A New Product of Bilirubin Degradation by H2O2 and Its Formation in Activated Neutrophils and in an Inflammatory Mouse Model.

Bilirubin (BR) is a tetrapyrrolic compound stemming from heme catabolism with diverse physiological functions. It can be oxidized by H2O2 to form several degradation products, some of which have been detected in vivo and may contribute to the pathogenesis of certain diseases. However, the oxidative degradation of BR is complex and the conditions that BR degradation occurs pathophysiologically remain obscure. Neutrophils are known to generate large amounts of reactive oxygen species, including H2O2, upon activation and they are mobilized to inflammatory sites; therefore, we hypothesized that activated neutrophils could cause BR degradation, which could occur at inflammatory sites. In the present study, we investigated BR degradation by H2O2 and identified hematinic acid (BHP1) and a new product BHP2, whose structure was characterized as 2,5-diformyl-4-methyl-1H-pyrrole-3-propanoic acid. An LC-MS/MS method for the quantitation of the two compounds was then established. Using the LC-MS/MS method, we observed the concentration-dependent formation of BHP1 and BHP2 in mouse neutrophils incubated with 10 and 30 µM of BR with the yields being 16 ± 3.2 and 31 ± 5.9 pmol/106 cells for BHP1, and 25 ± 4.4 and 71 ± 26 pmol/106 cells for BHP2, respectively. After adding phorbol 12-myristate 13-acetate, a neutrophil agonist, to 30 µM of BR-treated cells, the BHP1 yield increased to 43 ± 6.6 pmol/106 cells, whereas the BHP2 one decreased to 47 ± 9.2 pmol/106 cells. The two products were also detected in hemorrhagic skins of mice with dermal inflammation and hemorrhage at levels of 4.5 ± 1.9 and 0.18 ± 0.10 nmol/g tissue, respectively, which were significantly higher than those in the non-hemorrhagic skins. BHP2 was neurotoxic starting at 0.10 µM but BHP1 was not, as assessed using Caenorhabditis elegans as the animal model. Neutrophil-mediated BR degradation may be a universally pathophysiological process in inflammation and can be particularly important under pathological conditions concerning hemorrhage.

Factors associated with prior acute pancreatitis episodes among patients with chronic pancreatitis.

BACKGROUND: The relationship between chronic pancreatitis (CP) and acute pancreatitis (AP) is complex and not well understood. CP could be preceded by antecedent episodes of AP. AIMS: The aim of this study was to explore both genetic and environmental factors associated with AP episodes before the diagnosis of CP. METHODS: This was a cross-sectional study including 1022 patients. Detailed demographic, genetic, and clinical data were collected. Based on the presence of AP episode(s) before diagnosis of CP, patients were divided into AP group (further classified into single episode of AP group and recurrent AP group) and non-AP group. Related factors among these groups were assessed using multivariate logistic regression model. RESULTS: Before diagnosis of CP, 737 patients (72.1%) had a history of AP. Smoking(P = 0.005) and heavy alcohol consumption(P = 0.002) were risk factors for AP while age at CP onset(P < 0.001), harboring the SPINK1 mutation(P < 0.001), diabetes(P < 0.001) and steatorrhea(P < 0.001) were protective factors. Further, alcoholic CP(P = 0.019) was the only independent risk factor for recurrent AP attacks while age at onset of CP(P < 0.001), pancreatic stones(P = 0.024). and pseudocysts(P = 0.018) served as protective factors. CONCLUSIONS: SPINK1 mutations served as protective factor for AP episodes, suggesting SPINK1 mutation might play a pathogenic role in CP occurrence with occult clinical manifestations.

Clinical characteristics associated with long-term viral shedding in patients with coronavirus disease 2019.

