bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Indel Variation of NPC1 Gene Associates With Risk of Sudden Cardiac Death
Authors: Zhao Wenfeng , Zhang Qing , Wang Jiawen , Yu Huan , Zhen Xiaoyuan , Li Lijuan , Qu Yan , He Yan , Zhang Jianhua , Li Chengtao , Zhang Suhua , Luo Bin , Huang Jiang , Gao Yuzhen 
Published: April 2022

Background and Aims: Sudden cardiac death (SCD) was defined as an unexpected death from cardiac causes during a very short duration. It has been reported that Niemann-Pick type C1 (NPC1) gene mutations might be related to cardiovascular diseases. The purpose of the study is to investigate whether common genetic variants of NPC1 is involved in SCD susceptibility.Methods: Based on a candidate-gene-based approach and systematic screening strategy, this study analyzed an 8-bp insertion/deletion polymorphism (rs150703258) within downstream of NPC1 for the association with SCD risk in Chinese populations using 158 SCD cases and 524 controls. The association of rs150703258 and SCD susceptibility was analyzed using logistic regression. Genotype-phenotype correlation analysis was performed using public database including 1000G, expression quantitative trait loci (eQTL), and further validated by human heart tissues using PCR. Dual-luciferase assay was used to explore the potential regulatory role of rs150703258. Gene expression profiling interactive analysis and transcription factors prediction were performed.Results: Logistic regression analysis exhibited that the deletion allele of rs150703258 significantly increased the risk of SCD [odds ratio (OR) = 1.329; 95% confidence interval (95%CI):1.03–1.72; p = 0.0289]. Genotype-phenotype correlation analysis showed that the risk allele was significantly associated with higher expression of NPC1 at mRNA and protein expressions level in human heart tissues. eQTL analysis showed NPC1 and C18orf8 (an adjacent gene to NPC1) are both related to rs150703258 and have higher expression level in the samples with deletion allele. Dual-luciferase activity assays indicate a significant regulatory role for rs150703258. Gene expression profiling interactive analysis revealed that NPC1 and C18orf8 seemed to be co-regulated in human blood, arteries and heart tissues. In silico analysis showed that the rs150703258 deletion variant may create transcription factor binding sites. In addition, a rare 12-bp allele (4-bp longer than the insertion allele) of rs150703258 was discovered in the current cohort.Conclusion: In summary, our study revealed that rs150703258 might contribute to SCD susceptibility by regulating NPC1 and C18orf8 expression. This indel may be a potential marker for risk stratification and molecular diagnosis of SCD. Validations in different ethnic groups with larger sample size and mechanism explorations are warranted to confirm our findings.
Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia
Authors: Tada Hayato , Kojima Nobuko , Yamagami Kan , Nomura Akihiro , Nohara Atsushi , Usui Soichiro , Sakata Kenji , Fujino Noboru , Takamura Masayuki , Kawashiri Masa-Aki 
Published: April 2022

Objective: It has been shown that pathogenic variants are associated with poor clinical outcomes in patients with familial hypercholesterolemia (FH). However, data on the effect of different types of pathogenic variants on FH phenotype is limited.Methods: We retrospectively investigated the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of major adverse cardiac events (MACEs), defined as cardiovascular death, myocardial infarction, unstable angina, or coronary artery revascularization, in patients with FH (N = 1,050, male/female = 490/560). Based on genotype, the patients were divided into the following three groups: patients without pathogenic variants, patients with missense variants, and patients with protein-truncating variants (PTVs). Cox proportional hazard model was used to identify the factors associated with MACEs.Results: The median follow-up duration was 12.6 years (interquartile range = 9.5–17.9 years). There were 665 patients with FH-mutation (277 patients with missense variants and 388 patients with PTVs) and 385 patients without FH-mutation. Over the follow-up duration, 175 MACEs were observed. We identified 89 different pathogenic variants in the 665 patients with FH. LDL cholesterol level was found to be significantly higher in patients with PTVs (256 mg/dl) than in patients with missense variants (236 mg/dl) and patients without pathogenic variants (216 mg/dl). It was also found that PTVs and missense variants are significantly associated with MACEs (hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.08–2.08, p = 0.0033 and HR = 3.24, 95% CI = 2.12–4.40, p = 3.9 × 10−6, respectively), independent of classical risk factors.Conclusion: Pathogenic variants, especially PTVs, are significantly associated with poor outcomes in patients with FH. Genetic testing is useful for the diagnosis and risk stratification of patients with FH.
The R93C Variant of PCSK9 Reduces the Risk of Premature MI in a Chinese Han Population
Authors: Yang Lincheng , Pu Tian , Zhang Yan , Yan Hua , Yu Haiyi , Gao Wei 
Published: April 2022

