Schizophrenia is a mental illness associated with cardiovascular disease at a younger age than in the general population. Endothelial dysfunction has predictive value for future cardiovascular events; however, the impact of a diagnosis of schizophrenia on this marker is unknown.We tested the hypothesis that subjects with schizophrenia have impaired endothelial function.P=0.442), sex (P>0.999), and smoking status (P=0.842). Peripheral artery microvascular and conduit vessel endothelial function was measured using hyperemic velocity time integral (VTI), pulse arterial tonometry (PAT), and flow-mediated dilation (FMD).A total of 102 subjects (34.5±7.5 years) participated in this study. This sample consisted of 51 subjects with a diagnosis of schizophrenia and 51 healthy subjects, who were matched for age (P<0.001), whereas FMD (P=0.933) and PAT (P=0.862) did not differ between the two groups. A multivariable-linear-regression analysis, built on data from univariate and partial correlations, showed that only schizophrenia, sex, lipid-lowering medications, antihypertensive medications, and low-density lipoprotein (LDL)-cholesterol were predictive of attenuated VTI, whereas age, ethnicity, family history of cardiovascular disease, smoking status, systolic blood pressure, waist circumference, HDL-cholesterol, triglycerides, C-reactive protein, and homeostatic model assessment-insulin resistance (HOMA-IR), antidiabetic medications, antidepressant medications, mood stabilizers, benzodiazepines, and anticholinergic medications did not predict VTI in this model (adjusted R2=0.248).Significantly lower values of VTI were noted in subjects with schizophrenia (104.9±33.0 vs. 129.1±33.8 cm, Our findings suggest that a diagnosis of schizophrenia is associated with impaired microvascular function as indicated by lower values of VTI, irrespective of many other clinical characteristics. It might be an early indicator of cardiovascular risk in schizophrenia, and might help to identify high-risk individuals. The causes of morbidity and mortality among subjects with schizophrenia follow closely the general population, and heart disease and cerebrovascular incidents accounting for ~50% of deaths.5 The life expectancy in schizophrenia is reduced by up to 20 years, with deaths from CVD being far more common than suicide in this population.5–7 For instance, the standardized mortality rate from CVD is double in schizophrenia patients compared with those without,8 and is particularly elevated in subjects under 50 years of age.9 There are some lines of evidence showing that medication side effects and other lifestyle factors do not fully explain the higher burden of cardiovascular morbidity and mortality in schizophrenia patients.9Schizophrenia is a severe mental illness that affects ~1% of the population,11 Endothelial dysfunction has been shown to occur before the onset of CVD, making it a potential screening tool13 and it continues to be recognized as a potential marker of cardiovascular risk.15 Vascular function has different anatomic compartments; for instance, conduit vessel function represents the macrovasculature, whereas microvascular function is a measure of smaller arteries. Microvascular function can be measured non-invasively via the increase in brachial artery velocity in response to a post-occlusive hyperemic stimulus, the velocity time integral (VTI). VTI has gained acceptance as a surrogate marker of cardiovascular risk in persons without overt CVD17 and appears to be the optimal measure of microvascular function.18 Microvascular function can also be measured using pulse arterial tonometry (PAT),19 which may be used in risk stratification of cardiovascular risk.20 On the other hand, flow-mediated dilation (FMD) of the brachial artery is the gold standard for the conduit vessel function.21The vascular endothelium is a monolayer of cells that covers the inner surface of blood vessels, and its dysfunction has been implicated in many different disorders.To date, there are no studies that assess peripheral endothelial function via VTI, FMD, and PAT in subjects with schizophrenia. The primary purpose of this study was to compare endothelial function in subjects with schizophrenia and an age-, sex-, and smoking status-matched control group. In view of the significant CVD burden in schizophrenia, we hypothesize that there is evidence of impaired endothelial function in this population, and it might help to identify individuals at particularly high risk.This study was conducted at the University of Calgary, Calgary, AB, Canada. A total of 102 individuals (51 subjects with schizophrenia and 51 controls) between 18 and 45 years of age were recruited for this study. Recruitment was performed with posters within the hospital and outpatient clinics as well as with postings on the Internet. All interested participants were screened over the telephone, and subjects with known CVD, active alcohol and/or substance use, active medical illness, and age above 45 years were excluded from participation. CVD was defined as any history of coronary artery disease, cerebrovascular disease, heart failure, cardiomyopathy, arrhythmia, valvular heart disease, and peripheral vascular disease. As this study focused on a population at risk for the aforementioned conditions, subjects were excluded if overt CVD was present. Subjects with schizophrenia had an illness duration of at least 5 years, which was obtained with patient report and chart review. These subjects were recruited from the Outpatient Schizophrenia Service at the Foothills Medical Centre in Calgary, AB, Canada, and were stabilized with treatment. The diagnosis was primarily made by chart review; however, a physician evaluated all participants with a clinical interview and examination as well. Healthy controls were not allowed to have current or past psychiatric illness or any psychotropic medication use, and they were matched for sex, age, and smoking status. This study was approved by the ethics board of the University of Calgary, and informed consent was obtained from all participants. The recruitment of all participants was conducted from February 2012 to March 2013.22. Again, we inquired about pre-existing CVD, as outlined above, and excluded participants with pre-existing conditions. For patients with schizophrenia, we also cross-referenced their charts for any pre-existing CVD. Again, we asked about drug and alcohol use at that time; however, no samples for drug screening were obtained in this study. We obtained a history about the current antipsychotic medication use  from the participants and by chart review, as well as other medications and supplements. The short form of the International Questionnaire for Physical Activity was previously validated in schizophrenia and was used to quantify the amount of physical activity in both the control and study groups, indicated as metabolic equivalent of task (MET) minutes per week.24All participants underwent a baseline assessment including a detailed psychiatric and medical history. Demographics included age, sex, ethnicity, duration of illness, and age of onset of schizophrenia, which was validated by chart review in patients with schizophrenia. We used a well-established and validated protocol for the evaluation of cardiac risk factors  and other medical conditions 25A physical examination followed, including heart rate, blood pressure, weight, height, body mass index, and waist circumference and hip circumference. A resting electrocardiogram as well as fasting blood work -cholesterol, and HDL-cholesterol) were obtained for all subjects. Glucose and insulin levels were used to calculate homeostatic model assessment-insulin resistance (HOMA-IR). The presence of metabolic syndrome was defined according to the US National Cholesterol Education Program Adult Treatment Panel III guidelines.26 The assessment of the endothelial function followed a standardized protocol in a temperature- and noise-controlled environment by a single trained sonographer.28 The participants were asked to lie on a stretcher and the EndoPAT-probes  were placed on each index finger to measure PAT. The brachial artery was imaged just above the antecubital fossa using a 12-MHz linear phase-arrayed ultrasound transducer and an iE33 ultrasound machine . We measured the PAT and the baseline diameter of the brachial artery and velocity of blood flow via ultrasound. We then assessed the endothelium-dependent FMD. A blood pressure cuff was placed on the right forearm and was inflated to 50 mm Hg above systolic blood pressure for 5 min. Immediately after cuff release we recorded hyperemic velocity with Doppler, and VTI was calculated by tracing the area under the curve (AUC) of the first beat after the release of the cuff. Arterial diameter was sampled at 39 frames/s for 2 min immediately after the Doppler was obtained to determine maximum hyperemic diameter. Analysis of the brachial artery ultrasound images was performed using an automatic edge-detection software . The protocols used for calculation of FMD, VTI and PAT are described elsewhere.29 In short, FMD is calculated as follows: (hyperemic diameter−baseline diameter)/baseline diameter×100%. PAT is calculated using an algorithm that is incorporated in the software. The value is normalized to the control arm and other hemodynamic parameters. During the evaluation of all endothelial markers, the subjects’ arms did not move after a comfortable position was found. Only minimal manipulation occurred while adjusting the ultrasound probe above the antecubital fossa, and there was no movement of the shoulder, elbow, wrist, and fingers.Subjects refrained from eating, smoking, and caffeine ingestion for a minimum of 4 h. We did not measure nicotine or caffeine withdrawal specifically, but we asked the participants about any physical or emotional complaints at the time of study. All vasoactive medications were held for at least 12 h before the scan and blood draw.t-test for parametric data, Mann–Whitney U-test for nonparametric data, and the χ2-test for categorical data. Univariate correlations between parametric data were calculated with Pearson’s product–moment correlation; Spearman’s rank correlation was used for nonparametric and categorical data. Pearson’s partial correlations were used to account for possible confounding factors of the vascular parameters, and to build a backward multiple linear regression model to assess the effects of other cardiovascular risk factors on the measures of endothelial function. The following independent variables were used in the model: diagnosis of schizophrenia, age, sex, ethnicity, family history of CVDe, smoking status, systolic blood pressure, waist circumference, HDL-cholesterol, LDL-cholesterol, triglycerides, C-reactive protein, HOMA-IR, lipid-lowering medication use, antihypertensive medication use, antidiabetic medication use, antidepressant medication use, mood stabilizers, benzodiazepines, and anticholinergic medication use. These variables were selected on the basis of known cardiovascular risk factors, emerging risk factors,31 and significant findings from the univariate and partial correlation analyses. In order to avoid overfitting, colinear measures  were not used.32. A two-sided P value of less than 0.05 was considered to be significant. IBM SPSS Version 19  was used for statistical analysis.Variables that are normally distributed are presented as mean±s.d., whereas the median (25th percentile and 75th percentile) was used for non-normally distributed variables . Comparisons between the two groups were conducted using Student’s The baseline characteristics of the two study groups (subjects with schizophrenia and controls) were similar across a variety of demographic and clinical characteristics see . Six inin=30 in each group) and ranged in age between 19 and 46 years . The mean age for each group was not significantly different (P=0.442). The mean duration of schizophrenia was 13.5 years in the study group. Smoking status did not differ between the two study groups (P=0.842), but pack years of smoking were different (P<0.001). In terms of other cardiovascular risk factors we did not find a difference for hypertension, diabetes , or family history of CVD. However, the mean body mass index and waist circumference were significantly higher in the schizophrenia group (both P<0.001) as well as the frequency of dyslipidemia (P=0.014).Participants were 59% male . The effect size for the group difference is d=0.72. The other two primary vascular end points, FMD and PAT, were not significantly different between the two groups.Vascular parameters were different in the schizophrenia and control groups, which can also be seen in R=−0.331, P<0.001), but not with FMD  and PAT . Correlations