemic immunity.Materials and MethodsThis single-center retrospective study was approved by the Institutional Review Board. From August 1, 2019, to March 30, 2021, patients with uHCC who received the combination therapy of TACE+ICIs+TKIs were included. Peripheral blood samples were collected at baseline and once a month for 4 months after treatment. Lymphocyte subsets were measured by flow cytometry. Immunoglobulins were measured using the immune turbidimetric method. The dynamic change trend of circulating parameters was tested using simple linear regression.ResultsFifty-three patients with a mean age of 59 ± 10.6 years were included. TTP was 8.0 months (95% CI, 5.5–10.5) and PFS was 8.5 months (95% CI, 5.4–11.5). ORR was 52.8% and DCR was 81.1%. Twenty patients had completed analysis of biomarkers in peripheral blood. For cellular immune response, the level of circulating CD8+, CD3+ T cells and NK cells increased, the frequency of CD4+T cells and the CD4+/CD8+ ratio decreased, and among them, CD8+ T cells increased significantly. For humoral immune response, there was a significant decrease in B cells and a significant increase in Ig G, Ig κ, and Ig λ. Moreover, Ig G, Ig κ, and Ig λ were related to tumor response.ConclusionTACE+ICIs+TKIs showed considerable efficacy in patients with uHCC. This triple therapy activated not only cell immune but also humoral immune activation. Circulating Ig G, Ig λ, and Ig κ can serve as potential biomarkers.
In vitro Relative Fitness, in vivo Intestinal Colonization and Genomic Differences of Escherichia coli of ST131 Carrying blaCTX–M–15
Authors: Hertz Frederik Boëtius , Marvig Rasmus L. , Frimodt-Møller Niels , Nielsen Karen Leth 
Published: February 2022

IntroductionExtended-spectrum beta-lactamase (ESBL) producing Escherichia coli have become prevalent worldwide, with E. coli of sequence type 131 (ST131) as the dominant genotype. E. coli ST131 predominantly exhibits the serotype O25, is associated with the ESBL CTX-M-15 and belongs to a well-defined subclade within the FimH30-R clade, FimH30-Rx/C2. Multidrug resistance may have fitness costs for the bacteria. The aim of the current study was to investigate the fitness burden compared to a susceptible ST131 isolate without resistance genes in vitro and in vivo and describe genetic differences between fit and less fit isolates.Materials and methodsFrom a collection of clinical ESBL and non-ESBL E. coli isolates from urinary tract infection, we selected 16 blaCTX–M–15-positive isolates of ST131. The in vitro fitness was examined, and relative bacterial fitness (fitt) was determined by direct competition with a fully susceptible ST131 isolate and illustrated in percent, with &lt;100% resulting in a lower fitness, compared to the susceptible reference isolate. The isolates were subjected to whole-genome sequencing and analyzed for resistance markers, plasmids, phage content, and serotype. In vivo competition was tested in a mouse colonization model.ResultsThe majority (12 out of 16) of the CTX-M-15-producing isolates had a slightly lower relative fitness compared to the susceptible ST131 isolate (mean, 97.6%; range, 82.6–108%) in vitro. Three isolates had a better fitness than the susceptible ST131 isolate, and one isolate had an identical fitness to the susceptible ST131 isolate. The in vitro fitness showed no correlation to the number of plasmids, number of phages, number of resistances, or genome size. For the in vivo competition assays, all three ESBL-producing isolates showed better colonization of the ESBL-resistant ST131 isolates compared to the susceptible ST131 isolate.ConclusionThis study shows that ESBL-producing ST131/H30-Rx are not necessarily burdened by multidrug resistance, however, have a better in vitro fitness than the susceptible isolate. These data contribute to the understanding of the success of ST131/H30-Rx, although they do not indicate ways to overcome this highly fit, virulent, and antimicrobial-resistant clone.
Consistent Biofilm Formation by Streptococcus pyogenes emm 1 Isolated From Patients With Necrotizing Soft Tissue Infections
Authors: Skutlaberg Dag Harald , Wiker Harald G. , Mylvaganam Haima ,   The INFECT Study Group, Norrby-Teglund Anna , Skrede Steinar 
Published: February 2022