Background: Dyslipidemia is a common risk factor for premature myocardial infarction (PMI). Our previous work has shown that single-nucleotide polymorphisms (SNPs) of LDLR, APOB, and PCSK9 are associated with dyslipidemia, but how these SNPs correlate with risk for PMI is unknown.Objective: This study aims to evaluate the association between SNPs of LDLR, APOB, and PCSK9 and risk of PMI in Chinese Han population.Methods: Two cohorts were established. In Cohort 1 (413 in the PMI group and 1,239 in the control group), SNPs of APOB, LDLR, and PCSK9 with minor allele frequency (MAF) &gt; 1%, which has been shown to impact the risk of PMI in a Chinese Han population, were thoroughly examined, and gene–environment interactions were analyzed. A model for PMI risk prediction was developed in Cohort 1 and externally validated in Cohort 2 (577 in the PMI group and 270 in the control group).Results: The distribution of the T allele at the PCSK9 R93C variant (rs151193009, C &gt; T) was lower in the PMI group than that in the control group (PMI vs. Control in Cohort 1, 0.8% vs. 2.3%, Padjust &lt; 0.05; in Cohort 2, 1.0% vs. 2.4%, Padjust &lt; 0.05). The T allele at PCSK9 R93C variant (rs151193009, C &gt; T) reduced the risk of PMI by ∼60% regardless of adjusting for confounding factors (in Cohort 1, adjusted odds ratio (OR) 0.354, 95% confidence interval (CI) 0.139–0.900, p = 0.029; in Cohort 2, adjusted OR 0.394, 95% CI 0.157–0.987, p = 0.047). No gene–environment interactions were observed between the R93C variant and diabetes/hypertension/smoking in PMI occurrence in this Chinese Han population. Our model showed good performance in predicting the risk of PMI in Cohort 1 (AUC 0.839, 95% CI 0.815–0.862, p &lt; 0.001) and in an external cohort (AUC 0.840, 95% CI 0.810–0.871, p &lt; 0.001).Conclusions: The PCSK9 R93C variant was associated with significantly reduced risk of PMI in the Chinese Han population, and the model we developed performed well in predicting PMI risk in this Chinese Han population.
A Multi-Omics Study of Familial Lung Cancer: Microbiome and Host Gene Expression Patterns
Authors: Chen Ying , Huang Yunchao , Ding Xiaojie , Yang Zhenlin , He Liang , Ning Mingjie , Yang Zhenghong , He Daqian , Yang Lijuan , Liu Zhangyi , Chen Yan , Li Guangjian 
Published: April 2022

BackgroundInherited susceptibility and environmental carcinogens are crucial players in lung cancer etiology. The lung microbiome is getting rising attention in carcinogenesis. The present work sought to investigate the microbiome in lung cancer patients affected by familial lung cancer (FLC) and indoor air pollution (IAP); and further, to compare host gene expression patterns with their microbiome for potential links.MethodsTissue sample pairs (cancer and adjacent nonmalignant tissue) were used for 16S rRNA (microbiome) and RNA-seq (host gene expression). Subgroup microbiome diversities and their matched gene expression patterns were analyzed. Significantly enriched taxa were screened out, based on different clinicopathologic characteristics.ResultsOur FLC microbiome seemed to be smaller, low-diversity, and inactive to change; we noted microbiome differences in gender, age, blood type, anatomy site, histology type, TNM stage as well as IAP and smoking conditions. We also found smoking and IAP dramatically decreased specific-OTU biodiversity, especially in normal lung tissue. Intriguingly, enriched microbes were in three categories: opportunistic pathogens, probiotics, and pollutant-detoxication microbes; this third category involved Sphingomonas, Sphingopyxis, etc. which help degrade pollutants, but may also cause epithelial damage and chronic inflammation. RNA-seq highlighted IL17, Ras, MAPK, and Notch pathways, which are associated with carcinogenesis and compromised immune system.ConclusionsThe lung microbiome can play vital roles in carcinogenesis. FLC and IAP subjects were affected by fragile lung epithelium, vulnerable host-microbes equilibrium, and dysregulated immune surveillance and response. Our findings provided useful information to study the triple interplay among environmental carcinogens, population genetic background, and diversified lung microbiome.
The Systemic Lupus Erythematosus Interventional Trials in Mainland China: A Continuous Challenge
Authors: Tian Jingru , Zhou Hang , Liu Juan , Xiong Feng , Yi Ping , Cao Pengpeng , Fang Dorthy , Zhang Bo , Lu Qianjin 
Published: April 2022

