Propensity score matched analysis also showed that the matched-pressor group had a higher risk of the outcome than the matched-control group . Moreover, the Bayesian network showed a direct causal relationship from the use of pressor approaches to the outcome. The use of oral vasopressors , intravenous injection of vasopressors  and normal saline  were associated with a high risk of the outcome. In conclusion, this study showed that the use of pressor approaches during HD may be an independent risk factor for death.Because hypotension during hemodialysis (HD) makes continuation of HD difficult and is associated with mortality, pressor approaches are necessary for patients with hypotension. However, the relationships between the pressor approaches and the risk of death have not been clarified yet. We analyzed data from a nationwide prospective cohort study of the Japanese Society for Dialysis Therapy Renal Data Registry . The outcome was all-cause one-year death. The association between the use of pressor approaches and the outcome was examined using Cox proportional hazards models adjusted for baseline characteristics, propensity score matched analysis and Bayesian networks. The background features of the patients were as follows: male, 59.6%; average age, 64.5 ± 12.5 years; and patients with diabetes mellitus, 31.5%. The pressor group showed a higher risk of the outcome than the control group [adjusted hazard ratio (aHR) 1.33 ,  Because CVD is strongly associated with blood pressure, the control of blood pressure is one of the most essential strategies for hemodialysis (HD) patients.Cardiovascular disease (CVD) is one of the leading causes of death in dialysis patients in Japan, and the CVD-caused death was 32.6%2. That is, the relationship between post-HD systolic blood pressure and CVD-caused death showed a U-shape. According to the Annual Dialysis Data Report 2005 of the Japanese Society for Dialysis Therapy (JSDT) Renal Data Registry (JRDR), which is a nationwide renal data registry and contains data of all dialysis patients  in Japan, the percentages of HD patients with post-HD systolic blood pressures lower than 100 mmHg and higher than 180 mmHg were 5.0% and 5.3%, respectively3.It has been reported that post-HD systolic blood pressures higher than 180 mmHg and lower than 110 mmHg indicated a high risk of CVD-caused death in HD patients4. HD-related hypotension includes as chronically sustained hypotension, intradialytic hypotension (IDH), and orthostatic hypotension5. The dialysis outcomes and practice patterns study (DOPPS) showed that the risk of death in HD patients is high at a pre-HD systolic blood pressure of lower than 130 mmHg6. HD-associated hypotension is a risk factor for death7. IDH is associated with CVD and CVD-caused death8.Hypotension is often encountered in HD patients5. A systematic review of ten studies showed that post-HD systolic and diastolic blood pressures were increased by midodrine treatment9. In Japan, the most commonly used vasopressors per os (po) were midodrine hydrochloride, amezinium metilsulfate, etilefrine hydrochloride, and droxidopa. Etilefrine hydrochloride is also used as a vasopressor administered by intravenous injection (iv). Catecholamine preparations are used as vasopressors (iv), but at a low frequency. And a systematic review showed that low-temperature dialysis improves blood pressure during HD and reduces the rate of IDH10. However, a cohort study have reported that midodrine is associated with high risk of death11. The effects of the treatment of IDH may not be always beneficial.When hypotension occurs during HD, HD continuation is sometimes difficult. Therefore, to prevent hypotension, its management is required such as discontinuation of ultrafiltration, enhancement of plasma refilling, administration of vasopressors, low-temperature dialysis, and changing to other methods of dialysisAlthough pressor approaches are necessary for patients with hypotension, its effect on HD patients’ prognosis has not been clarified yet as far as our literature research has shown. Because a randomized controlled trial can hardly show which combination of pressor approaches is effective in preventing hypotension and improving HD patients’ prognosis, there is no evidence of how to use pressor approaches. Therefore, the aims of this study were to investigate the relationships between the use of pressor approaches and one-year all-cause death, and to determine the appropriate methods to use such approaches on the basis of JRDR data.From the JRDR data, pressor approaches included low-temperature dialysis, the vasopressors (po), and the intravenous injection of medicines . The subjects were categorized into the pressor and nonpressor groups on the basis of the use of pressor approaches. The baseline characteristics including biochemical data are shown in Table The pressor group showed larger numbers of females, subjects with CVD, and subjects with diabetes mellitus (DM) as the cause of end-stage renal disease (ESRD); older age; higher body mass index (BMI); lower serum albumin and creatinine levels; higher serum C-reactive protein (CRP) level; and higher fluid removal rate. The mean pre-HD, post-HD blood pressures and minimum systolic and diastolic blood pressures during HD were lower in the pressor group than in the nonpressor group.The multivariate logistic regression model showed that the pressor group tended to include a high rate of females, older age, CVD, DM, long vintage, high BMI, low serum albumin and creatinine levels, high serum CRP level, and high hemoglobin level, and high fluid removal rate, and low blood pressures Table .Table 2PAll-cause, CVD-caused, and infection-caused deaths were more frequently observed in the pressor group than in the nonpressor group Table . U-shapeThere were no significant differences between the baseline characteristics of the matched pressor and matched nonpressor groups except for post-HD and minimum systolic and diastolic blood pressures , and vasopressors (po) on patients’ prognosis were observed. On the other hand, low-temperature dialysis, and injection of high-concentration sodium chloride solution and high-concentration glycerin were not associated with the risk of all-cause death. Normal saline is usually given to replace intravascular volume as a method of acute management of IDH, and to effectively maintain blood pressure14. The harmful effects of sodium loading have been reported15. Some of the harmful effects of normal saline are the acute change in circulating plasma volume, poor cardiac function, and complications of IDH. However, considering that the use of high-concentration sodium chloride solution and high-concentration glycerin was not associated with the risk of all-cause death, intravascular volume loading may have a strong effect on the risk of all-cause death, and the effect of sodium loading may not be strong.IDH is caused by many factors, such as low dry weight, excessive ultrafiltration, decrease in osmolality, and autonomic neuropathy11. There were also reports that midodrine hydrochloride and amezinium metilsulfate might have worsened the leg ulcers in HD patients17. IDH causes hypoperfusion in organs causing myocardial infarction, stroke, and bowel ischemia, and leads to myocardial fibrosis and cardiac remodeling18. HD-induced myocardial stunning is associated with the development of heart failure and increased risk of all-cause death in HD patients21. IDH is associated with low cardiac index and high peripheral resistance22. Considering the mechanism of action of vasopressors, vasoconstriction induced by the vasopressors may decrease the blood supply to peripheral arteries, and worsen HD patients’ prognosis. If an HD patient’s blood pressure can be maintained during HD by pressor approaches excluding the use of vasopressors, it would be better to avoid using vasopressors as much as possible.Our study showed the relationship between the use of vasopressors and the risk of all-cause death. A cohort study showed that the use of midodrine is associated with risk of death10. The candidate mechanisms underlying the favorable effects of low-temperature dialysis on HD are the improvement of intradialytic hemodynamics by the preservation of cardiac output and central blood volume, and the slowing of the progression of HD-associated cardiomyopathy, brain protection, and improvement of nocturnal sleep27. These effects are different from those of vasopressors, and may affect patients’ prognosis. Although discomfort is more often observed in low-temperature dialysis than in normal-temperature dialysis, low-temperature dialysis can be a candidate therapy to prevent IDH. Low-temperature dialysis is also recommended by the guidelines13.Low-temperature dialysis is used for IDH by increasing peripheral vascular resistance and improving cardiac output. In our study, low-temperature dialysis was not associated with a risk of all-cause death. A systematic review of 26 studies showed that low-temperature dialysis reduces the rate of IHD and increases intradialytic mean arterial pressure29. Patients with severe hypotension that is difficult to control have a high risk of all-cause death. According to previous studies, comorbid conditions such as coronary artery disease, systolic dysfunction, left ventricular hypertrophy, and autonomic dysfunction are observed in patients with IDH31. These factors indicate the difficulty of fluid removal, and hidden risks of cardiac dysfunction in such patients.In this study, logistic regression models and BN were used to investigate the factors associated with the use of pressor approaches. Logistic regression models and BN showed the common factors such as gender, old age, a history of CVD, DM, high fluid removal rate, and low blood pressure. These characteristics were in accordance with previous studies32. To control hypoalbuminemia, it is important to identify its underlying causes and treat them.No relationship between serum albumin level and the use of pressor approaches was observed. However, this does not suggest that a low serum albumin level is not an important risk factor, but means that hypotension due to hypoalbuminemia may be difficult to control using pressor approaches. Albumin preparations are blood products and are difficult to use for daily HD. Hypoalbuminemia is caused by not only malnutrition but also inflammation and comorbid conditions13. Moderate fluid removal should be a key therapeutic strategy, for which reassessment of dry weight, regulation of ultrafiltration rate, extended hours of HD, and changes to other modes such as extracorporeal ultrafiltration method, hemodiafiltration, daily HD, and nocturnal HD may be effective34.In this study, the numbers of the subjects using vasopressor (po) and normal saline were higher than those using other pressor approaches. This finding might reflect a tendency that in Japan, a vasopressor (po) is commonly used for IDH as the first choice, and that normal saline is used when a patient’s blood pressure suddenly decreases. However, considering these results of our study and the JSDT and K/DOQI guidelines, the acute management of IDH by increasing intravascular volume using normal saline and use of vasopressors should be avoided4. More studies are needed to investigate the pathophysiological mechanism of IDH and medication. Seventh, there were some differences in the factors associated with the use of pressor approaches between the logistic regression models and BN such as increases in BMI and hemoglobin level. The logistic regression models might not be appreciable to the complex relationships between variables. More details on medication are needed to determine the mechanisms of development of IDH.This study has several limitations. First, because of the observational nature of this study, the results may be biased by unmeasured confounders. To overcome this limitation, propensity matching analysis was conducted. However, JRDR data did not include the baseline characteristics of HD patients at the time of their first use of pressor approaches. Thus, to examine the causal relationship between vasopressors and the risk of all-cause death, BN was conducted, and these analyses showed similar results. Although propensity matching analysis and BN were conducted, there remains some bias. For example, pressor approaches were often used for patients with high risk of death. Second, we did not include the patients with missing data in this study, which might have caused selection bias. Third, the JRDR data did not standardize the methods of blood pressure measurement. However, the methods were almost similar throughout