Effectiveness of simulation-based clinical research curriculum for undergraduate medical students - a pre-post intervention study with external control.

BACKGROUND: Simulation is widely utilized in medical education. Exploring the effectiveness of high-fidelity simulation of clinical research within medical education may inform its integration into clinical research training curricula, finally cultivating physician-scientist development. METHODS: Standard teaching scripts for both clinical trial and cross-sectional study simulation were designed. We recruited undergraduates majoring in clinical medicine at 3th grade into a pre-post intervention study. Additionally, a cross-sectional survey randomly selected medical undergraduates at 4th or 5th grade, medical students in master and doctor degree as external controls. Self-assessment scores of knowledge and practice were collected using a 5-point Likert scale. Changes in scores were tested by Wilcoxon signed-rank test and group comparisons were conducted by Dunn's tests with multiple corrections. Multivariable quantile regressions were used to explore factors influencing the changes from baseline. RESULTS: Seventy-eight undergraduates involved the clinical trial simulation and reported improvement of 1.60 (95% CI, 1.48, 1.80, P < 0.001) in knowledge and 1.82 (95% CI, 1.64, 2.00, P < 0.001) in practice score. 83 undergraduates involved in the observational study simulation and reported improvement of 0.96 (95% CI, 0.79, 1.18, P < 0.001) in knowledge and 1.00 (95% CI, 0.79, 1.21, P < 0.001) in practice. All post-intervention scores were significantly higher than those of the three external control groups, P < 0.001. Higher agreement on the importance of clinical research were correlated with greater improvements in scores. Undergraduates in pre-post study showed high confidence in doing a future clinical research. CONCLUSION: Our study provides evidence supporting the integration of simulation into clinical research curriculum for medical students. The importance of clinical research can be emphasized during training to enhance learning effect.

Multi-view feature representation and fusion for drug-drug interactions prediction.

BACKGROUND: Drug-drug interactions (DDIs) prediction is vital for pharmacology and clinical application to avoid adverse drug reactions on patients. It is challenging because DDIs are related to multiple factors, such as genes, drug molecular structure, diseases, biological processes, side effects, etc. It is a crucial technology for Knowledge graph to present multi-relation among entities. Recently some existing graph-based computation models have been proposed for DDIs prediction and get good performance. However, there are still some challenges in the knowledge graph representation, which can extract rich latent features from drug knowledge graph (KG). RESULTS: In this work, we propose a novel multi-view feature representation and fusion (MuFRF) architecture to realize DDIs prediction. It consists of two views of feature representation and a multi-level latent feature fusion. For the feature representation from the graph view and KG view, we use graph isomorphism network to map drug molecular structures and use RotatE to implement the vector representation on bio-medical knowledge graph, respectively. We design concatenate-level and scalar-level strategies in the multi-level latent feature fusion to capture latent features from drug molecular structure information and semantic features from bio-medical KG. And the multi-head attention mechanism achieves the optimization of features on binary and multi-class classification tasks. We evaluate our proposed method based on two open datasets in the experiments. Experiments indicate that MuFRF outperforms the classic and state-of-the-art models. CONCLUSIONS: Our proposed model can fully exploit and integrate the latent feature from the drug molecular structure graph (graph view) and rich bio-medical knowledge graph (KG view). We find that a multi-view feature representation and fusion model can accurately predict DDIs. It may contribute to providing with some guidance for research and validation for discovering novel DDIs.

Triglyceride-glucose index for predicting repeat revascularization and in-stent restenosis in patients with chronic coronary syndrome undergoing percutaneous coronary intervention.