BACKGROUND: To delineate the clinical characteristics associated with long-term viral shedding (>21 days) in patients with coronavirus disease 2019 (COVID-19). METHODS: In this retrospective study, factors associated with long-term (>21 days) severe acute respiratory coronavirus 2 (SARS-CoV-2) RNA shedding were evaluated in a conhort of 609 patients from two hospitals in Wuhan. RESULTS: The median duration of SARS-CoV-2 viral shedding was 19 days (interquartile range, 10-28 days) among all patients. There were 42% of patients having prolonged viral shedding time (>21 days), in which the longest viral shedding time was 58 days. When comparing patients with early (≤21 days) and late viral RNA clearance (>21 days), prolonged viral shedding was associated with age <65 (P=0.015), female sex (P=0.028), cough (P=0.025), fatigue (P=0.035), sore throat (P=0.013), aspartate aminotransferase (P=0.038), procalcitonin (P=0.010), albumin (P=0.003), D-dimer (P=0.011), lung involvement (P=0.014), reticular shadow (P<0.001) and lung consolidation (P=0.004). Age range (<65 years) (odds ratio [OR], 1.46 [95% CI, 1.05-2.03]) and female sex (odds ratio [OR], 1.40 [95% CI, 1.00-1.94]) were independent risk factors. CONCLUSIONS: Long-term viral shedding (>21 days) is not a rare phenomenon among COVID-19 infectious patients. Age range (<65) and female sex are independent risk factors for long-term viral shedding. Early antiviral treatment should be considered for COVID-19 patients with such risk factors. Further study should be conducted to know the infectivity of patients with long-term viral shedding in order to develop reasonable control measures.

Risk factors for sinistral portal hypertension and related variceal bleeding in patients with chronic pancreatitis.

OBJECTIVES: Sinistral portal hypertension (SPH) is an uncommon complication of chronic pancreatitis (CP) and can result in severe gastrointestinal bleeding. The aim of this study was to determine the prevalence and the potential risk factors for SPH and related gastrointestinal variceal bleeding in patients with CP. METHODS: We retrospectively reviewed all patients with SPH due to CP admitted to our hospital from July 2014 to June 2019 in this case-control study. Patients with CP without SPH were randomly selected as controls during the study period (case: control  =  1:2). The characteristics, medical history, course of CP, characteristics associated with SPH, and follow-up evaluations of the patients were documented in detail. The prevalence rate of SPH in patients with CP and related gastrointestinal bleeding was calculated. Risk factors for SPH and related variceal bleeding were analyzed using univariate or multivariate logistic regression analysis. RESULTS: The prevalence of SPH was 2.7% (89/3358) in patients with CP. Independent risk factors for SPH included alcohol consumption (P = 0.030), history of acute pancreatitis (P = 0.010), diabetes mellitus (P < 0.001), and pseudocysts (P < 0.001). Overall 17 (19.1%) patients suffered from related gastrointestinal bleeding. Between the bleeding and non-bleeding groups, there were significant differences in the types of CP, existence of stones, gastric varices diagnosed before bleeding, splenomegaly and hypersplenism by univariate analysis. CONCLUSION: SPH is a rare complication of CP that is associated with a relatively low risk of variceal bleeding.

A Bunyavirus-Inducible Ubiquitin Ligase Targets RNA Polymerase IV for Degradation during Viral Pathogenesis in Rice.

The ubiquitin-proteasome system (UPS) is an important post-translational regulatory mechanism that controls many cellular functions in eukaryotes. Here, we show that stable expression of P3 protein encoded by Rice grassy stunt virus (RGSV), a negative-strand RNA virus in the Bunyavirales, causes developmental abnormities similar to the disease symptoms caused by RGSV, such as dwarfing and excess tillering, in transgenic rice plants. We found that both transgenic expression of P3 and RGSV infection induce ubiquitination and UPS-dependent degradation of rice NUCLEAR RNA POLYMERASE D1a (OsNRPD1a), one of two orthologs of the largest subunit of plant-specific RNA polymerase IV (Pol IV), which is required for RNA-directed DNA methylation (RdDM). Furthermore, we identified a P3-inducible U-box type E3 ubiquitin ligase, designated as P3-inducible protein 1 (P3IP1), which interacts with OsNRPD1a and mediates its ubiquitination and UPS-dependent degradation in vitro and in vivo. Notably, both knockdown of OsNRPD1 and overexpression of P3IP1 in rice plants induced developmental phenotypes similar to RGSV disease symptomss. Taken together, our findings reveal a novel virulence mechanism whereby plant pathogens target host RNA Pol IV for UPS-dependent degradation to induce disease symptoms. Our study also identified an E3 ubiquitin ligase, which targets the RdDM compotent NRPD1 for UPS-mediated degradation in rice.

Meta-analysis of the impact of the SPINK1 c.194 + 2T > C variant in chronic pancreatitis.

