Robust and accurate estimation of cellular fraction from tissue omics data via ensemble deconvolution.

MOTIVATION: Tissue-level omics data such as transcriptomics and epigenomics are an average across diverse cell types. To extract cell-type-specific (CTS) signals, dozens of cellular deconvolution methods have been proposed to infer cell-type fractions from tissue-level data. However, these methods produce vastly different results under various real data settings. Simulation-based benchmarking studies showed no universally best deconvolution approaches. There have been attempts of ensemble methods, but they only aggregate multiple single-cell references or reference-free deconvolution methods. RESULTS: To achieve a robust estimation of cellular fractions, we proposed EnsDeconv (Ensemble Deconvolution), which adopts CTS robust regression to synthesize the results from 11 single deconvolution methods, 10 reference datasets, 5 marker gene selection procedures, 5 data normalizations and 2 transformations. Unlike most benchmarking studies based on simulations, we compiled four large real datasets of 4937 tissue samples in total with measured cellular fractions and bulk gene expression from different tissues. Comprehensive evaluations demonstrated that EnsDeconv yields more stable, robust and accurate fractions than existing methods. We illustrated that EnsDeconv estimated cellular fractions enable various CTS downstream analyses such as differential fractions associated with clinical variables. We further extended EnsDeconv to analyze bulk DNA methylation data. AVAILABILITY AND IMPLEMENTATION: EnsDeconv is freely available as an R-package from https://github.com/randel/EnsDeconv. The RNA microarray data from the TRAUMA study are available and can be accessed in GEO (GSE36809). The demographic and clinical phenotypes can be shared on reasonable request to the corresponding authors. The RNA-seq data from the EVAPR study cannot be shared publicly due to the privacy of individuals that participated in the clinical research in compliance with the IRB approval at the University of Pittsburgh. The RNA microarray data from the FHS study are available from dbGaP (phs000007.v32.p13). The RNA-seq data from ROS study is downloaded from AD Knowledge Portal. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis.

Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome-wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress did not reflect well gene expression patterns from humans with community-acquired sepsis. Our work indicates that improved preclinical murine sepsis modeling can better replicate both the phenotypic and transcriptomic responses to surgical sepsis, but cannot be extrapolated to other sepsis etiologies. Importantly, these improved models can be a useful adjunct to human-focused and artificial intelligence-based forms of research in order to improve septic patients' morbidity and mortality.

Transcriptomic and Proteomic Characterization of the Immune Response to Elective Spinal Reconstructive Surgery: Impact of Aging and Comparison with Traumatic Injury Response.

BACKGROUND: Major surgery triggers trauma-like stress responses linked to age, surgery duration, and blood loss, resembling polytrauma. This similarity suggests elective surgery as a surrogate model for studying polytrauma immune responses. We investigated stress responses across age groups and compared them with those of polytrauma patients. STUDY DESIGN: Patients undergoing major spinal reconstruction surgery were divided into older (age >65 years, n = 5) and young (age 18 to 39 years, n = 6) groups. A comparison group consisted of matched trauma patients (n = 8). Blood samples were collected before, during, and after surgery. Bone marrow mononuclear cells and peripheral blood mononuclear cells were analyzed using cellular indexing of transcriptomes and epitopes sequencing or single-cell RNA sequencing. Plasma was subjected to dual-platform proteomic analysis (SomaLogic and O-link). RESULTS: Response to polytrauma was highest within 4 hours. By comparison, the response to surgery was highest at 24 hours. Both insults triggered significant changes in cluster of differentiation 14 monocytes, with increased inflammation and lower major histocompatibility complex-class 2 expression. Older patient's cluster of differentiation 14 monocytes displayed higher inflammation and less major histocompatibility complex-class 2 suppression; a trend was also seen in bone marrow mononuclear cells. Although natural killer cells were markedly activated after polytrauma, they were suppressed after surgery, especially in older patients. In plasma, innate immunity proteins dominated at 24 hours, shifting to adaptive immunity proteins by 6 weeks with heightened inflammation in older patients. Senescence-associated secretory phenotype proteins were higher in older patients at baseline and further elevated during and after surgery. CONCLUSIONS: Although both major surgery and polytrauma initiate immune and stress responses, substantial differences exist in timing and cellular profiles, suggesting major elective surgery is not a suitable surrogate for the polytrauma response. Nonetheless, distinct responses in young vs older patients highlight the utility of elective spinal in studying patient-specific factors affecting outcomes after major elective surgery.