between the three vascular markers VTI, FMD, and PAT were not significant. VTI was correlated with waist circumference , HDL-cholesterol , and antihypertensive medication use , but not with the other demographic or cardiovascular factors, including the presence of metabolic syndrome, or other cardiac risk-modifying medications. It was also not correlated with specific antipsychotic medications (including duration and mean dose) or other psychotropic medications. The correlation between VTI and antipsychotic medication use did not provide additional information, as all patients with schizophrenia, but none of the control subjects, were taking antipsychotic medications; this was already established with the correlation between a diagnosis of schizophrenia and VTI.In a univariate correlation analysis, we only noted a significant association of a diagnosis of schizophrenia with VTI . All data from univariate and partial correlations are available in Partial correlations between VTI and a diagnosis of schizophrenia accounting for age, gender, ethnicity, family history of CVD, smoking status (pack years of smoking yielded no different results), systolic blood pressure (diastolic blood pressure yielded no different results), waist circumference, HDL-cholesterol, LDL-cholesterol, triglycerides, C-reactive protein, HOMA-IR, antihypertensive medication use, antidiabetic medication use, lipid-lowering medication use, antidepressant medication use, mood stabilizers, benzodiazepines, and anticholinergic medication use led to significant results for all factors independently. A combined analysis that included all possible confounders was still significant (R2=0.248).Endothelial function is a well-established predictor of cardiovascular risk. This study assessed the association between a diagnosis of schizophrenia and a comprehensive set of measures of endothelial function in subjects under the age of 45. Our results indicate that patients with schizophrenia have evidence of microvascular dysfunction on the basis of lower VTI. This association remained significant even after adjusting for other clinical risk factors for CVD. Subjects with schizophrenia and healthy controls were under the age of 45, and were well matched for demographic factors and smoking status. The significant difference in VTI may represent an early surrogate marker for the increased risk for CVD in schizophrenia, and it might be helpful in identifying high-risk individuals. It may also provide more insight into the underlying mechanisms.17 VTI measures an increase in blood flow following a period of ischemia that is mediated by the local reduction in vascular resistance in the blood vessels. VTI can be seen as an integrated measure of microvascular function, anatomically as well as functionally. It is only partially nitric oxide (NO)-dependent, instead of relying on a number of other mediators that are more relevant to the microcirculation. The increase in blood flow, as seen in VTI, causes a higher shear stress in the brachial artery, which subsequently leads to a NO-dependent vasodilation.33 Local release of NO by the endothelium drives the dilation of the conduit arteries, and this response is seen ~30 s after cuff release and is mainly dependent on shear stress.34 In schizophrenia, there is also evidence of altered NO metabolism in the brain 35 and small studies showed an improvement in psychiatric symptoms by infusion of sodium nitroprusside, an exogenous NO donor.36 The exact mechanism how NO is implicated in schizophrenia is still under debate; however, exogenous NO seems to improve N-methyl-D-aspartate receptor hypofunction.36There may be several explanations for these findings. Endothelial function is generally divided into microvascular function, measured with VTI and PAT, and macrovascular function, which can be quantified with FMD. VTI is a global marker of microvascular function, in part related to the vascular endothelium. Increasing evidence shows that microvascular dysfunction precedes macrovascular changes.37 Martin et al. observed a weak relationship between PAT and VTI in a population with diagnosed CVD. In this study we focused on a much younger population without a history of CVD. Changes in endothelial function, as indicated by lower PAT indices may not yet be evident in our study population. Our findings of microvascular endothelial dysfunction, indicated by the lower VTI, may represent a very early disease state in high-risk individuals. An older study population with more pronounced changes in endothelial function might show additional differences in PAT and FMD. Macrovascular endothelial dysfunction is characterized by a diminished vasodilatory response of the brachial artery, and this occurs predominantly in later stages of arteriosclerosis.16 Again, the young age of our study population and the lack of manifest CVD may explain the lack of changes in macrovascular endothelial function.PAT is another marker of microvascular function, for which studies noticed concordant changes with VTI.We performed a linear regression model, which showed only schizophrenia, sex, lipid-lowering medication use, antihypertensive medication use, and LDL-cholesterol as predictors of VTI. We did not find an association with the other demographic factors, laboratory markers, and psychotropic medication use, even though some of these factors differed between the control and schizophrenia group as well as there being significant univariate correlation of VTI with waist circumference and HDL-cholesterol. These results suggest that a diagnosis of schizophrenia is a predictor of VTI along with other demographic or clinical factors.38, with drug-naive patients showing signs of abnormal glucose metabolism;39 however, there is also evidence that unmedicated patients have similar rates of metabolic syndrome compared with the general population.41 As all patients were medicated with antipsychotics, it is difficult to distinguish the effects of schizophrenia itself from the effects of the medication. There is a myriad of literature on the metabolic effects of antipsychotics,42 and there is also some lines of evidence that certain antipsychotic medications impair endothelial function in animal models.43 Currently available antipsychotics can adversely affect physical health, as they are associated with an increased incidence of cardiovascular risk factors. Antipsychotics seem to have different pathways of increasing cardiovascular mortality. On the one hand, vascular disease burden is mediated through long-term effects of all major risk factors for atherosclerosis, including dyslipidemia and diabetes.45 Treatment with antipsychotics carries the risk of potentiating the baseline cardiometabolic risk,46 even in early stages of psychotic disorders.47 We indeed noted differences in the metabolic profiles of patients with schizophrenia. Glucose metabolism was impaired, indicated by higher fasting glucose levels, hemoglobin A1c, insulin levels as well as HOMA-IR values, which is an indicator for basal insulin resistance.48 There is evidence that insulin as well as insulin resistance can cause endothelial dysfunction. A study from 2002 found that insulin itself impaired endothelial function, indicated by lower FMD.49 There was a difference in frequency of metabolic syndrome between the schizophrenia and control group. The frequency of metabolic syndrome in the schizophrenia group was 29.4%, which is in the same range as findings from other studies.41 Metabolic syndrome is known to impair mircovascular function, indicated by attenuated VTI.33There is evidence that schizophrenia can be a risk factor for insulin resistance and diabetes mellitus51 or applied retinal vasculature assessment.52 Although both groups were matched for age, sex, and smoking status, we still observed differences in other demographic and clinical parameters. All 51 subjects with schizophrenia in this study were taking antipsychotics at the time of the study, which we could not control for. As there is little literature on the effects of antipsychotic medications on endothelial microvascular dysfunction, it cannot be excluded that this may represent a significant confounding factor. However, analysis of individual antipsychotic medications, including the mean dose and duration, did not identify a particular antipsychotic that is associated with lower VTI value. We relied on patient reports and chart reviews for medication data, and this might explain the possible heterogeneity of the obtained data. Although matching for age, gender, and smoking status occurred, we still found a significant difference in waist circumference and body mass index. There was a significant univariate correlation between VTI and waist circumference, HDL-cholesterol, and antihypertensive medication use; however, the connection between a diagnosis of schizophrenia and VTI in partial correlations and multivariable analysis remained significant. Still, obesity (as indicated by higher waist circumferences) and low HDL-cholesterol could be a link between antipsychotic use and impaired endothelial function. Therefore, future longitudinal studies with drug-naive subjects may help to disambiguate the effect of schizophrenia itself and drug effects, and if endothelial function changes over time in course of illness and with drug therapy. Furthermore, prospective studies are needed to establish whether impaired endothelial function increases risk for CVD in schizophrenia later in life. Participants in this study were no older than 45 years. This age limit was chosen to examine a population at risk for CVD, but with no overt manifestations. However, this cutoff might limit the generalizability of the results to different age groups.Our study provides a comprehensive assessment of macro- and microvascular endothelial functions via VTI, PAT, and FMD in subjects with schizophrenia and matched healthy controls to the age of 45. Our findings are consistent with other studies that have found a attenuation of microvascular endothelial function; however, these studies used Laser-Doppler flowmetry, which measures blood flow in the superficial dermal plexus16 As VTI is an easy and reliable marker of vascular function, it may be a useful marker of cardiovascular risk. Whereas VTI has shown to offer prognostic information in certain populations without mental illness,16 it needs to be evaluated in prospective studies in psychiatric populations. It must also be determined whether therapeutic interventions on the basis of changes in vascular function will be beneficial. Our findings may help to identify subjects at high risk for cardiovascular complications. A recent study from Sweden shows that subjects with schizophrenia were less likely to be diagnosed with CVD before fatal cardiovascular events.7The present study elicited novel information on the vascular function in patients with schizophrenia. VTI, a simple measure of microvascular function, was significantly lower in this population with a fairly large difference in effect size. There is increasing literature that supports that VTI is a useful surrogate marker in cardiovascular risk assessment and it helps to classify individual risk.54 and schizophrenia being a systemic disorder, affecting multiple organs and systems.56 The difference in VTI may be an early indication of their cardiovascular risk. Mental illness has a significant burden on the somatic health of individuals and we need to better understand the interface of mental and physical health.This study shows that peripheral microvascular dysfunction is present in patients with schizophrenia under the age of 45. The two cohorts of subjects with schizophrenia and healthy controls were similar in many demographic characteristics. This study adds to the increasing body of evidence of abnormal vasculature in schizophrenia