Japan. Therefore, despite the difference in the method of measuring blood pressure, the relationship between pressor approaches and the risk of all-cause death is considered robust. Fourth, in this study, the use of high-concentration sodium chloride and normal saline, which increase intravascular volume, tended to be avoided in patients with CVD. There were biases in the indication of the use of pressor approaches in this study, and biases in the difference in sample size between pressor approaches. However, although the glycerin group showed a higher risk of death than other groups, the Cox proportional hazard models showed no statistically significant relationship between the use of glycerin and the risk of death. The indication bias might not be strong and might be adjusted in the models. Because the details on the use of pressor approaches were not included in the JRDR data, we were unable to evaluate the effects of the patterns of the use of pressor approaches. Randomized controlled trials are needed to evaluate the effects of the use of pressor approaches on dialysis patients’ mortality. Fifth, there was some bias due to the medical situations with regard to the use of pressor approaches in Japan such as their coverage by national health insurance and health care policies at facilities. Because there may be differences in IDH treatment between countries, to show external validity, comparison of the use of pressor approaches between countries is needed. Sixth, although IDH is pathophysiologically associated with cardiac output, arterior vasoconstrictrion, and autonomic system, in this study, we lacked pathophysiological data or details on CVD death such as myocardial infarction and arrythmiaIn conclusion, this study showed that the HD patients for whom pressor approaches were used during HD have high risk of death. In particular, the use of normal saline, and vasopressors is associated with a poor prognosis. To improve HD patients’ prognosis, it may be effective to prevent a situation that requires acute management of IDH.This is a prospective cohort study of maintenance HD patients using JRDR data. JSDT has been conducting annual year-end surveys of dialysis facilities in Japan since 1968. The JRDR data from 2005 to 2006 were used in this study. This study was approved by the ethics committee of JSDT and was exempt from the need to obtain informed consent from participants (JSDT No. 18). The study was performed in accordance with the relevant guidelines and the Declaration of Helsinki.The subjects of this cohort study were the 245,441 patients. The exclusion criteria were as follows: patients younger than twenty years; patients on hemodiafiltration, hemofiltration, or peritoneal dialysis; patients with missing values or outlier values of laboratory data; patients who had a limb amputated; and patients with a HD vintage of less than one year. Thus, 29,309 subjects were included in the analysis. The sample size was evaluated to maximize statistical power.5. Blood pressure was measured under fixed conditions in either the seated or supine position depending on the setup at each facility. Pre-HD blood pressure was measured before the start of dialysis. Post-HD blood pressure was measured just before returning the blood at the end of dialysis. The lowest blood pressure was recorded as the minimum blood pressure during HD. Information on depressors [angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)] used was collected. Information on methods used for raising blood pressure (pressors) was also collected, namely, low-temperature dialysis, vasopressors (po), and medicines for intravenous injection .The baseline data were as follows: gender; age; history of CVD; DM as a cause of ESRD; vintage; post-HD BMI; serum albumin, creatinine, and CRP levels; hemoglobin level; and fluid removal rate. The laboratory data were measured before HD. Fluid removal rate (%) was calculated as follows: (post-HD weight − pre-HD weight)/pre-HD weight × 100. Data on Pre-HD, post-HD blood pressures and minimum systolic and diastolic blood pressures during HD were collected. In this study, methods of blood pressure measurement were not standardized, because JDRD data were collected by survey of dialysis facilities. However, the general method of blood pressure measurement in Japan at that time was as followsThe primary outcome was all-cause death within one year. CVD- and infection-caused deaths within one year were also evaluated. Subjects were categorized on the basis of the use of pressor approaches: the pressor and nonpressor groups.Normally distributed variables are presented as mean ± standard deviation; otherwise, the median and interquartile ranges are presented. Highly skewed variables were transformed with the natural logarithm function prior to their use in models . Intergroup comparisons of parameters were performed using the chi-square test, t-test, and Mann-Whitney U test as appropriate after the F-test of equality of variances between the groups.Using the Kaplan–Meier method, we compared the pressor and nonpressor groups in terms of the incidence of the primary outcome, and statistical significance was evaluated using the log-rank and Wilcoxon tests. A multivariate Cox PHM was used to evaluate the relationships of the pressor and nonpressor groups with mortality. This multivariate Cox PHM was adjusted for baseline characteristics  and blood pressures using the splines of the blood pressures. The results were presented as HRs with 95% confidence intervals (CIs). In the analysis of competing risks of cause-specific death, Fine and Gray competing risk regression models adjusted for the baseline characteristics were also examined.A propensity score-matched cohort for the use of pressor approaches was conducted. Possible confounders were chosen for baseline characteristics, including baseline characteristics , and pre-HD systolic blood pressure. The predicted probability of the use of pressor approaches was calculated by applying a logistic regression model including these possible confounders. Next, we performed propensity score matching using the following algorithm: 1:1 nearest neighbor match within a caliper width defined as ±0.2 of a standard deviation (SD) of the logit of the propensity score and no replacement. Comparisons of baseline characteristics were based on the chi-square test, t-test, Mann-Whitney U, and standardized differences. The incidence of the primary outcome was compared between the matched pressor and nonpressor groups using the Kaplan–Meier method. A Cox PHM was used to evaluate the association between the matched pressor and nonpressor groups and the primary outcome. Adjustment in the multivariate Cox PHM was demonstrated for variables that showed absolute standardized differences (10% in baseline characteristics) between the matched pressor and nonpressor groups. The relationship between the types of pressor approaches and the risk of all-cause death was also evaluated using multivariate Cox PHMs adjusted for baseline characteristics and blood pressures.p < 0.05.BN is a kind of probabilistic graphical model that shows variables and their causal relationships via a directed acyclic graph, and represents the probabilistic relationships between diseases and symptoms. BN was used to evaluate the relationship between the variables described above. The incremental association Markov blanket method was used for structure learning algorithm for BN. The resulting directed acyclic graph was interpreted as the causal BN. Continuous variables were discretized by cutoff levels determined by receiver operating characteristic curves for the prediction of the primary outcome. Blood pressures were categorized as follows: systolic blood pressures, 100 mmHg, 150 mmHg, and 200 mmHg; diastolic blood pressures, 50 mmHg, 100 mmHg. These analyses were conducted using SAS version 9.4  and R version 3.4.1 . Statistical significance was defined as Supplementary information


The EuroQol-5 Dimension (EQ-5D), developed in 1990, is a most widely used generic tool to measure the health-related quality of life (HRQoL) and considered suitable for patients with asthma. In 2009, the EuroQol Group developed a new EQ-5D version to overcome limitations related to its consistently reported high ceiling effect. To enhance the sensitivity for assessing the HRQoL in further patient populations, the number of responses of EQ-5D was increased from 3 to 5 levels (EQ-5D-5L). Moreover, the availability of well-defined requirements for its Web-based administration allows EQ-5D-5L use to monitor the HRQoL in electronic health  programs. No study has evaluated the metric properties of the new EQ-5D-5L in patients with asthma yet.This study aims to examine the distribution, construct validity, and reliability of the new EQ-5D-5L questionnaire administered online to adults with asthma.We evaluated patients with asthma (age: 18-40 years) from a primary care setting in France and England, who self-completed the EQ-5D-5L questionnaire online. The inclusion criteria were persistent asthma defined as >6 months of prescribed inhaled corticosteroids and long-acting beta-agonists or inhaled corticosteroids alone during the 12 months prior to inclusion. The EQ-5D index was obtained by applying the English preference value set for the new EQ-5D-5L and the French 3L-5L crosswalk value set. Both value sets produced single preference-based indices ranging from 1  to negative values , where 0=death, allowing the calculation of quality-adjusted life years. Responses to dimensions and index distribution, including ceiling and floor effects, were examined. The construct validity was assessed by comparing the means of known groups by analyses of variance and calculation of effect sizes.P<.001). Differences between extreme groups defined by chronic conditions , short-acting beta-agonists (SABAs) canisters in the last 12 months (P=.02 and P=.03), or SABA use during the previous 4 weeks (P=.03 and P=.01) were of moderate magnitude with effect sizes around 0.5.Of 312 patients answering the baseline Web-based survey, 290 completed the EQ-5D-5L (93%). The floor effect was null, and the ceiling effect was 26.5% (74/279). The mean EQ-5D-5L index was 0.88 (SD 0.14) with the English value set and 0.83 (SD 0.19) with the French 3L-5L crosswalk value set. In both indices, large effect sizes were observed for known groups defined by the Asthma Control Questionnaire (1.06 and 1.04, The new EQ-5D-5L questionnaire has an acceptable ceiling effect, a good construct validity based on the discriminant ability for distinguishing among health-related known groups, and high reliability, supporting its adequacy for assessing the HRQoL in patients with asthma. EQ-5D-5L completion by most Web-based respondents supports the feasibility of this administration form. The impact of asthma on the patients’ health has been traditionally assessed by either clinical markers or functional tests . PatientIn asthma, disease-specific HRQoL measures have been more widely used than generic ones, as they could be more sensitive. Adding generic HRQoL domains important to patients with asthma has been proposed  because The EQ-5D was considered a suitable generic measure in a systematic review  of patie5); this is a low number compared with other generic preference-based instruments such as the Health Utilities Index [5) [The traditional EQ-5D descriptive system, composed of 5 dimensions with 3 levels of severity, defines 243 distinct health states resulting from all the possible combinations  .The new EQ-5D-5L has already been tested in some disease-specific samples, such as patients with cancer ,25 and wIn this study, we analyzed baseline data of adults (age: 18-40 years) enrolled in the ASTRO-LAB cohort who completed the EQ-5D-5L questionnaire. The ASTRO-LAB project is a prospective longitudinal study of asthmatic patients designed to provide new evidence regarding the safety of long-acting beta-agonists (LABAs) in routine primary care in France and the United Kingdom. Details of the study are described elsewhere .The inclusion criteria were as follows: persistent asthma and age <40 years. Patients were considered to have persistent asthma when they had >6 months of prescribed treatment with inhaled corticosteroids (ICs) and LABAs or ICs alone during the 12 months prior to inclusion. Persistent asthma requires controller therapy on a regular basis, whereas intermittent asthma can be treated with rescue medication as needed. The ASTRO-LAB persistent asthma definition was based on a minimal prescription duration level of antiasthmatic drugs because this method is considered