BACKGROUND: The triglyceride-glucose (TyG) index, a reliable surrogate indicator of insulin resistance, is independently associated with coronary artery disease of various clinical manifestations. This study aimed to investigate the prognostic value of the TyG index in predicting repeat revascularization and in-stent restenosis (ISR) in chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI). METHODS: A total of 1414 participants were enrolled and divided into groups according to the tertiles of the TyG index. The primary endpoint was a composite of PCI complications, including repeat revascularization and ISR. The associations between the TyG index and the primary endpoint were assessed by multivariable Cox proportional hazards regression analysis with restricted cubic splines (RCS). The TyG index was calculated as Ln (fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2). RESULTS: Over a median follow-up of 60 months, 548 (38.76%) patients had experienced at least one primary endpoint event. The follow-up incidence of the primary endpoint increased with the TyG index tertiles. After adjusting for potential confounders, the TyG index was independently associated with the primary endpoint in CCS patients (HR, 1.191; 95% CI 1.038-1.367; P = 0.013). Additionally, the highest tertile of the TyG group was correlated with a 1.319-fold risk of the primary endpoint compared with the lowest tertile of the TyG group (HR, 1.319; 95% CI 1.063-1.637; P = 0.012). Furthermore, a linear and dose-response relationship was observed between the TyG index and the primary endpoint (non-linear P = 0.373, P overall = 0.035). CONCLUSIONS: An increased TyG index was associated with elevated risk for long-term PCI complications, including repeat revascularization and ISR. Our study suggested that the TyG index could be a potent predictor in evaluating the prognosis of CCS patients undergoing PCI.

Appropriate Duration of Perioperative Intravenous Administration of Lidocaine to Provide Satisfactory Analgesia for Adult Patients Undergoing Colorectal Surgery: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Perioperative lidocaine infusion has been reported to alleviate pain intensity after colorectal surgery. However, there is no consensus on whether prolonged lidocaine infusion is more effective than short lidocaine infusion. This meta-analysis aimed to determine an appropriate duration of lidocaine infusion in patients undergoing colorectal surgery. METHODS: We searched the PubMed, EMBASE, Web of Science, and Cochrane Library databases to identify articles published before December 17, 2021. Randomized controlled trials comparing intravenous lidocaine with placebo for pain relief in patients undergoing colorectal surgery were included. The primary outcome was pain scores (visual analog scale [VAS], 0-10 cm) at 24 hours postoperatively at rest and on movement. Secondary outcomes included pain scores at 12, 48, and 72 hours postoperatively, analgesic consumption (mg), gastrointestinal function return (hour), length of hospital stay (days), and incidence of complications. According to the duration of lidocaine infusion, studies were grouped into infusion for at least 24 hours (prolonged lidocaine infusion) and less than 24 hours (short lidocaine infusion) to assess the impact of lidocaine infusion duration on the outcomes of interests. Quantitative analyses were performed using a random effects model. RESULTS: Eleven studies with 548 patients were included. Five studies used prolonged lidocaine infusion, while 6 studies used short lidocaine infusion. Prolonged lidocaine infusion reduced postoperative pain scores versus placebo at 24 hours at rest (mean difference [MD], -0.91 cm; 95% confidence interval [CI], -1.54 to -0.28; P = .02) and on movement (MD, -1.69 cm; 95% CI, -2.15 to -1.22; P < .001), while short lidocaine infusion showed no benefit. Compared with placebo, prolonged lidocaine infusion reduced pain scores at 12 hours at rest and at 12 and 48 hours on movement, but short lidocaine infusion did not. However, there was no significant difference in pain scores between the prolonged and short lidocaine infusion groups at these time points. Compared with placebo, prolonged lidocaine infusion shortened the length of hospital stay (MD, -1.30 days; 95% CI, -1.72 to -0.88; P < .001) and time to first postoperative defecation (MD, -12.51 hours; 95% CI, -22.67 to -2.34; P = .02). There were no differences between groups regarding the other outcomes. CONCLUSIONS: The analgesic effect of intravenous lidocaine may depend on the duration of infusion, and our results suggest that lidocaine infusion should be administered for at least 24 hours after colorectal surgery. Since overall evidence quality was low, further high-quality, large-sample trials are needed to explore an optimal lidocaine infusion strategy in patients undergoing colorectal surgery.

ATM participates in fine particulate matter-induced airway inflammation through regulating DNA damage and DNA damage response.