BACKGROUND AND AIMS: The SPINK1 c.194 + 2T > C variant has been increasingly recognized as an important risk factor for chronic pancreatitis (CP). However, there is no clear agreement on its contribution to different ethnicities and CP etiologies. To address this issue, a meta-analysis of literature was performed. METHODS: Studies addressing the presence of the SPINK1 c.194 + 2T > C variant in CP patients and controls were retrieved from the PubMed, EMBASE and Cochrane databases. Initial analysis included all CP patients, followed by subgroup analyses for East Asian and non-East Asian patients, and for idiopathic CP (ICP) and non-ICP. RESULTS: A total of 13 studies were retrieved for analysis, comprising 2097 cases and 4019 controls. There were 126 cases (10.01%) carrying the SPINK1 c.194 + 2T > C variant in cases, while only two controls were carriers (0.05%). Overall, the variant was significantly associated with an increased risk of CP (OR = 25.73). In the subgroup, the variant was significantly associated with increased risk of CP in East Asians (OR = 73.16), and in non-East Asians (OR = 10.21). Further, the contribution of the variant in ICP (OR = 35.31) was found to be higher than in non-ICP (25.75). CONCLUSIONS: The SPINK1 c.194 + 2T > C variant is a strong risk factor for CP, especially in East Asian patients with ICP.

Effects of Se substitution and transition metal doping on the electronic and magnetic properties of a MoSxSe2-x/h-BN heterostructure.

The van der Waals heterostructures created by stacking two monolayer semiconductors have been rapidly developed experimentally and exhibit various unique physical properties. In this work, we investigate the effects of Se atom substitution and 3d-TM atom doping on the structural, electronic, and magnetic properties of the MoSe2/h-BN heterostructure, by using first-principles calculations based on density functional theory (DFT). It is found that Se atom substitution could considerably enhance the band gaps of MoSe2/h-BN heterostructures. With an increase in the substitution concentration, the energy band changes from an indirect to a direct band gap when the substitution concentration exceeds a critical value. For 3d-TM atom doping, it is shown that V-, Mn-, Fe-, and Co-doped systems exhibit a half-metallic state and magnetic behavior, while there is no spin polarization in the Ni-doped case. The results provide a theoretical basis for the development of diluted magnetic semiconductors and spin devices based on the MoSxSe2-x/h-BN heterostructure.

Development and Validation of a Simplified Chinese Version of the Assessment Tool for Students' Perceptions of Medical Professionalism.

Professionalism is crucial in all professions and is particularly important in the medical field. Measuring students' perceptions of professionalism can help to form education targeting the enhancement of professionalism. This study aimed to validate an effective assessment tool for the measurement of medical students' perceptions of medical professionalism in mainland China. The cross-sectional survey was conducted in three medical colleges in Guangdong, China. Of the 2103 eligible medical students, 1976 responded, and 1856 questionnaires were deemed valid. Students from clinical medicine in these three medical colleges were randomly selected by cluster sampling. First, a Simplified Chinese Version questionnaire to measure Student's Perception of Medical Professionalism (SCV-SPMP) was constructed. Second, questionnaires from 1856 students majoring in clinical medicine at three medical colleges were included in the analysis. Third, exploratory factor analysis, Cronbach's alpha, item-subscale correlation, and confirmatory factor analysis were conducted to test the validity and reliability of the SCV-SPMP. Nine items were eliminated following exploratory factor analysis, and four subscales were extracted from the analysis. All internal consistency reliability exceeded the minimum standard. The overall Cronbach's alpha was 0.94, and four subscales' alphas were 0.82 (Accountability and excellence), 0.81 (Duty), 0.89 (Honor and integrity), and 0.85 (Practice habits and respect for others), respectively. The model fit was good. The convergent validity and discriminant validity were acceptable. The modified SCV-SPMP was found to be a valid and reliable tool to capture the main features of Chinese students' perceptions of medical professionalism in four dimensions, and it provides a quantitative method for the measurement of the students' perceptions in mainland China..

SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis.

