bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymorphism in INSR Locus Modifies Risk of Atrial Fibrillation in Patients on Thyroid Hormone Replacement Therapy
Authors: Soto-Pedre Enrique , Siddiqui Moneeza K. , Maroteau Cyrielle , Dawed Adem Y. , Doney Alex S. , Palmer Colin N. A. , Pearson Ewan R. , Leese Graham P. 
Published: June 2021

AimsAtrial fibrillation (AF) is a risk for patients receiving thyroid hormone replacement therapy. No published work has focused on pharmacogenetics relevant to thyroid dysfunction and AF risk. We aimed to assess the effect of L-thyroxine on AF risk stratified by a variation in a candidate gene.Methods and ResultsA retrospective follow-up study was done among European Caucasian patients from the Genetics of Diabetes Audit and Research in Tayside Scotland cohort (Scotland, United Kingdom). Linked data on biochemistry, prescribing, hospital admissions, demographics, and genetic biobank were used to ascertain patients on L-thyroxine and diagnosis of AF. A GWAS-identified insulin receptor-INSR locus (rs4804416) was the candidate gene. Cox survival models and sensitivity analyses by taking competing risk of death into account were used. Replication was performed in additional sample (The Genetics of Scottish Health Research register, GoSHARE), and meta-analyses across the results of the study and replication cohorts were done. We analyzed 962 exposed to L-thyroxine and 5,840 unexposed patients who were rs4804416 genotyped. The rarer G/G genotype was present in 18% of the study population. The total follow-up was up to 20 years, and there was a significant increased AF risk for patients homozygous carriers of the G allele exposed to L-thyroxine (RHR = 2.35, P = 1.6e–02). The adjusted increased risk was highest within the first 3 years of exposure (RHR = 9.10, P = 8.5e–04). Sensitivity analysis yielded similar results. Effects were replicated in GoSHARE (n = 3,190).ConclusionHomozygous G/G genotype at the INSR locus (rs4804416) is associated with an increased risk of AF in patients on L-thyroxine, independent of serum of free thyroxine and thyroid-stimulating hormone serum concentrations.
Reduced Energy Metabolism Impairs T Cell-Dependent B Cell Responses in Patients With Advanced HBV-Related Cirrhosis
Authors: Huang Chunhong , Shao Junwei , Lou Congcong , Wu Fengtian , Ge Tiantian , Gao Hainv , Zheng Xiaoping , Dong Xuejun , Xu Lichen , Chen Zhi 
Published: June 2021

Background and AimsPatients with decompensated HBV-related liver cirrhosis (HBV D-LC) showed compromised immune responses, which manifested as a proneness to develop infections and hyporesponsiveness to vaccines, resulting in accelerated disease progression. The alterations in T cell-dependent B cell responses in this pathophysiological process were not well understood. This study aimed to investigate T cell-dependent B cell responses in this process and discuss the mechanism from the perspective of metabolism.MethodsChanges in phenotypes and subsets of peripheral B cells between HBV D-LC patients and healthy controls (HCs) were compared by flow cytometry. Isolated B cells were activated by coculture with circulating T follicular (cTfh) cells. After coculture, the frequencies of plasmablasts and plasma cells and immunoglobin levels were analyzed. Oxidative phosphorylation (OXPHOS) and glycolysis were analyzed by a Seahorse analyzer. Mitochondrial function and the AKT/mTOR pathway were analyzed by flow cytometry.ResultsThe proliferation and differentiation capacities of B cells after T cell stimulation were impaired in D-LC. Furthermore, we found that B cells from D-LC patients showed reductions in OXPHOS and glycolysis after activation, which may result from reduced glucose uptake, mitochondrial dysfunction and attenuated activation of the AKT/mTOR pathway.ConclusionsB cells from HBV D-LC patients showed dysfunctional energy metabolism after T cell-dependent activation. Understanding the regulations of B cell metabolic pathway and their changes may provide a new direction to rescue B cell hyporesponsiveness in patients with HBV D-LC, preventing these patients be infected and improving sensitivity to vaccines.
Transfer of PBMC From SSc Patients Induces Autoantibodies and Systemic Inflammation in Rag2-/-/IL2rg-/- Mice
Authors: Yue Xiaoyang , Petersen Frank , Shu Yaqing , Kasper Brigitte , Magatsin Junie D. Tchudjin , Ahmadi Marjan , Yin Junping , Wax Jacqueline , Wang Xiaoqing , Heidecke Harald , Lamprecht Peter , Müller Antje , Yu Xinhua , Riemekasten Gabriela 
Published: June 2021

