bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer
Authors: Yan Yi-Dan , Cui Jiu-Jie , Fu Jie , Su Ying-Jie , Chen Xiao-Yu , Gu Zhi-Chun , Lin Hou-Wen 
Published: December 2021

BackgroundImmune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. However, adverse events (AEs), particularly immune–related AEs (irAEs), caused by these drugs have aroused public attention. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI–based regimens in patients with advanced lung cancer.MethodsWe systematically searched the PubMed, EMBASE, and Cochrane Library databases (from inception to 19 April 2021) for relevant randomized controlled trials (RCTs) that compared two or more treatments, with at least one ICI administered to patients with advanced lung cancer. The primary outcomes were treatment–related AEs and irAEs, including grade 1–5 and grade 3–5. The secondary outcomes were grade 1–5 and grade 3–5 irAEs in specific organs. Both pairwise and network meta-analyses were conducted for chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy for all safety outcomes. Node–splitting analyses were performed to test inconsistencies in network. Sensitivity analyses were adopted by restricting phase III RCTs and studies that enrolled patients with non–small cell lung cancer.ResultsOverall, 38 RCTs involving 22,178 patients with advanced lung cancer were enrolled. Both pooled incidence and NMA indicated that treatments containing chemotherapy increased the risk of treatment–related AEs when compared with ICI-based regimens without chemotherapy. As for grade 1–5 irAEs, dual ICIs + chemotherapy was associated with the highest risk of irAEs (probability in ranking first: 50.5%), followed by dual-ICI therapy (probability in ranking second: 47.2%), ICI monotherapy (probability in ranking third: 80.0%), ICI monotherapy + chemotherapy (probability in ranking fourth: 98.0%), and finally chemotherapy (probability in ranking fifth: 100.0%). In grade 3–5 irAEs, subtle differences were observed; when ranked from least safe to safest, the trend was dual ICIs therapy (60.4%), dual ICIs + chemotherapy (42.5%), ICI monotherapy (76.3%), ICI monotherapy + chemotherapy (95.0%), and chemotherapy (100.0%). Furthermore, detailed comparisons between ICI–based options provided irAE profiles based on specific organ/system and severity.ConclusionsIn consideration of overall immune–related safety profiles, ICI monotherapy + chemotherapy might be a better choice among ICI–based treatments for advanced lung cancer. The safety profiles of ICI–based treatments are various by specific irAEs and their severity.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42021268650
Durability of Antibody Responses to SARS-CoV-2 Infection and Its Relationship to Disease Severity Assessed Using a Commercially Available Assay
Authors: Alshami Alanoud , Al Attas Rabab , Anan Hadeel , Al Maghrabi Aroub , Ghandorah Salim , Mohammed Amani , Alhalimi Abdulbary , Al-Jishi Jumana , Alqahtani Hadi 
Published: December 2021

Background: Assessing the humoral immune response to SARS-CoV-2 is crucial for inferring protective immunity from reinfection and for assessing vaccine efficacy. Data regarding the durability and sustainability of SARS-CoV-2 antibodies are conflicting. In this study, we aimed to determine the seroconversion rate of SARS-CoV-2 infection in a cohort of reverse-transcriptase polymerase chain reaction (RT–PCR)-confirmed SARS-CoV-2 infections and the antibody dynamics, durability, and the correlation of antibody titers with disease severity using the commercially available SARS-CoV-2 anti-spike (S1/S2) protein.Methods: A total of 342 subjects with PCR-confirmed COVID-19 were enrolled. A total of 395 samples were collected at different time points (0–204) after the onset of symptoms or from the day of positive PCR in asymptomatic patients. Demographics, clinical presentation and the date of PCR were collected. All samples were tested using the automated commercial chemiluminescent system (DiaSorin SARS-CoV-2 S1/S2 IgG) on the LIAISONXL® platform (LIAISON).Results: The seroconversion rate for samples collected 14 days after the onset of infection was much higher than that for samples collected before 14 days (79.4% vs. 39.4%). The rate of seroconversion in symptomatic participants (62.1%) was similar to that of asymptomatic participants (56.1%) (p = 0.496). The IgG titer distribution was also similar across both groups (p = 0.142), with a median IgG level of 27.86 AU/ml (3.8–85.5) and 15 AU/ml (3.8–58.85) in symptomatic and asymptomatic participants, respectively. However, IgG titers were significantly higher in ICU patients, with a median of 104 AU/ml (3.8–179) compared to 34 AU/ml (3.8–70) in the non-ICU participants (p &lt; 0.0001). Furthermore, the median time to seroconversion occurred significantly faster in ICU patients than in non-ICU participants (19 versus 47 days) (P &lt; 0.0001). IgG titers were also higher in subjects ≥50 years compared to those &lt;50 years (p &lt; 0.009), male compared to female (p &lt; 0.054) and non-Saudi compared to Saudi (p &lt; 0.003). Approximately 74% of all samples tested beyond 120 days were positive.Conclusion: Antibodies can persist in circulation for longer than 4 months after COVID-19 infection. The majority of patients with COVID-19 mounted humoral immune responses to SARS-CoV-2 infection that strongly correlated with disease severity, older age and male gender. However, the population of individuals who tested negative should be further evaluated.
A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability
Authors: Kwok A , Camacho IS , Winter S , Knight M , Meade RM , Van der Kamp MW , Turner A , O’Hara J , Mason JM , Jones AR , Arcus VL , Pudney CR 
Published: December 2021