The relationship between fine particulate matter (PM2.5) and chronic airway inflammatory diseases, such as chronic obstructive pulmonary disease and asthma, have garnered public attention, while the detailed mechanisms of PM2.5-induced airway inflammation remain unclear. This study reveals that PM2.5 induces airway inflammation both in vivo and in vitro, and, moreover, identifies DNA damage and DNA damage repair (DDR) as results of this exposure. Ataxia telangiectasia-mutated heterozygous (ATM+/- ) and wild-type C57BL/6 (WT) mice were exposed to PM2.5. The results show that, following exposure to PM2.5, the number of neutrophils in broncho alveolar lavage fluid and the mRNA expression of CXCL-1 in lung tissues of the ATM+/- mice were lower than those of the WT mice. The mRNA expression of FANCD2 and FANCI were also down-regulated. Human bronchial epithelial (HBE) cells were transfected with ATM-siRNA to induce down-regulation of ATM gene expression and were subsequently stimulated with PM2.5. The results show that the mRNA expression of TNF-α decreased in the ATM-siRNA-transfected cells. The mRNA expression of CXCL-1 and CXCL-2 in peritoneal macrophages, derived from ATM-null mice in which experiments showed that the protein expression of FANCD2 and FANCI decreased, were also decreased after PM2.5 exposure in ATM-siRNA-transfected HBE cells. In conclusion, PM2.5-induced airway inflammation is alleviated in ATM+/- mice compared with WT mice. ATM promotes PM2.5-induced airway inflammation, which may be attributed to the regulation of DNA damage and DDR.

The Application of Computer Technology to Clinical Practice Guideline Implementation: A Scoping Review.

Implementation of clinical practice guidelines (CPG) is a complex and challenging task. Computer technology, including artificial intelligence (AI), has been explored to promote the CPG implementation. This study has reviewed the main domains where computer technology and AI has been applied to CPG implementation. PubMed, Embase, Web of science, the Cochrane Library, China National Knowledge Infrastructure database, WanFang DATA, VIP database, and China Biology Medicine disc database were searched from inception to December 2021. Studies involving the utilization of computer technology and AI to promote the implementation of CPGs were eligible for review. A total of 10429 published articles were identified, 117 met the inclusion criteria. 21 (17.9%) focused on the utilization of AI techniques to classify or extract the relative content of CPGs, such as recommendation sentence, condition-action sentences. 47 (40.2%) focused on the utilization of computer technology to represent guideline knowledge to make it understandable by computer. 15 (12.8%) focused on the utilization of AI techniques to verify the relative content of CPGs, such as conciliation of multiple single-disease guidelines for comorbid patients. 34 (29.1%) focused on the utilization of AI techniques to integrate guideline knowledge into different resources, such as clinical decision support systems. We conclude that the application of computer technology and AI to CPG implementation mainly concentrated on the guideline content classification and extraction, guideline knowledge representation, guideline knowledge verification, and guideline knowledge integration. The AI methods used for guideline content classification and extraction were pattern-based algorithm and machine learning. In guideline knowledge representation, guideline knowledge verification, and guideline knowledge integration, computer techniques of knowledge representation were the most used.

Ozonated triglyceride protects against septic lethality via preventing the activation of NLRP3 inflammasome. / é ¸åŒ–è„‚è‚ªé ¸é ¯é€šè¿‡æŠ‘åˆ¶NLRP3炎症小体活化减少脓毒症致死（英文）.