ObjectiveThe contribution of sustained autologous autoantibody production by B cells to the pathogenesis of systemic sclerosis (SSc) and granulomatosis with polyangiitis (GPA) is not fully understood. To investigate this, a humanized mouse model was generated by transferring patient-derived peripheral blood mononuclear cells (PBMC) into immunocompromised mice.MethodsPBMC derived from patients with SSc and GPA as well as healthy controls (HD) were isolated, characterized by flow cytometry, and infused into Rag2-/-/IL2rg-/- mice. In addition, PBMC from SSc patients treated with rituximab were transferred into mice. Twelve weeks later, human autoantibodies were determined in blood of the recipient mice and affected tissues were analyzed for pathological changes by histology and immunohistochemistry.ResultsMice engrafted with PBMC derived from SSc patients developed autoantibodies such as antinuclear antibodies (ANA) mimicking the pattern of the respective donors. Moreover, cellular infiltrates dominated by B cells were observed in lung, kidney and muscles of the recipient mice. By contrast, PBMC derived from HD or GPA patients survived in recipient mice after transfer, but neither human autoantibodies nor inflammatory infiltrates in tissues were detected. Furthermore, these pathological changes were absent in mice transferred with PBMC from rituximab-treated SSc patients.ConclusionThis humanized mouse model is indicative for cross-reactivity of human lymphocytes to murine autoantigens and argues for a pivotal role of B cells as well as of sustained autoimmunity in the pathogenesis of SSc. It provides a powerful tool to study interstitial lung disease and so far, under-recognized disease manifestations such as myositis and interstitial nephritis.
Immunological Responses to Transgene-Modified Neural Stem Cells After Transplantation
Authors: Wei Naili , Sun Zhenxing , Yu Jimei , Jia Yanfei , Zheng Peiqi , Tang Hailiang , Chen Jian 
Published: June 2021

Neural stem cell (NSC) therapy is a promising therapeutic strategy for stroke. Researchers have frequently carried out genetic modification or gene editing of stem cells to improve survival or therapeutic function. However, NSC transplantation carries the risk of immune rejection, and genetic modification or gene-editing might further increase this risk. For instance, recent studies have reported on manipulating the stem cell genome and transplantationviathe insertion of an exogenous gene derived from magnetotactic bacteria. However, whether transgene-modified stem cells are capable of inducing immunological reactions has not been explored. Although NSCs rarely express the major histocompatibility complex (MHC), they can still cause some immunological issues. To investigate whether transgene-modified NSCs aggravate immunological responses, we detected the changes in peripheral immune organs and intracerebral astrocytes, glial cells, and MHC-I and MHC-II molecules after the injection of GFP-labeled ormms6-GFP-labeled NSCs in a rat model. Xenogeneic human embryonic kidney (HEK-293T) cells were grafted as a positive control group. Our results indicated that xenogeneic cell transplantation resulted in a strong peripheral splenic response, increased astrocytes, enhanced microglial responses, and upregulation of MHC-I and MHC-II expression on the third day of transplantation. But they decreased obviously except Iba-1 positive cells and MHC-II expression. When injection of bothmms6-GFP-labeled NSCs and GFP-labeled NSCs also induced similar responses as HEK-293T cells on the third days, but MHC-I and MHC-II expression decreased 3 weeks after transplantation. In addition,mms6transgene-modified NSCs did not produce peripheral splenic response responses as well as astrocytes, microglial cells, MHC-I and MHC-II positive cells responses when compared with non-modified NSCs. The present study provides preliminary evidence that transgenic modification does not aggravate immunological responses in NSC transplantation.
Different Effects of Total Bilirubin on 90-Day Mortality in Hospitalized Patients With Cirrhosis and Advanced Fibrosis: A Quantitative Analysis
Authors: Qiao Liang , Tan Wenting , Wang Xiaobo , Zheng Xin , Huang Yan , Li Beiling , Meng Zhongji , Gao Yanhang , Qian Zhiping , Liu Feng , Lu Xiaobo , Shang Jia , Liu Junping , Yan Huadong , Gu Wenyi , Zhang Yan , Xiang Xiaomei , Hou Yixin , Zhang Qun , Xiong Yan , Zou Congcong , Chen Jun , Huang Zebing , Jiang Xiuhua , Luo Sen , Chen Yuanyuan , Gao Na , Liu Chunyan , Yuan Wei , Mei Xue , Li Jing , Li Tao , Zheng Rongjiong , Zhou Xinyi , Chen Jinjun , Deng Guohong , Zhang Weituo , Li Hai 
Published: June 2021