less biased than the practitioner’s classification of asthma, and it is frequently used in database studies . The ASTThe exclusion criteria were as follows: chronic oral corticosteroid use (≥15 consecutive days 3 months before inclusion), history of omalizumab therapy, and any other concomitant chronic respiratory disease . Owing to ASTRO-LAB’s main focus being LABAs safety, the abovementioned criteria based on the administration of other medications aimed at avoiding confounding with their adverse effects, implying that most patients with severe persistent asthma were excluded.The ASTRO-LAB study has been approved by the Ethics and Regulatory Boards in France and the United Kingdom and was conducted in accordance with the Declaration of the World Medical Association. In France, approval was obtained from CCTIRS (Comité consultatif sur le traitement de l’information en matière de recherche dans le domaine dela santé) on November 21, 2012 (Dossier N°12702), and the authorization from Commission Nationale d’Informatique et Liberté was obtained in May 17, 2013 (DR-2013-264). In the United Kingdom, according to the UK Research Governance Framework, the study was submitted to The West London Research Ethics Committee (REC), and the final approval was obtained on April 15, 2013 (REC Reference 12/LO/20139). Following the UK regulatory process, the ASTRO-LAB consortium submitted the protocol to the National Institute for Health Research Clinical Research Network (NIHR CRN) to launch the review by Primary Care Trust local sites. The first local approval was granted by the West London Primary Care Consortium on May 22, 2013. Informed consent was obtained from all participants prior to inclusion.Clinical data were extracted from medical records, and patient-reported information was obtained by the following 2 administration modes: patient-completed Web-based survey and telephone interviews with patients performed by trained interviewers. The EQ-5D-5L was only administered in the Web-based survey.Information on age, gender, body mass index, comorbidity, and treatment prescribed was obtained; in France, general practitioners completed a Web-based survey at patient inclusion, while in the United Kingdom, this information was directly extracted from medical records. The history of 4 associated pathologies , was registered and transformed into a count variable. The total number of short-acting beta-agonist (SABA) canisters prescribed in the 12 months prior to inclusion was transformed into a variable of 3 categories—0, 1-4, and ≥5 canisters.Patients received instructions during the recruitment contact to self-complete a Web-based survey, which included the EQ-5D-5L to measure the HRQoL and sociodemographic data, such as their highest level of education and current work situation, among others.The EQ-5D-5L is a brief, multiattribute, generic, health status measure composed of 5 questions with Likert response options (descriptive system) and a visual analog scale (EQ-VAS). The latter asks patients to rate their own health from 0 to 100 . The descriptive system covers 5 dimensions of health  with 5 levels of severity in each dimension .Preference value sets used to obtain the index of the EQ-5D-5L were the 3L-5L crosswalk from the French 3L version , and theThe telephonic interviews were computer-assisted to standardize the process. Trained interviewers administered questions to patients about their asthma control and treatment use, among others. Asthma control is defined as the extent to which the manifestations of asthma can be observed in a patient, or have been reduced or removed by treatment ,33; it r1% predicted, and daily rescue bronchodilator use. A shorter version called ACQ-symptoms only [The Asthma Control Questionnaire (ACQ) is composed of 7 items—the top scoring 5 symptoms, FEVoms only  was deveoms only . The resoms only .The following question was asked to patients with SABA therapy prescription: “How often have you usually taken your ‘reliever medication’ (brand name) in the past 4 weeks? Every day; almost every day; once or twice every week; less than once a week; or I don’t know.”Sample characteristics were described by calculating percentages, or mean (SD) values, according to the variable type (detailed in tables and figures). To examine the nonresponse bias, subjects who completed the Web-based survey were compared with those who had not completed this survey by a t test and chi-square test.We calculated the percentages of responses to each EQ-5D-5L dimension. To examine the distribution of the EQ-5D index, we calculated statistics of central tendency, dispersion, asymmetry, and tail extremity, as well as the proportion and 95% CI of the individuals in the best possible (ceiling) and the worst possible (floor) health states . To asseThe construct validity examines whether the instrument adequately assesses the concept that it intends to measure , in thisTo evaluate the discriminative capacity of the EQ-5D index and EQ-VAS among the known groups mentioned above, mean scores were compared using one-way analysis of variance and the Tukey studentized range (honestly significant difference) test for post-hoc comparisons; alpha was set at.05. To assess the magnitude of the differences Cohen effect sizes were calculated. General guidelines define an effect size of 0.2 as small, 0.5 as moderate, and 0.8 as large . All anaP=.03), and presented higher ACQ mean scores (worse control) in comparison to respondents but did not differ in body mass index, treatment, number of other chronic conditions, SABA canisters prescribed last year, and frequency of SABA used in the previous 4 weeks.Of 581 subjects with asthma aged 18-40 years composing the ASTRO-LAB cohort, 312 filled in the baseline Web-based survey , but 22 of these did not complete the EQ-5D-5L . Of 290 who fulfilled the EQ-5D-5L, 11 were excluded because they had missing data on all the variables selected to define known groups; hence, 279 patients were finally included in this analysis. To the best of our knowledge, this is the first study evaluating metric properties of the new EQ-5D-5L in patients with asthma. In this study, this generic preference-based instrument showed adequate distribution and reliability, with 26.5% (74/279) of patients reporting the best possible health state (ceiling effect). In addition, it showed good construct validity, given its capacity of discriminating among groups differing in the number of chronic conditions and symptom control. The distribution of the EQ-5D-5L index was less skewed than the previously published one for the 3-level version owing to its lower ceiling effect ,17.In this study, 53.7% (312/581) of participants completed the Web-based baseline survey, and almost all of these completed the EQ-5D-5L . The internet era has led to implementing Web-based surveys to take advantage of the known benefits such as completeness ,42, low Despite being higher than the 15%  establisStudies that directly elicit preferences from representative general population samples to derive value sets for the new EQ-5D-5L, using a harmonized protocol, have already been published for several countries ,47-51, bThe EQ-5D-5L index could discriminate among different known groups in the hypothesized direction. In all the variables evaluated, differences between extreme groups ranged from 0.07 to 0.2, therefore being equal to or higher than the minimal important difference, previously estimated as 0.07 . The magSome potential limitations of this study need to be considered. First, a direct comparison with the EQ-5D-3L was not possible. Although previous EQ-5D-3L studies in asthma patients -17 showeThis study has several strengths that need to be highlighted. First, embedding this study in an observational cohort in routine care allowed us to select several appropriate known groups for evaluating the EQ-5D-5L’s construct validity in patients with asthma. The relationship between comorbid chronic conditions and health is well established, and the associations of symptoms control  with theIn summary, our results provide support to the construct validity of the EQ-5D-5L administered online to patients with asthma, based on its discriminant ability for distinguishing among health-related known groups, as well as its lower ceiling effect than previously reported for the traditional 3-level version ,17. The


Paediatric critical care practitioners often make use of pressure support (PS) to overcome the perceived imposed work of breathing (WOBimp) during an extubation readiness test (ERT). However, no paediatric data are available that shows the necessity of adding of pressure support during such tests. We sought to measure the WOBimp during an ERT with and without added pressure support and to study its clinical correlate. This was a prospective study in spontaneously breathing ventilated children < 18 years undergoing ERT. Using tracheal manometry, WOBimp was calculated by integrating the difference between positive end-expiratory pressure (PEEP) and tracheal pressure (Ptrach) over the measured expiratory tidal volume (VTe) under two paired conditions: continuous positive airway pressure (CPAP) with and without PS. Patients with post-extubation upper airway obstruction were excluded.2O. WOBimp was significantly higher without PS  than with added PS . Although there were statistically significant changes in spontaneous breath rate  and higher ET-CO2  and expiratory Vt decreased  in the absence of PS, these changes appeared clinically irrelevant since the Comfort B score remained unaffected . Multivariable analysis showed that changes in WOBimp occurred independent of endotracheal tube size.A total of 112 patients were studied. Median PS during the ERT was 10 cmHWithholding PS during ERT does not lead to clinically relevant increases in WOBimp, irrespective of endotracheal tube size.The online version of this article (10.1186/s13613-019-0549-0) contains supplementary material, which is available to authorized users. Assessment of extubation readiness in mechanically ventilated children remains challenging despite the relatively low failed extubation rate (2–20%) –4. Patie2O) more accurately reflected physiologic conditions after extubation [At the same time, the practice of adding PS may also be questioned. A recent meta-analysis of 16 studies examining patient effort during various spontaneous breathing trials (SBT) confirmed that although PS reduced respiratory effort, only using T-piece , but also entails the work a patient has to generate to overcome the resistive properties of the ETT and patient circuit. The energy to overcome this is coined imposed WOB (WOBimp), which is calculated by integrating the difference between positive end-expiratory pressure (PEEP) and tracheal pressure (Ptrach) over the measured tidal volume (VTe). To date, clinicians do not routinely measure Ptrach necessary for calculating WOBimp, making it difficult to determine what causes increased WOB during a SBT (i.e. WOBimp or WOBphys) . In the 2O, FiO2 < 0.4 and an adequate coughing reflex). Patients were eligible if they have been invasively ventilated for at least 24 h and the attending physician confirmed extubation readiness and extubation was expected within 8 h. For logistical reasons, patients were only studied on weekdays from 7 am to 5 pm if they had been intubated > 24 h prior to the ERT. Patients with depressed respiratory drive inherent to congenital or acquired central nervous system disorders, congenital or acquired injury to the phrenic nerve or diaphragmatic dysfunction, unstable haemodynamics (i.e. increase in vasoactive support or fluid boluses < 6 h before ERT), congenital or acquired neuro- and/or myopathy, continuous muscular paralysis 12 h before the ERT, patients who had a tracheostomy and patients with ETT leakage > 20% were not studied. Importantly, patients with clinically identified post-extubation upper airway obstruction were removed from analysis because we also wanted to explore the relationship between WOBimp and extubation outcome. The institutional review board (IRB) approved the study and waived the need for informed consent.This study was designed as a prospective, observational study in invasively mechanically ventilated children admitted to the paediatric intensive care unit (PICU) of the Beatrix Children’s Hospital between March 2017 and June 2018 who were identified by the attending physician to be ready for extubation. Our clinical algorithm describes weaning as follows: weaning starts when ventilator pressures and/or mandatory breath rate can be decreased. During this process, patients are assessed daily during