Methods: Dual-energy scans in monochromatic spectral imaging mode were performed on a peripheral arterial phantom with use of three gemstone spectral imaging (GSI) protocols, three pitch values, and four kiloelectron volts (keV) ranges. A total of 15 stents of different sizes, materials, and designs were deployed in the phantom. Image noise, the signal-to-noise ratio (SNR), different levels of adaptive statistical iterative reconstruction (ASIR), and the four levels of monochromatic energy for DECT imaging of peripheral arterial stents were measured and compared to determine the optimal protocols. Results: A total of 36 scans with 180 datasets were reconstructed from a combination of different protocols. There was a significant reduction of image noise with a higher SNR from monochromatic energy images between 65 and 70 keV in all investigated preset GSI protocols (p < 0.05). In addition, significant effects were found from the main effect analysis for these factors: GSI, pitch, and keV (p = 0.001). In contrast, there was significant interaction on the unstented area between GSI and ASIR (p = 0.015) and a very high significant difference between keV and ASIR (p < 0.001). A radiation dose reduction of 50% was achieved. Conclusions: The optimal scanning protocol and energy level in the phantom study were GSI-48, pitch value 0.984, and 65 keV, which resulted in lower image noise and a lower radiation dose, but with acceptable diagnostic images.Objective: To identify the optimal dual-energy computed tomography (DECT) scanning protocol for peripheral arterial stents while achieving a low radiation dose, while still maintaining diagnostic image quality, as determined by an  The increasing prevalence of peripheral artery disease (PAD) is an important cardiovascular disease risk factor ,2,3. SteThe latest MDCT systems, such as dual-source computed tomography (DSCT) and dual-energy computed tomography (DECT), are capable of addressing these weaknesses . In partin vitro phantom study.Most of the previous studies on DECT were performed on dual-source DECT, which uses two X-ray tubes ,17,18,19p < 0.05). A significant reduction was observed at 65 keV for the unstented area, and for large diameter stents and small diameter stents with both GSI-48 and GSI-51. However, the mean HU was reduced as the keV increased for all protocols, as shown in A total of 180 series acquired with virtual MEI imaging at 4-kiloelectron volts (keV) and 5-adaptive statistical iterative reconstruction (ASIR) levels were reconstructed to determine the interaction between peripheral arterial stent image quality factors and scanning protocols. There was a significant reduction of image noise with MEI between 65 and 70 keV in all investigated preset GSI protocols (p = 0.001). Similar findings were observed in the unstented area with highly significant effects. In addition, significant effects were found for these factors—GSI, pitch, and keV (p = 0.001). In contrast, there was another significant interaction on the unstented area between GSI and ASIR (p = 0.015) and a very highly significant difference between keV and ASIR (p < 0.001). Although for noise level, two of the 3-way interactive terms were statistically significant, namely the GSI, pitch, and keV, and the GSI, pitch, and ASIR (p < 0.001); the main effects and interactions for these are shown in The phantom data were analyzed with a 3-GSI * 3-Pitch * 4-keV factorial ANOVA. Each effect was tested with a mean standard error (MSE) of 71.27. There was highly significant interaction of image noise and SNR with the GSI and pitch (p = 0.001). There was no significant interaction between keV and GSI or pitch factors in the stented area. However, this does not mean that there was no effect of keV on image quality, but the effect of keV on image noise was not dependent on GSI or pitch. Therefore, the four noise-level means for keV ranged from 83.94 to 64.30 HU and, incidentally, decreasing image noise occurred monotonically with increasing keV. Thus, the effect of keV on image noise was independent of any other design effect. A similar effect was observed with the SNR. Unlike its effect on the unstented area, the effect of keV was found to be highly significant for both image noise and SNR (p < 0.001). A significance interaction was observed on the unstented area. Also, the main effects of GSI and pitch on noise level are highly significant (p < 0.001), as shown in The interaction of GSI by pitch is highly statistically significant , significant changes were observed. These changes varied both with respect to magnitude and direction, and presented as the significant interaction of GSI by pitch.The noise level in the unstented area showed a direct relationship between image noise and pitch value, with noise increasing when pitch increased. However, with large stents, lower image noise was found in GSI-36 and GSI-48 protocols, with a pitch value of 0.984. The medium sized stent showed that a lower noise was achieved by a GSI-48 and pitch of 0.984, while result is different from that for the small stents where the best visualization was achieved with use of GSI-51 and pitch of 0.516, as shown in A radiation dose reduction of about 50% was achieved in all protocols when the pitch value 0.984 was used. However, a minimal reduction was observed when the pitch value was changed from 0.984 to 1.375.The subjective grading of image quality showed a discrepancy between the readers with a kappa value of 0.24. This might be explained by the limited experience of those readers in clinical research. The box plots of the noise level for the three radiologists are shown in vice versa. The lowest radiation dose with sufficient image noise was obtained with the GSI-48 protocol with a pitch of 0.984 and 65 keV. Overall, the GSI-51 protocol achieved the highest SNR and lowest noise level values with pitch values of 0.516 and 1.375; however, a pitch value of 0.516 was associated with the highest radiation dose, whereas a pitch value of 1.375 was associated with the highest image noise. To our knowledge, no studies have been published comparing different DECT protocols with different pitch values. Results of this study show that the effect of the pitch value on image noise was strongly dependent on rotation time, as the protocol with the shorter rotation time (GSI-36) achieved both the highest SNR and the lowest image noise, and the protocol with the longer rotation time (GSI-51) achieved the highest image noise, even when mAs was higher than that of the other protocols. This phantom study indicates that the effect of the pitch factor on the keV and radiation dose is an important indicator for determining both radiation dose and image quality, as the lowest pitch is associated with the highest radiation dose and et al [et al [et al. [et al [et al. [It was found that the images acquired with approximately 65–70 keV had less image noise and higher SNR compared to other energies that have a lower noise level and lower SNR. Our results are similar to those reported from a chest study by Cheng et al  who founl [et al , who stul [et al . Similar [et al.  reported. [et al  compared [et al. . They foWhen iterative reconstruction is evaluated there is a significant difference between the unstented and stented areas. In the unstented area, the image quality was improved when the ASIR was increased from 40% to 50%. This is similar to previous studies that showed that an ASIR of less than 40% did not improve the image quality when compared with conventional PEIs ,24,25,26The optimal protocol that has been evaluated and identified in this study is currently being tested in a clinical study to validate its clinical value and outcome. Despite these protocols being tested on a GE scanner, results of this study can be applicable to other MDCT manufacturers as long as the dual-energy function is available on these scanners.Our study has some limitations. First, although the experimental setup was developed to simulate a peripheral vascular tree, the idealized anatomic environment did not have surrounding organs, vessel walls, or tissues. The nature of body vessels varies from those in the phantom, and this could affect visualization of stents to some extent. Another limitation is that this custom-made phantom represented only an average-sized adult, while absorption of low-energy radiation will differ for large- or small-sized patients. Finally, the default manufacturer’s setting of 0.3 as the weighting factor for the low-energy tube was used to create virtual 120 KV reconstructions; however, there have been reports that a weighting factor of 0.5 improves image quality and therefore would be better for vascular imaging . This suThe custom-made peripheral arterial phantom consisting of a main peripheral arterial tree and arterial branches was developed with use of a computer-aided design program to represent realistic anatomic dimensions. The phantom was made of poly methyl methacrylate material with anatomical dimensions similar to the normal anatomy of a peripheral arterial tree, as shown in A total of 15 expired stents with different sizes (diameters), materials, and designs were used in the experiments. Details of the stents are shown in vol with acceptable diagnostic image quality to evaluate peripheral arterial stents. These GSI preset protocols have been fixed by the manufacturer to maintain constant tube power when switching the tube voltage back and forth. Therefore, changing the radiation dose in these preset protocols was only possible by adjusting the pitch and/or rotation time. As a result, the three available pitch values, 0.516, 0.984, and 1.375 were tested, with a beam collimation of 40 mm in all of these protocols and fixed rotation times of 0.5, 0.7, and 0.8 second per rotation, respectively, for each protocol. The phantom was then positioned in the gantry in an orientation parallel to the z-axis of the scanner.DECT scans were performed with a fast kilovoltage-switching 64-slice CT scanner . Of the GSI-protocols that the manufacturer has developed as default settings, 3 GSI protocols  were selected for this study based on the lowest CTDIThe scanning parameters for the selected preset GIS-protocols are summarized in A simulated intravenous contrast medium  was used to represent the actual contrast-enhanced CT angiography. The contrast medium was diluted with normal saline to reach the attenuation of 250 Hounsfield unit (HU), which is the acceptable CT attenuation in peripheral CT angiography. The contrast medium was injected into the simulated arteries, which were sealed at both ends .Quantitative measurements were performed for DECT images at 1 mm slice thickness on a separate independent workstation with the GSI Viewer . The mean HU was obtained by placing a circular region of interest (ROI) in selected areas of the phantom for the 15 stents . Two ROIs were selected; the first one was placed in the common femoral artery to measure the noise on an unstented area of the phantom. The second ROI was placed in the stented lumen area on the axial images to measure the noise for all stents without inclusion of stent struts, as shown in The selected ROI in an unstented area was in the femoral artery and within each stent at the same location for all protocols to measure the mean CT attenuation and also image noise that was defined as the standard deviation (SD). Moreover, the signal-to-noise ratio (SNR) for both the stented and unstented areas was calculated with the following formula:Three radiologists with 5, 15, and 20 years of experience in CT imaging, respectively, performed qualitative evaluation on the GSI viewer with identical window width, window level, and FOV. Different MEI series from the each GSI protocol were evaluated randomly , with a total of 180 series reviewed by each reviewer. The readers were blinded to all scanning parameters, except for the different energies, because different values of keV could easily be determined by visual inspection of the images. Intraobserver variability was not estimated because each radiologist assessed the images only once. Visualization of the stent lumen was assessed using a 3-point scale .A fixed scan length of 29.9 cm was used for all examinations. The volume CT dose index (CTDIvol) and dose-length products (DLP) were recorded for calculation of effective dose, as shown in All of the data were entered into SPSS Statistics version 22.0  for statistical analysis. Two data sets—the noise level and SNR (independent variable) responses obtained when ASIR = 0—were used to produce 36 observations in a 3-factor factorial analysis of variance (univariate ANOVA) model: GSI , pitch , and keV .p values obtained in the F-tests corresponding to the main effect of GSI as well as to the interaction effect of pitch, keV, and ASIR. All tests were performed at the 5% significance level.The second part of the statistical analysis relates to the noise level and SNR in the nonstented area when ASIR ≥ 40; 3-levels: 40, 50, 60 were used to produce 108 observations in a 4-factor factorial model. The highest order interaction in each analysis was employed as an estimate of residual (error) variation; therefore, when there was no significant interaction, the main effect was considered. Statistical significance was assessed by comparing the In conclusion, all preset GSI protocols were found to be suitable for the evaluation of peripheral arterial stents. This study recommends use of the faster rotation time with a pitch value of 0.984 and keV of 65–70 with 50% ASIR for peripheral arterial stent visualization with DECT, as this protocol results in both lower image noise and radiation dose, but with acceptable diagnostic images.