A unified model-based framework for doublet or multiplet detection in single-cell multiomics data.

Droplet-based single-cell sequencing techniques rely on the fundamental assumption that each droplet encapsulates a single cell, enabling individual cell omics profiling. However, the inevitable issue of multiplets, where two or more cells are encapsulated within a single droplet, can lead to spurious cell type annotations and obscure true biological findings. The issue of multiplets is exacerbated in single-cell multiomics settings, where integrating cross-modality information for clustering can inadvertently promote the aggregation of multiplet clusters and increase the risk of erroneous cell type annotations. Here, we propose a compound Poisson model-based framework for multiplet detection in single-cell multiomics data. Leveraging experimental cell hashing results as the ground truth for multiplet status, we conducted trimodal DOGMA-seq experiments and generated 17 benchmarking datasets from two tissues, involving a total of 280,123 droplets. We demonstrated that the proposed method is an essential tool for integrating cross-modality multiplet signals, effectively eliminating multiplet clusters in single-cell multiomics data-a task at which the benchmarked single-omics methods proved inadequate.

Effects of heme oxygenase-1 upregulation on blood pressure and cardiac function in an animal model of hypertensive myocardial infarction.

In this study, we evaluate the effect of HO-1 upregulation on blood pressure and cardiac function in the new model of infarct spontaneous hypertensive rats (ISHR). Male spontaneous hypertensive rats (SHR) at 13 weeks (n = 40) and age-matched male Wistar (WT) rats (n = 20) were divided into six groups: WT (sham + normal saline (NS)), WT (sham + Co(III) Protoporphyrin IX Chloride (CoPP)), SHR (myocardial infarction (MI) + NS), SHR (MI + CoPP), SHR (MI + CoPP + Tin Mesoporphyrin IX Dichloride (SnMP)), SHR (sham + NS); CoPP 4.5 mg/kg, SnMP 15 mg/kg, for six weeks, one/week, i.p., n = 10/group. At the sixth week, echocardiography (UCG) and hemodynamics were performed. Then, blood samples and heart tissue were collected. Copp treatment in the SHR (MI + CoPP) group lowered blood pressure, decreased infarcted area, restored cardiac function (left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), +dp/dt(max), (-dp/dt(max))/left ventricular systolic pressure (LVSP)), inhibited cardiac hypertrophy and ventricular enlargement (downregulating left ventricular end-systolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and heart weight/body weight (HW/BW)), lowered serum CRP, IL-6 and Glu levels and increased serum TB, NO and PGI2 levels. Western blot and immunohistochemistry showed that HO-1 expression was elevated in the SHR (MI + CoPP) group, while co-administration with SnMP suppressed the benefit functions mentioned above. In conclusion, HO-1 upregulation can lower blood pressure and improve post-infarct cardiac function in the ISHR model. These functions may be involved in the inhibition of inflammation and the ventricular remodeling process and in the amelioration of glucose metabolism and endothelial dysfunction.

Correlation between sex hormone levels and obesity in the elderly male.

OBJECTIVE: To investigate the levels of sex hormones and androgen receptor (AR) in elderly male patients and to explore a possible correlation with obesity. METHODS: The cross-sectional study included 314 Elderly males (age ≥ 65 year). Of these subjects, 104 were healthy (age range 65-92 year; mean 71.38 ± 5.154 year), 74 were obese (65-87 year; 71.32 ± 4.74 year), and 111 were overweight (65-85 year; 71.43 ± 5.03 year). The following parameters were measured: total testosterone (TT), free testosterone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), estradiol (E2), luteinizing hormone, follicle-stimulating hormone and AR. RESULTS: (i) The levels of TT and SHBG in the obesity group were significantly lower than those in non-obese subjects. (ii) Body mass index (BMI) negatively correlated with TT and SHBG. (iii) Multiple regression analysis revealed that TT (ß: -0.230; p = 0.045) and SHBG (ß: -0.163; p = 0.02) were statistically correlated with BMI. CONCLUSION: Testosterone levels in the obese population were significantly lower than in the non-obese population and there is a significant association between testosterone levels and the extent of obesity.

