Objective. To investigate the risk factors of DR in Chinese T2DM patients. Methods. 2009 patients with T2DM were included in this cross-sectional study. All patients underwent eye examination, and the DR stage was defined by an ophthalmologist. Correlation analysis was performed to evaluate the relation between DR and clinical variables. Logistic regression models were used to assess risk for those factors associated with DR. Results. A total of 597 T2DM patients (29.7%) had DR, of which 548 (27.3%) were nonproliferative diabetic retinopathy and 49 (2.4%) were proliferative diabetic retinopathy. Positive correlations were found between DR and duration of diabetes, systolic blood pressure (SBP), diastolic blood pressure, glycated hemoglobin, glycated albumin, 24 hurinary albumin excretion, peripheral atherosclerosis (PA), diabetes nephropathy (DN), diabetic peripheral neuropathy, and anemia. Negative correlations were found between DR and C-peptide and glomerular filtration rate. Logistic regression analysis revealed that duration of diabetes, SBP, DN, anemia, PA, and C-peptide were each independent risk factors of DR. Conclusion. The duration of diabetes, SBP, DN, anemia, and PA are positively associated with DR in Chinese T2DM patients, while C-peptide is negatively associated with DR. Monitoring and evaluation of these related factors will likely contribute to the prevention and treatment of DR. Type 2 diabetes mellitus (T2DM) is one of the fastest growing diseases in China and has become a major public health challenge. The most common complication of T2DM is diabetic retinopathy (DR), which is a leading cause of preventable blindness in working-aged people. It has been estimated that diabetic individuals are 25 times more likely than their nondiabetic counterparts to suffer severe, permanent vision loss . AlthougA retrospective, cross-sectional analysis was performed in T2DM patients who had been admitted to the Endocrinology Department of Shanghai Jiaotong University Affiliated Sixth People's Hospital from January 2008 to December 2009. All of the patients had been admitted specifically for management of their diabetes. Diagnosis of diabetes was performed according to the 1999 World Health Organization criteria. Patients were excluded according to the presence of type 1 diabetes mellitus, any other non-type 2 diabetes , poor general condition, severe infection, acute cerebrovascular disease, recent surgery, impaired cardiac function (III-IV degree according to NYHA classification), or severely impaired hepatic or renal function.2. Hypertension was defined as diastolic blood pressure (DBP) ≥ 90 mmHg, SBP ≥ 140 mmHg, or self-reported use of antihypertensive medication. Dyslipidemia was defined as an elevation of total cholesterol (TC) ≥ 6.1 mmol/L and/or of triacylglycerol (TG) ≥ 2.26 mmol/L, or an elevated low-density lipoprotein cholesterol (LDL-C) ≥ 4.14 mmol/L or a decreased high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol/L, according to the American National Cholesterol Education Program (Adult Treatment Panel III) [99mTc-diethylene-triamine-pentaacetic acid (99mTc-DTPA). The 99mTc-DTPA renal dynamic imaging (modified Gate's method) was measured by a Siemens Signature e.cam SPECT . Anemia was defined according to Chinese anemia sex-based criteria, which is hemoglobin (Hb) concentration of <12 g/dL for men and <11 g/dL for women. In addition, the patients with anemia were further subdivided into two groups: mild anemia (Hb ≥ 9 g/dL) and moderate and severe anemia (Hb < 9 g/dL).Clinical data was extracted from the departments medical records for each patient and included age, gender, duration of diabetes, and previous history of hypertension and dyslipidemia. Patients' medical examinations on the day of admission had included measurements of height, body weight, and blood pressure. BMI was calculated as kg/mnel III) . CoronarFasting blood samples were drawn before breakfast on the second day of hospitalization for measurements of fasting plasma glucose (FPG), HbA1c, glycated albumin (GA), C-peptide, Ua, TC, TG, LDL-C, and HDL-C. The 2 h postprandial glucose (2 h PG) levels were drawn after a mixed meal. The plasma glucose concentration was measured using a glucose oxidase method . Serum lipids and renal function indices were determined by enzymatic procedures using an autoanalyzer . Serum C-peptide was determined by radioimmunoassay . HbA1c was estimated by high-performance liquid chromatography using the HLC-723G7 analyzer . GA was measured by a liquid enzymatic assay kit . The 24 h urinary albumin concentration was determined by nephelometry using an N antiserum to Human Albumin Assay and BN II analyzer . Hb was measured using an automated blood analyzer .Fundus photographic imaging was carried out by following a standardized protocol. Both eyes of each participant were photographed with a 45-degree 6.3-megapixel digital nonmydriatic camera . According to the International Clinical Diabetic Retinopathy and Diabetic Macular Edema Disease Severity Scales , the sevt-test were performed to compare means of normally distributed variables. The Mann-Whitney U test was used to evaluate nonnormally distributed variables. Spearman's rank correlation analysis was also used to examine the association of clinical variables with DR. Chi-square (χ2) test was used to analyze categorical variables. Trend χ2 test was used to compare proportions among groups. The significance level for the above statistical analyses was set as α = 0.05, and a P value < 0.05 (two-tailed) was considered as statistically significant. All statistical analyses were carried out using the Statistical Package for the Social Sciences software version 16.0 . Numerical variables of normal distribution were expressed as mean ± SD, while those of nonnormal distribution were expressed as median (quartile). One-way ANOVA and P value, for which <0.05 was considered as statistically significant. The ability of each independent factor to relate to DR was determined by partial regression coefficient (B) and odds ratio (OR = EXP(B)), along with its 95% confidence interval (95% CI). OR above 1 represented positive correlation, and OR below 1 represented negative correlation.In this study, binary logistic regression was primarily used to estimate the association of independent factors and DR by Wald and According to the inclusion and exclusion criteria mentioned above, a total of 2009 T2DM patients were included in this analysis. There were 1145 (57%) males and 864 (43%) females, with mean age of 59.69 ± 12.28 years and diabetic duration of 8.05 ± 6.71 years. Of all the subjects, 597 (29.7%) were diagnosed with DR, of which 548 (27.3%) had NPDR and 49 (2.4%) had PDR. Comparisons between the two groups (NDR versus DR) revealed a significantly higher prevalence of anemia, hypertension, DN, DPN, and PA in the DR group. In contrast, no differences were found between the two groups for dyslipidemia, CHD, CVD, and hyperuricemia/gout. PA, DN, DPN, hypertension, and anemia were positively correlated with DR .Comparisons of clinical parameters according to the retinopathy status are shown in Age, gender, duration of diabetes, BMI, dyslipidemia, HbA1c, SBP, DBP, C-peptide, anemia, DN, DPN, and PA were entered into a logistic regression model. The results of the logistic regression analyses are displayed in P < 0.01)  .The results of this clinic-based study suggest that independent factors associated with DR in Chinese patients include duration of diabetes, SBP, C-peptide, DN, PA, and anemia. In particular, the severity of DR was found to be increased in conditions of lower C-peptide levels and elevated levels of the other independent factors. In our study, the duration of diabetes was found to be significantly higher in patients with DR than in those without, and the longer the duration of diabetes the higher the prevalence of retinopathy. Our findings agree with those from previously published studies in populations of other ethnic groups that also identified duration of diabetes to be an independent risk factor for retinopathy –15. It iHbA1c and GA were found to be significantly higher in DR patients from our Chinese study population. However, they did not retain significance in the final logistic regression analysis. This was different from the results of previous studies , 16–19. The current study in Chinese patients showed that the prevalence of hypertension was higher in subjects with DR than in those without, and the study found that SBP was positively associated with DR. The UKPDS also found that the incidence of retinopathy was associated with SBP in their largely Caucasian population; specifically, the relative risk for DR was found in the UKPDS to be 1.5 for systolic pressures between 125 and 139 mmHg and 2.8 for systolic pressures higher than 140 mmHg . It is kDyslipidemia was not shown in our study population to be associated with retinopathy, which was consistent with the reported results from some of the other studies in the literature , 23. HowAlbuminuria excretion was significantly higher in our patient population with DR than in those without, and GFR was negatively correlated to DR. Further analysis showed that DN was observed to be an independent risk factor for the development of DR, with odds of 1.614 times. Moreover, the severity of DR in patients with T2DM appeared to be aggravated with an increasing severity of DN. Higher risk of concomitant DR might be predicted in patients with DN or renal dysfunction. This could be explained by the fact that both nephropathy and retinopathy are related to endothelial dysfunction-mediated microvascular complications of diabetes mellitus (DM). A number of previous studies have published evidence to support the suggestion that DR and DN progress in a parallel manner; thus, the presence of one is believed to predict the development of the other , 28, 29.+-K+-ATPase, endothelial nitric oxide synthase activities [κB activation of endothelial cells, all of which are enzyme systems of significant benefit in the prevention and treatment of DR. Furthermore, an experimental study has shown that C-peptide is involved in regulating extracellular matrix (ECM) protein composition, which is one of the characteristic features of DR [C-peptide was negatively correlated with DR in our study, indicating it as a protective factor against DR. Our results were consistent with a previous study that also found reduced serum C-peptide to be associated with a higher prevalence of retinopathy in T2DM . Considetivities –37, and es of DR .In agreement with findings of previous studies , 40, we Anemia was found in our study to be another risk factor of DR in Chinese patients, perhaps because of anemia-induced retinal hypoxia. Individuals with anemia were 1.857 times more likely to develop DR than individuals without anemia. Moreover, the prevalence of PDR was significantly increased in patients with moderate-severe anemia than those with absolutely no detectable anemia. These results are consistent with those reported in the ETDRS, in which low hematocrit was identified as an independent risk factor for the development of high-risk PDR and visual impairment . These rThere were several limitations to the present study that should be noted here, as they may affect the generalization of our findings. Because this was a cross-sectional study, the results do not provide definite information on a cause-and-effect relationship. In addition, because our study population was composed solely of patients from a single center, there was unavoidable bias of selection, information, and confounding variables. Prospective and larger studies are required to overcome these limitations.