ObjectivesMore than a quarter of single-country systemic lupus erythematosus (SLE) interventional randomized clinical trials (RCTs) were conducted in China. To help develop management guidelines and set benchmarks for future SLE research, a systematic review of current trials is needed.MethodsWe searched systematically three databases and four registries to summarize the interventional RCTs in mainland China and identify factors associated with participant loss. The internal validity of trials was assessed using the Cochrane risk-of-bias tool for assessing risk of bias. The odds ratio (OR) was defined as the ratio of the odds of less than 10% loss to follow-up in the presence or absence of different factors.ResultsA total of 188 trials met our inclusion criteria, and 15·5% of trials conducted in mainland China ranked low risk of bias. Participant loss was significantly higher among trials that had a defined primary outcome or were registered {primary outcome identification (0·02 [0·00-0·23]) and registration (0·14 [0·03-0·69])}. Trials examining traditional Chinese medicine (TCM) pharmacological treatments had an 8·16-fold (8·16 [1·28-51·98]) higher probability of having low participant loss than trials examining non-TCM pharmacological treatment trials, and trials that did not report masking status had a 15·95-fold (15·95 [2·45-103·88]) higher probability of having low participant loss than open-label trials. In addition, published articles in Chinese also had higher probability of having low participant loss (5·39 [1·10-26·37]).ConclusionSLE trials conducted in mainland China were of relatively poor quality. This situation, including nonrigorous design, lack of registration, and absence of compliance reporting, needs to be ameliorated. To maintain the fundamental repeatability and comparability of mainland China SLE RCTs, transparency of the clinical trial process and complete reporting of the trial data are crucial and urgently needed.
Construction of a Novel LncRNA Signature Related to Genomic Instability to Predict the Prognosis and Immune Activity of Patients With Hepatocellular Carcinoma
Authors: Zhu Jinfeng , Huang Qian , Liu Sicheng , Peng Xingyu , Xue Ju , Feng Tangbin , Huang Wulang , Chen Zhimeng , Lai Kuiyuan , Ji Yufei , Wang Miaomiao , Yuan Rongfa 
Published: April 2022

BackgroundGenomic instability (GI) plays a crucial role in the development of various cancers including hepatocellular carcinoma. Hence, it is meaningful for us to use long non-coding RNAs related to genomic instability to construct a prognostic signature for patients with HCC.MethodsCombining the lncRNA expression profiles and somatic mutation profiles in The Cancer Genome Atlas database, we identified GI-related lncRNAs (GILncRNAs) and obtained the prognosis-related GILncRNAs through univariate regression analysis. These lncRNAs obtained risk coefficients through multivariate regression analysis for constructing GI-associated lncRNA signature (GILncSig). ROC curves were used to evaluate signature performance. The International Cancer Genomics Consortium (ICGC) cohort, and in vitro experiments were used for signature external validation. Immunotherapy efficacy, tumor microenvironments, the half-maximal inhibitory concentration (IC50), and immune infiltration were compared between the high- and low-risk groups with TIDE, ESTIMATE, pRRophetic, and ssGSEA program.ResultsFive GILncRNAs were used to construct a GILncSig. It was confirmed that the GILncSig has good prognostic evaluation performance for patients with HCC by drawing a time-dependent ROC curve. Patients were divided into high- and low-risk groups according to the GILncSig risk score. The prognosis of the low-risk group was significantly better than that of the high-risk group. Independent prognostic analysis showed that the GILncSig could independently predict the prognosis of patients with HCC. In addition, the GILncSig was correlated with the mutation rate of the HCC genome, indicating that it has the potential to measure the degree of genome instability. In GILncSig, LUCAT1 with the highest risk factor was further validated as a risk factor for HCC in vitro. The ESTIMATE analysis showed a significant difference in stromal scores and ESTIMATE scores between the two groups. Multiple immune checkpoints had higher expression levels in the high-risk group. The ssGSEA results showed higher levels of tumor-antagonizing immune cells in the low-risk group compared with the high-risk group. Finally, the GILncSig score was associated with chemotherapeutic drug sensitivity and immunotherapy efficacy of patients with HCC.ConclusionOur research indicates that GILncSig can be used for prognostic evaluation of patients with HCC and provide new insights for clinical decision-making and potential therapeutic strategies.
Meibomian Glands and Tear Film Findings in Type 2 Diabetic Patients: A Cross-Sectional Study
Authors: Wu Huping , Fang Xie , Luo Shunrong , Shang Xumin , Xie Zhiwen , Dong Nuo , Xiao Xianwen , Lin Zhirong , Liu Zuguo 
Published: April 2022