The prevalence, risk factors and prognosis of aspirin resistance in elderly male patients with cardiovascular disease.

AIM: Aspirin resistance is recognized in different population. However, the prevalence and clinical events of aspirin resistance in elderly male patients with cardiovascular disease (CVD) have not been reported. METHODS: We enrolled 304 elderly male patients with CVD receiving daily aspirin therapy (≥ 75 mg) more than 1 month. Platelet aggregation was measured by light transmission aggregometry (LTA) and thrombelastography platelet mapping assay (TEG). The median follow-up time was 1.8 years. The primary outcome was the composite of death, myocardial infarction, unstable angina, stroke and transient ischemic attack. RESULTS: By LTA, 25 (8.2%) of elderly patients were aspirin resistant and 106 (34.9%) patients were semiresponders. According to TEG, 62 patients (20.4%) were found to be resistant to aspirin therapy. Of the 62 patients with aspirin resistance by TEG, 21 patients were aspirin resistant by LTA. Twenty-two of the 106 semiresponders by LTA were aspirin resistant by TEG. Patients with aspirin resistance or aspirin semiresponders were at increased risk of the composite outcome compared with aspirin-sensitive patients by LTA (18.3% vs 9.8%, Hazard ratio (HR) = 1.864, 95% confidence interval (CI): 1.046-3.324 p = 0.039). However, aspirin resistance was not associated with an increased risk of clinical vascular events compared to aspirin-sensitive patients by TEG (17.7% vs 10.9%, p = 0.452). In addition, Cox proportional hazard regression modeling demonstrated that aspirin resistance or semiresponders (HR = 3.050, 95% CI: 1.464-6.354, p = 0.003) and diabetes (HR = 2.055, 95% CI: 1.060-3.981, p = 0.033) were associated with major adverse long-term outcomes. CONCLUSIONS: Aspirin resistance or semiresponders, defined by LTA, are associated with an increased risk of adverse clinical events in elderly male patients with CVD.

LONGITUDINAL ANALYSIS OF TRANSCRIPTOMIC SUBTYPES IN TRAUMA PATIENTS.

ABSTRACT: Objective: We previously identified two transcriptomic subtypes (Signature Groups: SG1 vs. SG2) in trauma patients at 12 hours postinjury, with SG1 associated with worse outcomes. In this study, we aimed to further characterize the changes in SG subtype categorization of trauma patients over time after injury and define the corresponding association with outcomes based on the timing of the subtype designation. Methods and Results: This study was a secondary analysis of published data of whole-blood leukocyte transcriptomics, a longitudinal data from 167 severe blunt trauma patients. We assigned trauma patients to SG1 or SG2 subtype for time points between 12 hours and 28 days, inclusive, postinjury and characterized their longitudinal outcomes. SG1 assignment, regardless of time point, was associated consistently with slower recovery. Further analysis revealed that additional prognostic information could be obtained by assessing SG subtype at both 12 hours and 1 day. Conclusions: This study provides a proof of concept that immune status can worsen after admission and highlights the benefit of longitudinally monitoring SG subtypes in trauma patients.

The independent prognostic value of global epigenetic alterations: An analysis of single-cell ATAC-seq of circulating leukocytes from trauma patients followed by validation in whole blood leukocyte transcriptomes across three etiologies of critical illness.