BP-pm1 on chromosome 13, LOD 3.78; BP-pm2 on chromosome 11, LOD 2.76; BP-pm3 on chromosome 2, LOD 2.61; BP-pm4 on chromosome 4, LOD 2.50) and two suggestive BP-QTLs , four of which  were unique to this post-menopausal cohort. These data demonstrate distinct polygenic susceptibility underlying post-menopausal salt-sensitive hypertension providing a pathway towards the identification of mechanism-based therapy for post-menopausal hypertension and ensuing target-organ complications.Essential hypertension affects 75% of post-menopausal women in the United States causing greater cardiovascular complications compared with age-matched men and pre-menopausal women. Hormone replacement and current anti-hypertensive therapies do not correct this post-menopausal increased risk suggesting a distinct pathogenic framework. We investigated the hypothesis that distinct genetic determinants might underlie susceptibility to salt sensitive hypertension in pre-menopausal and post-menopausal states. To determine whether distinct genetic loci contribute to post-menopausal salt-sensitive hypertension, we performed a genome-wide scan for quantitative trait loci (QTLs) affecting blood pressure (BP) in 16-month old post-menopausal F2 (Dahl S×R)-intercross female rats characterized for blood pressure by radiotelemetry. Given identical environments and high salt challenge, post-menopausal BP levels were significantly higher than observed in pre-menopausal  and ovariectomized  F2-intercross female rats. We detected four significant to highly significant BP-QTLs ( Cumulative observations indicate that sex-specific susceptibility exists in various traits The increased prevalence of salt-sensitive hypertension in post-menopausal women To investigate the genetic determinants that contribute to post-menopausal salt-sensitive hypertension we performed a genome scan for QTLs affecting blood pressure in an F2 (Dahl S×R)-intercross post-menopausal female rat population characterized for blood pressure by radiotelemetry. We implemented the following experimental design: Female F2 hybrids were maintained from weaning on a low salt (0.008% NaCl) diet until challenge with high salt (8% NaCl) at post-menopause confirmation at 14 months of age. BP-implant surgery was done at 13.5 months of age; after 12 days, baseline BP levels were obtained. We characterized 130 subjects for blood pressure. The cohort was genotyped with 100 informative markers for our (Dahl S×R) intercross with an average density of 23.9 Mbp.16m) and previously reported pre-menopausal (6m) 6m) P<10−4), diastolic (DBP P<10−4) and mean arterial pressures (MAP P<10−4) significantly compared with BP in pre-menopausal rats  detected with suggestive linkage  using 16 m-old post-menopausal F2 (Dahl S×R)-intercross female rats.  linkage . AdditioBP-pm1 on rat chromosome 13, BP-pm2 on rat chromosome 11, BP-pm3 on rat chromosome 2 and BP-pm4 on rat chromosome 4 . All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.Inbred Dahl S/jrHsd and Dahl R/jrHsd rats were obtained from Harlan . Parental strains  were crossed to produce F1 progeny. The F2 subjects were derived from brother-to-sister mating of F1 hybrids to produce the F2 female (n = 130) segregating population.In order to ascertain post-menopausal status of the female F2 hybrids to be characterized for blood pressure daily vaginal smears were performed on females to determine the stage of their estrous cycle  essentially as described Blood pressure (BP) was measured essentially as described P value<0.01 for the interaction effect.Phenotype distributions were analyzed for normality; data transformations were done when necessary and datasets that passed Kolmogorov-Smirnov normality testing (SigmaStat) were used for linkage analysis. QTL analysis was performed using SBP and DBP as quantitative traits. Linkage maps, marker regression and composite interval mapping were done with the Map Manager QTXb19 (MMQTXb19) program for windows SNP genotyping was carried out on an Applied Biosystems 7900 Real-Time PCR System. SNPs (n = 97) and SSLP markers (n = 3) were selected from the RGD SNP database. SNP assays (TaqMan assays) were procured from Applied Biosystems and were validated in our laboratory.We performed one-way ANOVA followed by all pairwise multiple comparisons using Tukey test for blood pressures as indicated per experimental comparison.


Increases in inspired oxygen fraction (FiO2) are related to improvement on PbrO2, but other approaches that aim to improve oxygenation, like increasing positive-end expiratory pressure (PEEP), were not deeply evaluated in humans.Brain tissue oxygen pressure . Seventeen patients remained in the study according to the following inclusion criteria: ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2 ratio) <300; cerebral perfusion pressure (CPP) >60 mmHg; intracranial pressure (ICP) <20 mmHg; PtiO2 >20 mmHg; absence of any signal of brain deterioration. These patients were submitted to PEEP levels of 5, 10 and 15 cmH2O, each one for at least 20 minutes. During the three PEEP levels, PtiO2, pulse oxygen saturation (SpO2), ICP and CPP were monitored and statistically analyzed by ANOVA and Bonferroni methods. P < 0.05 was considered statistically significant.From February 2007 to February 2011, 36 severe TBI patients admitted to our intensive neurological unit were monitored with PtiO2O increased SpO2 from 95.5 ± 2.1 to 98.6 ± 1.2 (P = 0.0001) and PtiO2 from 27.8 ± 6.5 mmHg to 33.9 ± 6.7 mmHg, respectively (P = 0.0001). On the other hand, ICP and CPP did not present statistical significance according to the increase of PEEP levels . The main characteristics of the evaluated patients are described in Table 2 and CPP according to the PEEP levels are represented in Figures The increase of PEEP level from 5 to 15 cmH2O increased PtiO2, without increasing ICP and/or decreasing CPP. Increasing PEEP levels can be an alternative ventilatory approach to improve brain oxygenation besides FiO2.In hypoxemic severe TBI patients, increasing PEEP levels from 5 to 10 and 15 cmH


The contribution of glycemic variability to macrovascular complications remains unclear. We therefore investigated the association between glycemic variability and cervical and/or intracranial atherosclerosis in Chinese type 2 diabetic patients.1c of 8.3 ± 1.7% and a median diabetes duration of 9.0 years. The standard deviation of blood glucose values (SDBG) and the mean amplitude of glycemic excursion (MAGE) were calculated from continuous glucose monitoring system data for assessing glycemic variability while 24h mean blood glucose (MBG) was calculated for measuring overall blood glucose level. Magnetic resonance angiography (MRA) was used to detect cervical and/or intracranial plaque, and ultrasonography was used to quantify carotid intima-media thickness (IMT) as an index of subclinical atherosclerosis.We conducted a cross-sectional study in 216 type 2 diabetic patients with a hemoglobin An = 63), SDBG  and MAGE  were both correlated with carotid IMT and these relationships remained significant in multiple linear regression analysis (multiple R2 = 0.314 for the model including SDBG and multiple R2 = 0.268 for the model including MAGE). However, SDBG and MAGE were not significantly different among patients with different stenosis degrees.One hundred and fifty-three patients (70.8%) presented with cervical and/or intracranial lesions on MRA among 216 patients in the study. Elder age, increased systolic blood pressure, increased MBG and elevated low density lipoprotein cholesterol were independent contributors to plaque formation. In patients without stenosis (Glycemic variability is associated with subclinical atherosclerosis in Chinese type 2 diabetic patients. Macrovascular diseases such as coronary artery disease and cerebrovascular disease are major complications of type 2 diabetes. Previous studies have shown the association between averaged mean levels of glycemia and macrovascular complications ,2. MeanwAtherosclerosis is a complex multifactorial disease, often preceding the development of diabetic macrovascular complications. Carotid intima-media thickness (IMT), measured noninvasively by ultrasonography, is accepted as an indicator of subclinical atherosclerosis, and has been reported to be directly associated with an increased risk of cardiovascular and cerebrovascular diseases . FurtherThe study was carried out over a period of 12 months between 1 January 2008 and 31 December 2008. We included 216 type 2 diabetic patients who consulted for complications screening at the Department of Endocrinology and Metabolism in our hospital on an annual basis. Type 2 diabetes was diagnosed according to 1999 World Health Organization (WHO) criteria [Subcutaneous interstitial glucose was monitored continuously for 3 consecutive days using a retrospective CGM system . The sensor of the CGM system was inserted on day 0 and removed after 72 h; this generated a daily record of 288 continuous sensor values. A minimum of four capillary blood glucose readings per day, as measured by a SureStep blood glucose meter , were entered into the CGM system for calibration. The 24h mean blood glucose (MBG) level was calculated from the 288 consecutive sensor readings over a 24h period. The 24h MBG and intraday glycemic variability were based on the mean values taken on days 1 and 2. Intraday glycemic variability parameters include the standard deviation of blood glucose values (SDBG)  and the Patients were instructed to adhere to a standard diet during the three-day period of CGM sensor monitoring. The diet was designed to ensure a total daily caloric intake of 25 kcal/kg/day, with 55% of calories coming from carbohydrates, 17% from proteins, and 28% from fats. Written instructions were provided to achieve the appropriate caloric content and to guide the consumption times, which included breakfast , lunch , and dinner .All MRA examinations were performed using a 3.0 tesla MR system . Intracranial MRA was performed using a 3D-TOF-MRA sequence with an 8-channel head coil or a 16-channel craniocervical joint coil. The 3D-TOF-MRA was obtained with repetition time/echo time (TR/TE) 30/3.2 msec, flip angle 20°, field of view (FOV) 250 × 220 mm, four slabs (180 slices), 1.2 mm slice thickness, matrix 1024 × 1024 and an acquisition time of 8 min 56 s. The acquired images were then transferred to a separate workstation  to obtain both the maximum-intensity projection (MIP) and volume rendering (VR) images. Cervical MRA was performed using the high spatial resolution CEMRA sequence with a 16-channel craniocervical joint coil. Parameters were as follows: a 4.7/1.79 msec TR/TE; 27° flip angle; 320 × 320 mm FOV; 150 slices; 1.0 mm slice thickness, matrix 704 × 704 and an acquisition time of 1 min 27 s. A 1 ml bolus dose of gadolinium  was administered intravenously at a flow rate of 2.5 ml/s by a power injector, followed by 21 ml of saline flush to measure the time taken for the gadolinium to reach the aortic arch. Subsequently, 19 ml of gadolinium was injected at the same rate. The average scanning delay time was 13 s (11–19 s).The intracranial portion of the internal carotid artery (I-ICA), the anterior, middle, and posterior cerebral arteries , the intracranial vertebral artery (I-VA), and the basilar artery (BA) were evaluated by intracranial MRA. The common carotid artery (CCA), the extracranial portion of the internal carotid artery (E-ICA), the extracranial vertebral artery (E-VA), the external carotid artery (ECA), and the subclavian artery (SUB) were evaluated by cervical MRA. All MRA findings were reviewed by two investigators who were blind to patient clinical data. The severity of arterial stenosis was rated into five grades depending on the narrowing of the arteries: without any reduction of arterial diameter; <10% reduction of arterial diameter; 10–50% reduction; 51–99% reduction; and complete occlusion . If stenCommon carotid arteries were assessed using a high resolution B-mode ultrasound  equipped with a 10 MHz probe, as previously described . A singlEach patient had a physical examination including measurements of height, weight, and blood pressure in an air-conditioned, quiet room. We calculated body mass index (BMI) as weight (kg) divided by squared height (m). The blood pressure was measured indirectly using a mercury sphygmomanometer. Sitting blood pressure was measured after 5-min rest with a blood pressure cuff appropriately sized to arm circumference and placed on the subject’s non-dominant arm. The average of three measurements at two minute intervals was used for the analysis. Smoking status was based on an interview. Subjects were classified as nonsmokers or current smokers.1c (HbA1c) was measured by high-performance liquid chromatography with a Variant II Hemoglobin A1c analyzer .On a separate day from 3-day CGM measurement, venous blood sample was drawn on 6 AM after a 10 hour overnight fasting to test the biochemical measurements. Hepatic biomarkers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST); renal function biomarkers including blood urea nitrogen (BUN), plasma creatinine, and uric acid; triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C), were determined by standard enzymatic methods using a biochemical analyzer . Fasting plasma glucose levels were assayed by the glucose oxidase method. Hemoglobin AU test with Bonferroni correction. In addition, a chi-squared test was used to determine the differences between groups in categorical variables. Variables that did not follow a normal distribution were log-transformed. Logistic regression analysis was performed to identify independent factors for cervical and/or intracranial plaque formation. The results of the regression were expressed as odds ratios (OR) with 95% confidence intervals (CI). In patients with negative finding on MRA, Spearman correlation coefficients were employed for correlation analysis between carotid IMT and variables. Multiple regression models were used to explore the influence of different variables on carotid IMT and to adjust for covariates. We calculated the number of patients required for the study to reject the null hypothesis 90% of the time  when r was 0.40 or higher with a 2-tailed type I error at the 0.05 level of significance. Because this calculation led to a sample size of at least 61, the number 63 of patients who had negative finding on MRA was sufficient. A P value of <0.05 (two-tailed) was considered to indicate statistical significance.Statistical analyses were performed using SPSS software version 17.0 . Normally distributed data are presented as mean ± SD, whereas skewed variables are presented as median (interquartile range: 25th to 75th percentile). Clinical characteristics that followed a normal distribution were compared among groups using one-way analysis of variance with post-hoc LSD test, while those with non-normal distribution were compared using the Kruskal–Wallis test followed by Mann–Whitney 1c levels of 8.3 ± 1.7 %, and a median (interquartile range) diabetes duration of 9.0 (5.0–13.3) years. Patients were classified according to the presence and severity of arterial stenosis: patients without stenosis (n = 63); <10% stenosis group: patients with less than 10% stenosis in the most severely stenotic artery (n = 105); 10–50% stenosis group: patients with 10–50% stenosis in the most severely stenotic artery (n = 40); 51–99% stenosis group: patients with 51–99% stenosis in the most severely stenotic artery (n = 8); no patient had complete occlusion on MRA. The baseline characteristics and laboratory data are shown in Table P < 0.05). However, SDBG and MAGE were not statistically different among the three groups (both P > 0.05).Subjects had a mean ± SD age of 63 ± 10 years (range: 40–86 years), mean HbAMRA findings are summarized in Table 1c, MBG, MAGE, SDBG, blood pressure, TG, HDL-C, LDL-C, ALT, AST, diabetes treatment, dyslipidemia treatment, antihypertensive treatment and aspirin use.Of potential confounding risk factors, multiple logistic regression analysis revealed that age , systolic blood pressure , MBG  and LDL-C  were independent factors for the presence of cervical and/or intracranial lesions. The independent variables included age, sex, BMI, smoking status, diabetes duration, HbAn = 63) and subjects with plaque (n = 153). In the former group, when carotid IMT was tested for simple linear correlations against markers of glucose control and nonglycemic clinical and laboratory variables, statistically significant correlations were found with age , MAGE  and SDBG  , carotid IMT only correlated with age  among all the markers of glycemic and nonglycemic variables and no correlation was observed with MAGE  and SDBG .Patients were classified into 2 groups according to MRA results: subjects without plaque (aque n = 53. In thn = 63)  in the univariate analysis, 2 independent models were tested, 1 including the SDBG (model 1) and 1 the MAGE (model 2). Both SDBG  and MAGE  remained significant in stepwise regression analysis (multiple R2 = 0.314 for the model including SDBG and multiple R2 = 0.268 for the model including MAGE). The regression equations are as follows: Model 1: Carotid IMT (mm) = 0.270 mm + (0.007 mm * Age) + (0.065 mm *SDBG). Model 2: Carotid IMT (mm) = 0.272 mm + (0.007 mm * Age) + (0.023 mm * MAGE).Next, multiple linear regression analyses were performed to assess the independent effects of glycemic and nonglycemic variables on carotid IMT in patients without plaque n = 6  SDBG and MAGE correlated with carotid IMT only in patients without atherosclerotic plaque; (2) conventional risk factors including elder age, hypertension, increased MBG and increased LDL-C were independent predictors of plaque formation; and (3) SDBG and MAGE were not significantly different among groups with different degrees of arterial stenosis.1c level in elderly male patients with type 2 diabetes [Chronic hyperglycemia and glycemic variability are two major glucose characteristics of diabetes. The relationships between chronic hyperglycemia and chronic complications have been well-studied . By contdiabetes , albeit diabetes . On the diabetes . So far,Until now, few studies have addressed the association between glycemic variability and atherosclerosis. Chen et al.  studied in vitro and epidemiological studies suggesting that glucose fluctuation can harm the arterial wall through oxidative stress and/or endothelial dysfunction [Using the CGM system we report that, in diabetic patients without atherosclerotic lesions, SDBG and MAGE were significantly related to carotid IMT, raising the intriguing possibility that glycemic variability plays a key role in the subclinical stage of atherosclerosis. Our results are partly in agreement with several function ,5. Meanwfunction ,27. Suzufunction  found thfunction  found thfunction . For exafunction .We speculate that endothelial dysfunction may underlie the association between glycemic variability and subclinical atherosclerosis. Although atherosclerosis is commonly described as the presence of plaque obstructing the lumen of the conduit arteries, endothelial dysfunction is regarded as the initial step in the development of atherosclerosis and can be observed preceding structural atherosclerotic changes in the vascular wall or ultrasonic evidence of plaque ,33. HashOur study revealed that glycemic variability is related to subclinical atherosclerosis before the plaque is formed. On the other hand, we identified conventional risk factors such as age, hypertension, dyslipidemia and increased mean blood glucose level as important independent predictive factors for atherosclerotic plaque formation instead of glycemic variability. Indeed, substantial evidence suggests that chronic hyperglycemia plays a specific role in atherosclerosis progression in patients with diabetes . NeedlesIn light of these results, we highlight the importance of adopting a multifactorial approach to the prevention of macrovascular disease in type 2 diabetic patients. Identifying patients at risk for atherosclerotic lesions using MRA technique may be a priority. In patients with lesions, strict blood-pressure control, lipid-lowering therapy should be emphasized. For those who have negative finding by MRA, early initiation of glycemic variability management is likely to be beneficial in preventing the development and progression of atherosclerosis.The present study has some limitations. First, even though all the included patients received stable therapeutic regimen for 3 months before the study, a 2-day CGM profile may not sufficiently reflect the actual glycemic condition over a longer period. Second, because this was a cross-sectional study, our conclusions are based essentially only on correlation analysis. A larger prospective investigation is required in order to further demonstrate the role that glycemic variability plays in the process of atherosclerosis. Third, we did not assess the relationship between endothelial dysfunction and glycemic variability in the study to substantiate our results. Further studies are needed in the future.In conclusion, glycemic variability is associated with subclinical atherosclerosis in type 2 diabetic patients. Further studies will be necessary to clarify the role of glucose variability as a potential contributory factor to the complex processes of atherosclerosis development.1c: Hemoglobin A1c; FMD: Flow-mediated dilation.CGM: Continuous glucose monitoring; IMT: Intima-media thickness; 3D-TOF-MRA: 3D time-of-flight magnetic resonance angiography; CEMRA: Contrast-enhanced magnetic resonance angiography; MBG: Mean blood glucose; SDBG: Standard deviation of blood glucose; MAGE: Mean amplitude of glycemic excursions; I-ICA: Intracranial portion of the internal carotid artery; ACA: Anterior cerebral artery; MCA: Middle cerebral artery; PCA: Posterior cerebral artery; I-VA: Intracranial vertebral artery; BA: Basilar artery; CCA: Common carotid artery; E-ICA: Extracranial portion of the internal carotid artery; E-VA: Extracranial vertebral artery; ECA: External carotid artery; SUB: Subclavian artery; BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; TG: Triglycerides; TC: Total cholesterol; HDL-C: High density lipoprotein cholesterol; LDL-C: Low density lipoprotein cholesterol; HbAThe authors declare that they have no competing interests.YM, JZ, ML and WJ conceived and designed the study. XM, DL, WL and CH recruited samples, ML and ML reviewed all the MRA results, YM, JZ and ML wrote the first draft of the paper. YW and YB critically reviewed the paper and contributed to discussion, and all authors revised the manuscript for important intellectual content and have approved the final version.