BackgroundThe characteristics of the meibomian gland and tear film in patients with type 2 diabetes (T2D) with different glycemic control levels and diabetic durations remain largely unexplored. This study aimed to identify the association of dry eye and meibomian gland dysfunction (MGD) in T2D.Materials and MethodsNinety-nine patients with type 2 diabetes mellitus (DM group), 33 dry eye patients without diabetes mellitus (DE group), and 40 normal subjects (NC group) were recruited for this study. Participants were evaluated with an Ocular Surface Disease Index (OSDI) questionnaire, tear film breakup time (BUT), the Schirmer I test (SIT), corneal fluorescein staining (FL), lipid layer thickness (LLT), and MGD parameters. Glycosylated hemoglobin (HbA1c) and duration of diabetes were recorded.ResultsThe SIT value in the DM group was higher than that of the DE group (p &lt; 0.05). The BUT and LLT were lower, and MGD parameters were higher in the DM group than those of the DE and NC groups (p &lt; 0.05). In the DM group, 47 patients were diagnosed with dry eye (DM + DE group), whereas 40 patients without dry eye were categorized as the DM − DE group. The SIT, BUT, and LLT values in the DM − DE group were higher (p &lt; 0.01), and MGD parameters were lower (p &lt; 0.01) in the DM − DE group than those of the DM + DE group. The MGD parameters were higher in the DM − DE group than those in the NC group (p &lt; 0.05). The HbA1c levels were correlated with OSDI, BUT, LLT, FL, and MGD parameters (p &lt; 0.001) in the DM group. However, in patients with low HbA1c, normal SIT value, and low OSDI, the MGD parameters were higher than those in the NC group (p &lt; 0.05). The duration of diabetes positively correlated with MGD parameters (p &lt; 0.001).ConclusionAsymptomatic MGD may be an early sign of dry eye and ocular discomfort in T2D. The MGD parameters were associated with the HbA1c level and diabetic duration.
Does Autologous Transfusion Decrease Allogeneic Transfusion in Liposuction Surgery of Lymphedema Patients?
Authors: Chen Linfeng , Chang Kun , Chen Yan , Xu Zhenhua , Shen Wenbin 
Published: April 2022

Background and ObjectiveLiposuction is an effective treatment for fat disposition in lymphedema. Blood transfusion has been seldom investigated in lymphedema liposuction surgery. The purpose of the study was to analyze clinical factors associated with blood transfusion in liposuction surgery of lymphedema patients and compare the autologous and allogeneic transfusion patterns.MethodsA total of 1,187 cases of liposuction due to lymphedema were recruited. Demographic, laboratory tests and operation information were collected. Patients were divided into a transfusion and a non-transfusion group. Different transfusion patterns were compared and analyzed.ResultsBetween the two groups, there is a significant difference in postoperative hemoglobin levels, and as well as gender, age, surgery duration, body weight change, intraoperative transfusion volume and blood loss, hospital length of stay, and surgical site distribution. There is a significant difference in the comparison of hospital stay length, autologous transfusion volume, combined allogeneic volume, operative blood loss, intraoperative transfusion volume, and change in hemoglobin levels between predonation and acute normovolemic hemodilution (ANH) transfusion. In comparison with the allogeneic transfusion-only patients, the mean allogeneic transfusion volume in either ANH group, predonated transfusion group, or mixed group is statistically lower. Allogeneic transfusion volume in the predonated-only group is significantly lower than that of either the ANH-only group or the mixing ANH with predonation group. Ordinary least squares regression analysis suggests that autologous transfusion in the ANH-only mode is statistically associated with allogeneic transfusion.ConclusionsThis study described the blood transfusion in lymphedema liposuction surgery and compared autologous and allogeneic transfusion patterns in these patients. Autologous transfusion can reduce the transfusion volume of allogeneic blood and might be a beneficial mode of transfusion in these patients.
Prognostic Effects of Inappropriate Empirical Antimicrobial Therapy in Adults With Community-Onset Bacteremia: Age Matters
Authors: Hung Yuan-Pin , Chen Po-Lin , Ho Ching-Yu , Hsieh Chih-Chia , Lee Chung-Hsun , Lee Ching-Chi , Ko Wen-Chien 
Published: April 2022