BACKGROUND: While bulk and single cell transcriptomic patterns in circulating leukocytes from trauma patients have been reported, how these relate to changes in open chromatin patterns remain unstudied. Here, we investigated whether single-cell ATAC-seq would provide further resolution of transcriptomic patterns that align with patient outcomes. METHODS: We performed scATAC-seq on peripheral blood mononuclear cells from four trauma patients at <4 h, 24 h, 72 h post-injury and four matched healthy controls, and extracted the features associated with the global epigenetic alterations. Three large-scale bulk transcriptomic datasets from trauma, burn and sepsis patients were used to validate the scATAC-seq derived signature, explore patient epigenetic heterogeneity (Epigenetic Groups: EG_hi vs. EG_lo), and associate patterns with clinical outcomes in critical illness. FINDINGS: Patient subsets with gene expression patterns in blood leukocytes representative of a high global epigenetic signature (EG_hi) had worse outcomes across three etiologies of critical illness. EG_hi designation contributed independent of the known immune leukocyte transcriptomic responses to patient prognosis (Trauma: HR=0.62 [95% CI: 0.43-0.89, event set as recovery], p=0.01, n=167; Burns: HR=4.35 [95% CI: 0.816-23.2, event set as death], p=0.085, n=121; Sepsis: HR=1.60 [95% CI: 1.10-2.33, event set as death], p=0.013, n=479; Cox proportional hazards regression). INTERPRETATION: The inclusion of gene expression patterns that associate with global epigenetic changes in circulating leukocytes improves the resolution of transcriptome-based patient classification in acute critical illnesses. Early detection of both the global epigenetic signature and the known immune transcriptomic patterns associates with the worse prognosis in trauma, burns and sepsis. FUNDING: This project was supported by an R35 grant from National Institutes of Health: 1R35GM127027-01 (T.B.).

Lipidomic signatures align with inflammatory patterns and outcomes in critical illness.

Alterations in lipid metabolism have the potential to be markers as well as drivers of pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. The previously reported survival benefit of early thawed plasma administration was associated with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers in causal modelling. Phosphatidylethanolamines (PE) were elevated in patients with persistent critical illness and PE levels were prognostic for worse outcomes not only in trauma but also severe COVID-19 patients. Here we show selective rise in systemic PE as a common prognostic feature of critical illness.

Contrasting Trends of Surface PM2.5, O3, and NO2 and Their Relationships with Meteorological Parameters in Typical Coastal and Inland Cities in the Yangtze River Delta.

The contrasting trends of surface particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) and their relationships with meteorological parameters from 2015 to 2019 were investigated in the coastal city of Shanghai (SH) and the inland city of Hefei (HF), located in the Yangtze River Delta (YRD). In both cities, PM2.5 declined substantially, while O3 and NO2 showed peak values during 2017 when the most frequent extreme high-temperature events occurred. Wind speed was correlated most negatively with PM2.5 and NO2 concentrations, while surface temperature and relative humidity were most closely related to O3. All of the studied pollutants were reduced by rainfall scavenging, with the greatest reduction seen in PM2.5, followed by NO2 and O3. By contrast, air pollutants in the two cities were moderately strongly correlated, although PM2.5 concentrations were much lower and Ox (O3 + NO2) concentrations were higher in SH. Additionally, complex air pollution hours occurred more frequently in SH. Air pollutant concentrations changed more with wind direction in SH. A more effective washout effect was observed in HF, likely due to the more frequent strong convection and thunderstorms in inland areas. This research suggests pertinent air quality control measures should be designed accordingly for specific geographical locations.

Single-Cell Transcriptomics Reveals Compartment-Specific Differences in Immune Responses and Contributions for Complement Factor 3 in Hemorrhagic Shock Plus Tissue Trauma.