Continuous systolic blood pressure (SBP) and interbeat intervals (IBI) recordings reveal sequences of consecutive beats in which SBP and heart rate change in opposite direction, representing negative feedback baroreflex mechanisms, as well as sequences in which SBP and heart rate change in the same direction (non-baroreflex), believed to represent feedforward control mechanisms. The present study was undertaken to assess the relationship between baroreflex and non-baroreflex sequences in end stage renal insufficiency.b coefficients (the regression line slope of SBP-IBI correlation) were determined using a newly developed 1 minute sliding window method, the classical sequence technique and the "Z" coefficient method. Analysis using the 1 minute sliding window showed an increased proportion of baroreflex episodes in controls and HD, and predominance of nonbaroreflex episodes in TX. An increased proportion of nonbaroreflex episodes in TX patients relative to HD was also revealed by the "Z" method. Baroreflex and nonbaroreflex b coefficients obtained by all methods were markedly decreased in HD. This alteration was reversed at least partly in TX. In HD, both baroreflex and nonbaroreflex b coefficients were inversely correlated to age and CRP levels; in TX, the nonbaroreflex b coefficient was influenced by the type of calcineurin inhibitor.Continuous beat-to-beat SBP and IBI monitoring was performed in patients on chronic hemodialysis , in age-matched patients after renal transplantation  and healthy (control) individuals . The proportion of baroreflex and nonbaroreflex episodes and the Renal status affects the contribution of baroreflex and nonbaroreflex mechanisms and the strength of SBP-IBI relationship. The predominant contribution of nonbaroreflex mechanisms in TX may be suggestive of enhanced central sympathetic control. Our data may be relevant for understanding of the pathogenesis and selection of appropriate treatment of post-transplant hypertension. Blood pressure and heart rate changes are related through various nervous and hormonal mechanisms. Sympathetic nervous system has a major role in arterial blood pressure control. Sympathetic outflow increases arterial pressure via vasoconstriction (feedforward) while elevations in blood pressure suppress sympathetic outflow via baroreflex (feedback) mechanism. Baroreflex activity is characterized by an inverse relationship between systolic blood pressure (SBP) and heart rate. Continuous recordings of systolic blood pressure (SBP) and interbeat intervals (IBI) reveal time-sequences of spontaneously occurring consecutive beats in which blood pressure and heart rate change in opposite direction . These sequences are considered to be an expression of the negative feedback mechanisms of baroreflex origin ,2. In maSequence analysis is a popular method of identifying both baroreflex and non-baroreflex sequences . The seqSpectral analysis of SBP and IBI fluctuations with calculations of α coefficient is a frequently used method to estimate baroreceptor sensitivity (BRS). This technique, however, cannot discriminate between negative and positive feedback components, i.e. is not able to identify nonbaroreflex mediated activity ,15.The estimation of "Z"-index is based on the computation of the statistical dependence between SBP and heart rate values with the Z coefficient . This meThe aim of the present paper was to analyze the interrelation between baroreflex and nonbaroreflex sequences in the larger context of end stage renal insufficiency. Within this purpose, we developed a sliding window methodology to estimate SBP-IBI correlation for longer periods of time. SBP-IBI correlations calculated during one-beat overlapping 1 minute epochs were compared with estimations obtained using the traditional sequence method , the frequency domain analysis and the Z method. We studied patients with end- stage renal disease on chronic hemodialysis and after renal transplantation as compared with normal individuals.Continuous beat to beat blood pressure recordings were obtained in 72 non-diabetic patients on chronic hemodialysis (HD), in 41 age-matched patients after renal transplantation (TX) and in 34 aged-matched normal individuals . The healthy individuals were recruited among hospital staff and medical students. The study was approved by Hadassah-Hebrew University Medical Center Ethics Committee for Clinical Research. The patients signed an informed consent form before taking part in the study.Patients with chronic atrial fibrillation or frequent ventricular premature beats, debilitating illness and frequent hospital admissions, permanent pacemakers and severely decreased radial pulses following multiple vascular accesses surgical interventions were excluded from the study. Antihypertensive drugs were stopped 12-14 hr before the study. Patients’ clinical and demographic characteristics are presented in 2) and the mean urea reduction rate (% URR) in all patients was 65-75%. The duration of the recordings was 3.5 to 5 hr for the dialysis patients and 45 min to 1.5 hr for controls and transplanted patients. In hemodialysis patients, the studies were performed on a midweek dialysis day. The mean values of indices obtained over the extended time , were considered to be most representative for dialysis patients in whom significant fluctuations in fluid balance and metabolic status occur at least 3 times weekly. All dialysis patients were treated with recombinant erythropoietin and phosphate binders  as needed.The hemodialysis patients ] 0.84 (2.10) yr) were dialyzed three-four times weekly, 3.5 to 5 hours each time. Hemodialysis was performed using a polyamide high flux dialyzer (1.3 mThe studies in transplanted patients (duration of transplantation (median [interquartile range] 0.786 [6.77]) were performed at least 3 months after recovery of renal function. Thirty six patients have been in chronic hemodialysis before transplantation; pre-emptive transplantation was performed on the remaining 6 patients. The plasma creatinine level (mean ± SD) was 115±31 µmol/l. Their maintenance immunosuppressive therapy included corticosteroids, mycophenolate mofetil or azathioprine, calcineurin inhibitors or mTOR inhibitors . Mean  levels were obtained in all dialysis and transplanted patients.Blood pressure and inter-beat intervals were measured noninvasively by Finometer 1.10 . Continuous beat to beat recording of the finger arterial pressure waveform was performed using the volume-clamp method of Penaz  and the The raw data were downloaded into a PC and analyzed by the BeatScope Software  and our specifically designed programs. The BeatScope software performs beat to beat analysis of the raw finger arterial pressure and uses filtering and level correction to calculate reconstructed brachial pressures from finger pressures. The resulting data files containing beat to beat values of hemodynamic variables such as inter-beat intervals (IBI), systolic (SBP), diastolic and mean blood pressures, were used for further processing.bsl) were calculated and compared for Control, HD and TX groups. Positive bsl were considered to be representative of the sensitivity of the baroreflex-mediated changes, while negative bsl were considered to be representative of the sensitivity of those mediated by nonbaroreflex mechanisms.Overlapping one minute time windows at one beat steps were selected for analysis of beat to beat IBI-SBP relationship during the whole recording session for each patient. The correlation coefficient and the slope of the regression line between IBI and SBP were calculated for each one minute epoch. One minute epochs with correlation coefficients higher than 0.5 were selected for analysis . The perAlthough the latter method does not distinguish between increased or decreased SBP, a good estimate is obtained for distinguishing between direct and inverse correlation of SBP-IBI. Periods longer than 1 minute did not show good correlations due to the non-stationary character of SBP and IBI changes. Overlapping periods with one beat steps are beneficial to this analysis since every stretch of data is covered and epochs with good correlations are not missed.Beat to beat systolic blood pressure (SBP) and inter-beat intervals (IBI) were scanned for sequences of SBP increase or decrease (ramps) and for sequences in which SBP and IBI either increase or decrease for at least 3 beats. The thresholds for IBI and SBP beat to beat change were 6 msec and 1 mmHg respectively.Sequences were evaluated within four categories of slope: 1. increased SBP-increased IBI, 2. decreased SBP-decreased IBI, 3.increased SBP-decreased IBI, and 4. decreased SBP-increased IBI. Representative examples of the four categories of sequences are demonstrated in 1, b2, b3 and b4). Patients’ mean slope was calculated for all valid sequences in which the correlation coefficient (R) was greater than 0.85. b1 and b2 were the regression line slopes of sequences where both SBP and IBI increase or decrease were considered as due to baroreflex response. b3 and b4 were the regression line slopes of sequences in which SBP and IBI changed in opposite directions and were considered as due to non-baroreflex episodes. Accordingly, b1 and b2 were combined as the baroreflex slope bseq, while b3 and b4 were combined as the non-baroreflex slope bseq.The derived parameters were: 1. the percent of sequences in each category out of the total number of sequences , and, 2. the slope of the regression line between IBI and SBP for at least 3 beats for each category  was defined as the square root of the ratio between the average power spectral densities of IBI and SBP in the frequency band:where The values of the above parameters were averaged for all epochs chosen for an examined subject. The α coefficient was averaged for epochs with a coherence above 0.5.Estimation of the "Z" index is a statistical method to assess the spontaneous cardiac baroreflex developed by Ducher et al ,17. A thT represents the total number of beats recorded, N  the number of occurrences of  couples and NSBP and NHR the number of occurrences of each class of SBP and IBI respectively. The number of beats in each quadrant was counted for couples with more than 10 beats in each interval and the percent from the total count of beats in the four quadrants was calculated (where Nlculated .bz) of the regression line in quadrants 1 and 3 was considered as an index of the spontaneous baroreflex sensitivity (BRS), while the value of the slope of the regression line in quadrants 2 and 4 was considered to be an index of strength of non-baroreflex relationship if the linear adjustment was significant (p<0.001).The linear regression between selected SBP and HR values were calculated for each couple with more than 10 occurrences and Z > 0. In order to emphasize couples with frequent occurrence and a strong dependence, each couple was weighted by P x Z, where P represents the estimated conditional probability of observing HR and SBP, while Z was defined above . The abs2 test. Age, SBP, DBP and