Alagille syndrome is a multisystem disorder, which is characterized by hypoplasia of the intrahepatic bile ducts, malformations of the cardiovascular system, eyes, and vertebral column, and abnormal facies. Several of the characteristics of Alagille syndrome may result in an especially high risk of fracture. The majority of patients suffer from chronic cholestasis, which can have a variety of adverse effects on bone metabolism. In Alagille syndrome, fractures primarily occur in the lower limb long bones in the absence of significant trauma.A 9-year-old Japanese girl with Alagille syndrome was admitted to our institution with marked hyperbilirubinemia and a pathological fracture of the femur. She had been diagnosed with biliary atresia at the age of 1 month and treated with surgical bile duct reconstruction, vitamins D and K, and ursodeoxycholic acid. However, her liver dysfunction and hyperbilirubinemia worsened. The pathological fracture of the femur was treated with low-intensity pulsed ultrasound stimulation (LIPUS) and an Ilizarov ring fixator. Seventy-four days after surgery, the patient had anatomically and functionally recovered. There was no leg-length discrepancy and no angular malalignment of the lower extremities as measured clinically and radiographically. The range of motion of the hip, knee, and ankle of the patient’s operative leg matched the range of motion in the nonoperative leg.To the best of our knowledge, there are no reports on use of the Ilizarov frame and LIPUS in diaphyseal femoral fractures in Alagille syndrome. This case report provides evidence that this procedure is successful for managing such diaphyseal fractures in Alagille syndrome. JAGGED1 gene in the overwhelming majority of cases, and by mutations in the NOTCH2 gene in 1–2% of cases [Alagille syndrome is a multisystem disorder, which is characterized by hypoplasia of the intrahepatic bile ducts, malformations of the cardiovascular system, eyes, and vertebral column, and abnormal facies . Major cof cases . A genetSeveral of the characteristics of Alagille syndrome may result in patients having an especially high risk of fracture. The majority of patients suffer from chronic cholestasis , which c2. There was no need for additional external immobilization. Physical therapy involving walking with weight-bearing on the operated leg was started immediately after surgery. The patient could walk without any support 1 week later. The hospital stay was 14 days. The patient was well after being discharged from hospital and enjoying school life with the frame. Use of LIPUS was continued, and the patient was allowed to walk without crutches. Radiographs showed healing of the fracture at 53 days postoperatively , application of skeletal traction with a heavy weight was difficult. On examination, she was malnourished with stunted growth . She had most of the features of Alagille syndrome, including a characteristic face, mild peripheral pulmonary artery stenosis, butterfly vertebrae, posterior embryotoxon, and hyperbilirubinemia. Blood tests revealed anemia  and liver dysfunction with high serum aspartate transaminase (186 U), alanine aminotransferase 253 U), gamma-glutamyl-transpeptidase 1445 IU/L), serum total cholesterol (23.5 mmol/L), and serum alkaline phosphatase (3546 U) levels, as well as hyperbilirubinemia (218.9 μmol/L). Radiographs showed a left femoral shaft fracture (Orthopaedic Trauma Association classification: 32–A3.2)  days . FollowiThis case report provides satisfactory evidence that LIPUS and an Ilizarov ring fixator are successful for managing diaphyseal fractures in Alagille syndrome. Some reports have described that although internal fixation is better tolerated by patients with lower morbidity and better  mobility, it is associated with some complications, such as delayed weight-bearing, implant failure, need for further surgery, and less mobility in the knee and ankle. Although technically demanding, the procedure reported here is a reliable and efficient method of treating simple femoral shaft fractures in Alagille syndrome because it resulted in adequate healing time, immediate ambulation and weight-bearing, excellent ankle and knee motion, and no complications. Based on the final clinical and radiographic outcomes, this technique proved to be adequate for managing a simple diaphyseal femoral fracture in Alagille syndrome. LIPUS treatment is an effective, non-invasive adjuvant method to enhance callus maturation in fracture healing. Using this treatment, the healing time and duration of external fixation can be reliably shortened.Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.The authors declare that they have no competing interests.KN performed the surgery. YS helped with surgery and helped to draft the manuscript. SY assisted with surgery. YK, NM, and AN helped draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/15/225/prepub


Drosophila melanogaster. We monitored the grooming responses of decapitated flies to compounds known to activate the immune system, e.g., dead Escherichia coli (Ec) and lipopolysaccharides (LPS), and to tastants such as quinine, sucrose, and salt. LPS, quinine, and Ec were quite effective in triggering grooming movements when touching the distal border of the wings and the legs, while sucrose had no effect. Contact chemoreceptors are necessary and sufficient to elicit such responses, as grooming could not be elicited by LPS in poxn mutants deprived of external taste sensilla, and as grooming was elicited by light when a channel rhodopsin receptor was expressed in bitter-sensitive cells expressing Gr33a. Contact chemoreceptors distributed along the distal border of the wings respond to these tastants by an increased spiking activity, in response to quinine, Ec, LPS, sucrose, and KCl. These results demonstrate for the first time that bacterial compounds trigger grooming activities in D. melanogaster, and indicate that contact chemoreceptors located on the wings participate in the detection of such chemicals.In social insects, grooming is considered as a behavioral defense against pathogen and parasite infections since it contributes to remove microbes from their cuticle. However, stimuli which trigger this behavior are not well characterized yet. We examined if activating contact chemoreceptive sensilla could trigger grooming activities in  Insects, especially Diptera, devote a considerable amount of time to self-grooming. Grooming involves brushing the body and the wings with the legs, and cleaning the legs and the antenna with the mouthparts. In cockroaches, grooming helps cleaning external chemosensory receptors  and lipopolysaccharides (LPS), and with non-volatile chemicals known to be either aversive (quinine), appetitive (sucrose) or both depending on the concentration (NaCl and KCl)  flies. Flies devoid of external taste sensilla were Poxn70/Cyo; MKRS, Sb/TM6B, Tb (Poxn70).Gr33a-Gal4 construction (generously given by J. Carlson) with flies carrying UAS-channel rhodopsin (UAS-CHR2) . Since the balancer chromosome of this construction carried the defect curly (CyO), we could select in the progeny individuals which did not express the construction  and others (siblings) which expressed the phenotype. For Gr33a, the genotype was Gr33a-Gal4[1] /CyO; Dr/TM3, Sb, Ser × UAS-H134R-CHR2, where the siblings expressed the curly wing phenotype and the mutants had normal wings. During development, the larvae were fed on normal medium added with 1 mM trans-retinal . This suspension was subsequently diluted 100, 102, 104, and 106 fold.The TOP 10 strain of Escherichia coli 0111:B4, Sigma), sucrose, quinine, NaCl, and KCl were provided by Sigma-Aldrich and dissolved in distilled water.LPS . 4-day old flies were used for all tests.For optogenetic experiments, flies were exposed to a continuous pulse of blue light for 3 min, over the whole body. Headless flies were placed on a filter paper as usual, but the experiment was conducted in a dark condition. The intensity of the grooming response was scaled from 0 to 5  placed over the abdomen. Recordings were performed on the wing part near LV2 . Taste bristles of the wing margin  were stimulated by covering their tip with a glass electrode containing an electrolyte (1 mM KCl) and the stimulus during 2 s. To avoid adaptation, consecutive stimulations were applied at least 2 min apart. The stimulus tested were E. coli, LPS, sucrose, quinine, and NaCl at the same concentrations as in the grooming tests (see above). As a control, we used increasing concentrations of KCl . Recordings were performed on 10 females and 10 males for each stimulus category.Flies (4-day old) were secured to a support with tape and electrically grounded via a silver electrode contacting a drop of electrocardiogram gel   was applied. For the analysis of fly visits, in the 2-choices assay, a Dunnett test was applied. Optogenetic induction of grooming Decapitated flies are capable of self-grooming movements following a stimulation. In order to induce this behavior, we gently brushed their wing margin or one of their leg with the tip of a toothpick. Flies which never exhibited grooming in response to stimulation with a toothpick dipped into a chemical stimulus never showed grooming after stimulation with water alone. These movements mostly involved the meta-thoracic legs which were raised and moved independently in a succession of strokes, brushing the wings, the abdomen and the dorsum or which were extended under the abdomen and touched each other in a series of reciprocal sliding movements  and LPS induced grooming responses in 4-day old adults , the front legs (p < 0.001), and the hind legs (p < 0.001). Responses to LPS were obtained from the wings (p < 0.001) but not from the legs .Dead s Figure . Responsp = 0.692) did not trigger any grooming response at any concentration tested . Quinine elicited a more intense grooming response than NaCl, and also triggered a dose-dependent response of the frontlegs (p = 0.002) but not of the hindlegs (p = 0.696). NaCl was not effective as quinine, but it induced a dose-dependent response from the hindleg (p = 0.008). The other tastants did not trigger responses when brought in contact with the legs (p > 0.1). There were no obvious differences between genders , a bitter (quinine), and a salty one (NaCl). As in the previous experiments, water did not induce grooming responses. Also, sucrose  or of the legs  and females (p = 0.044) in the absence of any chemosensory stimulus. We found a sexual dimorphism in the flies carrying the construction as photoactivation induced more grooming in males than in females . With LPS, flies avoided walking on side treated with LPS  , to the concentration (p < 0.001), to sex (p < 0.001), and according to the sensillum position in the row . However, we did not find any difference between dorsal and ventral sensilla . These observations confirm that wing contact chemoreceptive sensilla are functional, that they respond to classical taste stimuli. These sensilla show dose-dependent responses to LPS and E. coli suspensions. They also respond in a dose-dependent way to NaCl, to KCl, to quinine, but apparently not to sugar.We thus counted the total number of spikes occurring