ABSTRACT: Hemorrhagic shock with tissue trauma (HS/T) leads to the activation of a system-wide immune-inflammatory response that involves all organs and body compartments. Recent advances in single-cell analysis permit the simultaneous assessment of transcriptomic patterns in a large number of cells making it feasible to survey the landscape of immune cell responses across numerous anatomic sites. Here, we used single-cell RNA sequencing of leukocytes from the blood, liver, and spleen to identify the major shifts in gene expression by cell type and compartment in a mouse HS/T model. At 6 h, dramatic changes in gene expression were observed across multiple-cell types and in all compartments in wild-type mice. Monocytes from circulation and liver exhibited a significant upregulation of genes associated with chemotaxis and migration and a simultaneous suppression of genes associated with interferon signaling and antigen presentation. In contrast, liver conventional DC exhibited a unique pattern compared with other myeloid cells that included a pronounced increase in major histocompatibility complex class II (MHCII) gene expression. The dominant pattern across all compartments for B and T cells was a suppression of genes associated with cell activation and signaling after HS/T. Using complement factor 3 (C3) knockout mice we unveiled a role for C3 in the suppression of monocyte Major Histocompatibility Complex class II expression and activation of gene expression associated with migration, phagocytosis and cytokine upregulation, and an unexpected role in promoting interferon-signaling in a subset of B and T cells across all three compartments after HS/T. This transcriptomic landscape study of immune cells provides new insights into the host immune response to trauma, as well as a rich resource for further investigation of trauma-induced immune responses and complement in driving interferon signaling.

A road map from single-cell transcriptome to patient classification for the immune response to trauma.

Immune dysfunction is an important factor driving mortality and adverse outcomes after trauma but remains poorly understood, especially at the cellular level. To deconvolute the trauma-induced immune response, we applied single-cell RNA sequencing to circulating and bone marrow mononuclear cells in injured mice and circulating mononuclear cells in trauma patients. In mice, the greatest changes in gene expression were seen in monocytes across both compartments. After systemic injury, the gene expression pattern of monocytes markedly deviated from steady state with corresponding changes in critical transcription factors, which can be traced back to myeloid progenitors. These changes were largely recapitulated in the human single-cell analysis. We generalized the major changes in human CD14+ monocytes into 6 signatures, which further defined 2 trauma patient subtypes (SG1 vs. SG2) identified in the whole-blood leukocyte transcriptome in the initial 12 hours after injury. Compared with SG2, SG1 patients exhibited delayed recovery, more severe organ dysfunction, and a higher incidence of infection and noninfectious complications. The 2 patient subtypes were also recapitulated in burn and sepsis patients, revealing a shared pattern of immune response across critical illness. Our data will be broadly useful to further explore the immune response to inflammatory diseases and critical illness.

Pre-operative exercise therapy triggers anti-inflammatory trained immunity of Kupffer cells through metabolic reprogramming.

Pre-operative exercise therapy improves outcomes for many patients who undergo surgery. Despite the well-known effects on tolerance to systemic perturbation, the mechanisms by which pre-operative exercise protects the organ that is operated on from inflammatory injury are unclear. Here, we show that four-week aerobic pre-operative exercise significantly attenuates liver injury and inflammation from ischaemia and reperfusion in mice. Remarkably, these beneficial effects last for seven more days after completing pre-operative exercising. We find that exercise specifically drives Kupffer cells toward an anti-inflammatory phenotype with trained immunity via metabolic reprogramming. Mechanistically, exercise-induced HMGB1 release enhances itaconate metabolism in the tricarboxylic acid cycle that impacts Kupffer cells in an NRF2-dependent manner. Therefore, these metabolites and cellular/molecular targets can be investigated as potential exercise-mimicking pharmaceutical candidates to protect against liver injury during surgery.

Lipidomic Signatures Align with Inflammatory Patterns and Outcomes in Critical Illness.

Alterations in lipid metabolism have the potential to be markers as well as drivers of the pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. Early in the clinical course, Fresh Frozen Plasma administration led to improved survival in association with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers. Late over-representation of phosphatidylethanolamines with critical illness led to the validation of a Lipid Reprogramming Score that was prognostic not only in trauma but also severe COVID-19 patients. Our lipidomic findings provide a new paradigm for the lipid response underlying critical illness.

Epigenetic activation of HORMAD1 in basal-like breast cancer: role in Rucaparib sensitivity.

Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype with features similar to the basal cells surrounding the mammary ducts. Treatment of patients with BLBC has been challenging due to the lack of well-defined molecular targets. Due to the clinical and pathological similarities of BLBC with BRCA-deficient breast cancers, the effectiveness of Poly (ADP-ribose) polymerase inhibitors (PARPi) has been tested in early phase clinical trials for patients with advanced BLBC, with limited clinical responses. Recently, it was reported that HORMAD1 overexpression sensitizes BLBC to HR-targeting agents by suppressing homologous recombination. Our independent analysis suggests that HORMAD1 is aberrantly overexpressed in about 80% of BLBC, and its expression in normal tissues is restricted to testis. Our experimental data suggests that HORMAD1 overexpression correlates with focal hypomethylation in BLBC. On the other hand, investigation of the Genomics of Drug Sensitivity in Cancer dataset revealed significantly reduced sensitivity of HORMAD1-overexpressing BLBC cell lines to Rucaparib, a commonly used PARPi. To further assess the role of HORMAD1 in PARPi sensitivity, we generated three HORMAD1-overexpressing xenograft models using the HORMAD1-low BLBC cell lines HCC1954, HCC1806, and BT20; we then subjected these xenograft models to Rucaparib treatment. Ectopic expression of HORMAD1 enhances tumor formations in two of these models, and significantly reduces sensitivity to Rucaparib in the HCC1954 model. Taken together, our data suggest that epigenetic activation of HORMAD1 by hypomethylation in BLBC may endow reduced sensitivity to Rucaparib treatment in some tumor models.

Inhibition of human cytochromes P450 in vitro by ritonavir and cobicistat.

OBJECTIVES: Ritonavir and cobicistat are strong inhibitors of human cytochrome P450-3A (CYP3A) isoforms, and are used clinically as pharmacokinetic boosting agents for other antiretroviral drugs. Data reported by the manufacturer suggest that cobicistat is a more selective inhibitor of CYP3A than ritonavir. However, this claim has not been validated in clinical studies. This study evaluated the in-vitro inhibitory potency of ritonavir and cobicistat vs a series of human CYP isoforms. METHOD: The model system utilized human liver microsomes and isoform-selective index substrates. KEY FINDINGS: Ritonavir and cobicistat both were strong inhibitors of CYP3A4, with IC50 values of 0.014 and 0.032 µm, respectively. A component of inhibition was time-dependent (mechanism-based). Neither drug meaningfully inhibited CYP1A2 (IC50  > 150 µm). CYP2B6, CYP2C9, CYP2C19 and CYP2D6 were inhibited by both drugs, but with IC50 values exceeding 6 µm. CONCLUSIONS: Consistent with previous reports, both ritonavir and cobicistat were highly potent inhibitors of CYP3A. Both drugs were weaker inhibitors of other human CYPs, with IC50 values at least two orders of magnitude higher. There was no evidence of a meaningful difference in selectivity between the two drugs.

Establishing a predictive model for aspirin resistance in elderly Chinese patients with chronic cardiovascular disease.

BACKGROUND: Resistance to anti-platelet therapy is detrimental to patients. Our aim was to establish a predictive model for aspirin resistance to identify high-risk patients and to propose appropriate intervention. METHODS: Elderly patients (n = 1130) with stable chronic coronary heart disease who were taking aspirin (75 mg) for > 2 months were included. Details of their basic characteristics, laboratory test results, and medications were collected. Logistic regression analysis was performed to establish a predictive model for aspirin resistance. Risk score was finally established according to coefficient B and type of variables in logistic regression. The Hosmer-Lemeshow (HL) test and receiver operating characteristic curves were performed to respectively test the calibration and discrimination of the model. RESULTS: Seven risk factors were included in our risk score. They were serum creatinine (> 110 µmol/L, score of 1); fasting blood glucose (> 7.0 mmol/L, score of 1); hyperlipidemia (score of 1); number of coronary arteries (2 branches, score of 2; ≥ 3 branches, score of 4); body mass index (20-25 kg/m(2), score of 2; > 25 kg/m(2), score of 4); percutaneous coronary intervention (score of 2); and smoking (score of 3). The HL test showed P ≥ 0.05 and area under the receiver operating characteristic curve ≥ 0.70. CONCLUSIONS: We explored and quantified the risk factors for aspirin resistance. Our predictive model showed good calibration and discriminative power and therefore a good foundation for the further study of patients undergoing anti-platelet therapy.