PP (mean and standard deviation) were compared using Student’s t test. b indices, LF α and HF α are given as medians and interquartile ranges. Mann-Whitney U test was performed to compare bsl, bseq and bz between groups and between tertiles of hemodialysis vintage. Correlations of the absolute value of the bsl with bseq and bz, with age and with LF α and HF α coefficients were performed by Pearson correlation and linear regression analysis.Demographic and clinical categorical variables were compared by χIschemic heart disease was defined by documentation of prior myocardial infarction or of coronary interventions, the presence of significantly abnormal Q waves on a 12 lead electrocardiogram, symptomatic angina pectoris or a thallium perfusion scan suggestive of myocardial ischemia. Patients with high triglyceride or/and high LDL cholesterol levels were considered to be hyperlipidemic.Patients’ clinical data are depicted in Representative examples of baroreflex and nonbaroreflex sequences obtained by the 1 minute epochs tracings, the sequence method and the "Z' coefficient method, with direct and inverse correlations of IBI-SBP, are shown in The proportion  of baroreflex and non- baroreflex episodes obtained by 1 minute epochs (sliding-window) method, by the sequence technique and by the "Z" method are depicted in When the traditional sequence method was used, baroreflex sequences in which SBP and IBI were directly proportional, were more frequent, while the number of nonbaroreflex sequences in which SBP and IBI were inversely correlated was significantly smaller in all groups (The proportion (% of beats) of baroreflex and non-baroreflex episodes detected by the Z method is shown in bsl obtained by the 1min sliding window analysis, bseq, obtained by the sequence method and bz, obtained by the Z technique) from the three patient groups are shown in The regression slopes of baroreflex- and nonbaroreflex episodes obtained by the three above methods  in HD patients as compared to Controls were detected by all methods. The slopes of non baroreflex episodes were also significantly decreased in HD patients. A trend to an increase in the slopes of both baroreflex and nonbaroreflex episodes after TX was noted using all methods; in these patients, the increases in the baroreflex slope (bseq) using the sequence method (bz) using the "Z" method  individual and in a transplanted patient  are shown in bsl coefficient, while the remaining 45% with a negative bsl coefficient were non-baroreflex. A similar tracing for a transplanted patient is shown in Representative tracings of bsl) with those obtained using the sequence (bseq) and the "Z" (bz) methods. bsl was strongly correlated to bseq both baroreflex and nonbaroreflex episodes in all patient groups and to a lesser extent to bz, especially for TX patients. In each of the three methods, the baroreflex slopes were significantly correlated to nonbaroreflex slopes for all patients groups . Significant correlations of baroreflex and nonbaroreflex bsl slopes were also found with LFα and HFα coefficients, representative of both baroreflex and nonbaroreflex function determined by power spectrum technique  baroreflex episodes was higher in men (95%) than in women . Neither baroreflex nor non-baroreflex episodes were affected by age, basic renal or background diseases, biochemical data, antihypertensive or immunosuppressive drugs (not shown in figures). The effect of dialysis vintage on the proportion of baroreflex episodes in HD and TX patients is shown in bsl slopes of both baroreflex and nonbaroreflex episodes in all study groups were markedly negatively correlated to age . Similar correlations with age and CRP were also noted for bseq (data not given). There were no correlations of the b coefficients with other biochemical parameters.d to age . In HD pb coefficients  of baroreflex episodes were similar in patients treated with cyclosporine or tacrolimus. In nonbaroreflex episodes, bsl, bseq and bz (median (interquartile range)) were 3.10 (1.90), 8.85 (4.10) and 0.26 (0.17) in patients treated with cyclosporine and 2.20 (1.30), 7.10 (5.20) and 0.31 (0.20) in those treated with tacrolimus  of SBP-IBI correlation of both baroreflex and nonbaroreflex episodes was decreased in HD patients as compared to controls; a similar decrease was also detected by other methods. A mild increase of both baroreflex and nonbaroreflex slopes, independent of methodology, was noted in TX  windows. This method made possible the assessment of SBP-IBI relationship for longer time epochs, as compared with the analysis of short transient sequences of few cardiac beats in the sequence method. Analysis of overlapping 1 minute epoch time windows also provided different correlations between SBP and IBI than those obtained by the "Z" method that is based on the statistical dependence between SBP and heart rate. The main findings of the evaluation by overlapping 1 minute epochs window methodology were: 1. baroreflex episodes were predominant in Controls and HD, while nonbaroreflex episodes were predominant in TX. A higher proportion of non-baroreflex episodes in TX as compared to HD was also revealed by the "Z" methodology. In contrast, the sequence technique demonstrated a higher proportion of baroreflex than the nonbaroreflex episodes in all groups, independent of renal status . 2. The ed in TX . 3. bsl ts group . The b cIt is generally believed that the control of arterial blood pressure occurs by both feedforward  and negative feedback (baroreflex) responses. Thus, sympathetic outflow increases of the arterial pressure via vasoconstriction (feed forward) may be counterbalanced by baroreflex feedback elicited by the elevation in the blood pressure. The preponderance of one mechanism over the other has been debated by several investigators ,23. A rePrevious studied performed in healthy individuals using the sequence techniques have shown a higher proportion of baroreflex than that of nonbaroreflex sequences ,26. StudIn our study, using the new sliding windows 1 min epochs technique and the less frequently used "Z" methodology, we were able to show a predominance of the baroreflex mediated episodes (feedback) in Controls and also in HD, and of non- baroreflex (feedforward) episodes in TX. For TX patients, the 1 min epochs technique was most discriminatory. The classical sequence technique, which analyses transient variations in blood pressure and heart rate, is based on the presence of short sequences as defined (see Methods); in many cases, even during long term  recordings, only scarce sequences meeting the above criteria could be found, thus limiting the ability of the technique to differentiate between groups. In contrast, many 1 min epochs with significant (r>0.5) SBP-IBI correlations (the sliding window method), as well as dependent (SBP- heart rate) couples with Z>0 (the "Z" method) could be found in each patient group. Moreover, the 1 min epoch sliding window yields information on SBP- IBI coupling on a longer timescale than the sequence method. The relevance of the timescale in assessing has been pointed out by a previous study that assessed fluctuations in SBP and IBI using both short term (sequence) technique and cross correlation (long term) functions . In thatThe prevailing nonbaroreflex-mediated episodes in TX may suggest a different type of regulation of the arterial pressure in these patients. The nonbaroreflex type of SBP heart rate relationship is believed to be representative of centrally mediated sympathetic activity. This hypothesis is supported by studies performed in experimental animal and in humans that showed that the non-baroreflex activity is abolished by sympathectomy or complete autonomic blockade, but may increase after parasympathetic blockade ,16,17,26b coefficient, i.e. the regression slope of SBP-IBI correlation, is a measure of the strength of blood pressure-heart rate relationship. The b coefficient of the baroreflex episodes determined by the sequence technique (bseq) representing the magnitude of the heart rate response to spontaneous blood pressure changes, is one of the most commonly used methods of baroreflex sensitivity determination and is strongly affected by the renal function [bseq, bsl and bz are decreased in HD patients, and restored at, least partly in TX [bseq of baroreflex episodes was significantly correlated with b coefficient determined by 1min sliding windows epoch (bsl), and to a lesser extent to bz . Both types of b slopes were significantly correlated to α coefficients and negatively correlated to age  of nonbaroreflex episodes in patients treated with cyclosporine may support previous observations [In TX patients, the finding of greater rvations  that shorvations .The main shortcoming of our study is the use of noninvasive methodology of assessment of autonomic nervous function, since MSNA studies were not available or not-applicable to the majority of our patient population. Because of the relative small number of transplanted patients, only limited comparisons of specific effects of drugs, such as cyclosporine versus tacrolimus, could be performed. Our study patient population included many elderly individuals with multiple comorbidities. These patients however, are most characteristic of the present day hemodialysis and even transplant population.Using the new 1 min epochs sliding windows method as well as conventional techniques, we showed that renal status may affect the distribution of baroreflex and nonbaroreflex activity, as well as the strength of systolic blood pressure-heart rate relationship. Baroreflex sequences are more frequent in hemodialysis patients, while nonbaroreflex episodes are most frequently encountered in transplanted patients.b coefficients, representative of the magnitude of heart rate response to blood pressure oscillations, are significantly decreased and inversely correlated to the inflammatory marker CRP. In transplanted patients, this decrease is at least partially reversed, and seems to be related to the type of calcineurin inhibitor. Our data may be relevant for understanding of the pathogenesis and selection of appropriate treatment of post-transplant hypertension.The predominant nonbaroreflex contribution may suggest enhanced sympathetic control in these patients. In hemodialysis patients, both baroreflex and nonbaroreflex