BackgroundStudies have reported the effects of delayed administration of appropriate antimicrobial therapy (AAT) on the short-term prognosis of patients with bloodstream infections; however, whether there is an age-related difference in these effects remains debated.MethodsIn this 4-year multicenter case-control study, patients with community-onset bacteremia were retrospectively categorized into the “middle-aged” (45–64 years), “old” (65–74 years), and “very old” (≥75 years) groups. Two methods were adopted to investigate the prognostic effects of delayed AAT in each age group. First, its effects were, respectively, investigated, after adjustment for the independent predictors of 30-day mortality. Second, patients in each age group were matched by the closest propensity-score (PS), which was calculated by independent predictors of mortality; the survival curves and Pearson chi-square tests were adopted to disclose its effects in each PS-matching group.ResultsEach hour of delayed AAT resulted in an average increase in the 30-day crude mortality rate of 0.2% (P = 0.03), 0.4% (P &lt; 0.001), and 0.7% (P &lt; 0.001) in middle-aged (968 patients), old (683), and very old (1,265) patients, after, respectively, adjusting the independent predictors of mortality in each group. After appropriate PS-matching, no significant proportion differences in patient demographics, bacteremia characteristics, severity of bacteremia and comorbidities, and 15-day or 30-day crude mortality rates were observed between three matched groups (582 patients in each group). However, significant differences in survival curves between patients with delayed AAT &gt; 24 or &gt;48 h and those without delayed administration were demonstrated in each age group. Furthermore, the odds ratios of 30-day mortality for delayed AAT &gt; 24 or &gt;48 h were 1.73 (P = 0.04) or 1.82 (P = 0.04), 1.84 (P = 0.03) or 1.95 (P = 0.02), and 1.87 (P = 0.02) or 2.34 (P = 0.003) in the middle-aged, old, and very old groups, respectively. Notably, the greatest prognostic impact of delayed AAT &gt; 24 or &gt;48 h in the very old group and the smallest impact in the middle-aged group were exhibited.ConclusionFor adults (aged ≥45 years) with community-onset bacteremia, the delayed AAT significantly impacts their short-term survival in varied age groups and the age-related differences in its prognostic impact might be evident.
Changes in the Cardiac Index Induced by Unilateral Passive Leg Raising in Spontaneously Breathing Patients: A Novel Way to Assess Fluid Responsiveness
Authors: Zhao Zhiyong , Zhang Zhongwei , Lin Qionghua , Shen Lihua , Wang Pengmei , Zhang Shan , Xia Zhili , Li Fangfang , Xing Qian , Zhu Biao 
Published: April 2022

BackgroundEvaluation of fluid responsiveness in intensive care unit (ICU) patients is crucial. This study was to determine whether changes in the cardiac index (CI) induced by a unilateral passive leg raising (PLR) test in spontaneously breathing patients can estimate fluid responsiveness.MethodsThis was a prospective study, and 40 patients with spontaneous breathing activity who were considered for volume expansion (VE) were included. CI data were obtained in a semirecumbent position, during unilateral PLR, bilateral PLR, and immediately after VE. If the CI increased more than 15% in response to the expansion in volume, patients were defined as responders.ResultsThe results showed that a unilateral PLR-triggered CI increment of ≥7.5% forecasted a fluid-triggered CI increment of ≥15% with 77.3% sensitivity and 83.3% specificity with and an area under the receiver operating characteristic (ROC) curve of 0.82 [P &lt; 0.001]. Compared with that for bilateral PLR, the area under the ROC curve constructed for unilateral PLR-triggered changes in CI (ΔCI) was not significantly different (p = 0.1544).ConclusionΔCI &gt;7.5% induced by unilateral PLR may be able to predict fluid responsiveness in spontaneously breathing patients and is not inferior to that induced by bilateral PLR.Trial RegistrationUnilateral passive leg raising test to assess patient volume responsiveness: Single-Center Clinical Study, ChiCTR2100046762. Registered May 28, 2021.