Introduction: Total bilirubin (TB) is a major prognosis predictor representing liver failure in patients with acute on chronic liver failure (ACLF). However, the cutoff value of TB for liver failure and whether the same cutoff could be applied in both cirrhotic and non-cirrhotic patients remain controversial. There is a need to obtain the quantitative correlation between TB and short-term mortality via evidence-based methods, which is critical in establishing solid ACLF diagnostic criteria.Methods: Patients hospitalized with cirrhosis or advanced fibrosis (FIB-4 &gt; 1.45) were studied. TB and other variables were measured at baseline. The primary outcome was 90-day transplantation-free mortality. Multi-variable Cox proportional hazard model was used to present the independent risk of mortality due to TB. Generalized additive model and second derivate (acceleration) were used to plot the “TB-mortality correlation curves.” The mathematical (maximum acceleration) and clinical (adjusted 28-day transplantation-free mortality rate reaching 15%) TB cutoffs for liver failure were both calculated.Results: Among the 3,532 included patients, the number of patients with cirrhosis and advanced fibrosis were 2,592 and 940, respectively, of which cumulative 90-day mortality were 16.6% (430/2592) and 7.4% (70/940), respectively. Any increase of TB was found the independent risk factor of mortality in cirrhotic patients, while only TB &gt;12 mg/dL independently increased the risk of mortality in patients with advanced fibrosis. In cirrhotic patients, the mathematical TB cutoff for liver failure is 14.2 mg/dL, with 23.3% (605/2592) patients exceeding it, corresponding to 13.3 and 25.0% adjusted 28- and 90-day mortality rate, respectively. The clinical TB cutoff for is 18.1 mg/dL, with 18.2% (471/2592) patients exceeding it. In patients with advanced fibrosis, the mathematical TB cutoff is 12.1 mg/dL, 33.1% (311/940) patients exceeding it, corresponding to 2.9 and 8.0% adjusted 28- and 90-day mortality rate, respectively; the clinical TB cutoff was 36.0 mg/dL, 1.3% (12/940) patients above it.Conclusion: This study clearly demonstrated the significantly different impact of TB on 90-day mortality in patients with cirrhosis and advanced fibrosis, proving that liver failure can be determined by TB alone in cirrhosis but not in advanced fibrosis. The proposed TB cutoffs for liver failure provides solid support for the establishment of ACLF diagnostic criteria.
Association of Aortic Stiffness and Cognitive Decline: A Systematic Review and Meta-Analysis
Authors: Liu Qian , Fang Jinghuan , Cui Chaohua , Dong Shuju , Gao Lijie , Bao Jiajia , Li Yanbo , Ma Mengmeng , Chen Ning , He Li 
Published: June 2021

Background: Increased aortic stiffness has been found to be associated with cognitive function decline, but the evidence is still under debate. It is of great significance to elucidate the evidence in this debate to help make primary prevention decisions to slow cognitive decline in our routine clinical practice.Methods: Electronic databases of PubMed, EMBASE, and Cochrane Library were systematically searched to identify peer-reviewed articles published in English from January 1, 1986, to March 16, 2020, that reported the association between aortic stiffness and cognitive function. Studies that reported the association between aortic pulse wave velocity (PWV) and cognitive function, cognitive impairment, and dementia were included in the analysis.Results: Thirty-nine studies were included in the qualitative analysis, and 29 studies were included in the quantitative analysis. The aortic PWV was inversely associated with memory and processing speed in the cross-sectional analysis. In the longitudinal analysis, the high category of aortic PWV was 44% increased risk of cognitive impairment (OR 1.44; 95% CI 1.24–1.85) compared with low PWV, and the risk of cognitive impairment increased 3.9% (OR 1.039; 95% CI 1.005–1.073) per 1 m/s increase in aortic PWV. Besides, meta-regression analysis showed that age significantly increased the association between high aortic PWV and cognitive impairment risk.Conclusion: Aortic stiffness measured by aortic PWV was inversely associated with memory and processing speed and could be an independent predictor for cognitive impairment, especially for older individuals.
Genomic Landscape of Chinese Clear Cell Renal Cell Carcinoma Patients With Venous Tumor Thrombus Identifies Chromosome 9 and 14 Deletions and Related Immunosuppressive Microenvironment
Authors: Niu Shaoxi , Liu Kan , Xu Yong , Peng Cheng , Yu Yao , Huang Qingbo , Wu Shengpan , Cui Bo , Huang Yan , Ma Xin , Zhang Xu , Wang Baojun 
Published: June 2021