within the first 2 s of the stimulation Figure . When anp < 0.001 for all chemicals except KCl, p = 0.002 in males and p < 0.001 in females and NaCl, p = 0.254 in males and p = 0.420 in females, analysis of covariance). However, with sucrose, the initial burst peaked at 30–35 spikes/s which may indicate that 1 mM sucrose already elicits a response. As the concentration of each stimulus increased, the firing rate globally increased. For salts, it was mostly the tonic part of the response which was affected, while with quinine, E. coli and LPS both the phasic and tonic parts of the responses increased with the dose tested. On the contrary, the spiking activities were markedly depressed in both sexes when the concentration of sucrose was raised from 1 mM to 1 M.We further analyzed the temporal course of the responses by computing the number of spikes occurring during consecutive 100 ms bins Figures , S2. At D. melanogaster adults are triggered by bacterial suspensions of E. coli, its surface compound, LPS, and by aversive chemicals like quinine and NaCl at a high concentration. Mechanosensation is not required to elicit this response as sucrose and water did not induce grooming, and Poxn70 mutants deprived of their external taste receptors were insensitive to LPS. Furthermore, grooming activities could be elicited without physical contact with a substrate by optogenetic activation of cells expressing the bitter receptor Gr33a. Since our behavioral observations indicated that grooming reactions were elicited by stimulating the costal outer vein of the wings, we examined the contact chemoreceptors located there using tip-recording. These sensilla were found to house contact chemoreceptive neurons increasing their firing activity in response bacterial extracts, LPS, quinine, and to high salt concentrations thus supporting the hypothesis that these wing contact chemoreceptors contribute to triggering grooming responses in decapitated flies.We demonstrate for the first time that grooming activities in In this work, we recorded grooming by scoring the intensity of the behavior in relation to the number of strokes made by the legs and by the duration of this reaction. A more detailed analysis of this behavior was not relevant here as we focused on finding chemical stimuli which could trigger this behavior. In order to simplify the experimental procedures, we also observed the reactions of decapitated insects. In such insects, the responses induced bypass the downstream control normally exerted by higher order nervous centers in intact animals. Our observations are thus by no mean representative of the normal grooming behavior but they give us a good indication of the strength of the sensory stimuli sent to the local ganglia.While self-grooming has been described to occur in response to touch  to drive the expression of a calcium-sensitive probe, G-cAMP (Nakai et al., Gr family, thus confirming that contact chemoreceptive sensilla of the wings of Drosophila are fully functional and respond at least to some sapid molecules detected by contact chemoreceptors located on the legs and on the proboscis.Raad  introducIn our tests, sucrose is the only stimulus which did not elicit grooming in our panel of stimuli. The electrophysiological responses obtained from wing taste sensilla did not show any increase of the firing activity with the dose, but on the contrary revealed an inhibition of the basal firing activity. This observation is consistent with recent results obtained by Raad  on fly wD. melanogaster. Our study shows that LPS induces vigorous grooming activities from flies and also elicits consistent spiking activities in contact chemoreceptors of the wing. LPS has been used repeatedly in multiple organisms as an inducer of the immune system. LPS and bacterial peptidoglycans are strong inducers of the immune system in Drosophila (Charroux et al., So far, our findings support that contact chemicals play a decisive role in triggering hygiene grooming in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


With the global economic crisis and industrial restructuring, the unemployed are suffering from job loss-related stress and loss of income, which is believed to impair their mental and physical health, while coping and self-efficacy could combat the adverse effects of unemployment on health. Thus, this study aims to describe quality of life (QOL) among unemployed Chinese people and explore the associated factors. A cross-sectional study was conducted by convenience sampling, composed of 1825 unemployed people, from January 2011 to September 2011. Questionnaires pertaining to demographic characteristics, the 36-item Short-Form Health Survey (SF-36), the abbreviated version of the Cope Inventory (Brief COPE) and self-efficacy scales were used to collect information from unemployed people in the eastern, central, and western regions of China. Hierarchical multiple regression analysis was performed to explore the related factors of QOL. A structural equation model (SEM) was used to test the relations among coping, self-efficacy, and QOL. Mental QOL was significantly lower than physical QOL in Chinese unemployed people. Coping had significant effects on both physical component summary (PCS) and mental component summary (MCS), while self-efficacy played the mediating role in the association between Coping and QOL. Unemployed Chinese people’s mental QOL was disrupted more seriously than their physical QOL. An increase in coping could improve QOL by promoting better management of issues brought about by unemployment. In addition, self-efficacy has the ability to reduce the impact of unemployment on QOL, through the mediating path of coping on QOL. This study highlights the need of coping skills training and self-efficacy enhancement for better management of unemployment in order to improve QOL and well-being. With the global economic crisis and industrial restructuring, unemployment problem has become an important social issue in China. The 2011 annual statistical bulletin of the development of Human Resources and Social Security reported that the urban registered unemployment rate was 4.1% in 2011. The ratio between the registered unemployed and the employed was 1:13.8. When the hidden number of the unemployed people was taken into account, the ratio between the unemployed and the employed would be 1:10.1 . UnemploRecent publications indicated that the health of the unemployed was associated with household income, duration of unemployment, and the negative effects of chronic disease ,14,15. SThe transactional stress model theory proposed by Lazarus and Folkman 1984 , indicatThe transactional stress model also indicates that, appraisals of situations and coping are affected by personal resources such as perceived control, self-efficacy, personality, and social resources . Self-efA cross-sectional study was conducted from January 2011 to September 2011. The sample employed in this study consisted of 2500 unemployed individuals. Multi-stage convenience sampling was adopted in this study. During the first stage, a total of 11 provinces and one municipality in the eastern, central, and western regions of China were selected . During the second stage, two cities were randomly extracted from each province . During the third stage, the unemployed people based on the criteria of North America , by convIf the selected persons agreed to participate, they were asked to sign consent forms. All of the participants were well-informed of the contents and aim of the questionnaire. After obtaining written informed consent about the conduct of the survey, the unemployed were interviewed face-to-face by trained college students from China Medical University. The procedures followed were in accordance with, and approved by, the ethical standards of the Committee on Human Experimentation of China Medical University. All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of China Medical University (CMU1210400026).Among the 2500 unemployed individuals, 456 declined to participate, resulting in an 81.76% consent rate. Eighty-six were excluded because they dropped out of the study, and 133 were excluded because of missing values exceeding 20% in the questionnaire. The characteristics  of the remaining 1825 respondents included in the analysis were similar to those of the 542 individuals who were excluded. Of all the participants, 1825 individuals took part in and answered the questionnaire effectively, resulting in a valid response rate of 73.0%.Demographic characteristics included age , gender, marital status , educational level, household monthly income, and chronic diseases. Educational level was categorized as “≤ senior high school or below”, and “> senior high school”. Household monthly income (RMB) was classified as “≤1000 Yuan”, “1001–1500 Yuan”, “1501–2000 Yuan”, or “>2000 Yuan”. “Chronic diseases” was defined as “yes” if any common chronic disease  had ever been diagnosed. Unemployed time was categorized as “1–2 months”, “3–5 months”, “6–11 months”, and “≥12 months”.The 36-item Short-Form Health Survey (SF-36) ,34, whicCoping was evaluated by means of an abbreviated version of the Cope Inventory (Brief COPE) . The BriSelf-efficacy was measured with an adapted General Self-efficacy Scale by Song Zhaoli , which w2-value. Structural equation modeling (SEM) was also used to test the set of hypothesized relations among variables. Sobel tests were used in order to confirm the mediating role of self-efficacy in the association of coping and QOL. In the SEM model, QOL (PCS and MCS) were modeled as dependent variables, coping  as independent variables, and self-efficacy as a mediator. The indicators included the χ2/df, goodness of fit index (GFI), comparative fix index (CFI), Tucker-Lewis index (TLI), and root mean square error of approximation (RMSEA), and were used as the criteria to assess the structural model. The adequate fit of the model was evaluated by the following indicators: χ2/df < 5, GFI, CFI, TLI > 0.90, and RMSEA < 0.08. If there was a reduction in the size of direct path coefficients of coping on QOL, or a disappearance of statistical significance when the mediator was added in model, the possibility of mediation was speculated. Then, the bootstrapping strategies were used to examine the mediating roles (a × b product) of self-efficacy on the associations of coping with QOL [The comparisons of QOL in categorical variables were evaluated using t-test and one-way analysis of variance (ANOVA). Pearson’s correlation coefficient was used to determine the relationship of QOL, coping and self-efficacy. Hierarchical multiple regression (HMR) analysis was conducted to test the incremental variance of any given set of independent variables. The unemployed individuals’ QOL scores were used as dependent variables. The independent variables were entered in the following steps: Step 1: demographic characteristics; Step 2: coping; and Step 3: self-efficacy. The analysis proceeded in stages by successively inputting several blocks of independent variables in the regression model. Blocks of variables entered in later stages were, thus, tested for their extra contribution. The relative importance of the variables