OBJECTIVES: Rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes have been strongly associated with a risk of developing chronic pancreatitis (CP). However, their potential impact on the age of disease onset and clinical outcomes, as well as their potential interactions with environmental risk factors, remain unclear. These issues are addressed here in a large Chinese CP cohort. METHODS: We performed targeted next-generation sequencing of the four CP-associated genes in 1061 Han Chinese CP patients and 1196 controls. To evaluate gene-environment interactions, the patients were divided into three subgroups, idiopathic CP (ICP; n = 715), alcoholic CP (ACP; n = 206), and smoking-associated CP (SCP; n = 140). The potential impact of rare pathogenic variants on the age of onset of CP and clinical outcomes was evaluated using the Kaplan-Meier model. RESULTS: We identified rare pathogenic genotypes involving the SPINK1, PRSS1, CTRC, and/or CFTR genes in 535 (50.42%) CP patients but in only 71 (5.94%) controls (odds ratio = 16.12; P < 0.001). Mutation-positive patients had significantly earlier median ages at disease onset and at diagnosis of pancreatic stones, diabetes mellitus and steatorrhea than mutation-negative ICP patients. Pathogenic genotypes were present in 57.1, 39.8, and 32.1% of the ICP, ACP, and SCP patients, respectively, and influenced age at disease onset and clinical outcomes in all subgroups. CONCLUSIONS: We provide evidence that rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes significantly influence the age of onset and clinical outcomes of CP. Extensive gene-environment interactions were also identified.

Ubiquitination modification precisely modulates the ABA signaling pathway in plants.

Protein post-translational modification by ubiquitination is essential for the activity and stability of proteins in the eukaryotic life cycle. In the past few years, it has been found that ubiquitination subtly modulates the abscisic acid (ABA) signaling pathway to regulate plant growth, development and stress responses, such as drought, salinity and cold stress responses. In this review, how the ubiquitin-proteasome system and ubiquitination-related membrane trafficking pathway affect ABA synthesis and signal transduction will be addressed and analysed. Also, the challenging questions in this field will be raised. These comprehensive views on the regulatory role of ubiquitination modification in the ABA pathway will shed light on future researches on how the ubiquitination-related process affects other hormone signaling pathways.

Association between alcohol consumption and the risk of incident type 2 diabetes: a systematic review and dose-response meta-analysis.

BACKGROUND: Previous cohort studies have shown that moderate alcohol consumption was associated with a lower risk of type 2 diabetes (T2D). However, whether these associations differ according to the characteristics of patients with T2D remains controversial. OBJECTIVE: The purpose of this study was to explore and summarize the evidence on the strength of the association between alcohol consumption and the subsequent risk of T2D by using a dose-response meta-analytic approach. DESIGN: We identified potential studies by searching the PubMed, Embase, and Cochrane Library databases up to 24 March 2015. Prospective observational studies that evaluated the relation between alcohol consumption and the risk of T2D and reported its effect estimates with 95% CIs were included. RESULTS: Analyses were based on 706,716 individuals (275,711 men and 431,005 women) from 26 studies with 31,621 T2D cases. We detected a nonlinear relation between alcohol consumption and the risk of T2D, which was identified in all cohorts (P-trend < 0.001, P-nonlinearity < 0.001), in men (P-trend < 0.001, P-nonlinearity < 0.001), and in women (P-trend < 0.001, P-nonlinearity < 0.001). Compared with the minimal category of alcohol consumption, light (RR: 0.83; 95% CI: 0.73, 0.95; P = 0.005) and moderate (RR: 0.74; 95% CI: 0.67, 0.82; P < 0.001) alcohol consumption was associated with a lower risk of T2D. However, heavy alcohol consumption had little or no effect on subsequent T2D risk. Furthermore, the summary RR ratio (RRR; male to female) of the comparison between moderate alcohol consumption and the minimal alcohol categories for T2D was significantly higher, and the pooled RRR (current smoker to never smoker) of light alcohol consumption was significantly reduced. CONCLUSIONS: Light and moderate alcohol consumption was associated with a lower risk of T2D, whereas heavy alcohol consumption was not related to the risk of T2D.

Tea consumption and risk of cardiovascular outcomes and total mortality: a systematic review and meta-analysis of prospective observational studies.