Although patients have more problems using metered dose inhalers, clinical comparisons suggest they provide similar control to dry powder inhalers. Using real-life situations this study was designed to evaluate asthma control in outpatients with moderate to severe persistent asthma and to compare efficacy of fixed combinations of inhaled corticosteroids (ICS) and long acting beta-agonists (LABA).This real-life study had a cross-sectional design. Patients using fixed combinations of ICS and LABA had their asthma control and spirometry assessed during regular visits.111 patients were analyzed: 53 (47.7%) received maintenance therapy of extrafine beclomethasone-formoterol (BDP/F) pressurized metered dose inhaler (pMDI), 25 (22.5%) fluticasone-salmeterol (FP/S) dry powder inhaler (DPI), and 33 (29.7%) budesonide-formoterol (BUD/F) DPI. Severity of asthma at time of diagnosis, assessed by the treating physician, was comparable among groups. Asthma control was achieved by 45.9% of patients; 38.7% were partially controlled and 15.3% were uncontrolled. In the extrafine BDF/F group, asthma control total score, daytime symptom score and rescue medication use score were significantly better than those using fixed DPI combinations  and the mean daily ICS dose were significantly lower.pMDI extrafine BDP/F combination demonstrated better asthma control compared to DPIs formulated with larger particles. This could be due to the improved lung deposition of the dose or less reliance on the optimal inhalation technique or both. While asthma represents a global public health issue due to high prevalence rates in the general population (ranging from 1% to 18% of the population in different Countries), several studies now indicate that the impact on public health is even more severe due to the difficulty in achieving full disease control with available therapies . Indeed,However, RCTs are performed under highly controlled settings and in selected populations of patients. Under these controlled conditions, good inhalation technique is usually checked and granted and the importance of compliance is emphasized. Such a level of adherence is not to be expected in real-life settings. In an effort to find a strategy leading to improved asthma care, the International Primary Care Respiratory Group (IPCRG) examined the main factors contributing to poor control of the disease . Among tInhalers for fixed combinations of ICS and LABA include pMDIs and DPIs. It is known that choice of the correct inhaler device is crucial since sub-optimal inhalation techniques can result in reduced drug delivery and efficacy and it should be adjusted to different patients ,8. A metA new fixed combination of BDP/F has been recently developed. The innovative formulation of BDP/F pMDI is characterized by extrafine particle size  which reThe aim of this observational study was to evaluate the level of asthma control in a group of patients with moderate or severe persistent asthma (at the time of diagnosis) and to compare, in a real-life setting, efficacy outcomes achieved with extrafine BDP/F delivered via pMDI vs. ICS-LABA combinations (FP/S and BUD/F) delivered via DPIs.This real-life study had a cross-sectional design and involved a group of asthmatic outpatients from the Department of Pulmonology, Semmelweis University Budapest, Hungary. Patients were consecutively recruited during their regular visits to the outpatient department from May 2008 until August 2008.Male and female asthma patients aged above 18 years were eligible for inclusion in the study if: 1) they had a diagnosis of moderate or severe persistent asthma confirmed by chest physician; 2) diagnosis occurred at least 6 months before the beginning of the study; 3) they were treated with fixed combination of ICS and LABA as maintenance therapy; 4) they did not change their medication within the last 4 weeks prior to start of study; 5) they had no asthmatic exacerbation within the last 6 weeks prior to start of study. Patients were excluded if they had any other chronic disease (except chronic rhinitis), extreme obesity, or if any acute disease occurred within the last 6 weeks prior to start of study. Patients were enrolled regardless of their smoking history or habit. Asthma severity was evaluated at the time of diagnosis and assessed by the treating physician.The study was approved by the institutional Ethics Committee of the Department of Pulmonology, Semmelweis University. No consent was obtained from the participants as it was a non-interventional retrospective data analysis of the real-life data collected on the usual visits of patients. No intervention was done only for the sake of the study.Asthma control was assessed by patients using a questionnaire Table  developeTo determine if other factors may influence the level of asthma control, the following information was collected from patient records: date of diagnosis, smoking status, history of allergy, asthma maintenance and reliever therapy.1), peak expiratory flow (PEF), forced expiratory flow between 25 and 75% (FEF 25-75%), maximum expiratory flow (MEF) 25%, and MEF 75% were collected. Lung function was analyzed using an electronic spirometer  according to the American Thoracic Society (ATS) guidelines [Spirometric measurements were performed and data on forced expiratory volume at 1 s . For the purpose of the study, patients were divided in two groups depending on the inhaler device they were using (pMDI or DPI). No significant difference in patient characteristics between these two groups was found Table . The sevThe proportions of patients with different levels of asthma control in the two study groups and in the whole study population are shown in Table Mean asthma control score was significantly lower for the extrafine pMDI group as compared to the DPI group (p = 0.016) indicating a better asthma control in extrafine pMDI-treated patients Figure . When loNotably, the mean daily ICS dose was significantly lower in the extrafine pMDI group as compared to the DPI group, suggesting an overall better asthma control with a lower steroid load , 38.74% of the patients proved to be controlled, 38.74% and 22.52% partially controlled and uncontrolled, respectively.Current or previous smoking was common in asthmatic patients enrolled in this study (35%), with a mean smoking history of 19.0 ± 3.6 pack/years. No gender difference between smokers was noted. While smoking status did not influence steroid dose used, it significantly increased the proportion of uncontrolled patients as compared to never smokers . Asthma control in smokers is summarized in Table This is the first real-life study comparing the clinical effects of BDP/F extrafine to other combinations. Previously published RCTs found that there were no differences between BDP/F extrafine pMDI and BUD/F or FP/S in terms of lung function, use of rescue medications, exacerbations and safety ,23. HoweThe results show that asthma control was significantly better in patients receiving BDP/F extrafine pMDI formulation compared to the DPI group. Daytime symptoms and use of rescue medications were significantly lower in the BDP/F extrafine pMDI group, further supporting a greater control of asthma in a real-life setting. Asthma is an inflammatory disorder affecting both central and peripheral airways ,25, whicIn our real-life study, current or former smokers were not excluded since they represent a large proportion of asthmatic patients. Generally, the level of asthma control in smokers was similar to that in non smokers; however, the proportion of uncontrolled patients was significantly increased in these patients as compared to never smokers. Smoking asthmatics are mostly excluded from clinical trials, therefore only sparse data are available on asthma control in current or former smoker asthmatic patients.Notably, these results were obtained with a lower mean daily ICS dose indicating that BDP/F extrafine delivers a greater efficacy per μg of steroid when compared to BUD/F and FP/S. This is of interest considering that reduced compliance in asthmatic patients is often due to steroid phobia, an issue that can be decreased by offering a medication with a low corticosteroid dose .In the studied population, 45.9% of patients had controlled asthma, 38.7% were partially controlled, and 15.3% were uncontrolled. These findings are in agreement with recent observational trials focusing on asthma control. A study performed across 10 different European countries showed that asthma is suitably controlled in 45% of non-inhaled corticosteroid users and only in 15% of patients using ICS .This real-life observational study shows that GINA-based asthma control is achieved in a good proportion of asthmatic patients treated with fixed combinations of ICS and LABA. Patients treated with BDP/F extrafine pMDI achieved a greater level of asthma control as compared to patients treated with FP/S or BUD/F larger particle combinations, suggesting that differences in inhaler devices and formulations can have an impact on important clinical outcomes and should be therefore taken into consideration when managing patients with asthma.In asthmatic patients with comparable disease severity, the use of extrafine BDP/F combination formulated in a pMDI demonstrated better asthma control than using DPI fixed dose combinations formulated with larger particles. This could be due to the improved lung deposition and distribution of the dose or less reliance on the optimal inhalation technique or both.Henry Chrystyn has no shares in any pharmaceutical companies. He has received sponsorship to carry out studies, together with consultant arrangements with Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Innovata Biomed, Meda, Napp Pharmaceuticals, Orion, Teva, Truddell and UCB. Research sponsorship has also been received from grant awarding bodies (EPSRC and MRC).Lilla Tamasi, Veronika Müller, Gabriella Galffy and György Losonczy have no shares in any pharmaceutical companies. All of them have consultant arrangements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, Pfizer and Nycomed.Andrea Bizzi and Gabriele Nicolini are employees of Chiesi Farmaceutici S.p.A.The study was conducted by Semmelweis Medical University, Department of Pulmonology, Budapest, Hungary, without financial support from any pharmaceutical company.VM, GG, TL participated in conception and design of the study, acquisition, analysis and interpretation of data, as well as in drafting of the manuscript. EN, LGY participated in study design, analysis and interpretation of data and have been involved in drafting of the manuscript. GN and AB participated in drafting and reviewing the manuscript. HC provided external advice and received regular updates. He participated in the design and analysis of the data as well as involvement with drafting of the paper. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/11/40/prepub