retained in the final multiple regression models contributed to the explained variance of the QOL, which was represented as the standardized β . Fit of with QOL . BootstrThe basic characteristics of the participants are provided in The QOL scores of this study are listed in Physical and mental QOL were significantly worse in individuals with low educational levels or who were married, and among persons with chronic diseases. Physical health was also significantly worse in women or participants with the ages of 30 and above. Respondents with a longer period of unemployment had a lower level of physical and mental health than those who had been unemployed for a shorter period. Adaptive coping and self-efficacy were significantly and positively correlated with PCS and MCS, while maladaptive coping was negatively correlated with PCS and MCS .2 change indicated that coping contributed most to the variance of MCS (17.4% of variance), while demographic characteristics contributed most to the variance of PCS (16.7% of variance). It also indicated that coping contributed second-most to the variance of PCS (11.4% of variance). Demographic characteristics, including household monthly income, chronic diseases, and unemployed time), coping , and self-efficacy were strong predictors of both PCS and MCS. Moreover, adaptive coping and self-efficacy were positively associated with QOL, while maladaptive coping was negatively associated with PCS and MCS.p < 0.01) and MCS , and significantly negative associations of maladaptive coping with PCS  and MCS  .The direct pathways of coping with QOL through self-efficacy are illustrated in  < 0.01) . This mo2/df < 5, RMSEMA = 0.063, CFI = 0.957, GFI = 0.972, AGFI = 0.946, and TLI = 0.933). Thus, coping directly affects PCS and MCS, and also influences PCS and MCS indirectly by the self-efficacy path.The mediating role of self-efficacy on the associations of coping with QOL is illustrated in The results from this study indicated that most unemployed Chinese individuals suffered from impaired QOL, which were lower than the levels of the employed Chinese population ,44,45,46In this study, demographic characteristics held the greatest importance in interpretation of physical health, accounting for 16.7% of the observed variability in PCS. Gender and age were the significant predictors of physical QOL. As for gender, females experienced slightly lower levels of physical health than males, while there was no difference in mental health between the males and females. Unemployed women may confront the loss of savings and social exclusions subsequent to job loss; as a result, they would experience a greater drive to survive. Thus, they would have to spend more time taking care of their family and undertaking a variety of domestic duties, which may result in physical health problems, and this was consistent with a previous study . The oldLow household income seemed to be also strongly and negatively associated with QOL, which was in accordance with previous studies ,53. The Chronic disease was the most significant predictor of QOL. The individuals suffering from chronic diseases along with job loss usually encountered numerous negative additional impacts on their own health, as they were probably more susceptible to the adverse effects of unemployment. The individuals who suffered from a chronic disease had a significantly higher probability to lose physical strength and other detriments of their health . In addition, individuals who had been unemployed for a longer period of time exhibited poorer physical and mental health. These findings support the link between unemployment duration and poor health . WinefieHowever, the extent of perceived QOL does not only rely on the demographic characteristics, but also considerably relies on coping. In this study, the transactional stress model theory was expanded to test the associations of coping, self-efficacy, and QOL. This model indicated that an individual’s reaction to stress could be influenced by the process of coping with an event that has been appraised as stressful, and coping are affected by personal resources, like self-efficacy, which has yielded various findings in regards to individuals’ health . As hypoThe study findings also indicated that self-efficacy mediated the effects of coping on QOL, which was in support with previous studies  that copThe present study bears the limitations that it is characterized by cross-sectional research, therefore, one cannot derive any conclusion on the causality of the associations observed between unemployment and QOL. Additionally, unemployed individuals were selected by convenience sampling, which may limit the generalizability of this study to other populations. However, despite the above limitations, this study has notable strong points. Firstly, the sample size was quite large. Secondly, unemployed individuals were selected from 23 cities in eastern, central, and western regions of China with a wide coverage of the country, which might indicate the health status of the unemployed in the whole country. Finally, there was a high response rate, most likely due to the fact that face-to-face interviews allowed for greater collection of information.Unemployed Chinese people suffered from more impaired mental QOL than physical QOL. Investment in coping could improve QOL by promoting better management of issues brought about by unemployment. In addition, self-efficacy has the ability to reduce the impact of unemployment on QOL, by mediating coping. This study highlights the need of coping for better management of unemployment in order to improve QOL, and the enhancement of self-efficacy to improve coping abilities. Specifically, we propose that human resource development strategies aim at enhancing the components of employees’ positive coping or self-efficacy to reduce their perceptions of the adverse effects of unemployment on QOL.


Aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay of therapy for the treatment of idiopathic pericarditis (IP). A comprehensive review consisting of pertinent clinical literature, pharmacokinetic, and pharmacodynamic considerations, has not been released in recent years. This review will facilitate the clinician’s understanding of pharmacotherapeutic considerations for using ASA/NSAIDs to treat IP. Data were compiled using clinical literature consisting of case reports, cohort data, retrospective and prospective studies, and manufacturer package inserts. ASA, ibuprofen, indometacin, and ketorolac relatively have the most evidence in the treatment of IP, provide symptomatic relief of IP, and should be tapered accordingly. ASA is the drug of choice in patients with coronary artery disease (CAD), heart failure (HF), or renal disease, but should be avoided in patients with asthma and nasal polyps, who are naïve to ASA therapy. Ibuprofen is an inexpensive and relatively accessible option in patients who do not have concomitant CAD, HF, or renal disease. Indometacin is not available over-the-counter in the USA, and has a relatively higher incidence of central nervous system (CNS) adverse effects. Ketorolac is an intravenous option; however, clinicians must be mindful of the maximum dose that can be administered. While ASA/NSAIDs do not ameliorate the disease process of IP, they are part of first-line therapy , for preventing recurrence of IP. ASA/NSAID choice should be dictated by comorbid conditions, tolerability, and adverse effects. Additionally, the clinician should be mindful of considerations such as tapering, high-sensitivity CRP monitoring, bleeding risk, and contraindications to ASA/NSAID therapy. Pericarditis is the inflammation of the pericardium, the membranous sac which envelops the heart . Without2 (PGE2) are known to be released from the parietal layer of the pericardium [2 is predominant in inflammatory conditions, and potentiates nociception along with other mediators throughout the inflammatory cascade [Acute IP is thought to be potentiated by the visceral and parietal layers of the pericardium “rubbing together,” causing inflammation . This inicardium . PGE2 is cascade . HoweverAn important concept in the analgesic and anti-inflammatory actions of ASA/NSAIDs is their ability to bind irreversibly or reversibly, as well as their specificity in inactivating COX . For exaEven though ASA/NSAIDs are part of the first-line therapy regimen for treatment of acute IP and IRP, only a select group of agents have been studied specifically in IP; namely, ASA, ibuprofen, indometacin, and ketorolac tromethamine. It should be noted that in many Western countries, such as in the United States, the use of ASA and NSAIDs in the treatment of IP is not approved by the Food and Drug Administration and is considered “off-label.” The following two sections will focus on the clinical literature surrounding the use of ASA and NSAIDs in the treatment of IP. It should be noted that much of the literature characterizing ASA and NSAID use in pericarditis is circumvented around the benefit of colchicine in the treatment of IP and has been previously reviewed . Since tASA is rapidly absorbed orally, and analgesia increases with dose escalation . During versus 10.7%, respectively (p = 0.004); number needed to treat (NNT) = 5 (95% CI 3.1 to 10.0). Follow-up data also revealed that compared to ASA alone, the combination of ASA plus colchicine significantly decreased symptom persistence at 72 h and that no “severe adverse effects” were noted amongst either group. Minor adverse effects in the ASA-only group were documented in over 6% of patients and included abdominal pain and dyspepsia; these were not significantly different compared to the colchicine group. Ultimately, the COPE trial was the first study to emphasize the importance of using combination therapy with colchicine and ASA for the treatment of IP.COPE was the first landmark study to ascertain the safety and efficacy of colchicine as an adjunct to NSAIDs or ASA for the treatment of the first episode of acute IP. Prior to COPE, limited data regarding the use of ASA or NSAIDs as first-line monotherapy for the treatment of IP existed . In thisor recurrent pericarditis. In ICAP, the primary endpoint of incessant or recurrent pericarditis occurred in 20 patients (16.7%) in the colchicine group and in 45 patients (37.5%) in the placebo group ; NNT= 4. Similar to the COPE trial, secondary endpoints revealed that patients randomized to ASA or NSAIDs plus colchicine therapy had significantly less symptoms at 72 h, less incessant pericarditis, fewer recurrences, and higher rates of remission compared to ASA or NSAID monotherapy. Results were similar regardless of whether the concomitant anti-inflammatory therapy was ASA or ibuprofen. No serious adverse effects were reported. GI disturbance was the main adverse effect that occurred in 2.8% of patients treated with an ASA or NSAID alone, compared to 9.2% of patients receiving colchicine.Published in 2013, the Investigation on Colchicine for Acute Pericarditis (ICAP) study was a multicenter, double-blind, prospective trial to assess whether or not there was a difference in recurrent or incessant pericarditis  . Similarversus 24.0%, in patients receiving