It is now over 30 years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. While there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the tryptophan REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides, to multitryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibodies in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating biomolecular simulation with experimental data to yield novel insights.
Application of Artificial Intelligence Modeling Technology Based on Fluid Biopsy to Diagnose Alzheimer’s Disease
Authors: Sh Yuan , Liu Benliang , Zhang Jianhu , Zhou Ying , Hu Zhiyuan , Zhang Xiuli 
Published: December 2021

Background: There are no obvious clinical signs and symptoms in the early stages of Alzheimer’s disease (AD), and most patients usually have mild cognitive impairment (MCI) before diagnosis. Therefore, early diagnosis of AD is very critical. This paper mainly discusses the blood biomarkers of AD patients and uses machine learning methods to study the changes of blood transcriptome during the development of AD and to search for potential blood biomarkers for AD.Methods: Individualized blood mRNA expression data of 711 patients were downloaded from the GEO database, including the control group (CON) (238 patients), MCI (189 patients), and AD (284 patients). Firstly, we analyzed the subcellular localization, protein types and enrichment pathways of the differentially expressed mRNAs in each group, and established an artificial intelligence individualized diagnostic model. Furthermore, the XCell tool was used to analyze the blood mRNA expression data and obtain blood cell composition and quantitative data. Ratio characteristics were established for mRNA and XCell data. Feature engineering operations such as collinearity and importance analysis were performed on all features to obtain the best feature solicitation. Finally, four machine learning algorithms, including linear support vector machine (SVM), Adaboost, random forest and artificial neural network, were used to model the optimal feature combinations and evaluate their classification performance in the test set.Results: Through feature engineering screening, the best feature collection was obtained. Moreover, the artificial intelligence individualized diagnosis model established based on this method achieved a classification accuracy of 91.59% in the test set. The area under curve (AUC) of CON, MCI, and AD were 0.9746, 0.9536, and 0.9807, respectively.Conclusion: The results of cell homeostasis analysis suggested that the homeostasis of Natural killer T cell (NKT) might be related to AD, and the homeostasis of Granulocyte macrophage progenitor (GMP) might be one of the reasons for AD.
Clinical Efficacy and Safety of Lacosamide as an Adjunctive Treatment in Adults With Refractory Epilepsy
Authors: Hou Liyan , Peng Bingjie , Zhang Defu , Yang Jingjing , Wang Ying , Tong Li , Li Sheng , Wang Qingshan , Zhao Jie 
Published: December 2021