The objective of the study was to identify factors associated with hs-cTnT levels during AECOPD.A high-sensitivity cardiac troponin T (hs-cTnT) concentration above the 99We included 99 patients with AECOPD on admission. As 41 patients had one or more repeat admissions, there were 202 observations in the final analysis. We recorded clinical and biochemical data, medication, spirometry, chest radiographs, and ECGs. The data were analysed for cross-sectional and longitudinal associations using ordinary least square as well as linear mixed models with the natural logarithm of hs-cTnT as the dependent variable.1/FVC was 45%, and median hs-cTnT was 27.0 ng/L. In a multivariable model there was a 24% increase in hs-cTnT per 10 years increase in age (p < 0.0001), a 6% increase per 10 μmol/L increase in creatinine (p = 0.037), and a 2% increase per month after enrollment (p = 0.046). Similarly, the ratios of hs-cTnT between patients with and without tachycardia (heart rate ≥100/min) and with and without history of arterial hypertension were 1.25 (p = 0.042) and 1.44 (p = 0.034), respectively. We found no significant association between arterial hypoxemia and elevated hs-cTnT.Mean age at inclusion was 71.5 years, mean FEVAge, arterial hypertension, tachycardia, and serum creatinine are independently associated with the level of hs-cTnT on admission for AECOPD. Cardiovascular disease (CVD) is frequent in chronic obstructive pulmonary disease (COPD) -5. This th percentile (i.e. 14 ng/L), was present in 74% of patients admitted for acute exacerbation of COPD (AECOPD) and that such injury carried a markedly increased risk of subsequent mortality [We recently showed that myocardial injury, defined as high-sensitivity cardiac troponin T (hs-cTnT) above the 99ortality . We propth generation assay was positively associated with increasing serum creatinine, blood neutrophil cell count, and cardiac infarction injury score (CIIS), whereas it was negatively associated with hemoglobin level [In a previous cross-sectional study among patients hospitalised for AECOPD, we found that cardiac troponin T measured with a 4in level . In thatOur objective was to identify clinical factors that are associated with the level of hs-cTnT in patients admitted with AECOPD using cross-sectional as well as longitudinal analyses of the association between these determinants and concurrent hs-cTnT.2, PaO2), arterial oxygen saturation (SaO2), use of accessory respiratory muscles, wheezing, and chest pain. Mean arterial pressure (MAP) was estimated by the formula MAP = 1/3*systolic BP + 2/3*diastolic BP.During 23 months in 2005 and 2006 we prospectively included 99 unselected patients admitted with AECOPD. Among these, 41 patients had data recorded on readmission during the inclusion period, and in total we gathered data on 219 admissions. On each admission we recorded heart rate (HR), blood pressure (BP), body temperature, respiratory rate, arterial blood gas  was estimated by MDRD and Cockcroft-Gault formulae [Serum and plasma from blood drawn on admission were stored at −80 °C for subsequent analysis of creatinine and hs-cTnT . According to the manufacturer of the hs-cTnT assay, the lower limit of detection is 3.0 ng/L, and the 99formulae ,16. Fromformulae , and to formulae . Two phySpirometry during stable phase was recorded when available. When several measurements were done, post bronchodilatation measurements prior to inclusion were preferred. Body mass index (BMI) was calculated from weight and height as recorded on the spirometry report or from the hospital records when spirometry was missing. Medical history was obtained by patient interview and hospital records. Patients were categorised as current, former (>1 year abstinence) or never smokers. Further details regarding patient inclusion and data gathering are described in a previous paper .The study was approved by the Data Inspectorate and reviewed by the Regional Committee for Research Ethics. All included patients provided written informed consent to the participation in the study.t-test. The continuous variables were dichotomised at predifined cut-offs: Age at the mean, FEV1/FVC at the lower quartile, BMI at the lower limit of normal (i.e. 20 kg/m2), HR at 100/min, MAP at 90 mmHg, creatinine and neutrophil count at the upper quartile, pH at 7.30, PaCO2 at 6.3 kPa, PaO2 at 7.0 kPa, Hb at 12 g/dL in women and 13 g/dL in men, CRP at 50 mg/L, and CIIS at 20 points. In addition, the association between lnTnT and the following categorical variables were analysed: Gender, smoking status, history of coronary artery disease, heart failure, arterial hypertension, atrial fibrillation or diabetes, use of beta blockers, diuretics, ACE-inhibitors (ACEI) or angiotensin-II receptor blockers (ARB), statins, acetylic salicylic acid, or Warfarin, presence of atrial fibrillation, LVH, MI, or ischemia on ECG, peripheral edema, chest pain, and infiltrate or cephalisation on chest radiograph. Associations between continuous covariables at baseline and lnTnT were also analysed in a univariable linear regression model.Due to the skewed distribution of hs-cTnT, the natural logarithm of hs-cTnT (lnTnT) was used as the dependent variable in the analyses. Samples with hs-cTnT below the limit of detection (i.e. 3.0 ng/L), were assigned a value of 3.0. Outliers were identified by visual inspection of the data points. Individual assessment of outliers determined whether they were to be excluded from further analyses. The analyses were performed in four steps: First, we analysed cross-sectional associations between lnTnT and variables recorded on the index admission using Student Second, in patients with repeat admissions, we investigated the level of lnTnT over time; first graphically and then by using time and time squared as independent variables in a linear mixed model (LMM) .In the third step, we investigated intra-individual univariable associations between lnTnT and each of the continuous covariables. We identified the minimum and maximum values of continuous time-dependent variables along with the corresponding values of hs-cTnT. We then analysed the univariable associations between lnTnT and each of the continuous covariables using LMM with random intercept. From these analyses, the antilogarithm exp(β) of the coefficient (β) between lnTnT and each covariate can be interpreted as the relative change in lnTnT for a given change in the covariate.Fourth, the variables that were associated with lnTnT with a p-value <0.2 in the cross-sectional or longitudinal analysis were included in the initial multivariable LMM. In this model we investigated candidate covariance structures and a model with random intercept. The models were compared using the Akaike Information Criteria (AIC). Using the model with the lowest AIC, we then manually reduced the model by backward elimination of variables with p-values <0.05 unless their removal increased the AIC statistic. Finally, we investigated the changes made by adding survival status and neutrophil count to the final model. Gender was kept in the model by convention.All analyses were performed in SAS 9.2 , using PROC MIXED for the LMM.1/FVC was 45% (SD 0.14), and median hs-cTnT was 27.0 ng/L (interquartile range (IQR) 13.4–51.0). LnTnT was close to normally distributed with mean 3.24 (SD 0.97), corresponding to a geometric mean of hs-cTnT = 25.6 ng/L. Of the 219 samples, two (0.9%) had hs-cTnT below the detection limit. The distribution of hs-cTnT and lnTnT are shown in Figures Mean age at inclusion was 71.5 years (standard deviation (SD) 9.0), mean FEV2, and 2% were <30 mL/min/1.73 m2.Using the Cockcroft-Gault formula, mean GFR was 85 mL/min (SD 31). Using the MDRD formula, 15.5% of the 219 samples had estimated GFR <60 mL/min/1.73 mt-test p-values 0.692 and 0.367, respectively). Moreover, we did not find any association between hs-cTnT and lung function. The patients with FEV1/FVC in the lower quartile (<0.34%) had a geometric mean of hs-cTnT = 26.1 ng/L compared to 26.6 ng/L among patients with FEV1/FVC in the upper three quartiles (p = 0.945). When restricting the analysis to the 80 patients with post bronchodilatation measurements, the p-value was 0.890. There was no statistically significant difference in hs-cTnT level among patients who had spirometry recorded and those who had not .Spirometry was available in 88 patients. 80 of these 91%) were post bronchodilatation measurements. BMI was unavailable in five patients, and arterial blood gas was missing in eight. In total, complete datasets were available for 202 admissions. The results of the cross sectional univariable associations with hs-cTnT are shown in Table % were po2, and heart rate (borderline) were significantly associated with lnTnT.41 patients had one or more (maximum 10) repeat admissions, adding up to a total of 161 readmissions. Table 2 and PaO2. In this model BMI, Hb, HR, PaCO2, and PaO2 were dichotomised as previously described. A model with fixed effects only gave the lowest AIC statistic, and a spatial exponential covariance structure had the best fit. Reduction of the full model gave the final model (model 1) shown in Table 2  failed to reach significance, it is adjusted for in the final model as their removal increased the AIC statistic.According to the criteria outlined above, the following variables were included in the initial multivariable model: age, gender, time since inclusion, history of coronary artery disease or arterial hypertension, smoking, BMI, chest pain, Hb, creatinine, cephalisation, use of diuretics, ACEI/ARBs or a statin, HR, PaCOWhen survival status was added to the final model, it proved significantly associated with hs-cTnT, with a relative value of 1.58  among individuals who died during follow-up, rendering model 2 in Table Removing the outlier from the analyses made no significant changes in any of the results above.In this study hs-cTnT was positively associated with age, history of arterial hypertension, tachycardia, creatinine, and follow-up time among patients hospitalised for AECOPD. The strength of this study is that the patients were followed prospectively, and that as many as 41% of the patients were investigated at two or more admissions. Consequently, the associations could be investigated longitudinally as well as cross-sectionally. We have also used the novel highly sensitive cardiac troponin T assay, allowing us to measure concentrations down to about 1/10 of what was previously possible, finding detectable cTnT in almost all samples.Regarding the association between hs-cTnT and arterial hypertension, one might speculate that this was due to the development of LVH, as LVH have been found to be associated with troponin in other studies ,21. HoweThe association between hs-cTnT level and creatinine deserves some comment. In clinical practice, we often experience elevated levels of troponin in patients with renal failure, but without overt cardiac disease. It has been previously debated whether this is due to reduced renal elimination of troponin, but it may rather be a result of subclinical release of cTnT in these patients, as renal and cardiac atherosclerotic disease are pathophysiologically similar and partly overlapping. It may be worth noting that the majority of our patients had normal creatinine, an observation that favors the latter of the two theories. It may be argued that due to reduced muscle mass, patients with advanced COPD may have decreased renal function in spite of creatinine within the reference range. The finding that the addition of low BMI improves the fit of the final model, adds to this argument. We therefore estimated GFR, but still found that renal function was preserved in the vast majority of patients.2 and hs-cTnT. Although we found such an association in the univariable longitudinal analysis, it was not significant in the cross sectional or multivariable