both ASA plus colchicine therapy (p = 0.02), with an absolute risk reduction of 26.6% ; NNT = 4. Similar to the COPE and ICAP trials involving patients with acute pericarditis, patients randomized to ASA plus colchicine had a significantly longer symptom-free period, compared to patients receiving only ASA. No serious adverse effects were recorded and no minor adverse effects were reported. Adverse effects were not significantly different for the ASA only group compared to the colchicine group.More data are available surrounding the use of ASA in the treatment of IRP, relative to NSAIDs. Shortly after the COPE trial was published in 2005, the Colchicine for Recurrent pericarditis (CORE) trial was published the same year [versus 24% of patients who received combination therapy with ASA or ibuprofen plus colchicine (p < 0.001); NNT = 3. Secondary endpoints of the trial also showed a significant decrease in symptom persistence at 72 h and an increase in remission rate in those patients randomized to colchicine plus ASA when compared to ASA alone. While no severe adverse effects were noted, gastrointestinal intolerance was reported in 5% of patients randomized to ASA or NSAIDs alone, and one case of hepatotoxicity related to hepatobiliary tract disease was observed in the ASA or NSAID alone group; adverse effects for the ASA or NSAID only group were not significantly different when compared to the colchicine group.Improving upon the design of the CORE trial, the Colchicine for Recurrent Pericarditis (CORP) trial was a randomized, prospective, placebo-controlled study that focused on the safety and efficacy of colchicine added to either ASA or ibuprofen for the secondary prevention of pericarditis in 120 patients . Patientversus ASA/NSAIDs as monotherapy in 240 patients [p = 0.0009); NNT = 5. Similar to previous trials, significantly more patients in the colchicine group had less symptom persistence at 72 h, a less incessant course, fewer pericarditis-related hospital admissions, and a significantly greater remission at one week, compared to ASA/NSAID therapy alone. Adverse effects that occurred in both the ASA or NSAID alone group and colchicine group were GI intolerance  and hepatotoxicity. There were no significant differences between groups.The most recent landmark study of the efficacy and safety of colchicine for treatment of recurrent pericarditis (CORP-2), evaluated the combination of ASA/NSAIDs plus colchicine patients . The CORThose NSAIDs with the most evidence for treating IP have similar pharmacokinetic profiles . NSAIDs,Ibuprofen is a non-selective COX inhibitor. In the United States, ibuprofen is available over-the-counter (without a prescription), and is also manufactured as an intravenous solution. Ibuprofen inhibits COX-1 approximately 2.5 times more potently than COX-2 . TherefoThe use of ibuprofen for the treatment of pericarditis dates back to the 1980s . It was versus ASA or NSAID as monotherapy. CORP-2 was the first trial to include indometacin in the treatment of IP, specifically in patients with idiopathic recurrent pericarditis.Indometacin is a reversible inhibitor of both COX-1 and COX-2 that is only available with a prescription in the United States. It is available as a capsule, suppository, intravenous solution, and an oral solution. Indometacin is rapidly absorbed, with a relatively short half-life of approximately 4.5 h. It is primarily metabolized via the liver and undergoes significant enterohepatic circulation. The fact that indometacin undergoes enterohepatic circulation explains why it may only need to be dosed two to three times daily. Additionally, unlike other NSAIDs, indometacin has been found to cross the blood-brain barrier, which accounts for its significant central nervous system (CNS)-related adverse effects. Relative to the aforementioned anti-inflammatory agents, the use of indometacin for the treatment of IP has been reported sporadically in the literature ,28,29. Iet al., a cohort of 22 patients were given ketorolac tromethamine for pericarditis [Ketorolac tromethamine is an NSAID that reversibly inhibits both COX-1 and COX-2. It is available in both a parenteral (IV and IM) and oral formulation. Ketorolac tromethamine is considered a potent analgesic with moderate anti-inflammatory effects. Notably, the analgesic activity of 30 mg of ketorolac tromethamine is estimated to be equivalent to approximately 12 mg of morphine sulfate, making this an attractive option for the acute management of pain . Despitecarditis . The majOverall, the literature seemingly shows that colchicine is paramount in preventing recurrence of pericarditis, and that ASA/NSAIDs should be administered with colchicine to prevent recurrence of pericarditis. However, it should be noted that colchicine is not considered an analgesic . ASA/NSAet al. studied the frequency of hs-CRP elevation in patients with acute pericarditis. They monitored time to normalization of hs-CRP, and its implications on diagnosis, therapy, and prognosis in IP. Hs-CRP is considered elevated at a concentration > 3.0 mg/L [De novo hepatic synthesis exceeds 3.0 mg/dL approximately 6 h after the start of inflammation and concentrations of hs-CRP peak at 48 h [In order to decrease the incidence of recurrent pericarditis, tapering of ASA or NSAID therapy has been routinely recommended. In all of the landmark trials reviewed, , the patients included in the trials were provided with an “attack dose” of ASA or NSAIDs for 7–10 days. The “attack dose” is used to decrease the acute pain associated with the profound inflammatory sequela of IP. This attack dose was then followed by a 3–4 week taper ,6,7,8. W3.0 mg/L . De novo at 48 h . From 20 at 48 h . Based o at 48 h . Therefo at 48 h . As disc at 48 h ,36.2 blockers. However, the associated increased incidence of diarrhea and abdominal pain, when misoprostol is used in combination with colchicine therapy, may limit its clinical utility for gastrointestinal prophylaxis in the setting of acute pericarditis [Since the COX-1 pathway produces prostaglandins that are responsible for maintaining the integrity of the gastrointestinal (GI) lining, inhibition of this process via ASA or NSAIDs can increase the risk for GI irritation and/or bleeding . Since rcarditis .et al. described ASA-induced hepatotoxicity in a patient treated with high-dose ASA therapy for acute pericarditis. The patient developed elevated hepatic transaminases and hepatic synthetic dysfunction within 48 h after the initiation of ASA therapy, with no other identifiable cause for hepatic dysfunction [Mild asymptomatic elevation of hepatocellular enzymes can also be seen in association with NSAID or ASA therapy, but serious hepatotoxicity is rare . The ratfunction . In the et al. found increased scar thinning after myocardial infarction in patients with PMIP treated with indometacin or ibuprofen when compared to patients who did not receive NSAID therapy [et al., many of the patients included in the study were treated for Dressler’s syndrome and postcardiotomy syndrome, ketorolac tromethamine is currently contraindicated for treatment of perioperative pain post coronary artery bypass graft (CABG) surgery [There are various cardiovascular safety concerns of which the clinician using ASA or NSAIDs to treat IP should be mindful. The FDA has recently issued a warning on all NSAIDs, that there is an increased risk of cardiovascular and cerebrovascular events in patients who have a history of coronary artery disease (CAD) and are simultaneously treated with NSAIDs. This risk appears to be related to the duration of therapy as well as to escalating dosage. The risk of events also appears to be increased in patients who have traditional risk factors for cardiovascular disease. In these patients, NSAIDS may contribute to adverse cardiovascular outcomes by causing unopposed propagation of COX-1 stimulation, possibly by interfering with the efficacy of ASA, by increasing the risk of GI bleeding when used in combination with ASA, by impairing scar formation post myocardial infarction, and by causing coronary vasoconstriction ,49. In a therapy . With re surgery . It is t surgery . Importa surgery . Therefo surgery . The selet al. treated five patients with idiopathic orthostatic hypotension with 75–150 mg of indometacin daily and found that indometacin therapy increased standing diastolic blood pressure by an average of 20–30 mmHg and resolved orthostatic symptoms in four out of the five patients. Blood pressure fell to pre-treatment levels and orthostatic symptoms resumed when indometacin therapy was discontinued [Although variable depending on the particular NSAID, there is also a recognized association with short-term NSAID therapy and hypertension . In a meontinued . Manufacontinued . While tontinued . Regardlet al. found a 2.2-fold increase in relative risk of heart failure hospitalization in patients on both NSAIDs and diuretics when compared to those not taking NSAID therapy (95% CI 1.7–2.9). This effect remained significant after adjustment for age, sex, and history of hospitalization  [Relative to ASA, NSAIDs have also been associated with diuretic resistance and volume retention in patients with clinical heart failure . In a re1.4–2.4) . Similar1.4–2.4) . The eff1.4–2.4) . We woulThe concern for hemopericardium is especially problematic in patients already on systemic anticoagulation in the setting of pericarditis. Presently, there is conflicting evidence as to whether or not the use of anticoagulation is a possible risk factor for the development or worsening of a hemorrhagic pericardial effusion that could potentially result in cardiac tamponade . The decversus benefit of continuing anticoagulation therapy concomitantly with high-dose ASA/NSAID therapy, as anticoagulation in the setting of pericarditis is associated with a poorer prognosis and may result in an increased risk of pericardial tamponade [12 receptor antagonist, and an anticoagulant, such as warfarin or the TSOAs. In these patients, clinicians should consider concomitantly administering a proton-pump inhibitor to decrease the risk of bleeding.Upon analysis of the available literature, it appears that the development of hemopericardium can manifest anywhere from weeks to months after the initiation of anticoagulation, and the clinician should be diligent in avoiding potentially-interacting pharmacotherapy and nutraceutical products, as well as ensuring dose adjustment in the setting of comorbid conditions, such as impaired renal and/or hepatic function. In patients that have an existing indication for chronic anticoagulation , clinicians must weigh the risk amponade . This iset al., in a prospective, double-blind trial of 24 patients with uremic pericarditis randomized to indometacin versus placebo in addition to conventional therapy , found a significant earlier reduction in symptoms in patients taking indometacin with no noted adverse events in the indometacin group [Due to their inhibition of the COX-1 pathway and the subsequent impaired prostaglandin regulation of renal blood flow, there is an increased incidence of adverse renal effects in patients receiving NSAID therapy for IP. Adverse effects may include acute renal