morning rounds by the attending physician for extubation readiness . Prior to the ERT, a 3.5 French (Fr) catheter for ETT < 4.5 mm and 5 Fr for ETT ≥ 4.5 mm  with the tip of the catheter at the distal end of the ETT was inserted. The patient was then switched to CPAP/PS with the level of PS set similar to the added pressure above the level of PEEP during controlled MV, targeting an expiratory Vt of 5–7 mL/kg actual bodyweight (as there was no obesity in the patient cohort). Vt was measured at the Y-piece of the patient circuit using a self-calibrating pneumotachometer . Flow trigger was set between 0.5 and 1.0 L/min. A heat moisture exchanger  was in situ between the patient circuit and the ETT.Patients were intubated with a cuffed ETT  and ventilated with the AVEAAfter a 5-min stabilisation period, data were recorded during 5 min of steady-state breathing. Subsequently, PS was turned down to zero and, after a 5-min stabilisation period, again data were recorded during a period of 5 min steady-state breathing.Ventilator recordings were sampled at 100 Hz using the VOXP protocol and a custom-build software program .2) and fraction inspired oxygen (FiO2) were recorded on case record forms at baseline (i.e. after the first 5-min stabilisation period), after 5 min of steady-state breathing on CPAP/PS, and after 5 min of steady-state breathing on CPAP. The Comfort B score was calculated at these same time points to assess patient comfort [Heart rate (HR), respiratory rate (RR), peripheral saturation (SpO comfort . Demogra comfort .Extubation failure was defined as the need for reintubation within 48 h or use of non-invasive ventilation (NIV) post-extubation.2 (ET-CO2), peak inspiratory flow rate (PIFR) and WOBimp was calculated for the 5-min recordings after removal of artefacts. Peak inspiratory resistance (cmH2O/L/S) was calculated using ETT size (3.0 mm–6.0 mm) and PIFR using formulae used by Khemani et al. [Ventilator recordings were analysed offline using a custom-build MatLab script . The median (IQR) of respiratory variables including peak inspiratory pressure (PIP), Ptrach, PEEP, mean airway pressure (mPaw), expiratory Vt number of breaths, RR, rapid shallow breathing index (RSBI), end-tidal COi et al. .. P values < 0.05 were considered statistically significant.Data were assessed for normality using the Kolmogorov–Smirnov test. Descriptive data were expressed as median (25–75 interquartile range) or percentage (%) of total. For the univariate analysis, data recorded during CPAP/PS were compared with data recorded during CPAP alone using the Wilcoxon signed rank test. Subsequently, multivariate linear regression analysis using backward selection was performed to study the independent contribution of ETT size, VTe, inspiratory time (Tinsp) and PIFR to changes in WOBimp (∆WOBimp) because we presumed these variables to be related to WOBimp. Statistical analysis was performed using SPSS v23 2O. Median ventilation time for the cohort was 68 (IQR 24–131) h. Nine patients (8%) had failed extubation and were reintubated. A total of 691 patients were admitted of whom 425 patients were mechanically ventilated. One hundred and sixty-one (37.9%) of these were studied of whom three failed the ERT; ultimately, data of 112 patients were eligible for analysis , higher ET-CO2 (p < 0.001) and significantly lower expiratory Vt (p < 0.001) , p = 0.006) when corrected for the measured WOBimp during CPAP/PS ventilation. Furthermore, the size of the endotracheal tube did not contribute to ∆WOBimp  ; for the larger tubes (i.e. ETT 7.5 mm) in the present study this was 5%. Reassuring, WOBimp values were the lowest in patients with ETT 3 and 3.5 mm and measured PIFRs were comparable with previously published data, indicating that the values found in this study in young children were not overestimated , 15, 21 There are a few limitations that need to be discussed. First, the present study is a single-centre study although our unit is comparable to most North-American and European centres and generalisability is high given the fact that this is a physiologic study. Second, we only included a heterogeneous group of patients extubated during office hours, thereby potentially introducing a selection bias by missing out on patients extubated during non-office hours. Third, we did not measure peak inspiratory resistance but calculated these values derived from bench testing, so the reported values of resistance may be over- or underestimated . HoweverIn conclusion, this study showed the WOBimp generated during extubation readiness testing in a heterogeneous group of mechanically ventilated children with and without lung injury was significantly increased when CPAP alone was used compared to CPAP/PS, although this appeared clinically irrelevant in terms of patient comfort. Our observations may challenge the routine use of PS during extubation readiness testing, even in very young children with small ETT sizes.Additional file 1. Figures and Tables.


Venous thromboembolic events (VTE), with their life-threatening manifestation as pulmonary embolism, are potential adverse effects of intravenous methylprednisolone (IVMP) pulse therapy, partially due to a hypercoagulable state. The aim of the study was to analyze the influence of IVMP on selected hemostatic parameters in patients with moderate-to-severe Graves’ orbitopathy (GO).26 euthyroid patients with GO were treated with 12 pulses of IVMP . Hemostatic variables  were analysed before, 24 and 48 h after 1st, 6th and 12th pulse.p < 0.00005). FVII decreased 24 h after each pulse . Fibrinogen level decreased 48 h after each pulse (P < 0.00005). We did not observe any statistically significant changes in hemostatic parameters in the long-term evaluation. Therapy was concluded in one patient after the 9th pulse due to pulmonary embolism.A constant, transient trend in changes of some hemostatic variables was observed after all assessed pulses. We discovered an increase in median activity of FVIII 24 and 48 h after pulses, with a shortening of aPTT 24 h after each IVMP pulse  contains supplementary material, which is available to authorized users. The alterations of coagulation and fibrinolysis parameters have been described in patients with endogenous Cushing’s syndrome (CS) –5 and thThis prospective study was conducted at an academic referral centre. Patients with active, moderate-to-severe GO according to EUGOGO classification were consecutively recruited in the Department of Endocrinology at the Medical University of Warsaw from 2011 to 2014. The inclusion criteria were: active, moderate-to-severe GO; age ≥ 18 years; euthyroidism for at least 1 month ; completion of at least the first six IVMP pulses. Exclusion criteria were: medical history of thromboembolic events; cardiovascular morbidity ; uncontrolled hypertension (defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg); liver disease ; active inflammation; nephritic syndrome; active neoplastic disease; previous GCs therapy within the last 6 months; trauma/surgery within the last 3 months; pregnancy or a bedridden state; use of: heparin, vitamin K antagonists, antiplatelet drugs, contraceptives or hormone replacement therapy. 26 patients were eligible for the study. All but two underwent the entire treatment schedule. Characteristics of the study group are shown in Table The participants received IVMP according to EUGOGO recommendations . Hemostatic variables  were analysed before, 24 h (24 h) and 48 h (48 h) after selected  IVMP pulses.Venous blood was collected in the morning following a 12-h fast. This was utilized for preparation of serum, 3.2% sodium citrate plasma, and citrate platelet—poor plasma after double centrifugation.Thyrotropin (TSH) and free thyroxine (FT4) were measured in serum using an electrochemiluminescence immunoassay  on Cobas 6000 Analyzer . D-dimer was determined by the immunoenzymatic method on analyzer VIDAS PC with VIDAS D-dimer Exclusion II . C-reactive protein (CRP) was measured in serum using an immunoturbidimetric method on Cobas 6000 Analyzer (Roche Diagnostics). PLT were determined by the impedance method on Sysmex XT Hematology Analyzer.Hemostatic parameters were analyzed within 1–1.5 h after blood sampling, except for FVIII activity measured in platelet—poor plasma stored frozen at − 70 °C until assay.Coagulation analyzer Option 4  was used for the measurement of aPTT with Dapttin TC , PT with rabbit brain thromboplastin  and factors: II, V and VII activities in one stage method with factor—deficient plasma (Technoclone).Analyzer BCS-XP  was used for fibrinogen measurement by Clauss method with Multifarben U, AT activity by the chromogenic method with Berichrom. AT and activity of FVIII by coagulometric method with FVIII—deficient plasma; all reagents from Siemens Healthcare Diagnostics Products GmbH .The end point of the study was a change in hemostatic variables’ levels in laboratory tests. There were short- and long-term hemostatic changes analysed during IVMP therapy: comparisons of laboratory tests before, 24 and 48 h after selected pulses, and between the beginning of 1st, 6th and 12th IVMP pulses, respectively. Moreover, analyses were performed concerning clinical data  between independent groups .n) or percentages (%). Changes of hemostatic variables between selected time points of the study were compared using parametric Student’s t test or non-parametric Wilcoxson matched pairs test. As far as analysis of clinical data between independent groups  is concerned, the following tests were used: Chi-squared method for categorical variables or Mann–Whitney U test for continuous data. After Bonferroni correction, results with a p value of < 0.0005 were deemed statistically significant.Statistical analysis was performed using STATISTICA software ver. 10.0. Continuous variables were demonstrated as mean ± standard deviation (SD) or median values (lower quartile–upper quartile). Categorical data was presented as numbers (2) than in non-obese patients .Baseline median values of all parameters are shown in Table Detailed outcomes of coagulation parameters for the 1st (0.5 g) IVMP pulse are shown in Table No statistically significant changes in hemostatic parameters were observed in long-term evaluation Table . We obse2) with well-controlled hypertension and a history of smoking. The patient was also being treated for chronic obstructive pulmonary disease. Moreover, an 8-h journey with immobilisation presented an additional risk factor. Detailed evaluation revealed correct coagulation parameters before therapy initiation . We observed a gradual increase of FVIII activity during the 1st and 6th IVMP pulses, from 118 to 219%, together with a shortening of aPTT from 35 to 29 s. Other coagulation parameters mentioned above remained within the reference ranges. Before administering the 10th pulse, which was consequentially cancelled, the patient had been complaining of increasing dyspnoea on exertion. The level of D-dimers increased to 7983 ng/dl and the diagnosis of thrombosis of the right posterior tibial vein, followed by PE, was made. Anticoagulation therapy with enoxaparin was initiated, followed by acenocoumarol treatment. The level of CRP at the time of thrombosis was 1.4 mg/l (reference range 0–10 mg/l). The patient was excluded from further participation in steroid therapy. The cumulative dose of IVMP received by the patient was 3.75 g.Therapy was concluded in one patient after the 9th pulse due to pulmonary embolism. The patient was a 67-year-old, obese man  between independent groups  (See Online Resource 3).IVMP pulses therapy as the first-line treatment for moderate-to-severe and active GO is more effective and has less side effects than orally administered GCs therapy –14. PatiThis is the first prospective study with such a complex analysis of the influence of the high-doses IVMP pulse therapy on hemostatic process after selected  IVMP pulses together with long-term evaluation. We found a significant increase of activity of FVIII 24 and 48 h after every IVMP pulse with simultaneous shortening of aPTT 24 h after each IVMP pulse. Increased FVIII activity with a shortening of aPTT indicates activation of the intrinsic system after every single IVMP administration regardless of dose (0.5 and 0.25 g), especially during the first 24 h. The median activity of FVIII was higher than 150% after 24 and 48 h after all IVMP pulses. No statistically significant changes in hemostatic parameters were observed in long-term evaluation. The elevated plasma activity of FVIII is a crucial, predominant independent and dose-dependent risk factor for VTE and recurrent VTE . Plasma Numerous