analyses. Hence, our data do not support that elevated hs-cTnT in these patients can be explained as a type 2 MI mediated hypoxemia. However, patients with normal arterial oxygen tension in the emergency room may have received oxygen therapy in the ambulance, yet have had severe arterial hypoxemia before admission to the hospital causing cTnT leakage from the cardiomyocytes. Thus, the lack of association between hypoxemia and elevated hs-cTnT should be interpreted with caution.Although the cross-sectional analyses of the baseline data indicated an inverse association between tachycardia and hs-cTnT, longitudinal multivariable analysis showed a significant positive association between elevated hs-cTnT and tachycardia. This may be due to an effect of heart rate per se, but it may also reflect worsening of pulmonary hypertension and increased myocardial strain, undiagnosed pulmonary embolism, or a type 2 MI caused by insufficient oxygen delivery relative to the increased demand during tachycardia. Along this line of thinking, we would also expect an association between reduced PaOOur analyses are based on data from repeat admissions by applying the linear mixed model . Among tOur group has previously published results from a retrospective cohort study of 441 patients with AECOPD, identifying creatinine, hemoglobin, neutrophil count, heart rate and CIIS as independent predictors of elevated cTnT (≥0.04 μg/L) . In the Other limitations of this study include the modest size of the cohort, which may explain the inconsistency regarding tachycardia, and the nonsignificant association with hypoxemia. Nevertheless, we identify associations that are both statistically significant and physiologically plausible. The strengths of the associations may be unimpressive, with an estimated 44% increase in hs-cTnT in patients with hypertension as the strongest association. The range of hs-cTnT concentrations is small, however, so strong associations can not be expected. Moreover, in spite of this narrow range, relatively small changes in hs-cTnT are associated with markedly adverse prognosis in this group . Thus, iAlthough patients with confirmed PE were excluded from the study, the diagnosis was not systematically investigated, and unrecognised PE may have influenced the results.Age, arterial hypertension, tachycardia, and serum creatinine are independently associated with the level of hs-cTnT at admission for AECOPD.The authors declare that they have no competing interests.All authors had full access to the original data and vouch for the completeness and veracity of the data and data analyses. All authors contributed to data interpretation and to the writing of the report, made final decisions on all parts of the report, and read and approved the final manuscript. PHB, TAH, TO and VS designed the study. PHB interviewed and enrolled the patients. AHD and VS confirmed the diagnoses, undertook the statistical analyses and generated tables and figures. AHD and PHB analysed the ECGs. VS reviewed the radiographs.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/12/22/prepub


The computational fluid dynamics method, which provides an estimation of the pressure drop in the airway before and after the stent implantation, is proposed in this study. This method is based on the finite volume model. The pressure field was solved by the Navier-Stokes equations. The proposed methodology was evaluated in seven health people (control group) and in fourteen patients who were assigned in two groups, in which one was tracheal stenosis and the other was bronchial stenosis. The results showed that the pressure drop after tracheal stent implantation became significantly smaller. For bronchial stent implantation cases, the airway resistance improved insignificantly. Airway tumors related to central airway compression produces dyspnea, stridor, hemorrhage, obstructive pneumonia, or combinative syndromes. These patients branded with a poor prognosis may not benefit from surgery with a curative intent; however, they will require procedures for palliation with the hopes of being provided with an improved quality of life. In 1915, Brunings and Albrecht . From thComputer tomography (CT) with two-dimensional (2D) or three-dimensional (3D) reconstruction image study can help to evaluate the improvement of the anatomic structure. However, the real alteration of airflow and the spread of gas particles in central airway before and after airway stents placement could not be accurately accessed before the Computational Fluid Dynamics (CFD) software was applied to mimic the internal luminal 3D airflow alteration , and to Our research was reviewed and approved by the Institutional Review Board (IRB) at our institution. Subjects were all recruited at the China Medical University Hospital in Taiwan who underwent tracheobronchial stents  placement in the airway. Twenty-one participants were classified into three groups and diagnostic data were listed in Table The computed tomographic images of the studied subjects were acquired by the GE Medical Systems, Light Speed or by the GE Medical Systems, Bright Speed. The matrix size was 512× 512, the field of view (FOV) was 360-370 mm. The corresponding volxel size was around 0.7 mm ×0.7 mm × 1.25 mm. The slices of CT images were from 198 to 325. The follow-up time interval for most of the patients receiving stent implantations was about 6 months. In some patients receiving bronchial stent implantation, however, the follow-up time period could be up to 12 months.The tracheal or bronchial stents were placed by flexible bronchoscope  from mouth to obstruction sites. Prior to the sent placement, each patient received intravenous sedation (midazolam 5 mg) and local anesthetic (2% xylocaine). After evaluation of the chest computed tomography (CT) images, an Ultraflex SEMS  guide wire was inserted from the proximal to distal site of obstruction in the tracheobronchial airway by a chest medicine doctor. The doctor determined the size of the stent and the location of the stent placement by taking into account of the type, length, and location of the airway stenosis. The overall process of stent setting up was shown in Figure In order to simulate the airflow in the airway, the CFD technique was used for modeling. In this study, we used the three software packages to reconstruct the 3D airway anatomy geometry, to generate the volume mesh, and to calculate the pressure drop before and after the stent implantation, as shown in Figure First, the segmented images from the original CT  DICOM images were processed by the Amira software package. The three-dimensional airway surface reconstruction was created with exclusion of the tracheal cartilage. Second, the volume mesh was generated by the ANSYS CFD ICEM 11.0. Third, the velocity/pressure field in the airway was solved by the CFD-ACE software package.-5 kg m-1s-1 in numerical simulation. According to the airflow rate of van Ertbruggen et al. [-1 and the constant pressure of the outlet was applied to 0 Pa in this study. The boundary conditions of the CFD model were shown in Figure Constant air pressure was imposed at the outlet when the constant flow rate was applied at the inlet. The wall of the airway was assumed as the no-slip boundary . The viscosity of air was set to 1.864.10n et al. , the air-1 and the outlet pressure was set to 0 Pa) . We analyzed the changes of the cross-sectional area of the inlet and outlet and pressure drop in the airway for these 7 subjects (the inlet flow rate was set to 100 ml sa) Table . In thesThe changes of the cross-sectional area and pressure drop before and after the tracheal stent implantations were listed in Table For 7 patients with bronchial stent placements, the values of the cross-sectional areas of the inlet before and after stenting were 2.81 ± 0.33 cm and 2.63 ± 0.24 cm respectively. There is a small difference of the area between before and after bronchial stenting implantations. The average pressure drop before bronchial stent placement was 0.97 ± 0.55 Pa. After bronchial stent placement, the average pressure drop was 1.24 ± 0.97 Pa after placement. When comparing the 7 healthy subjects and the 7 patients with bronchial stenosis diseases, the pressure drop for the patients before bronchial stent implantation was greater than that of the healthy people 0.70 Pa v.s. 1.24 Pa. On the other hand, the airway resistance was higher in patients with bronchial stenosis even after bronchial stent implementations.In the clinical measurements, we did pulmonary function test (PFT), including FEV1, PEF , FEV1%, and FEV1/FVC ratio  for some patients with stent placements. The results of two patients correlated with the results of numerical analysis of airflow alteration were given here. For the tracheal stenosis .For the bronchial stent implantation cases, the pressure drop of the airway changed insignificantly. Miyazawa  also demIn this study all the 14 patients were originally arranged to have the pulmonary function tests but not all of them can be completed for the study due to the general poor condition and dyspnea of the patients. Eventually only eight patients had pre-stent PFTs, five had post-stent PFTs, and four had both pre- and post-stent PFTs for comparison. From the two examples shown in Table There are some limitations of this pilot study. First, the case number is small and larger numbers are urgently needed for further evaluation. Second, the limited cases are of different tumor types and cancer stages so that the temporarily analyzing classification may not be so conclusive. Third, the lack uniform following up time schedule in this retrospective study, such as the time of computed tomography, may also cause some errors in the analysis.In conclusion, we provide a comprehensive model to systematically evaluate patients with obstructive lung tumor. From the limited examples we have found that CFD numerical results correlated well with the results of PFTs, indicating that CFD can potentially become a clinical prognosis prediction tool to assess lung cancer patients who have poor general condition and PFTs cannot be successfully applied to. Also, we found that tracheobronchial stent placement indeed improve cancer patients’ quality of life by lowering the resistance in their respiratory tract. The model is very helpful in not only evaluating the outcome of personalized stent placement but following up of each patient undergoes tracheal and/or bronchial stent placement.All the authors declare that they have no competing interests.CYH designed the case-control study used for this analysis, literature review, interpreted the results, and drafted the manuscript. HML and TCS ran the computer algorithm and did the computational fluid dynamics simulation of the airflow field in the airway. CYT and CMS recruited subjects and performed airway stent placement studies. CYH, MYLS and JHC designed the case-control study and interpreted the results. All authors read and edited the manuscript, and approved the final manuscript submitted for publication.