ObjectivesBiofilm formation has been demonstrated in muscle and soft tissue samples from patients with necrotizing soft tissue infection (NSTI) caused by Streptococcus pyogenes, but the clinical importance of this observation is not clear. Although M-protein has been shown to be important for in vitro biofilm formation in S. pyogenes, the evidence for an association between emm type and biofilm forming capacity is conflicting. Here we characterize the biofilm forming capacity in a collection of S. pyogenes isolates causing NSTI, and relate this to emm type of the isolates and clinical characteristics of the patients.MethodsBacterial isolates and clinical data were obtained from NSTI patients enrolled in a multicenter prospective observational study. Biofilm forming capacity was determined using a microtiter plate assay.ResultsAmong 57 cases, the three most frequently encountered emm types were emm1 (n = 22), emm3 (n = 13), and emm28 (n = 7). The distribution of biofilm forming capacity in emm1 was qualitatively (narrow-ranged normal distribution) and quantitatively (21/22 isolates in the intermediate range) different from other emm types (wide ranged, multimodal distribution with 5/35 isolates in the same range as emm1). There were no significant associations between biofilm forming capacity and clinical characteristics of the patients.ConclusionsThe biofilm forming capacity of emm1 isolates was uniform and differed significantly from other emm types. The impact of biofilm formation in NSTI caused by S. pyogenes on clinical outcomes remains uncertain.
Clinical Significance of Composition and Functional Diversity of the Vaginal Microbiome in Recurrent Vaginitis
Authors: Kim Min Jeong , Lee Seungok , Kwon Mi Yeon , Kim Myungshin 
Published: February 2022

ObjectiveThe vaginal microbiome protects the female genital tract from various diseases, such as vaginitis, a vaginal inflammation characterized by abnormal discharge, itching, and pain. To evaluate the clinical relationship between the vaginal microbiome and the pathophysiology of recurrent vaginitis (RV), we investigated the microbiome taxonomic profile (MTP) in the vaginal samples of Korean female patients with RV.MethodsForty women of reproductive age diagnosed with RV were enrolled. The vaginal MTP of patients was analyzed using 16S ribosomal RNA gene sequencing, and the results were compared with that of healthy women (n = 100). Further, the association of the vaginal community state type (CST) with the clinical characteristics was analyzed.ResultsThe species abundance of MTP was significantly lower in patients with RV than in healthy women (p &lt; 0.05), whereas species evenness and diversity were significantly higher in patients with RV than in healthy individuals (p &lt; 0.05). The proportion of the most common vaginal Lactobacillus spp. was significantly lower in the MTP of patients with RV than healthy women (p &lt; 0.01). The beta diversity distance was also significantly different between patients with RV patients and healthy individuals (p = 0.001). Based on the CST, the MTP of 40 RV samples was categorized as follows: 21 (52.5%) for CST IV, 8 (20.0%) for CST III, 5 (12.5%) for CST I, 2 (5.0%) for CST II, 1 for (2.5%) for CST V, and 3 (7.5%) for mixed CST. Patients with underlying uterine diseases (uterine leiomyoma, adenomyosis, and endometrial polyps; n = 17) showed higher species richness and diversity than those without (n = 23; p &lt; 0.05).ConclusionChanges in the species abundance and microbial diversity in the vagina were strongly associated with RV. A low proportion of Lactobacillus spp. was found in patients with RV than in healthy women. The abundance and diversity of bacterial taxa were significantly higher in patients with underlying gynecologic disease than those without. Our study offers an insight into the nature of the vaginal microbiome and proposes that surveying the vaginal microbiome is valuable for detecting and treating gynecologic diseases in the future.
A Neutrophil Extracellular Traps Signature Predicts the Clinical Outcomes and Immunotherapy Response in Head and Neck Squamous Cell Carcinoma
Authors: Chen Naifei , He Dongsheng , Cui Jiuwei 
Published: February 2022