BackgroundClear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with a poor clinical outcome. Although several studies have examined the genomic features of ccRCC, the genetic profile of VTT along with its matched primary tumor has not been fully elucidated.Materials and methodsSamples of VTT tissues and matched primary tumor tissues from ccRCC patients (n = 25), as well as primary tumor tissues from patients without VTT (n = 25) were collected and analyzed using whole-exome sequencing. Four additional ccRCC patients who were unfit for surgery were treated with an anti-programmed death receptor-1 (PD-1) monoclonal antibody (Toripalimab, 240 mg, Q3W, IV).ResultsBy comparing the primary kidney tumors from ccRCC patients with or without VTT, a relatively higher prevalence of BAP1 and KDM5C alterations were found in ccRCC patients with VTT, and these alterations were associated with worse overall survival in the kidney renal clear cell carcinoma (KIRC) database. Based on subclone analysis, VTT was predicted to primarily originate directly from the primary renal mass. A significantly higher prevalence of CELSR2 and TET2 alterations were identified in the VTTs compared with the matched primary tumors. An increased prevalence of DNA damage repair genes, especially those involved in homologous recombination repair and non-homologous end joining, was found in ccRCC patients with VTT. Notably, VTT was characterized by the increase incidence of copy number loss in the whole exome (p &lt; 0.05), particularly in the chromosome 9 and 14 regions. Deletion of chromosome 9 and 14 was associated with worse survival, unfavorable clinical features, and the presence of an immunosuppressive microenvironment, which was characterized by higher infiltration of regulatory T cells, follicular helper T cells, and resting mast cells, but lower counts of resting CD4 memory T cells and CD8 positive T cells. A significantly lower count of CD4+ and CD8+ tumor-infiltrated lymphocytes was identified in the VTT samples comparing with matched primary tumor. Of note, three out of the four ccRCC patients with VTT in our cohort who were treated with the anti-PD-1 therapy exhibited remarkable remission in the renal mass but no notable shrinkage in the VTT mass.ConclusionOur study revealed the genetic profile of Chinese ccRCC patients with VTT, and identified multiple features associated with known poor outcomes, including gene alterations and copy number loss. The deletions in chromosomes 9 and 14, and the associated immunosuppressive microenvironment may indicate limited sensitivity to anti-PD-1/PD-L1 monotherapy in VTT.
Machine-Learning-Derived Nomogram Based on 3D Radiomic Features and Clinical Factors Predicts Progression-Free Survival in Lung Adenocarcinoma
Authors: Liu Guixue , Xu Zhihan , Zhang Yaping , Jiang Beibei , Zhang Lu , Wang Lingyun , de Bock Geertruida H. , Vliegenthart Rozemarijn , Xie Xueqian 
Published: June 2021

BackgroundTo establish a machine-learning-derived nomogram based on radiomic features and clinical factors to predict post-surgical 2-year progression-free survival (PFS) in patients with lung adenocarcinoma.MethodsPatients with &gt;2 years post-surgical prognosis results of lung adenocarcinoma were included in Hospital-1 for model training (n = 100) and internal validation (n = 50), and in Hospital-2 for external testing (n = 50). A total of 1,672 radiomic features were extracted from 3D segmented CT images. The Rad-score was established using random survival forest by accumulating and weighting the top-20 imaging features contributive to PFS. A nomogram for predicting PFS was established, which comprised the Rad-score and clinical factors highly relevant to PFS.ResultsIn the training, internal validation, and external test groups, 69/100 (69%), 37/50 (74%) and 36/50 (72%) patients were progression-free at two years, respectively. According to the Rad-score, the integral of area under the curve (iAUC) for discriminating high and low risk of progression was 0.92 (95%CI: 0.77-1.0), 0.70 (0.41-0.98) and 0.90 (0.65-1.0), respectively. The C-index of Rad-score was 0.781 and 0.860 in the training and external test groups, higher than 0.707 and 0.606 for TNM stage, respectively. The nomogram integrating Rad-score and clinical factors (lung nodule type, cM stage and histological type) achieved a C-index of 0.845 and 0.837 to predict 2-year PFS, respectively, significantly higher than by only radiomic features (all p &lt; 0.01).ConclusionThe nomogram comprising CT-derived radiomic features and risk factors showed a high performance in predicting post-surgical 2-year PFS of patients with lung adenocarcinoma, which may help personalize the treatment decisions.
Incidence Trends and Risk Prediction Nomogram for Suicidal Attempts in Patients With Major Depressive Disorder
Authors: Liang Sixiang , Zhang Jinhe , Zhao Qian , Wilson Amanda , Huang Juan , Liu Yuan , Shi Xiaoning , Sha Sha , Wang Yuanyuan , Zhang Ling 
Published: June 2021