alterations of coagulation and fibrinolysis parameters have been described among patients with endogenous Cushing’s syndrome (CS) –6 and thPatients with CS present higher levels of: FII, FV, FVIII, FIX, FXI, FXII, FVIII, and von Willebrand factor (vWF), as well as increased levels of fibrinolytic inhibitors, e.g., plasminogen activator inhibitor type 1 , 23. ImpProlonged GCs therapy with higher doses can lead to a hypercoagulable state and VTE , 11. In It should be noticed that the basic activity of FVIII (before administration of IVMP) was above reference range (higher than 150%) in 38% of our patients. Hyperthyroidism is associated with increased activity of FVIII, achievement of euthyroidism in hyperthyroid patients leads to normalization of the previously elevated FVIII . We haveAdditionally, we observed that fibrinogen decreased 48 h after each pulse. The potential mechanism can be associated with reduced synthesis or secretion after IVMP. D-dimer levels has not changed during therapy (except one patient with PE) that indicates against activation of consumption. Fibrinogen level and CRP were within normal ranges in all patients before initiation of therapy, indicating the lack of inflammation.Contrary to previous studies, there was a decrease of FVII, a factor typically involved in the activation of the extrinsic pathway, 24 h after each IVMP pulse . This trPE was diagnosed in one patient after the 9th IVMP pulse. This patient was obese, with hypertension, chronic obstructive pulmonary disease and a long history of smoking. An additional risk factor (an 8-h journey with immobilisation) could be provocative for the resulting thromboembolism. However, we cannot exclude IVMP as the additional factor for the hypercoagulable state. Interestingly, the activity of FVIII in this patient before therapy was within the normal range, but during long-term evaluation (between the 1st and 6th IVMP pulses) the gradual increase from 118 to 219% was observed along with a shortening of aPTT from 35 to 29 s. Therefore, we suggest that, in some patients with additional risk factors  together with the IVMP therapy anticoagulation prophylaxis should be taken into consideration.The main question that comes to us is if changes in hemostatic parameters during IVMP therapy in weekly scheduled pulses are associated with higher risk of VTE. According to our results, an influence on clothing factors occurred after each pulse but is transient. The opposite situation is observed in patients with CS, in whom hypercoagulability remains during the whole period of hypercortisolemia , 29. GCsThe disadvantage of this trial is the small sample size of the study group. However, results were statistically significant and the same after each analysed pulse that confirmed stable trend Supplementary material 2 (PDF 155 kb)Supplementary material 3 (PDF 130 kb)Below is the link to the electronic supplementary material.


Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic < 140 and diastolic < 90 mmHg. In 5183 patients in whom measurements were available, mean blood pressure was 139.5 ± 20.4 / 79.3 ± 11.8 mmHg; 4985 (96.2%) of the patients were hypertensive. Awareness and treatment rates were > 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use.We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30–60 mL/min/1.73 m Chronic kidney disease (CKD) has been increasingly recognized as a global health burden , 2. The Blood pressure control is considered a mainstay of CKD management, in order to alleviate the progressive loss of kidney function, as well as to lower the risk of cardiovascular disease . The conWe enrolled >5200 patients treated by nephrologists into the German Chronic Kidney Disease (GCKD) study, a long-term observational cohort study . A cross2 or b) manifest proteinuria  if eGFR was >60 ml/min/1.73 m2. Patients were not able to participate if they previously underwent solid organ or bone marrow transplantation, had suffered a malignancy, had advanced heart failure, were under legal attendance or not able to provide informed consent. Written informed consent was obtained from all participants prior to their enrolment.The design of the study has been previously published in detail . The GCKhttp://www.whocc.no/). For the purpose of our analysis, all antihypertensive medications were grouped into the following 7 main categories: (1) inhibitors of the renin-angiotensin system ; (2) diuretics , (3) beta blockers, (4) central sympatholytic agents, (5) peripheral acting alpha-adrenergic antagonists, (6) calcium channel blockers, and (7) other vasodilators. All data presented in this manuscript  were taken from the GCKD baseline visit.The patients were examined by certified study nurses in the regional GCKD centers or in the nephrology practices of the participating nephrologists. The training of study nurses included the correct and standardized conduct of blood pressure measurements. Prior to the blood pressure measurements, upper arm circumference was determined in order to use the correct cuff size . Blood pressure was measured in a sitting position after 5 min of rest with an oscillometric device . Three measurements were taken in the presence of the study nurse (“observed measurements”) with two minutes between each measurement. The mean of the three measurements went into the current analysis. No specific instructions were given with regard to caffeine or tobacco intake on the day of the study visit. In addition, detailed information on the medical history and sociodemographic factors was obtained. Definitions of co-morbidities etc. were used according to international standards . Informahypertensive” if the mean of the 3 blood pressure measurements was ≥ 140 mmHg systolic, or ≥ 90 mmHg diastolic, or if any antihypertensive drug was currently prescribed. A hypertensive patient was defined as “aware” of hypertension if he or she described him- or herself as hypertensive in the patient questionnaire during the interview. The blood pressure was defined as “controlled” if the mean of 3 recordings yielded < 140 mmHg systolic and < 90 mmHg diastolic in a patient classified as hypertensive. A hypertensive patient was considered to suffer from “resistant hypertension” if the mean of the 3 blood pressure measurements was ≥ 140 mmHg systolic, or ≥ 90 mmHg diastolic, despite a current medication with at least 3 different antihypertensive drugs, including a diuretic.Patients were considered “2) estimated according to the 4-variable Modification of Diet in Renal Disease formula [Data is described using means ± standard deviations (SD) for continuous variables and frequency distributions with percentages for categorical variables. Odds ratios with 95% confidence intervals were calculated to analyze the univariate associations (or lack thereof) of controlled blood pressure with a number of factors, including antihypertensive medications , age category , sex, marital status , education, gross yearly income, type of health insurance (statutory or private), body mass index , smoking status , self-reported ethanol intake, diabetes mellitus (absence or presence), previous cardiovascular, cerebrovascular or peripheral vascular disease, stratum of urine albumin-to-creatinine ratio , and eGFR stratum . The distribution of blood pressure levels in the entire cohort is shown in In the univariate analysis, several factors were associated with the prevalence of hypertension but effects were rather small. For example, the prevalence rose with age from 91.6% in the 18–44 years group to 95.6% in the 45–64 years group and to 97.9% in the 65–74 years group. Effects of similar size were observed for gender (93.6% in women vs. 97.9% in men), education, income, eGFR and proteinuria stratum , body mass index, presence of diabetes (98.0% vs. 93.6% in non-diabetic patients) or history of cardiovascular disease. Remarkably, all subgroups in all analyses exhibited a prevalence of hypertension > 90% .Disease awareness was high among hypertensive patients . The control of hypertension, however, was rather low, despite the high awareness and treatment rates and the intense antihypertensive pharmacotherapy. Using the rather conservative blood pressure target level of < 140 mmHg systolic and < 90 mmHg diastolic, no fewer than 2529 of 4985 hypertensive patients (50.7%) failed to reach target levels. In most cases, the systolic component of blood pressure was not controlled . ReducinP<0.0001), male sex (OR 1.424 (1.208–1.678), P<0.0001), lower income (OR 1.273 (1.082–1.498) for annual gross income 25.000–50.000 € versus <25.000 €, OR 1.286 (1.011–1.636) for 50.000–100.000 € versus <25.000 €, and OR 1.635 (0.968–2.762) for >100.000 € versus <25.000 €, P = 0.0134), and higher proteinuria (OR 0.735 (0.621–0.871) for albuminuria ≥30≤300 versus <30 mg/g and OR 0.488 (0.406–0.587) for ≥300 versus <30 mg/g, P<0.0001). In contrast, eGFR strata, education, BMI, ethanol intake and presence of diabetes mellitus were no longer associated with blood pressure control in the multivariate analysis.In the univariate analysis , severalAlso, we analyzed the medication pattern with regard to the control of blood pressure . PatientThis cross-sectional analysis of a large cohort of CKD patients under nephrology specialist care in Germany confirmed the near universal prevalence of hypertension in CKD patients. Despite very high rates of hypertension awareness and treatment, the latter mostly employing combination pharmacotherapy with several antihypertensive drugs, the control of hypertension was disappointing: Only 49.3% of our patients reached the conservative blood pressure goal of < 140/90 mmHg. Analysis of medication patterns indicated that 51.0% of patients with uncontrolled blood pressure (i.e. one quarter of the study population) met the criteria for resistant hypertension.The very high prevalence of hypertension in CKD is not unexpected and in agreement with previous reports from similar cohorts of CKD patients in high-income countries, e.g. Japan , Spain , the U.KRates of control of blood pressure in CKD cohorts vary widely. For example, the investigators of the U.S. Chronic Renal Insufficiency Cohort (CRIC) study reported that 67.1% of their patients had blood pressure levels < 140/90 mmHg . In contWithin our study higher age and male sex were associated with lower odds for a successful control of hypertension, as also described in other studies of CKD patients , 20, 23.As awareness of hypertension and rates of pharmacological treatment were high, we investigated whether a high prevalence of treatment-resistant hypertension in our CKD patients may account for the low overall rates of controlled blood pressure. Our data show that approximately half of our patients with uncontrolled blood pressure had resistant hypertension. We used criteria for resistant hypertension adapted from the definition in the 2013 European Society of Hypertension / European Society of Cardiology hypertension guidelines : blood pAn important limitation of our study is that we collected information on the prescribed medications but not on the drug doses, intake schedules, or duration of treatment. Since we also did not assess the adherence to treatment, which is difficult to measure , we cannConversely, our results indicate that 49.0% of the patients with uncontrolled hypertension did not meet the definition of resistant hypertension. While this implies that there was room for use of more anti-hypertensive agents, the overall anti-hypertensive medication use was already substantial. More than 80% of the hypertensive patients received RAS inhibitors, as recommended by many guidelines , 11. TheA further limitation of our study is the use of office blood pressure measurements obtained during a single visit, even though they were obtained in a highly standardized way. A study which compared office and 24 hour ambulatory blood pressure measurements in CKD patients from a large registry in Spain recorded disagreement between both measurements in a third of the patients . SimilarIn summary, our data clearly show that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use. The fact that our observations are very similar to those in CRIC, a large, multi-ethnic cohort in the U.S. where patients were enrolled in large centers rather than small practices, indicates that this challenge exists independent of ethnicity, differences in environmental factors, health care coverage and treatment settings. Given that poorly controlled blood pressure is closely associated with progression of kidney disease as well as cardiovascular complications, intensified efforts to control blood pressure appear warranted.