Background: Neutrophil extracellular traps (NETs) play an important role in the occurrence, metastasis and immune escape of cancers. This study aimed to investigate NET-related genes, their clinical prognostic value and their correlation with immunotherapy and anticancer drugs in patients with head and neck squamous cell carcinoma (HNSCC).Methods: Differentially expressed NET-related genes in HNSCC were identified based on multiple public databases. To improve the clinical practicability and avoid overfitting, univariable, least absolute shrinkage and selection operator (LASSO) and multivariable Cox algorithms were used to construct a prognostic risk model. A nomogram was further used to explore the clinical value of the model. Internal and external validation were conducted to test the model. Furthermore, the immune microenvironment, immunophenoscore (IPS) and sensitivity to anticancer drugs in HNSCC patients with different prognostic risks were explored.Results: Six NET-related genes were screened to construct the risk model. In the training cohort, Kaplan–Meier (K-M) analysis showed that the overall survival (OS) of low-risk HNSCC patients was significantly better than that of high-risk HNSCC patients (p &lt; 0.001). The nomogram also showed a promising prognostic value with a better C-index (0.726 vs 0.640) and area under the curve (AUC) (0.743 vs 0.706 at 3 years, 0.743 vs 0.645 at 5 years) than those in previous studies. Calibration plots and decision curve analysis (DCA) also showed the satisfactory predictive capacity of the nomogram. Internal and external validation further strengthened the credibility of the clinical prognostic model. The level of tumor mutational burden (TMB) in the high-risk group was significantly higher than that in the low-risk group (p = 0.017), and the TMB was positively correlated with the risk score (R = 0.11; p = 0.019). Moreover, the difference in immune infiltration was significant in HNSCC patients with different risks (p &lt; 0.05). Furthermore, the IPS analysis indicated that anti-PD-1 (p &lt; 0.001), anti-CTLA4 (p &lt; 0.001) or combining immunotherapies (p &lt; 0.001) were more beneficial for low-risk HNSCC patients. The response to anticancer drugs was also closely correlated with the expression of NET-related genes (p &lt; 0.001).Conclusion: This study identified a novel prognostic model that might be beneficial to develop personalized treatment for HNSCC patients.
Correlation Between Thrombus Signal Intensity and Aneurysm Wall Thickness in Partially Thrombosed Intracranial Aneurysms Using 7T Magnetization-Prepared Rapid Acquisition Gradient Echo Magnetic Resonance Imaging
Authors: Sato Taku , Matsushige Toshinori , Chen Bixia , Gembruch Oliver , Dammann Philipp , Jabbarli Ramazan , Forsting Michael , Junker Andreas , Maderwald Stefan , Quick Harald H. , Ladd Mark E. , Sure Ulrich , Wrede Karsten H. 
Published: February 2022

ObjectiveThe objective of this study is to investigate the relationship between the thrombus signal intensity and aneurysm wall thickness in partially thrombosed intracranial aneurysms in vivo with magnetization-prepared rapid acquisition gradient echo (MPRAGE) taken using 7T magnetic resonance imaging (MRI) and correlate the findings to wall instability.MethodsSixteen partially thrombosed intracranial aneurysms were evaluated using a 7T whole-body MR system with nonenhanced MPRAGE. To normalize the thrombus signal intensity, its highest signal intensity was compared to that of the anterior corpus callosum of the same subject, and the signal intensity ratio was calculated. The correlation between the thrombus signal intensity ratio and the thickness of the aneurysm wall was analyzed. Furthermore, aneurysmal histopathological specimens from six tissue samples were compared with radiological findings to detect any correlation.ResultsThe mean thrombus signal intensity ratio was 0.57 (standard error of the mean [SEM] 0.06, range 0.25–1.01). The mean thickness of the aneurysm wall was 1.25 (SEM 0.08, range 0.84–1.55) mm. The thrombus signal intensity ratio significantly correlated with the aneurysm wall thickness (p &lt; 0.01). The aneurysm walls with the high thrombus signal intensity ratio were significantly thicker. In histopathological examinations, three patients with a hypointense thrombus had fewer macrophages infiltrating the thrombus and a thin degenerated aneurysmal wall. In contrast, three patients with a hyperintense thrombus had abundant macrophages infiltrating the thrombus.ConclusionThe thrombus signal intensity ratio in partially thrombosed intracranial aneurysms correlated with aneurysm wall thickness and histologic features, indicating wall instability.
A Quantitative Imaging Biomarker Supporting Radiological Assessment of Hippocampal Sclerosis Derived From Deep Learning-Based Segmentation of T1w-MRI
Authors: Rebsamen Michael , Radojewski Piotr , McKinley Richard , Reyes Mauricio , Wiest Roland , Rummel Christian 
Published: February 2022