Background: Lacosamide (LCM), a novel AED (antiepileptic drug), was used as an adjunctive treatment in patients with partial-onset seizures or without secondary generalization. However, no meta-analysis was performed to evaluate the efficacy of LCM as an adjunctive treatment in post-marketing clinical studies.Aims: To assess the safety and efficacy of LCM as an adjunctive treatment in adults with refractory epilepsy, a systematic review and meta-analysis of randomized controlled trials (RCTs) and real-world studies were performed.Methods: All studies were identified from electronic databases. Both RCTs and observational prospective studies were included. Primary outcomes included responder rate, adverse effects (AEs) and withdraw rate. The pooled rates (PR) with their corresponding 95% confidence intervals (CI) were calculated. Publication bias was assessed with Begg's or Egger's tests.Results: Total 16 studies (3,191 patients) including 5 RCTs and 11 real-word studies were enrolled. The pooled 50% responder rate and seizure-free rate were 48% (95% CI: 0.42, 0.54) and 9% (95% CI: 0.06, 0.11) in all studies, respectively. Subgroup analysis showed that the pooled 50% responder rate were 53% (95% CI: 0.44, 0.62) from observational studies and 38% (95% CI: 0.35, 0.42) from RCTs, respectively; the pooled seizure-free rate were 13% (95% CI: 0.09, 0.18) from observational studies and 4% (95% CI: 0.06, 0.11) from RCTs, respectively. Similar incidence of AEs were reported in real-world studies (0.57, 95% CI: 0.43, 0.72) and RCTs (0.59, 95% CI: 0.42–0.76). Finally, a total of 13% (95%CI: 0.09, 0.16) and 13% (95% CI: 0.08, 0.16) of all patients prescribed with LCM was withdrawn in RCTs and real-world studies, respectively, due to the occurrence of AEs. Furthermore, similar to the 50% responder rate, seizure-free rate, incidence of AEs and withdraw rate were reported at 6-month or at least 12-month of LCM adjunction. Publication bias was not detected in these studies.Conclusions: Our results revealed that LCM adjunctive therapy even with long-term treatment was efficacious and well tolerated in adults with refractory epilepsy.
Associations of Monocytes and the Monocyte/High-Density Lipoprotein Ratio With Extracranial and Intracranial Atherosclerotic Stenosis
Authors: Liu Zhu , Fan Qingli , Wu Shizheng , Lei Yancheng 
Published: December 2021

Background: Although the monocyte/high-density lipoprotein ratio (MHR) has been shown to be a potential marker of inflammatory of cardiovascular and cerebrovascular diseases, there are few studies on its relationships with the degree of intracranial and extracranial atherosclerotic stenosis and the stenosis distribution.Methods: In total, 271 patients were admitted for digital subtraction angiography (DSA) examination and were classified into a non-stenosis group and a stenosis group. (1) The two groups were compared and the arteries were categorized according to the degree of intracranial or extracranial atherosclerotic stenosis (if ≥two branches were stenotic, the artery with the most severe stenosis was used). (2) Clinical baseline data and laboratory indexes of patients grouped according to stenosis location (intracranial vs. extracranial) were collected.Results: (1) MHR × 102 [odds ratio (OR) = 1.119, p &lt; 0.001], age (OR = 1.057, p = 0.007), and lymphocyte count (OR = 0.273, p = 0.002) significantly affected the presence of cerebral atherosclerotic stenosis, with an MHR area of 0.82 under the receiver operating characteristic (ROC) curve (AUC) and an optimal diagnostic value of 0.486. Analyses of the moderate, mild, and severe stenosis groups showed that MHR × 102 (OR = 1.07, p &lt; 0.001) significantly affected the severity of stenosis in patients. (2) In the analysis of stenosis at different sites, the rate of extracranial artery stenosis in patients who smoked (OR = 3.86, p = 0.023) and had a reduced lymphocyte level (OR = 0.202, p = 0.001) was remarkably greater than that in patients who smoked (OR = 3.86, p = 0.023). With increasing age, the rate of extracranial artery stenosis raised sharply. With the increase in the MHR level, the stenosis rate of each group was highly greater than that of the non-stenosis group.Conclusion: The MHR has a predictive value for the diagnosis of extracranial and intracranial atherosclerotic stenosis and is correlated with the degree and distribution of stenosis.Trial Registration: Clinical Medical Research Center Project of Qinghai Province (2017-SF-L1). Qinghai Provincial Health Commission Project (Grant #2020-wjzdx-29).
Case Report: Long-Term Suppression of Paroxysmal Kinesigenic Dyskinesia After Bilateral Thalamotomy
Authors: Murakami Masato , Horisawa Shiro , Azuma Kenko , Akagawa Hiroyuki , Nonaka Taku , Kawamata Takakazu , Taira Takaomi 
Published: December 2021