Studies that investigated the association between tea consumption and the risk of major cardiovascular events have reported inconsistent results. We conducted a meta-analysis of prospective observational studies in order to summarize the evidence regarding the association between tea consumption and major cardiovascular outcomes or total mortality. In July 2014, we performed electronic searches in PubMed, EmBase, and the Cochrane Library, followed by manual searches of reference lists from the resulting articles to identify other relevant studies. Prospective observational studies that reported effect estimates, with 95% confidence intervals (CIs), for coronary heart disease (CHD), stroke, cardiac death, stroke death, or total mortality for more than two dosages of tea consumption were included. A random-effects meta-analysis was performed to determine the risk of major cardiovascular outcomes associated with an increase in tea consumption by 3 cups per day. Of the 736 citations identified from database searches, we included 22 prospective studies from 24 articles reporting data on 856,206 individuals, and including 8,459 cases of CHD, 10,572 of stroke, 5,798 cardiac deaths, 2,350 stroke deaths, and 13,722 total deaths. Overall, an increase in tea consumption by 3 cups per day was associated with a reduced risk of CHD (relative risk [RR], 0.73; 95% CI: 0.53-0.99; P = 0.045), cardiac death (RR, 0.74; 95% CI: 0.63-0.86; P < 0.001), stroke (RR, 0.82; 95% CI: 0.73-0.92; P = 0.001), total mortality (RR, 0.76; 95% CI: 0.63-0.91; P = 0.003), cerebral infarction (RR, 0.84; 95% CI: 0.72-0.98; P = 0.023), and intracerebral hemorrhage (RR, 0.79; 95% CI: 0.72-0.87; P < 0.001), but had little or no effect on stroke mortality (RR, 0.93; 95% CI: 0.83-1.05; P = 0.260). The findings from this meta-analysis indicate that increased tea consumption is associated with a reduced risk of CHD, cardiac death, stroke, cerebral infarction, and intracerebral hemorrhage, as well as total mortality.

Association between B vitamins supplementation and risk of cardiovascular outcomes: a cumulative meta-analysis of randomized controlled trials.

BACKGROUND: Observational studies suggest that B vitamin supplementation reduces cardiovascular risk in adults, but this association remains controversial. This study aimed to summarize the evidence from randomized controlled trials (RCTs) investigating B vitamin supplementation for the primary or secondary prevention of major adverse cardiovascular outcomes and to perform a cumulative meta-analysis to determine the evidence base. METHODOLOGY AND PRINCIPAL FINDINGS: In April 2013, we searched PubMed, Embase, and the Cochrane Library to identify relevant RCTs. We included RCTs investigating the effect of B vitamin supplementation on cardiovascular outcome. Relative risk (RR) was used to measure the effect using a random-effect model. Statistical heterogeneity scores were assessed using the Q statistic. We included data on 57,952 individuals from 24 RCTs: 12 primary prevention trials and 12 secondary prevention trials. In 23 of these trials, 10,917 major adverse cardiovascular events (MACE) occurred; in 20 trials, 7,203 deaths occurred; in 15 trials, 3,422 cardiac deaths occurred; in 19 trials, 3,623 myocardial infarctions (MI) occurred; and in 18 trials, 2,465 strokes occurred. B vitamin supplementation had little or no effect on the incidence of MACE (RR, 0.98; 95% confidence interval [CI]: 0.93-1.03; P = 0.37), total mortality (RR, 1.01; 95% CI: 0.97-1.05; P = 0.77), cardiac death (RR, 0.96; 95% CI: 0.90-1.02; P = 0.21), MI (RR, 0.99; 95% CI: 0.93-1.06; P = 0.82), or stroke (RR, 0.94; 95% CI: 0.85-1.03; P = 0.18). CONCLUSION/SIGNIFICANCE: B vitamin supplementation, when used for primary or secondary prevention, is not associated with a reduction in MACE, total mortality, cardiac death, MI, or stroke.

Effect and safety of dual anti-human epidermal growth factor receptor 2 therapy compared to monotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer: a systematic review.