PurposeHippocampal volumetry is an important biomarker to quantify atrophy in patients with mesial temporal lobe epilepsy. We investigate the sensitivity of automated segmentation methods to support radiological assessments of hippocampal sclerosis (HS). Results from FreeSurfer and FSL-FIRST are contrasted to a deep learning (DL)-based segmentation method.Materials and MethodsWe used T1-weighted MRI scans from 105 patients with epilepsy and 354 healthy controls. FreeSurfer, FSL, and a DL-based method were applied for brain anatomy segmentation. We calculated effect sizes (Cohen's d) between left/right HS and healthy controls based on the asymmetry of hippocampal volumes. Additionally, we derived 14 shape features from the segmentations and determined the most discriminating feature to identify patients with hippocampal sclerosis by a support vector machine (SVM).ResultsDeep learning-based segmentation of the hippocampus was the most sensitive to detecting HS. The effect sizes of the volume asymmetries were larger with the DL-based segmentations (HS left d= −4.2, right = 4.2) than with FreeSurfer (left= −3.1, right = 3.7) and FSL (left= −2.3, right = 2.5). For the classification based on the shape features, the surface-to-volume ratio was identified as the most important feature. Its absolute asymmetry yielded a higher area under the curve (AUC) for the deep learning-based segmentation (AUC = 0.87) than for FreeSurfer (0.85) and FSL (0.78) to dichotomize HS from other epilepsy cases. The robustness estimated from repeated scans was statistically significantly higher with DL than all other methods.ConclusionOur findings suggest that deep learning-based segmentation methods yield a higher sensitivity to quantify hippocampal sclerosis than atlas-based methods and derived shape features are more robust. We propose an increased asymmetry in the surface-to-volume ratio of the hippocampus as an easy-to-interpret quantitative imaging biomarker for HS.
Cerebrospinal Fluid TNF-α and Orexin in Patients With Parkinson's Disease and Rapid Eye Movement Sleep Behavior Disorder
Authors: Yuan Yuan , Zhang Yimeng , Cheng Yueyang , Hou Yue , Huang Zhaoyang , Ma Jinghong , Li Ning , Zhan Shuqin 
Published: February 2022

BackgroundParkinson's disease (PD) pathological changes begin before motor symptoms appear. Rapid eye movement sleep behavior disorder (RBD) has the highest specificity and predictive value of any marker of prodromal PD. Tumor necrosis factor α (TNF-α) plays a part in the pathology of PD and disease conversion in isolated RBD (iRBD). TNF can also directly impair the hypocretin system in mice in vivo. As a result, we intend to investigate the effect of TNF-α on orexin levels in PD patients with RBD.MethodParticipants were recruited from the Department of Neurology of Xuanwu Hospital, Capital Medical University to engage in assessments on motor symptoms, sleep, cognition, etc. Then we collected blood and cerebrospinal fluid of all patients and 10 controls' cerebrospinal fluid. The levels of TNF-α in the serum and cerebrospinal fluid, as well as the level of orexin in the cerebrospinal fluid, were measured in the patients.ResultsThe difference in TNF- levels in cerebrospinal fluid and serum between the three groups were not statistically significant. The levels of orexin in the three groups were not significantly lower than in the control group. UPDRS-III scores were significantly higher in the PD+RBD and PD-RBD groups than in the iRBD group. There was no statistically significant difference in H-Y stages, PSQI, or ESS scores between the PD+RBD and PD-RBD groups.ConclusionOur findings suggest that TNF-α may not have a significant effect on the orexinergic system in patients with Parkinson's disease and iRBD. As a result, it is necessary to investigate the changes in TNF-α and orexin levels in different disease stages and to enlarge the sample size to determine whether TNF-α affects the function of the orexin system, which may be related to the occurrence of RBD and disease progression in Parkinson's disease.
Small-Molecule Bi-DOTA Complex for High-Performance CT and Spectral CT Bioimaging
Authors: Dai Guidong , Zhang Yu , Wang Ximei , Wang Xingyu , Jia Juan , Jia Fei , Yang Lu , Yang Chunmei 
Published: February 2022