The Valsalva maneuver (VM) is widely used in daily life, and has been reported to cause high intraocular pressure (IOP). This study aimed to assess changes in IOP, the Schlemm’s canal (SC), autonomic nervous system activity, and iridocorneal angle morphology in healthy individuals during different phases of the VM.The high frequency (HF) of heart rate (HR) variability, the ratio of low frequency power (LF) and HF (LF/HF), heart rate (HR), IOP, systolic (SBP) and diastolic blood pressure (DBP), the area of SC (SCAR), pupil diameter (PD), and some iridocorneal angle parameters  were measured in 29 young healthy individuals at baseline, phase 2, and phase 4 of the VM. SBP and DBP were measured to calculate mean arterial pressure (MAP) and mean ocular perfusion pressure (MOPP). HF and the LF/HF ratio were recorded using Kubios HR variability premium software to evaluate autonomic nervous system activity. The profiles of the anterior chamber were captured by a Spectralis optical coherence tomography device (anterior segment module).P < 0.001), SCAR (mean) , and PD increased significantly, whereas MOPP, AOD500, TIA500, and TISA500 decreased significantly. In phase 4, DBP, MAP, AOD500, ARA750, TIA500and TISA500 were significantly lower than baseline value, while PD and HF were remarkably larger than baseline. The comparison between phase 2 and phase 4 showed that HR, IOP  and PD decreased significantly from phase 2 to phase 4, but there were no significant differences in other parameters.Compared with baseline values, in phase 2 of the VM, HR, LF/HF, IOP .This observational study was approved by the ethics committee of Tongji Hospital (Registration Number:  The original Valsalva maneuver (VM) was first described by Mario Antonio Valsalva , and theThe VM is considered to consist of 4 phases. In phase 1, increasing intrathoracic pressure caused by the initial straining during the maneuver translates to the arterial circulation. In phase 2, the strain is maintained, increased intrathoracic pressure and decreased venous return cause a decrease in blood pressure, with a reflexive increased heart rate (HR) because of reduced parasympathetic and increased sympathetic nervous system activity. In phase 3, release of the strain causes a rapid drop in intrathoracic pressure leading to a transient drop of blood pressure. In phase 4, the impediment to venous return to the heart is removed, and blood is ejected into the constricted vasculature by the heart, causing a pressure overshoot. Finally, parasympathetic activity is reflexively increased, resulting in a relatively quick slowing down of the heart –8.There is also evidence that the VM may lead to an increase in intraocular pressure (IOP), although the mechanisms remains unclear , 9–11. SThe VM is commonly performed during daily life, and is also a diagnostic technique in clinical practice , 7. ElevA total of 29 healthy individuals were recruited from students at Tongji Medical College, Huazhong University of Science and Technology. All participants signed written informed consent before entering the study, and the study was conducted in accordance with the tenets of the Declaration of Helsinki. All subjects underwent an ophthalmic examination, and data from their right eyes were included in the study.The criteria for inclusion of subjects were: (1) at least 18 years old; (2) IOP of 10–21 mmHg; (3) with a normal anterior chamber depth and open angle. Further, subjects should not have ingested caffeine for at least 24 h before the studies started, and should have no history of receiving any medicines affecting the circulatory system within 1 month prior to evaluation.Exclusion criteria were as follows: (1) systemic diseases , or a family history of these conditions; (2) current ocular diseases or previous ocular surgery; (3) refractive error (RE) ≤ − 6.0 D and RE ≥3.0 D, or best corrected visual acuity < 0.5 ; (4) best corrected visual acuity (BCVA) < 0.5; (5) abnormal pupil reflexes; and (6) poor compliance in performing VM correctly.Every subject struck a correct sitting pose on the measuring instrument before blowing, and held positions during the whole VM, after which the measurements were taken. All examinations were performed following standard operating procedures. In this study, no contact was required to avoid the influence of corneal contact on the parameters and participants’ health.Every subject was trained to perform a standardized VM. Subjects were asked to exhale into a mouthpiece connected to a mercury manometer, and to maintain an expiratory pressure of 40 mmHg for approximately 15 s to complete the image acquisition process. After training, every individual was able to manage the maneuver well. The resting state before breath holding, the continuous blowing state, and the immediate recovery of normal breathing state were recorded as baseline, phase 2, and phase 4, respectively of the VM. Each phase took 15 s. Participants were given a short break of at least 5 min between every 2 VMs. Each individual performed the maneuver a total of 5 times.The systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline, phase 2, and phase 4 of the VM for each individual were measured using an automatic sphygmomanometer . The mean arterial pressure (MAP) was calculated by the equation: MAP = DBP + (SBP - DBP)/3. Electrocardiograms were monitoring in real-time during the entire process, including in the resting state, continuous blowing state and immediately recovered normal breathing(15 s per period). HR was determined by measuring the R-R intervals. The heart rate variability (HRV) parameters of individuals were calculated in each state  by using software .In a sitting position, all participants received an anterior optical coherence tomography (AS-OCT) examination . Rectangular AS-OCT scans of the frontal, nasal, and temporal sides were collected in 3 phases. For frontal scans, the scan angle was horizontal  across the center of the pupil in 1 single image, while the subject stared at the internal fixation point. All AS-OCT tests were performed under standardized darkroom photopic condition (approximately 3.5 lx).2) in the same location of the nasal and temporal sides was measured using imaging software . The mean SCAR was calculated as the averaged SCAR of the nasal and temporal regions. The distance from 1 side of the pupillary tip of the iris to the opposite side on images acquired by AS-OCT was measured as the pupil diameter (PD). Measurements of SCAR and PD were performed by 2 observers, and the data were recorded and stored for later statistical analysis.Anterior chamber depth (ACD), the angle opening distance at 500 μm from the scleral spur (AOD500), the angle recess area at 750 μm from the scleral spur (ARA750), trabecular iris angle at 500 μm from the scleral spur (TIA500), and trabecular-iris space area at 500 μm from the scleral spur (TISA500) were measured by the built-in 2-dimensional analysis function of the Visante OCT. ACD was defined as the length of the central perpendicular line between the posterior surface of the cornea and the anterior surface of the lens. The anterior chamber angle was defined as the arms of the posterior cornea and opposite peripheral iris, with its apex in the angle recess Fig. . The SC The IOP at baseline, phase 2, and phase 4 of the VM were measured using a noncontact tonometer . The averaged IOP was calculated from measurements and recorded as the result. The mean ocular perfusion pressure (MOPP) was calculated as: MOPP = 2/3MAP-IOP .P value < 0.05.All statistical analyses were performed using statistical software , and data were plotted with graphing software . The intraclass correlation coefficients test was used to analyze the re-test reliability of the measurements of SCAR and PD, which were performed by 2 observers. All applicable data are presented as the mean ± standard deviation. Repeated measures analysis of variance was used to detect differences between every 2 different phases. Univariate linear regression analysis was adopted to examine the relationship between SCAR (mean) and HF, LF/HF and IOP. All tests were 2-tailed, and statistical significance was defined as a Twenty-nine individuals were enrolled in this study. A total of 29 right eyes  were included in the analyses. Baseline and demographic characteristics are shown in Table P = 0.004) and MAP , while there were no changes in other BP values different states. There was also a significant increase in HR between baseline and phase 2 , and a significant decrease in HR between phase 2 and phase 4  of the VM , and at phase2 compared with baseline . The ratio of low frequency power and high frequency power (LF/HF) indices also significantly increased from baseline to phase2 .Table P < 0.001) and a significant decrease from phase 2 to phase 4 . However, there were no differences in the IOP between baseline and phase 4 . . And the increase from phase 2 to phase 4 is not significant . Further, there was no difference in MOPP between baseline and phase 4 (P = 0.311). , and a significant decrease in PD from phase 2 to phase 4 . Further, there was a significant difference in PD between baseline and phase 4  in PD in the phase 2 of the VM , TIA500 , and TISA500  from baseline to phase 2.Further, compared with baseline, the AOD500 , ARA750 , TIA500  and TISA500 remained significantly lower in phase4  from baseline to maximum change Table a, b.TabThe VM, is widely used to examine autonomic nervous system function, and is divided into 4 physiological phases , 7. PhysThe key findings of the present study were the significant increase in the LF/HF ratio in phase 2 compare with baseline, reflecting an increased sympathetic activity, and the significant increase in HF indices in phase 4 compared with baseline, reflecting parasympathetic hyperfunction. Further, there was a significant increase in HR in phase 2 compared with baseline. These data are consistent with previous studies –8. We alThe elevation in IOP in healthy individuals during the continued strain of the VM has been widely reported in numerous studies , 10, 21.The SC is the vein at the chamber angle that collects aqueous humor from the anterior chamber and delivers it into the bloodstream . Chen etMOPP represents the gradient of efficient perfusion for all intraocular structures, including the optic nerve head and the retina . The marThe VM is widely used in daily life, and is done automatically and briefly . ChangesThis study has some limitations. First, subjects only performed the WM for 15 s before recovering normal breath, which may be too short for physiological indicators to resolve in all individuals. It also remains unclear whether similar effects of the VM are observed in elderly subjects or patients with glaucoma, as all of our individuals were young and healthy. Finally, we can’t measure the thickness of the anterior choroid in AS-OCT images. Thus, more detailed data sets are required in future studies, and mechanical and ischemic damage caused by the VM to the optic nerve head also needs further researches in the future.The expansion and collapse of the SC in different phases of the VM may be caused by changes in autonomic nervous system activity, while the effects of the VM on IOP may relate to changes in blood flow and ocular anatomy.