OBJECTIVES: Sepsis is a critical dysregulated host response with high mortality and current treatment is difficult to achieve optimal efficacy. Ozone therapy has been revealed to protect infection and inflammation-related diseases due to its role in antibiotic and immunoregulatory effect. Ozonated triglyceride is a key component of ozonated oil that is one of ozone therapy dosage form. However, the potential role of ozonated triglyceride in sepsis remains unclear. This study aims to explore the effect of ozonated triglyceride on septic mouse model and the molecular mechanism. METHODS: Intraperitoneal injection of lipopolysaccharide (LPS), cecal ligation and puncture (CLP) were applied to construct septic mouse model. The mouse serum was obtained for detection of cytokines, and lung tissues were collected for hematoxylin and eosin (HE) staining to evaluate the extent of lung injury in septic mouse with ozonated triglyceride treatment at different time and doses. The survival of septic mice was observed for 96 h and Kaplan-Meier analysis was used to analyze the survival rates. In addition, primary peritoneal macrophages and human acute monocytic-leukemia cell line (THP-1) were treated with inflammasome activators with or without ozonated triglyceride. The level of cytokines was detected by enzyme-linked immunosorbent assay (ELISA). The cleavage of caspase-1 and gasdermin-D (GSDMD) was detected by Western blotting. RESULTS: Ozonated triglyceride at different time and doses reduced the release of inflammasome-related cytokines [interleukin (IL)-1ß and IL-18] (all P<0.05) but not pro-inflammatory cytokines such as IL-6 and tumor necrosis factor-α (TNF-α) in septic mice (all P>0.05). Ozonated triglyceride significantly improved the survival rate of septic mice and reduced sepsis-induced lung injury (all P<0.05). Ozonated triglyceride significantly suppressed the canonical and non-canonical activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome (all P<0.05) but not affected absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) inflammasomes in vitro (all P>0.05). Ozonated triglyceride reduced the cleavage of caspase-1 and the downstream GSDMD. CONCLUSIONS: Ozonated triglyceride presents a protect effect on sepsis lethality via reducing cytokines release and sepsis-related organ injury. The mechanism is that ozonated triglyceride specifically suppresses the activation of NLRP3 inflammasome. Ozonated triglyceride is a promising candidate for sepsis treatment.

The causal association between smoking, alcohol consumption and risk of bladder cancer: A univariable and multivariable Mendelian randomization study.

Smoking and alcohol consumption are associated with bladder cancer risk in observational studies. We conducted a two-sample univariable and multivariable Mendelian randomization (MR) analysis to determine whether those associations are causal. We used 21, 126, 360, 39 single nucleotide polymorphisms (SNPs) as instrumental variables for number of cigarettes per day, lifetime smoking index, smoking initiation, and drinks per week, respectively. A total of 1115 cases with bladder cancer and 174 006 noncases from FinnGen consortium and 2883 cases with bladder cancer and 417 955 noncases from UK Biobank study were obtained. Genetic predisposition to cigarettes per day, lifetime smoking index and smoking initiation were positively associated with an increased risk of bladder cancer in both the FinnGen and UK Biobank consortium. The summary odds ratio (OR) of bladder cancer was 1.79 (95% confidence interval [CI], 1.31-2.45; P = .0002), 2.38 (95% CI, 1.45-3.88; P = .0005) and 1.91 (95% CI, 1.46-2.50; P = 1.59 × 10-06 ) for one SD increase in the number of cigarettes per day, lifetime smoking index and smoking initiation, respectively. The genetically instrumented number of drinks per week was not associated with bladder cancer (OR = 0.69; 95% CI, 0.44-1.10; P = .1237). Estimates were consistent in multivariable MR analyses by the adjustments of body mass index and education. Our study suggests a causal potential of the association of smoking but not alcohol consumption with bladder cancer according to current evidence.

Causal relationship between obesity, lifestyle factors and risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study.

BACKGROUND: Obesity (waist circumference, body mass index (BMI)) and lifestyle factors (dietary habits, smoking, alcohol drinking, Sedentary behavior) have been associated with risk of benign prostatic hyperplasia (BPH) in observational studies, but whether these associations are causal is unclear. METHODS: We performed a univariable and multivariable Mendelian randomization study to evaluate these associations. Genetic instruments associated with exposures at the genome-wide significance level (P < 5 × 10-8) were selected from corresponding genome-wide associations studies (n = 216,590 to 1,232,091 individuals). Summary-level data for BPH were obtained from the UK Biobank (14,126 cases and 169,762 non-cases) and FinnGen consortium (13,118 cases and 72,799 non-cases). Results from UK Biobank and FinnGen consortium were combined using fixed-effect meta-analysis. RESULTS: The combined odds ratios (ORs) of BPH were 1.24 (95% confidence interval (CI), 1.07-1.43, P = 0.0045), 1.08 (95% CI 1.01-1.17, P = 0.0175), 0.94 (95% CI 0.67-1.30, P = 0.6891), 1.29 (95% CI 0.88-1.89, P = 0.1922), 1.23 (95% CI 0.85-1.78, P = 0.2623), and 1.04 (95% CI 0.76-1.42, P = 0.8165) for one standard deviation (SD) increase in waist circumference, BMI, and relative carbohydrate, fat, protein and sugar intake, 1.05 (95% CI 0.92-1.20, P = 0.4581) for one SD increase in prevalence of smoking initiation, 1.10 (95% CI 0.96-1.26, P = 0.1725) and 0.84 (95% CI 0.69-1.02, P = 0.0741) for one SD increase of log-transformed smoking per day and drinks per week, and 1.31 (95% CI 1.08-1.58, P = 0.0051) for one SD increase in sedentary behavior. Genetically predicted waist circumference (OR = 1.26, 95% CI 1.11-1.43, P = 0.0004) and sedentary behavior (OR = 1.14, 95% CI 1.05-1.23, P = 0.0021) were associated with BPH after the adjustment of BMI. CONCLUSION: This study supports independent causal roles of high waist circumference, BMI and sedentary behavior in BPH.