failure , acute interstitial nephritis, and rarely acute renal papillary necrosis, all of which require prompt discontinuation of NSAID therapy . With thin group . There hin group ,76. Giveet al. in 1994, acetaminophen and NSAID therapy were associated with increased risk of renal disease in the general population, whereas ASA therapy did not increase the likelihood of renal disease [versus placebo in patients with chronic kidney disease. There was no significant increase in major bleeding and there was no increase in progression to end-stage renal disease in the ASA group when compared to placebo [Ultimately in this population, ASA is recommended as the initial treatment of choice. In a population-based cohort study by Perneger  disease . In 2005 placebo . As a re placebo . CurrentNSAID therapy has been associated with a variety of adverse effects on the central nervous system including headaches, ataxia, vertigo, dizziness, nystagmus, and rarely encephalopathy, seizures, and coma . The estIn patients with known salicylate sensitivity or known ASA-exacerbated respiratory disease (AERD), ASA therapy is contraindicated . AERD isWhile the combination of NSAIDs/ASA plus colchicine has been shown to significantly decrease the risk of recurrent pericarditis, many patients may present with contraindications to therapy due to co-morbid conditions discussed above, drug interactions, and/or intolerances. Moreover, despite adherence to combination therapy with NSAIDs/ASA plus colchicine, a subset of patients may still present with recurrent signs and symptoms of pericarditis . SeveralCorticosteroids, namely prednisone at 0.25 to 0.5 mg/kg/day weaned over a median of five months, have been recommended for patients who present with intolerances/contraindications to ASA/NSAIDs, or who have failed combination therapy with ASA/NSAIDs plus colchicine . Howeveri.e., pericardial effusion size via echocardiography, resolution of ECG manifestations, and/or resolution of pericardial friction rub). Additionally, hs-CRP should be obtained upon presentation and ideally monitored weekly for the duration of ASA/NSAID therapy. This is especially important in those patients who do not respond to an initial 7–10 days attack dose, and in patients with recurrent pericarditis. Relative to any of the NSAIDs, ASA has the most robust evidence for both the treatment of acute and recurrent IP. However, a subgroup analysis of CORP-2 revealed that there were similar proportions of recurrence of pericarditis in patients receiving ASA, ibuprofen, or indometacin therapy suggesting that there may potentially be no significant difference in effect between ASA and NSAIDs in the treatment of recurrent IP. These findings need to be further validated in a study designed to compare ASA and NSAIDs therapy in the treatment of IP from an efficacy and safety perspective [Despite being used as part of first-line treatment for IP and IRP, NSAIDs and ASA do not actually ameliorate the underlying inflammatory disease process that is associated with IP. Emerging research has suggested that IP may not be viral, but in fact may be due to an autoimmune processes. If this is the case, then it would explain why ASA/NSAIDs, while providing analgesia, may not actually change the underlying disease process of IP. Current guidelines recommend that, in the absence of contraindications, patients should be initiated on combination therapy with ASA or an NSAID tapered over 3–4 weeks, along with colchicine therapy for 3–6 months . The effspective . For thoThe authors report no conflicts of interest related to this manuscript. No external funding was received for the preparation of this manuscript. Dr. Schwier and Dr. Tran collectively conceived, designed, and wrote this review.


P = 0.004; 2I = 59%). In the subgroup analysis of race, Caucasians of DM showed decreased risk of gliomas . In the subgroup analysis of design, a statistically significant protective effect of DM on gliomas was observed in case-control studies , while no such effect was observed in cohort studies . In a further stratified analysis by gender, a significant association was found among males with DM . No significant association was found between females with DM and gliomas . In summary, this meta-analysis of current evidence suggests that DM is significantly associated with decreased gliomas risk in Caucasian and males.Some studies reported a statistically significant inverse association between diabetes mellitus (DM) and risk of gliomas. However, the result is still controversial. We thus did a meta-analysis and summarized the evidence on the incidence of gliomas that has been studied in its association with DM. Seven case-control studies and 4 cohort studies were selected in this meta-analysis (n = 5898251). DM was significantly associated with decreased risk of gliomas (OR = 0.79; 95% CI 0.67 – 0.93;  Gliomas account for almost 80% of primary malignant brain tumors, and fewer than 50% of glioma patients live longer than 5 years after diagnosis . DespiteDiabetes mellitus (DM) is the most common endocrine disorder that affects 246 million people worldwide. The International Diabetes Federation (IDF) predicts that the number of people with DM will increase up to 380 million within twenty years . HoweverA total of 237 potential studies were identified by preliminary searching PubMed, Web of Science, Science Direct, EMBASE, and Cochrane Library databases, among which 7 case-control studies and 4 cohort studies were selected, involving a total of 5898251 subjects in this meta-analysis. The detailed literature search strategy was showed in Figure P = 0.004; 2I = 59%). In the subgroup analysis of race, Caucasians of DM showed decreased risk of gliomas . In the subgroup analysis of design, a statistically significant protective effect of DM on gliomas was observed in case-control studies , while no such effect was observed in cohort studies . In a further stratified analysis by gender, a significant association was found among males with DM . No significant association was found between females with DM and gliomas . The results were showed in Table As shown in Figure P = 0.24).Sensitivity analysis was carried out repeatedly by precluding a single study at a time. The results demonstrated that the estimates before and after the deletion of each study were similar Figure . No evidThis is a comprehensive meta-analysis for clarification of the association between DM and risk of gliomas. Seven case-control studies and four cohort studies involving more than 580000 individuals were included in this study. The results suggested that DM was significantly associated with the decreased risk of gliomas. In the subgroup analysis by ethnicity, we noted that Caucasians with DM had decreased gliomas risk. However, there is no studies of Asians and other races. Although the pooled analysis from the case-control studies suggested a significant reduction in gliomas risk, the results from the cohort studies were non-significant, suggesting that our conclusion depend mainly on the case-control studies. It is generally thought that cohort studies provide stronger evidence regarding an association than case-control studies because they are less prone to recall or selection bias. In the subgroup analysis by gender, the inverse association between DM and gliomas was more apparent in men than women. Gender-specific hormonal changes in diabetic patients could serve as a possible explanation.Previous studies suggested that DM might be a prognostic factor for cancers. Song et al. suggests that long-term DM is associated with an increased risk of pancreatic cancer . Luo et Several limitations of this study should be noted. Firstly, only published studies that were included in the selected electronic databases were identified; it is possible that some relevant published or unpublished studies may have been missed. Secondly, no studies with Asians and other races was included in this meta-analysis. Thirdly, marked heterogeneity of studies was seen in this study. We attempted to find the exact factor that can account for the heterogeneity by subgroup analysis. Fortunately, the heterogeneity was decreased in the subgroup analysis of race. Fourthly, owing to the limited data in the included studies, we cannot analyze the associations between type 1 DM or type 2 DM and gliomas, separately. Finally, this study was meta-analysis of case-control study and cohort study. Confounding should be considered.In summary, this meta-analysis of current evidence suggests that DM is significantly associated with decreased gliomas risk.A systematic search was conducted in the PubMed, Web of Science, Science Direct, EMBASE, and Cochrane Library databases until Aug 16, 2015, with no limits. The search strategies were based on combinations of the following keywords: Gliomas, brain tumor, Diabetes mellitus, Diabetes, DM. The MeSH terms were glioma and diabetes mellitus. In addition, we checked relevant reviews on the topic of interest. We traced the reference lists of selected articles and used Google Scholar to find potential studies.Studies were included in the meta-analysis if they fulfilled the following inclusion criteria: 1) study design: case-control or cohort studies; 2) population: DM patients; 3) primary outcome: the effect of DM on the risk of gliomas. Studies were included in the meta-analysis if they presented estimates of the OR or relative risk (RR) and the corresponding CI on the association between DM and risk of gliomas. When multiple reports were published on the same study population, we included the study with the largest number of cases. Abstract, case reports, review articles, experimental studies and commentary articles were excluded.Two investigators extracted data from the included studies independently, and the respective studies were retrieved for further consideration if judged pertinent by one or two reviewers. Any discrepancies were identified and resolved by consensus. For each study, the following data were extracted: first author's name, year of publication, study design, race, age, gender, sample size, and covariant. A modification of the Newcastle–Ottawa Scale (NOS) was used as an assessment tool for selection, comparability, and outcome assessment.2 statistic were used to assess the degree of heterogeneity among the studies included in the meta-analysis. If heterogeneity was observed among the studies (I2 >50%), the random-effects model was used to estimate the pooled OR (the DerSimonian and Laird method). Otherwise, the fixed-effects model was adopted (the Mantel–Haenszel method). Subgroup analyses were carried out by ethnicity, design, and gender. Sensitivity analysis was performed through sequentially excluded individual studies to assess the stability of the results. The potential publication bias was examined visually in a funnel plot of log [OR] against its standard error (SE), and the degree of asymmetry was tested using Egger's test. All statistical tests were performed using Revman 5.1 software  and STATA 11.0 software . A P value < 0.05 was considered statistically significant.OR and 95% CI were employed to evaluate the strength of the association between DM and risk of gliomas. The I