BACKGROUND: Dual anti-human epidermal growth factor receptor 2 (HER2) therapies have been shown to improve outcomes of HER2-positive breast cancer patients. We undertook a systematic review to compare treatment outcomes for patients who received single or combined anti-HER2 therapies. METHODS: We identified randomized control trials that compared dual anti-HER2 therapy and anti-HER2 monotherapy in patients with HER2-positive breast cancer. Outcomes included pathologic complete response (pCR), overall survival (OS), progression-free survival (PFS), and adverse events. Included in the analysis were seven trials that recruited 2,609 patients. RESULTS: In the neoadjuvant setting, the pooled pCR rate in the dual anti-HER2 therapy and monotherapy groups in combination with chemotherapy was 54.8% and 36%, respectively. This difference was statistically significant (relative risk, 1.56; 95% confidence interval (CI), 1.23-1.97; p < 0.001). In the metastatic setting, dual anti-HER2 therapy demonstrated significant benefits in both PFS (hazard ratio (HR), 0.71; 95% CI, 0.62-0.81; p < 0.001) and OS (HR, 0.68; 95% CI, 0.57-0.82; p < 0.001). Subgroup analyses indicated that the addition of chemotherapy to dual anti-HER2 therapy could greatly improve pCR in the neoadjuvant settings. However, in the metastatic setting, similar PFS and OS were found in patients receiving dual anti-HER2 therapy with or without chemotherapy. Dual anti-HER2 therapy was associated with more frequent adverse events than monotherapy, but no statistical differences were observed in cardiac toxicity. CONCLUSIONS: This systematic review provides a summary of all the data currently available, and confirms the benefits and risks of dual anti-HER2 therapy for HER2-positive breast cancer.

Polyunsaturated fatty acid intake and risk of lung cancer: a meta-analysis of prospective studies.

BACKGROUND: Studies have reported inconsistent results for the existence of an association between polyunsaturated fatty acid (PUFA) intake and risk of lung cancer. The purpose of this study is to summarize the evidence regarding this relationship using a dose response meta-analytic approach. METHODOLOGY AND PRINCIPAL FINDINGS: We searched the PubMed, EmBase, and Cochrane Library electronic databases for related articles published through July 2013. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) of lung cancer incidence for greater than 2 categories of PUFA intake were included. We did random-effects meta-analyses of study-specific incremental estimates to determine the risk of lung cancer associated with a 5 g per day increase in PUFA intake. Overall, we included 8 prospective cohort studies reporting data on 1,268,442 individuals. High PUFA intake had little or no effect on lung cancer risk (risk ratio [RR], 0.91; 95% CI, 0.78-1.06; P = 0.230). Furthermore, the dose-response meta-analysis also suggested that a 5 g per day increase in PUFA has no significant effect on the risk of lung cancer (RR, 0.98; 95%CI: 0.96-1.01; P = 0.142). Finally, the findings of dose response curve suggested that PUFA intake of up to 15 g/d seemed to increase the risk of lung cancer. Furthermore, PUFA intake greater than 15 g/d was associated with a small beneficial effect and borderline statistical significance. Subgroup analyses for 5 g per day increment in PUFA indicated that the protective effect of PUFA was more evident in women (RR, 0.94; 95% CI, 0.87-1.01; P = 0.095) than in men (RR, 1.00; 95% CI, 0.98-1.02; P = 0.784). CONCLUSION/SIGNIFICANCE: Our study indicated that PUFA intake had little or no effect on lung cancer risk. PUFA intake might play an important role in lung cancer prevention in women.

Trends in in-hospital mortality among patients with stroke in China.

BACKGROUND: The incidence and burden of stroke in China is increasing rapidly. However, little is known about trends in mortality during stroke hospitalization. The objectives of this study were to assess trends of in-hospital mortality among patients with stroke and explore influence factors of in-hospital death after stroke in China. METHODS: 109 grade III class A hospitals were sampled by multistage stratified cluster sampling. All patients admitted to hospitals between 2007 and 2010 with a discharge diagnosis of stroke were included. Trends in in-hospital mortality among patients with stroke were assessed. Influence factors of in-hospital death after stroke were explored using multivariable logistic regression. RESULTS: Overall stroke hospitalizations increased from 79,894 in 2007 to 85,475 in 2010, and in-hospital mortality of stroke decreased from 3.16% to 2.30% (P<0.0001). The percentage of severe patients increased while odds of mortality (2010 versus 2007) decreased regardless of stroke type: subarachnoid hemorrhage (OR 0.792, 95% CI = 0.636 to 0.987), intracerebral hemorrhage (OR 0.647, 95% CI = 0.591 to 0.708), and ischemic stroke (OR 0.588, 95% CI = 0.532 to 0.649). In multivariable analyses, older age, male, basic health insurance, multiple comorbidities and severity of disease were linked to higher odds of in-hospital mortality. CONCLUSIONS: The mortality of stroke hospitalizations decreased likely reflecting advancements in stroke care and prevention. Decreasing of mortality with increasing of severe stroke patients indicated that we should pay more attention to rehabilitation and life quality of stroke patients. Specific individual and hospital-level characteristics may be targets for facilitating further declines.