Previous studies have found ischemic stroke is associated with atrial fibrillation. However, the causal association between ischemic stroke and atrial fibrillation is not clear. Furthermore, the network relationship among ischemic stroke, atrial fibrillation and its risk factors need further attention. This study aims to examine the potential causal association between ischemic stroke and atrial fibrillation and further to explore potential mediators in the causal pathway from ischemic stroke to atrial fibrillation.Summary statistics from the ISGC  were used as ischemic stroke genetic instruments, AFGen Consortium data  were used for atrial fibrillation, and other consortia data were used for potential mediators . Under the framework of network Mendelian randomization, two-sample Mendelian randomization study was performed using summary statistics from several genome-wide association studies. Inverse-variance weighted method was performed to estimate causal effect.P = 1.3 × 10−5). One-unit increase of genetically determined ischemic stroke was associated with 0.02  upper systolic and diastolic blood pressure levels. Higher genetically determined systolic and diastolic blood pressure levels were associated with higher atrial fibrillation risk . Specially, we also found the bidirectional causality between blood pressure and ischemic stroke.Blood pressure mediates the causal pathways from ischemic stroke to atrial fibrillation. The total odds ratio of ischemic stroke on atrial fibrillation was 1.05 (95% confidence interval [CI], 1.02 to 1.07; Our study provided a strong evidence that raised blood pressure in stroke patients increases the risk of atrial fibrillation and active acute blood pressure lowering can improve the outcome in ischemic stroke patients. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice and is associated with increased risk of stroke, dementia, falls, and death, among other outcomes  for ischemic stroke ; MAGIC Consortium (http://www.magicinvestigators.org/) for FastingInsulin; GIANT Consortium (https://www.broadinstitute.org/collaboration/giant/index) for body mass index, waist circumference and height ; Neale Lab  for systolic and diastolic blood pressure ; Astle W for white blood cell count ; MRC-IEU Consortium (http://www.bristol.ac.uk/integrative-epidemiology/) for procalcitonin ; AFGen Consortium (https://www.afgen.org/) for atrial fibrillation . They were commonly used in MR analyses and to obtain the associations of genetic variants on IS, risk factors and AF, respectively. Beta coefficients (logOR) and standard errors were obtained for the per allele association of each SNP with all exposures and outcomes from these data sources. The basic characters of these data is briefly presented in Table The GWAS summary statistics datasets we used in this study were from the ISGC Consortium (P ≤ 0.0005) with IS from the summary statistics for AF and its risk factors. As the extracted SNPs for IS might be correlated with each other, we pruned the variants by linkage disequilibrium (LD) . We then organized these SNPs by quantifying the heterogeneity and the proportion of variance explained by the genetic instruments . The method assumes that all valid instrumental variables (IV) should yield the same causal estimate. The associations of each SNP with the outcome should be proportional to their association with IS. Presence of any substantial heterogeneity would be suggestive evidence of pleiotropic effects of the SNPs.We used 103 IS-associated single-nucleotide polymorphisms (SNP) (explaining 6.1% of its variance) identified by Malik et al. as genetic instruments. This was conducted by first extracting the effect sizes for SNP associated (R2) of the trait explained by the genetic instruments will rise with the addition of more SNPs. However, the improvement beyond the optimum number of SNPs in the instrument will come increasingly as a result of heterogeneity. In order to determine the final tally of SNPs for inclusion in genetic instruments for each trait, the process is described as follows  of the trait as the initial element of the IV set.Step 2 Add a SNP from the remaining SNPs to IV set so that the IV set explains the largest proportion of variance (R2) of the trait and without heterogeneity.Step 3 Repeat the step 2 until there is heterogeneity.The proportion of variance . Finally, we matched SNPs across the data sources by aligning them to the same effect allele, which were checked for concordance. The details are presented in Additional file After the above three steps, the homogeneity assumption is ensured to be satisfied, which means instrumental variables-exposure, instrumental variables-outcome and exposure-outcome relationships with no effect heterogeneity. To some extent, it reduces the occurrence of pleiotropic. In terms of the rule of thumb proposed by Staiger and Stock , F statiMendelian randomization (MR) can be used to assess the causal effect of an exposure on an outcome using genetic variants as IVs . Three assumptions of Mendelian Randomization should be satisfied: 1) the genetic variants are associated with the exposure; 2) the genetic variants are not associated with any confounders of the exposure and the outcome; 3) the genetic variants are conditionally independent of the outcome given the exposure and confounders  is described in Fig. If causal associations are evaluated in all three steps, the conclusion can be drawn that the specific risk factor is a mediator.For the first step (I), 103 SNPs of genome-wide significance with IS in the GWAS from the International Stroke Genetics Consortium (ISGC) were used to estimate the causal effect of genetically determined IS on AF using the summary statistics from the AFGen consortium. The second step (II) used the same IVs for IS as described in the first step and estimated the causal effect of genetically determined IS on fasting insulin, body mass index, waist circumference, height, systolic and diastolic blood pressure from the respective GWAS summary statistics. Finally, the third MR analyses (III) were performed for risk factors on AF if IS was shown to have a causal effect on the risk factors in the second test (II). The association between IS and AF was mediated by DBP and SBP were tested in an additional analysis after DBP and SBP were identified as potential mediators. The detailed description of Mendelian Randomization analysis can be referred to the Additional file Sensitivity analyses were performed to test the sensitivity of the disproportionate effects of variants and the pleiotropy in MR analysis. These issues were analyzed by leave-one-out validation and MR-Egger regression . If the intercept differs from zero (the MR-Egger test), then there is the evidence of directional pleiotropy. The Instrument Strength Independent of Direct Effect (InSIDE) assumption needs to be satisfied, which means the effect of genetic variants on the exposure is independent of the direct effects of the genetic variants on the outcome.TwoSampleMR. Statistical power was calculated in http://cnsgenomics.com/shiny/mRnd/.Additionally, bidirectional MR . The intercept of MR-Egger regression for these 103 SNPs was not statistically significant (P = 0.397) so there is no evidence of directional pleiotropy. However, the results of leave-one-out indicated the SNP rs12646447 had strong influence on the estimation of causal association . Details are presented in Table The causal estimate using 103 SNPs as IVs showed that IS will increase the risk of developing AF . Analysis of the remaining SNPs yielded an effect size of IS on BMI was − 0.00248 . As a result, the MR analyses showed that IS had causal association with systolic and diastolic blood pressure. Details are presented in Table The causal estimates between genetically determined IS and risk factors, including fasting insulin, body mass index, waist circumference, height, systolic and diastolic blood pressure are listed in Table P = 0.012. SBP: OR, 1.18; 95% CI, 1.01--1.38; P = 0.04). The intercept of MR-Egger regression for these SNPs was not statistically significant , which means there is no evidence of directional pleiotropy. Therefore, DBP and SBP might act as mediators in the causal pathway from IS to AF and account for 6.7 and 7.4% of the total effect of IS on AF, respectively.Based on the first two steps of Network Mendelian randomization analysis, systolic and diastolic blood pressure were suspected to be potential mediators from higher DBP and SBP to increased risk of AF. Further, we evaluated whether DBP and SBP were associated with AF using MR analysis. We used 131 SNPs and 105 SNPs associated with DBP and SBP as the IVs, respectively. Higher DBP and SBP levels were associated with increased risk of AF . Therefore, the bidirectional causality between blood pressure and IS was verified. In other words, the causal association between blood pressure  and AF was simultaneously mediated by IS  to be associated with DBP and SBP as the IVs, respectively, and found that increased DBP and SBP levels were associated with higher risk of IS . The intercept of MR-Egger regression for these 103 SNPs was not statistically significant (P = 0.737) so there is no evidence of directional pleiotropy. Thus, there are bidirectional causality between AF and IS and they are risk factors for each other. Details are briefly presented in Table We additionally performed MR of AF on IS to examine the bidirectional causality between AF and IS. The causal estimate using 103 SNPs (explaining 1.1% of exposure’s variance) as IVs showed that AF will increase the risk of developing IS , large vessel disease (LVD), small vessel disease (SVD)) and results showed only a strong causal relationship from AF to cardiogenic stroke  and the outcome AFGen (AF), but there may still be individuals participating in multiple surveys that we cannot ascertain with available summary-level GWAS statistics. The test of InSIDE assumption in MR-Egger might be a problem. InSIDE assumption is that the effect of genetic variants on the exposure is independent of the direct effects of the genetic variants on the outcome, which is difficult to evaluate. Therefore, it is recommended to use individual data in one sample as much as possible to perform Mendelian randomization studies, so as to obtain higher accuracy and power. In addition, no matter in one-sample or two-sample MR analysis, potential violation of the second core assumption cannot be ruled out because of possible unmeasured confounders. While instrument strength can be verified by the calculation of F-statistics and pleiotropy can be tested by MR-Egger.In summary, we provided a causal diagram among blood pressure, IS and AF. We found that IS could increase the risk of AF and the effect of genetically determined IS on AF was partially mediated by blood pressure. Additionally, due to the bidirectional causality between blood pressure and IS, IS might also play a mediating role on the pathway between blood pressure and AF. Thus, raised blood pressure in stroke patients increases the risk of AF and active acute blood pressure lowering can improve outcome in IS patients, which is of significance in clinical application. Further validation of these findings is warranted based on large-scale longitudinal studies that repeat the measurements of IS, blood pressure, and AF.Additional file 1. Methods details including Inverse-variance weighted method, MR-Egger method, Weak Instruments and Mediation analysis. Leave-one-out plots in the sensitive analysis.Additional file 2. The basic characters of summary data used in this study. Details of instrumental invariables selected for each traits.