Clinical research capability enhanced for medical undergraduates: an innovative simulation-based clinical research curriculum development.

BACKGROUND: Clinical research has frequently not been taught in a practical way, often resulting in a very didactic approach rendering it not very accessible for medical undergraduates. Simulation can provide an immersive, interactive, and reflective experience and may be applied to the clinical research curriculum. METHODS: A 7-step model, modified from Kern's six-step approach and Khamis's stepwise model, was used to develop the curriculum. A questionnaire survey on undergraduates' attitude towards, knowledge and practice of clinical research and simulation education was conducted to generate a targeted needs assessment. The simulation framework was integrated into the development of educational strategies. Experts were consulted to assess the curriculum prior to implementation. RESULTS: Talent construction in China needs an innovative capability-enhanced clinical research curriculum. Sixty-six clinical undergraduates in our school completed the survey. 89.39% (59/66) of them hadn't participated in clinical research, while 93.94% (62/66) would like to conduct clinical trials if possible. 75.76% of respondents didn't have knowledge of or practical abilities in clinical trials. The mean score for practical ability (2.02 ± 0.92) was lower than that of knowledge (2.20 ± 0.93) (P < 0.01). The dimension of case report form got the lowest score among the five dimensions. Participating in clinical research (P = 0.04) and learning for themselves (P < 0.01) by a few students may have increased the total score. The curriculum was designed to simulate the whole process from protocol writing, registration, ethical approval, implementation, and data analysis to reporting based on one case study, and was divided into two parts to simulate different types of research: randomized controlled trials and observational studies. It was conducted in semesters 5 and 7 respectively, both including 16 sessions. After expert consultation, one session having a 29.01% coefficient of variation was adjusted and replaced. The final simulation class design scenario scripts are provided for reference. CONCLUSIONS: The targeted needs assessment exposed medical undergraduates' poor knowledge of and abilities in clinical research. This is the first report of a simulation-based clinical research curriculum developed in China, and adds curriculum development and design details to the limited related published studies.

Current views on neuropeptides in atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease involving skin barrier dysfunction and immune imbalance. However, the mechanism of AD is not clear completely and may be related to heredity and environment. Neuropeptides are a class of peptides secreted by nerve endings, they may play roles in promoting vasodilation, plasma extravasation, chemotaxis of inflammatory cells and mediating pruritus. Since itching and immune cell infiltration are the main manifestations of atopic dermatitis, to further investigate the impact of neuropeptides on AD, our review summarized the mechanisms of several common neuropeptides in AD and hypothesized that neuropeptides may be the novel potential targets in AD treatment.

Advanced Biomarkers: Therapeutic and Diagnostic Targets in Urticaria.

Urticaria is a type of skin disease characterized by rapid onset of hives (superficial dermis edema, erythema, pruritus, or burning sensation). According to whether the natural course exceeds 6 weeks, urticaria can be divided into acute and chronic urticaria (CU). At present, the evaluation of CU activity mainly depends on the Urticaria Activity Score (UAS), but the evaluation indicators are relatively single, and we need more reliable experimental data for evaluation. We typically summarize advanced biomarkers and several related pathogenic pathways discovered in recent years on urticaria, including the cell adhesion/chemotaxis pathway, interleukin (IL)-6/Janus tyrosine kinase/STAT pathway, IL-17/IL-23 pathway, basophil- and mast cell-related pathway, coagulation/fibrinolysis-related pathways, single-nucleotide polymorphism, and some other pathways. This review aims to find appropriate biomarkers so that we can evaluate disease activity, discover novel therapeutic targets, and predict the patients' response more accurately to therapeutic agents.