Background:Paroxysmal kinesigenic dyskinesia (PKD) is a movement disorder characterized by transient dyskinetic movements, including dystonia, chorea, or both, triggered by sudden voluntary movements. Carbamazepine and other antiepileptic drugs (AEDs) are widely used in the treatment of PKD, and they provide complete remission in 80–90% of medically treated patients. However, the adverse effects of AEDs include drowsiness and dizziness, which interfere with patients' daily lives. For those with poor compatibility with AEDs, other treatment approaches are warranted.Case Report:A 19-year-old man presented to our institute with right hand and foot dyskinesia. He had a significant family history of PKD; his uncle, grandfather, and grandfather's brother had PKD. The patient first experienced paroxysmal involuntary left hand and toe flexion with left forearm pronation triggered by sudden voluntary movements at the age of 14. Carbamazepine (100 mg/day) was prescribed, which led to a significant reduction in the frequency of attacks. However, carbamazepine induced drowsiness, which significantly interfered with his daily life, especially school life. He underwent right-sided ventro-oral (Vo) thalamotomy at the age of 15, which resulted in complete resolution of PKD attacks immediately after the surgery. Four months after the thalamotomy, he developed right elbow, hand, and toe flexion. He underwent left-sided Vo thalamotomy at the age of 19. Immediately after the surgery, the PKD attacks resolved completely. However, mild dysarthria developed, which spontaneously resolved within three months. Left-sided PKD attacks never developed six years after the right Vo thalamotomy, and right-sided PKD attacks never developed two years after the left Vo thalamotomy without medication.Conclusion:The present case showed long-term suppression of bilateral PKDs after bilateral thalamotomy, which led to drug-free conditions.
Cost-Effectiveness of Adjuvant Immunotherapy With Cytokine-Induced Killer Cell for Hepatocellular Carcinoma Based on a Randomized Controlled Trial and Real-World Data
Authors: Cho Jeong-Yeon , Kwon Sun-Hong , Lee Eui-Kyung , Lee Jeong-Hoon , Kim Hye-Lin 
Published: December 2021

BackgroundStudies using data from randomized controlled trials (RCTs) and real-world data (RWD) have suggested that adjuvant cytokine-induced killer (CIK) cell immunotherapy after curative treatment for hepatocellular carcinoma (HCC) prolongs recurrence-free survival (RFS) and overall survival (OS). However, the cost-effectiveness of CIK cell immunotherapy as an adjuvant therapy for HCC compared to no adjuvant therapy is uncertain.MethodsWe constructed a partitioned survival model to compare the expected costs, life-year (LY), and quality-adjusted life-year (QALY) of a hypothetical population of 10,000 patients between CIK cell immunotherapy and no adjuvant therapy groups. Patients with HCC aged 55 years who underwent a potentially curative treatment were simulated with the model over a 20-year time horizon, from a healthcare system perspective. To model the effectiveness, we used OS and RFS data from RCTs and RWD. We estimated the incremental cost-effectiveness ratios (ICERs) and performed extensive sensitivity analyses.ResultsBased on the RCT data, the CIK cell immunotherapy incrementally incurred a cost of $61,813, 2.07 LYs, and 1.87 QALYs per patient compared to no adjuvant therapy, and the estimated ICER was $33,077/QALY. Being less than the willingness-to-pay threshold of $50,000/QALY, CIK cell immunotherapy was cost-effective. Using the RWD, the ICER was estimated as $25,107/QALY, which is lower than that obtained using RCT. The time horizon and cost of productivity loss were the most influential factors on the ICER.ConclusionWe showed that receiving adjuvant CIK cell immunotherapy was more cost-effective than no adjuvant therapy in patients with HCC who underwent a potentially curative treatment, attributed to prolonged survival, reduced recurrence of HCC, and better prognosis of recurrence. Receiving CIK cell immunotherapy may be more cost-effective in real-world clinical practice.
Reinvestigating Tumor–Ventricle Relationship of Craniopharyngiomas With Predominantly Ventricular Involvement: An Endoscopic Endonasal Series Based on Histopathological Assessment
Authors: Fan Jun , Liu Yi , Wang Chaohu , Feng Zhanpeng , Pan Jun , Peng Yuping , Peng Junxiang , Bao Yun , Nie Jing , Qiu Binghui , Qi Songtao 
Published: December 2021