[Long-term effects of heme oxygenase 1 overexpression on post-infarction heart function in diabetic rats].

OBJECTIVE: To clarify the impact of increased heme oxygenase-1 (HO-1) expression on cardiac function of diabetic rats with myocardial infarction and its mechanism. METHODS: Sixty adult male Wistar rats were randomly divided into five groups (n = 12): sham operation group (sham), diabetes + sham operation group (DM + sham), diabetes + MI group (DM + MI) , diabetes + myocardial infarction + cobalt original porphyrin (CoPP) group (DM + MI + CoPP), diabetes + myocardial infarction + CoPP+ tin porphyrin (SnMP) group (DM + MI + CoPP + SnMP). CoPP 4.5 mg/kg or SnMP 15 mg/kg were administered at the day next to MI operation, for six weeks, once a week. At the 28th week post operation, the echocardiography, left heart via the carotid artery indoor intubation were used to observe the long-term influence of HO-1 inducer (cobalt protoporphyrin, CoPP) and activity of HO inhibitor (tin porphyrin, SnMP) on the indices of left ventricular remodeling and cardiac function after the intervention. Blood glucose (GLU), total cholesterol (TC), C-reactive protein (CRP), serum creatinine (Cr), aminotransferase (ALT) and other indicators were measured. ELISA was used to test interleukin-6 (IL-6), tumor necrosis factor (TNF), nitric oxide (NO), prostacyclin (PGI2), adiponectin, and ultra sensitive CRP (HsCRP) level. RESULTS: HO-1 inducer, CoPP, could ameliorate ± dp/dtmax, left ventricular ejection fraction and left ventricular shortening fraction in diabetic myocardial infarction rats. It could also decrease left ventricular end-diastolic diameter. The serum bilirubin, NO and PGI2 levels, myocardial phosphorylated endothelial nitric oxide synthasee(peNOS), phosphorylated activated protein kinase (pAkt), phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) expression were also significantly elevated, and the serum hs-CRP and TNF levels were significantly inhibited. Compared to inducer group, cardiac function were worse in the inhibitor group. CONCLUSION: Upregulated HO-1 level can improve the endothelial function, inhibite of the inflammatory response and enhance the antioxidant substances in serum bilirubin via peNOS-pAMPK pathway, which effectively inhibit ventricular remodeling and improve the long-term cardiac function after infarction in diabetic rats.

[Influence of epidural ropivacaine in combination with fentanyl for labor analgesia on the clinical outcome of labor].

OBJECTIVE: To investigate the effect of epidural ropivacaine in combination with fentanyl for labor analgesia on the clinical outcome of labor. METHODS: A retrospective study was conducted involving 281 healthy primiparas, including 106 undergoing spontaneous labor who received epidural 0.15% ropivacaine in combination with fentany (1microg/ml) and 175 without epidural analgesia. The active phase duration, durations of each labor stages, delivery modes, management of labor, postpartum hemorrhage, incidence of fetal distress and asphyxia neonatorum were recorded in the two groups. The visual analogue scale (VAS) was used to assess the pain of uterine contraction, and modified Bromage scoring system applied to evaluate the lower limb motor block. RESULTS: There were no significant differences in the duration of the first, third or the total labor stages between the two groups, but the second labor stage was prolonged in the labor analgesia group. The ratio of spontaneous labor, assisted vaginal delivery, and incidence of asphyxia neonatorum were higher, whereas the duration of the active stage was shortened in the analgesia group. CONCLUSION: Epidural ropivacaine in combination with fentanyl in labor can decrease the incidence of cesarean section, and the duration of the active stage can be shortened with application of ocytocin.