Immortal time bias exaggerates the effect of metformin on the risk of gastric cancer: A meta-analysis.

High heterogeneity has been reported among epidemiological studies exploring the relationship between metformin and the risk of gastric cancer. Immortal time bias might be one of the vital factors causing heterogeneity because of its widespread existence in pharmacological observational studies and it could severely exaggerate the drug's effectiveness. Immortal time bias could occur in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. In this study, we aimed to assess whether immortal time bias is responsible for the false assumption that metformin reduces the risk of gastric cancer. We searched PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies from the inception to August 9, 2020. The strength of the relationship was assessed using pooled relative risks (RRs) with corresponding 95% confidence intervals (95% CIs). Statistical analyses were carried out using a random-effects model. Pooled RR from 6 cohort studies with immortal time bias found a clear 33% reduced risk associated with metformin use (RR = 0.67, 95% CI = 0.59, 0.77; P < 0.001; I2 = 48.5%). However, pooled RR from 8 cohort studies without immortal time bias indicated no association between the use of metformin and gastric cancer risk (RR = 0.95, 95% CI = 0.85, 1.05; P = 0.317; I2 = 64.5%). From a univariate meta-regression model, the presence of immortal time bias was associated with a significant reduction of 29% in the effect estimate of metformin on gastric cancer risk (ratio of RR = 0.71, 95% CI = 0.58, 0.86; P = 0.002). This meta-analysis indicates that metformin use has no protective effect on gastric cancer risk. The relationship between metformin use and gastric cancer risk has been exaggerated as a result of the presence of immortal time bias. Further studies are required to confirm the results by controlling for immortal time bias based on appropriate study designs and statistical methods.

Association between short-term exposure to air pollution and ischemic stroke onset: a time-stratified case-crossover analysis using a distributed lag nonlinear model in Shenzhen, China.

BACKGROUND: Stroke, especially ischemic stroke (IS), has been a severe public health problem around the world. However, the association between air pollution and ischemic stroke remains ambiguous. METHODS: A total of 63, 997 IS cases aged 18 years or above in Shenzhen were collected from 2008 to 2014. We used the time-stratified case-crossover design combining with distributed lag nonlinear model (DLNM) to estimate the association between air pollution and IS onset. Furthermore, this study explored the variability across gender and age groups. RESULTS: The cumulative exposure-response curves were J-shaped for SO2, NO2 and PM10, and V-shaped for O3, and crossed over the relative risk (RR) of one. The 99th, 50th (median) and 1st percentiles of concentration (µg/m3) respectively were 37.86, 10.06, 3.71 for SO2, 116.26, 41.29, 18.51 for NO2, 145.94, 48.29, 16.14 for PM10, and 111.57, 49.82, 16.00 for O3. Extreme high-SO2, high-NO2, high-PM10, high-O3, and low-O3 concentration increased the risk of IS, with the maximum RR values and 95% CIs: 1.50(1.22, 1.84) (99th vs median) at 0-12 lag days, 1.37(1.13, 1.67) (99th vs median) at 0-10 lag days, 1.26(1.04, 1.53) (99th vs median) at 0-12 lag days, 1.25(1.04, 1.49) (99th vs median) at 0-14 lag days, and 1.29(1.03, 1.61) (1st vs median) at 0-14 lag days, respectively. The statistically significant minimal RR value and 95% CI was 0.79(0.66,0.94) at 0-10 lag days for extreme low-PM10. The elderly aged over 65 years were susceptible to extreme pollution conditions. Difference from the vulnerability of males to extreme high-SO2, high-NO2 and low-O3, females were vulnerable to extreme high-PM10 and high-O3. Comparing with the elderly, adults aged 18-64 year were immune to extreme low-NO2 and low-PM10. However, no association between CO and IS onset was found. CONCLUSIONS: SO2, NO2, PM10 and O3 exerted non-linear and delayed influence on IS, and such influence varied with gender and age. These findings may have significant public health implications for the prevention of IS.