ObjectiveCraniopharyngiomas (CPs) predominantly involving the third ventricle were commonly termed “intraventricular” lesions. The aim of this study was to clarify the anatomical relationship between the tumor and the third ventricle by both surgical and histological investigation.MethodsA retrospective review of primarily resected CPs by endoscopic endonasal surgery was performed. CPs with predominantly ventricular involvement were selected for study inclusion by preoperative imaging. The surgical procedure of each case was reviewed. The wholly removed tumor specimens were histologically analyzed, in all cases, to investigate the tumor–third ventricle relationship using hematoxylin and eosin, immunochemical, and immunofluorescence staining.ResultsTwenty-six primary CPs predominantly involving the third ventricle were selected from our series of 223 CPs treated by endoscopic endonasal surgery between January 2017 and March 2021. Gross-total resection was achieved in 24 (92.3%) of 26 patients, with achievement of near-total resection in the remaining patients. A circumferential layer of stretched third ventricle floor was identified surrounding the tumor capsule, which could be peeled off easily from the ventricle floor remnants at most areas of the plane of tumor attachment. Some portions of the tumor capsule tightly adhered to the third ventricle floor were removed together with the floor. A breach of various size was observed at the third ventricle floor after tumor removal in most cases, the floor remaining intact in only two cases (7.7%). Histological examination on marked portions of tumor capsule showed that the pia mater was frequently detected at most of the tumor–brain interface, except at the antero-frontal border of tumor contacting with the third ventricle floor. At this point, a layer of gliosis with various thickness was observed between the tumor and the neural tissue of the third ventricle floor.ConclusionCPs with predominantly ventricular involvement should be considered as lesions with an extraventricular, epi-pia topography rather than “intraventricular” or “subpial” topography. Accurate understanding of the relationship between the third ventricle and such tumors would predict the circumferential cleavage plane of dissection, and remind neurosurgeons of performing dissection along the safe surgical plane to achieve total tumoral resection with minimizing hypothalamic damage.
Comparison of Four Lymph Node Stage Methods for Predicting the Prognosis of Distal Cholangiocarcinoma Patients After Surgery
Authors: Huang Xiuyi , Niu Xiaoya , You Zhen , Long Youlin , Luo Fan , Ye Hui 
Published: December 2021

BackgroundThe metastatic status of regional lymph nodes is an effective risk factor for the prognosis of distal cholangiocarcinoma (dCCA). But existing lymph node staging is not accurate enough and is susceptible to interference. This study aims to explore the predictive ability of the log odds of positive lymph nodes (LODDS) staging system of dCCA compared with existing lymph node staging systems.MethodsA total of 928 dCCA patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database as the training cohort, and 207 dCCA patients from West China Hospital who underwent surgery were reviewed as the validation cohort. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression were conducted to identify the most meaningful factors relevant to prognosis. The performance of four lymph node stage systems was compared by a model-based approach.ResultAge at diagnosis, pathological grade, American Joint Committee on Cancer (AJCC) tumor 7th T stage, tumor size, radiotherapy, chemotherapy, and lymph node stage system were independent prognostic factors. The model with the LODDS system had a better model fit with the highest C-index (0.679) and 1-/3-/5- area under the receiver operating characteristic curve (AUC) (0.739/0.671/0.658) as well as the lowest Akaike information criterion (AIC) (5,020.52). External validation results from 207 dCCA patients showed a C-index of 0.647 and 1-/3-/5-AUC of 0.740/0.683/0.589. Compared with the lymph node ratio (LNR), AJCC 8th N system, and 7th N system, the 5-year net reclassification improvement (NRI) of the LODDS system was 0.030 (95% CI: −0.079 to 0.147), 0.042 (95% CI: −0.062 to 0.139), and 0.040 (95% CI: −0.057 to 0.146), respectively. The integrated discrimination improvement (IDI) of LODDS improved compared with the LNR model (0.016; 95% CI: −0.001 to 0.036), AJCC 8th N system (0.020; 95% CI: 0.003–0.037), and AJCC 7th N system (0.019; 95% CI: 0.002–0.036). Decision curve analysis (DCA) also shows a greater net benefit of LODDS. In lymph node-negative patients, LODDS reveals a positive linear relationship with the hazard ratio (HR). The stage capacity of LODDS in a subgroup analysis stratified by examined lymph node number (ELNN) was consistent.ConclusionsThe LODDS lymph node stage system has superior predictive performance as compared with the LNR, AJCC 7th, and 8th lymph node stage systems. Meanwhile, LODDS has a more detailed staging ability and good stability.