Background: Major depressive disorder (MDD) is often associated with suicidal attempt (SA). Therefore, predicting the risk factors of SA would improve clinical interventions, research, and treatment for MDD patients. This study aimed to create a nomogram model which predicted correlates of SA in patients with MDD within the Chinese population.Method: A cross-sectional survey among 474 patients was analyzed. All subjects met the diagnostic criteria of MDD according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). Multi-factor logistic regression analysis was used to explore demographic information and clinical characteristics associated with SA. A nomogram was further used to predict the risk of SA. Bootstrap re-sampling was used to internally validate the final model. Integrated Discrimination Improvement (IDI) and Akaike Information Criteria (AIC) were used to evaluate the capability of discrimination and calibration, respectively. Decision Curve Analysis (DCA) and the Receiver Operating Characteristic (ROC) curve was also used to evaluate the accuracy of the prediction model.Result: Multivariable logistic regression analysis showed that being married (OR = 0.473, 95% CI: 0.240 and 0.930) and a higher level of education (OR = 0.603, 95% CI: 0.464 and 0.784) decreased the risk of the SA. The higher number of episodes of depression (OR = 1.854, 95% CI: 1.040 and 3.303) increased the risk of SA in the model. The C-index of the nomogram was 0.715, with the internal (bootstrap) validation sets was 0.703. The Hosmer–Lemeshow test yielded a P-value of 0.33, suggesting a good fit of the prediction nomogram in the validation set.Conclusion: Our findings indicate that the demographic information and clinical characteristics of SA can be used in a nomogram to predict the risk of SA in Chinese MDD patients.
Behavioral Economic Assessment of Alcohol and Cigarette Demand in Smokers With Alcohol Use Disorder
Authors: Cui Yong , Linares Abrego Paulina , Yoon Jin Ho , Karam-Hage Maher , Cinciripini Paul M. , Ait-Daoud Tiouririne Nassima , Anthenelli Robert M. , Robinson Jason D. 
Published: June 2021

Background and Objectives: Behavioral economic purchase tasks are widely used to assess drug demand in substance use disorder research. Comorbid alcohol use is common among cigarette smokers and associated with greater difficulty in quitting smoking. However, demand for alcohol and cigarettes in this population has not been fully characterized. The present study addressed this gap by examining alcohol and cigarette demand among treatment-seeking smokers with alcohol use disorder (AUD).Methods: Alcohol and cigarette demand was assessed among 99 smokers with AUD. We conducted Principal Component Analysis (PCA) and correlational analyses on the demand indices.Results: Participants showed higher demand for alcohol than for cigarettes, as evidenced lower elasticity (resistance to increasing price) and higher Omax (maximum response output for drug). PCA revealed a two-factor structure (Persistence and Amplitude) for both alcohol and cigarette demand indices. Cigarette-related demand indices were positively correlated with nicotine dependence, but alcohol-related demand indices were not associated with alcohol dependence, suggesting dissociation between alcohol demand and use behaviors.Discussion and Conclusions: Our results suggest that smokers with AUD were more resistant to price elevations in relation to reducing alcohol consumption as compared to cigarette consumption, suggesting preferential demand for alcohol over cigarettes. However, it is unclear how acute substance exposure/withdrawal impacts the demand indices.Scientific Significance: Potentially differential alcohol and cigarette demands among smokers with AUD should be considered in the concurrent treatment of smoking and alcohol.
Odds of Anxiety and Depression Symptoms in School-Aged Children From Official Language Minority Communities
Authors: Dupuis Jérémie B. , Bourque Jimmy , El Adlouni Salah-Eddine 
Published: June 2021

Objectives:The aim of this paper is to assess the odds of suffering from anxiety or depression symptoms based on the presence of certain determinants of health for youth living in the province of New Brunswick, Canada, and in two linguistically different Official Language Minority Communities (OLMCs) in the same province.Methods:With a sample of 22,329 students from grades 7 to 12 in the province of New Brunswick, Canada, logistic regressions were performed to assess each determinant of health's effect on symptoms of anxiety and depression.Results:Some social determinants, like family support, social support and food insecurity, were identified as important determinants of mental health status regardless of linguistic group membership or community membership, while other determinants, such as alcohol use, cannabis use and natural environment, were more prominent in one OLMC than the other.Discussion:Social psychology and public health theories are used in an attempt to explain the results. Limitations and recommendations are also brought forward.