C-reactive protein (CRP) rs3093059C predicts poor mizolastine response in chronic spontaneous urticaria patients with elevated serum CRP level.

Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema, and nearly 35% patients respond poorly to non-sedating H1 antihistamine treatment. CRP gene encodes the C-reactive protein, which is involved in the pathogenesis of CSU. To investigate the impacts of CRP polymorphisms on the susceptibility and therapeutic efficacy in the South Han CSU patients, we enrolled 145 CSU patients in our study. After 4-week non-sedating H1 antihistamine monotherapy treatment, more than 50% reduction of the severity score is considered as effective, or else non-effective. The CRP rs3093059T/C and rs2794521G/A genotypes of patients were determined by Sequenom MassARRAY. Functional studies including relative luciferase assay and ß-hexosaminidase assay were conducted in HEK293T cells or RBL-2H3 cells to explore the function of variants. Forty (62.50%) CSU patients were effective when treated with mizolastine, and 55 (72.4%) patients were effective in the desloratadine group. We found that the patients carried with rs3093059TT genotype were significantly associated with good response (OR = 4.20, P = 0.015), had lower serum CRP, IL-6 and TNF-α levels than the CT/CC genotypes. In vitro, the rs3093059C allele exhibited significantly higher luciferase activity than wild allele (P < 0.001). From the ß-hexosaminidase assay, we observed the inhibiting degranulation effects by mizolastine and this effect is weakened when with a higher dose CRP in RBL-2H3 cells. Our findings suggested that CSU patients carrying the rs3093059C allele may respond poorly to mizolastine with elevated serum CRP level.

The Clinicopathological Characteristics of Henoch-Schönlein Purpura Nephritis with Presentation of Nephrotic Syndrome.

BACKGROUND: Henoch-Schönlein purpura nephritis (HSPN) is a common vasculitis involving the kidneys, with a lower incidence in adults. Meanwhile, nephrotic syndrome (NS) can appear in HSPN. However, the clinicopathological features and renal outcome of adult-onset HSPN presenting with NS (NS-HSPN) have not been well clarified. METHODS: A total of 191 HSPN patients were prospectively analyzed and comparisons were made between NS-HSPN and non-NS-HSPN. Multivariate Cox regression analysis was carried out to find the unfavorable factors of renal outcome of NS-HSPN. RESULTS: Among the 191 patients, 44 (23.0%) had NS-HSPN. Apart from edema and abdominal pain, patients with NS-HSPN tended to have lower levels of erythrocytes and hemoglobulin in blood as well as a greater number of erythrocytes in urine (p < 0.05). Mesangial proliferation was the most common pathological lesion in HSPN and the rates of crescent formation were significantly different, with 54.5% in NS-HSPN and 33.3% in non-NS-HSPN (p < 0.05). Notably, 18.2 and 4.8% of patients reached the composite endpoints in the NS-HSPN and non-NS-HSPN groups, respectively (p < 0.05), demonstrating that NS-HSPN patients were more likely to progress to end-stage renal disease and had a worse outcome. We also found that hypertension, estimated glomerular filtration rate (eGFR), cystatin, and tubular atrophy/interstitial fibrosis (HR > 1, p < 0.05) at onset were correlated with adverse outcome in NS-HSPN. CONCLUSION: NS-HSPN had more severe clinicopathological manifestations and poorer prognosis. The adverse predictors of NS-HSPN principally depend on clinicopathological presentation rather than on different therapies, and hypertension, eGFR, cystatin, and tubular atrophy/interstitial fibrosis can serve as independent risk factors in NS-HSPN.

[Association of CACNA1C gene genetic polymorphism with the susceptibility as well as prognosis for chronic spontaneous urticaria].