ObjectivesIt is necessary to develop a high-performance and biocompatible contrast agent to accurately diagnose various diseases via in vivo computed tomography (CT) imaging. Here, we synthesized a small molecular Bi-DOTA complex as a high-performance contrast agent for in vitro and in vivo CT bioimaging.Materials and MethodsIn our study, Bi-DOTA was fabricated through a facile and one-pot synthesis strategy. The formed Bi-DOTA complex was characterized via different techniques. Furthermore, Bi-DOTA was used for in vitro and in vivo CT bioimaging to verify its X-ray attenuation ability, especially in vivo kidney imaging, gastrointestinal tract CT imaging, and spectral CT imaging.ResultsA small molecular Bi-DOTA complex with a molecular mass of 0.61 kDa was synthesized successfully, which exhibited outstanding dispersion, good biocompatibility, and superior X-ray attenuation ability. Meanwhile, we showed that the obtained contrast agent was quite biocompatible and safe in the given concentration range as confirmed by in vitro and in vivo cytotoxicity assay. Also, the proposed contrast agent can be rapidly excreted from the body via the urinary system, avoiding the potential side effects caused by long-term retention in vivo. Importantly, Bi-DOTA was successfully used in high-quality in vitro CT imaging, in vivo kidney imaging, gastrointestinal tract CT imaging, and spectral CT imaging.ConclusionsThese superiorities allowed Bi-DOTA to be used as an efficient CT contrast agent and laid down a new way of designing high-performance CT contrast agents with great clinical transformation potential.
Cost-Utility Analysis of Once-Weekly Semaglutide, Dulaglutide, and Exenatide for Type 2 Diabetes Patients Receiving Metformin-Based Background Therapy in China
Authors: Hu Shanshan , Wang Shuowen , Qi Chendong , Gu Shengying , Shi Chenyang , Mao Lin , Fan Guorong 
Published: February 2022

Introduction: The substantial financial burden associated with type 2 diabetes (T2D) over a lifetime cannot be neglected. Therefore, the objective of this study was to evaluate the pharmacoeconomic value of three once-weekly GLP-1 RAs, namely subcutaneous semaglutide (sc. SEMA), dulaglutide (DULA), and extended-release exenatide (e-r EXEN), in treating patients with T2D that cannot be controlled with metformin-based background therapy, and to find a suitable price reduction for non-cost-effective medications, to provide reasonable recommendations to the administration for adjusting drug prices.Methods: The baseline characteristics of the simulation patient cohort were sourced from a comprehensive meta-analysis synthesizing 453 trials evaluating 21 hypoglycemic agents from nine categories of drugs. The UKPDS OM2 was applied to project the long-term effectiveness and costs from a Chinese health care provider’s perspective. After cost-utility analysis, the reasonable price adjustment of non-cost-effective options was explored via binary search. Uncertainty was measured by means of sensitivity analysis.Results: After a 40-year simulation, the sc. SEMA, DULA, and e-r EXEN groups yielded 9.6315, 9.5968, and 9.5895 quality-adjusted life years (QALYs), respectively. In terms of expenditure, the total costs for the sc. SEMA, DULA, and e-r EXEN groups were $42012.47, $24931.27, and $40264.80, respectively. DULA was dominant over e-r EXEN due to the higher QALYs and lower total costs. The ICURs of sc. SEMA vs. DULA and sc. SEMA vs. e-r EXEN were $492994.72/QALY and $41622.69/QALY (ICUR &gt; λ), respectively, indicating that sc. SEMA was not more cost-effective than DULA or e-r EXEN. The INMB and absolute NMB yielded the same conclusions which were robust to one-way, scenario, and probabilistic sensitivity analyses. After several assumptions in the binary search, sc. SEMA and e-r EXEN appear to become cost-effective when their annual costs are decreased by 57.67% and 70.34%, respectively, with DULA as a counterpart.Conclusion: From the cost-utility analysis, DULA appears to be the most cost-effective option among sc. SEMA, DULA, and e-r EXEN for the treatment of patients with T2D receiving metformin-based background therapy. With a 57.67% or 70.34% reduction in cost, sc. SEMA or e-r EXEN, respectively, would become as cost-effective as DULA in China.