Risk of treatment-related mortality with sorafenib in patients with cancer.

BACKGROUND: Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). We here performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. METHODS: Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. RESULTS: 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumour type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). CONCLUSIONS: It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.

Lipid management in the prevention of stroke: a meta-analysis of fibrates for stroke prevention.

BACKGROUND: Fibrates has been extensively used to improve plasma lipid levels and prevent adverse cardiovascular outcomes. However, the effect of fibrates on stroke is unclear at the present time. We therefore carried out a comprehensive systematic review and meta-analysis to evaluate the effects of fibrates on stroke. METHODS: We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings to identify studies for our analysis. We included randomized placebo controlled trials which reported the effects of fibrates on stroke. Relative risk (RR) was used to measure the effect of fibrates on the risk of stroke under random effect model. The analysis was further stratified by factors that could affect the treatment effects. RESULTS: Overall, fibrate therapy was not associated with a significant reduction on the risk of stroke (RR, 1.02, 95% CI, 0.90 to 1.16, P = 0.78). In the subgroup analyses, we observed that gemfibrozil therapy showed a beneficial effect on stroke (RR, 0.72, 95% CI, 0.53 to 0.98, P = 0.04). Similarly, fibrate therapy comparing to placebo had no effect on the incidence of fatal stroke. Subgroup analysis suggested that fibrate therapy showed an effect on fatal stroke when the Jadad score more than 3 (RR, 0.41, 95% CI, 0.17 to 1.00, P = 0.049). Furthermore, a sensitivity analysis indicated that fibrate therapy may play a role in fatal stroke (RR, 0.49, 95% CI, 0.26 to 0.93, P = 0.03) for patients with previous diabetes, cardiovascular disease or stroke. CONCLUSIONS: Our study indicated that fibrate therapy might play an important role in reducing the risk of fatal stroke in patients with previous diabetes, cardiovascular disease or stroke. However, it did not have an effect on the incidence of stroke.

[Research progress of layer-by-layer self-assembly technique in drug delivery].

Now the layer-by-layer self-assembling (LbL) technique has become an attention-getting reparative methodology for ultrathin film formation. Many scientists in different academic areas including bioengieering, medical science, drug controlled release, optoelectronics dive into this technology. Among of them, carriers with structures which can be flexibly controlled are more useful since functional structure units can be assembled in layer-by-layer fashion, which is simplicity, chemical mildness, concealment, can achieve targeted drug delivery and so on. In this review, we have discussed the advantage, development, influential factors and applications of LbL. We have focused on reviewing the applications and perspective of nanoparticles, microgels and capsules were both fabricated via the LbL assembling at drug delivery.

Characterization of fish IRF3 as an IFN-inducible protein reveals evolving regulation of IFN response in vertebrates.

In mammals, IFN regulatory factor (IRF) 3 is a critical player in modulating transcription of type I IFN and IFN-stimulated genes (ISGs). In this study, we describe the roles of crucian carp (Carassius auratus L.) IRF3 in activating fish IFN and ISGs. Fish IRF3 exhibits a large sequence divergence from mammalian orthologs. Whereas mammalian IRF3 is constitutively expressed, fish IRF3 protein is significantly upregulated by IFN, poly-IC, and other stimuli known as IFN inducers in mammals. The IFN-inducible property of fish IRF3 is consistent with the comparative analysis of 5' flanking regulatory region of vertebrate IRF3 genes, which reveals the presence of typical IFN-stimulated response elements in fish and amphibians, but an absence in tetrapods. Furthermore, either IFN or poly-IC induces phosphorylation and cytoplasmic-to-nuclear translocation of IRF3, which seems essential for its function in that phosphomimic active IRF3 exhibits stronger transactivation than wild type IRF3. Finally, overexpression of fish IRF3 activates production of IFN that in turn triggers ISG transcription through Stat1 pathway, whereas transfection of dominant negative mutant IRF3-DN abrogates poly-IC induction of ISGs, probably owing to blockade of IFN production. Therefore, regulation of IFN response by vertebrate IRF3 is another ancient trait. These data provide evidence of the evolving function of vertebrate IRF3 on regulating IFN response.