OBJECTIVE: To investigate the relationship between single nucleotide polymorphisms (SNPs) of CACNA1C (SNPs rs58619945, rs7316246 and rs216008) and susceptibility of chronic spontaneous urticaria (CSU) as well as the curative effect of non-sedating antihistamine drugs.
 Methods: Peripheral blood were extracted from 191 CSU patients to collect DNA. Urticaria Activity Score 7 (UAS7) and Dermatology Life Quality Index (DLQI) changes were collected from these patients with different non-sedating antihistamine drugs. PubMed retrieval system was used to select the 3 SNPs (rs58619945, rs7316246 and rs216008) of CACNA1C. Susceptibility of CSU and curative effect of non-sedating antihistamine drugs (desloratadine, mizolastine, fisofenadine) in 189 CSU patients and 105 controls with different SNPs were compared with Chi-squared test. Data of 105 southern Chinese controls were extracted from the 1 000 genome database.
 Results: Frequency of rs58619945 G allele in the CSU patients was significantly higher than that in the controls [OR(95%CI)=0.660(0.470-0.925), P=0.016]. However, there was no significant differences in rs7316246 and rs216008 between the CSU patients and the controls. Meanwhile there was no significant difference in general curative effect of the 3 drugs in the 3 SNPs (rs58619945: OR=0.843, P=0.454; rs7316246: OR=2.103, P=0.102; rs216008: OR=0.237, P=0.363). There was significant difference in different alleles of rs216008 in the patients administered by desloratadine [OR(95%CI)=0.480(0.247-0.933), P=0.029]. No difference was shown in the 3 SNPs in patients administered by mizolastine.
 Conclusion: The rs58619945 A/G might be related to susceptibility of CSU, and the rs216008 mutation might affect drug response of desloratadine.

Analysis of Long Non-Coding RNA Expression of Lymphatic Endothelial Cells in Response to Type 2 Diabetes.

BACKGROUND: Recent evidence has indicated that long non-coding RNA (lncRNA) is involved in the pathogenesis of type 2 diabetes, but nothing is known about lncRNA expression changes of lymphatic endothelial cells in response to type 2 diabetes. METHODS: The GSE38396 dataset was downloaded from the Gene Expression Omnibus database and the probe sets of Human Gnome U133 Plus2.0 microarray were annotated for lncRNA. Differentially expressed lncRNAs between diabetic and non-diabetic lymphatic endothelial cells were calculated. RESULTS: Compared with lymphatic endothelial cells in non-diabetic patients, 31 lncRNAs were down-regulated and 79 lncRNAs were up-regualted in lymphatic endothelial cells of type 2 diabetic patients. Several known lncRNAs were found, such as H19, GAS5, UCA1, CRNDE, GAS5, and LINC00312. Co-expression network of differentially expressed lncRNAs and mRNAs were constructed. Based on genomic regions of these lncRNAs, we found that binding sites of MAF and TCF3 were enriched and these lncRNAs may be related to insulin reporter signaling pathway and response to insulin stimulus. CONCLUSIONS: In a word, we found a set of lncRNAs were differentially expressed in lymphatic endothelial cells in response to type 2 diabetes and these lncRNAs may be involved in the pathogenesis of diabetes-related complications.

[Association between C reactive protein and clinical characteristics in patients with chronic spontaneous urticaria].

OBJECTIVE: To explore the association among C reactive protein (CRP) level, disease severity and non-sedating antihistamine drug efficacy in patients with chronic spontaneous urticaria.
 Methods: A total of 605 patients with chronic spontaneous urticaria from August 2013 to March 2015, diagnosed by dermatologist of Xiangya Hospital according to the guideline, were enrolled in present study. The patients were divided into two groups according to the weekly urticaria activity score (UAS): a response group (more than 50% reduction) and a nonresponse group (less than 50% reduction). T test and Pearson correlation analysis were used to analyze the correlation between the clinical characteristics (such as disease severity, drug efficacy) and CRP in patients with chronic spontaneous urticaria.
 Results: The CRP levels were significantly higher in patients with severe chronic spontaneous urticaria as compared to those with moderate chronic spontaneous urticaria (t=-2.715, P<0.01). Meanwhile, after treatment with secondary antihistamine drug, the patients with lower CRP levels showed better responses than those with higher CRP levels [(2.5764±2.5059) and (3.6715±4.7732) mg/dL respectively; t=-2.187, P<0.05].
 Conclusion: Serum CRP level before the treatment may be correlated with the severity of chronic spontaneous urticaria and efficacy of treatment.