Clinical features of cough variant asthma (CVA) in Chinese adults are largely uncertain.A total of 303 patients newly diagnosed as uncontrolled asthma (symptom control and future risk of adverse outcomes), including 175 CVA and 128 classic asthma (CA), were enrolled in this retrospective survey. Clinical features including basic characteristics, pulmonary function, airway hyperresponsiveness (AHR) and cell counts of induced sputum, were compared retrospectively. All patients were classified into four inflammatory subtypes based on the counts of induced sputum eosinophils and neutrophils as eosinophilic (E), neutrophilic (N), mixed granulocytic (M), and paucigranulocytic (P) subtypes. Inflammatory subtype distribution was also compared.1 after inhalation of bronchodilator (ΔFEV1%) .Compared with CA patients, CVA patients were younger (P = 0.009), had a higher prevalence of female patients (P = 0.001), higher parameter values of baseline pulmonary function , shorter duration of disease (P = 0.002), lower AHR (P = 0.001) and lower sputum eosinophil% (P = 0.009). There was a difference in the AHR distribution as the percentage of moderate and severe AHR in CVA was significantly lower than in CA . The inflammatory subtype distribution was different as the proportion of E and M subtypes in CVA was lower than in CA . The proportion of subtype P was the lowest and subtype M was the highest in both CVA and CA patients. There was a similar negative correlation of sputum eosinophil% with AHR in CVA and CA , and a positive correlation between sputum eosinophil% and improvement rate of FEVCVA patients showed a better pulmonary function and lower airway inflammation in contrast to CA patients, which may participate in the pathogenesis of chronic cough in CVA. Many patients in clinics are suffering from a chronic cough, which is defined as cough being the sole or predominant symptom lasting for at least 8 weeks, with absence of pulmonary disease . ChronicAirway inflammation in asthma is heterogeneous. It is important to fully understand its pathophysiology and clinical phenotypic characteristics for the investigation of pathogenesis and development of treatment strategies. Nevertheless, as we know, the majority of current researches are relevant to classic asthma, and non-typical asthma patients are often excluded. Studies of CVA are few and the sample size is small –9. There1% less than normal predicted value and/or any severe exacerbation due to asthma). Uncontrolled asthmatic patient had equal to or greater than 3 features as the above.Newly diagnosed asthma patients who visited respiratory clinics of Affiliated Third People’s Hospital of Guangzhou Medical University in Huizhou, were retrospectively included in this study from June 2016 to December 2017. All subjects were at uncontrolled stage. The level of asthma control was defined by asthma symptoms control  and future risk of adverse outcomes , and had no past history of upper respiratory tract infection in the last month. Result of chest radiograph or chest computed tomography was normal, excluding lung diseases . All subjects were over 17 years old, and had the cognitive competence to pass all the medical examinations under the guidance of doctors.Each subject underwent a clinical history inquiry, physical examination and imaging examination (chest radiography or computed tomography), pulmonary function test (PFT), AHR test or bronchodilator reversibility test, and finally sputum induction on the same day.1), forced vital capacity (FVC), FEV1/FVC ratio, maximal mid-expiratory flow (MMEF) and maximum forced expiratory flow (MEF) were recorded in PFT. The degree of central airways obstruction was divided into four levels based on FEV1% predicted value: mild (≥ 70%), moderate (60–69%), between moderate and severe (50–59%), severe (35–49%), extremely severe (< 35%) [PFT, methacholine challenge test (AHR test), and bronchodilator reversibility test were performed with a computerized spirometer  by professional technicians according to the 2014 Guideline for Pulmonary Function of Chinese Respiratory Society . The for (< 35%) .1 was measured after each inhalation. This test was stopped until a reducing in baseline FEV1 of 20%. AHR was calculated by PD20-FEV1 (cumulative dose of methacholine required to achieve a 20% decrease in FEV1) and defined by PD20-FEV1 ≤ 2.504 mg. AHR was divided into four levels based on PD20-FEV1 value: very mild (1.076–2.504 mg), mild (0.294–1.075 mg), moderate (0.035–0.293 mg), severe (< 0.035 mg) [AHR test was performed after PFT. Patients were asked to inhale gradually increasing doses of methacholine , and FEV.035 mg) .1% predicted value < 70% in PFT. Patients were required to inhale 400 μg salbutamol through an inhalation device, and repeated the aforementioned PFT after 20 min. The result was defined as positive (reversible airflow obstruction) if postbronchodilator FEV1 increased ≥ 12% and absolute value increased ≥ 200 ml of prebronchodilator, moreover, postbronchodilator FEV1/FVC < 70% [This test was performed on patients whose FEVVC < 70% .Before inducing sputum by the ultrasonic atomizer, patients were required to inhale 400 μg salbutamol. According to an established method , patientAll data were analyzed using SPSS version 19.0 (USA) and P < 0.05 was considered of statistical significance. Continuous variables were expressed as mean (SD) depending on normal distribution or median (interquartile range) for non-normal distribution, while classification variables analyzed with Chi square test were expressed as number (percentage). Two groups of continuous variables were compared with T-test  or Mann–Whitney U test . Correlation between sputum eosinophils% and AHR or bronchodilator reversibility was analyzed by Spearman rank correlation.Of the 200 subjects in CVA and 140 subjects in CA enrolled, twenty-five CVA and twelve CA patients were excluded due to failed sputum induction. 175 CVA subjects  and 128 CA subjects  were included in this analysis, both with the ages ranged from 17 to 84 years old. CVA subjects consisted of young adults , middle-age adults  and elderly adults . CA subjects consisted of young adults , middle-age adults  and elderly adults .As shown in Tables The AHR of CVA was significantly lower than CA (P = 0.001). There was a difference in the AHR distribution as the percentage of moderate and severe AHR in CVA was significantly lower than in CA  Table .Table 3DSputum eosinophil% in CVA was significantly lower than in CA (P = 0.009), while an opposite result was showed in the macrophage% (P = 0.0004). No significant difference in sputum neutrophil% (P = 0.128) or lymphocyte% (P = 0.058) was found.According to induced sputum eosinophil% (eos) and neutrophil% (neu), all patients were classified into four subtypes: eosinophilic (E) , neutrophilic (N) , mixed granulocytic (M)  and paucigranulocytic (P)  subtypes. There was a difference in the inflammatory subtype distribution as the proportion of E and M subtypes in CVA was lower than in CA . The proportion of subtype P was the lowest and subtype M was the highest in both CVA and CA  in CA patients  . There was also a significant correlation of sputum eosinophil% with the improvement rate in FEVThis is the first large-sample study on the clinical features of CVA patients in Chinese adults. With a broad range of all ages, a total of 175 CVA patients aged 17–84 years were evaluated in this study. Our study is superior to previous studies in such a broad range of all ages and a larger sample size. Therefore, the results of our study are reliable and may reflect the reality in practice.2 and neuropeptide substance P secreted by eosinophils, mild airway remodelling, lower total IgE and smaller numbers of sensitized allergens [This study retrospectively compared the baseline pulmonary function, AHR, and induced sputum cell counts in asthma patients. It showed that: (1) the parameter values of baseline pulmonary function in CVA, including indices of both central and peripheral airways obstruction, were significantly higher than in CA; (2) as with CA, eosinophilic airway inflammation (sputum eosinophil% ≥ 2.5) was also an important pathological feature of CVA; nevertheless, the AHR and eosinophilic airway inflammation of CA were significantly higher than those of CVA. These findings may be related to the mechanism of chronic cough without wheeze in CVA in contrast with CA. Some studies, with a small sample size, revealed that these factors, such as airflow obstruction at central airways, heightened cough sensitivity, higher wheezing threshold, lower AHR, prostaglandin-Ellergens –19 were 1% predicted value ≥ 70%); while 87.5% of CA patients showed a central airways obstruction, and 56.2% of CA patients had moderate to extremely severe central airways obstruction . These results indicate that there is no relationship between the site of airway obstruction  and chronic cough mechanism of CVA.There is also a controversy on peripheral or central airways obstruction of CVA. We noticed that 51.43% of CVA subjects showed normal or almost normal pulmonary function , and other subjects had a mild central airways obstruction  and peripheral blood eosinophil count. There is no unified classification standard for sputum cell counts in Chinese and Westerners. According to the definition of sputum eosinophil% ≥ 2.5 as eosinophilic inflammation and neutrophil% ≥ 65 as neutrophilic inflammation recommended in 2016 Chinese National Guidelines on Diagnosis and Management of Cough [Our study has some limitations. First, it was conducted in a retrospective fashion. Second, sputum neutrophil might increase by smoking cigarette, age and air pollution, while the sample size was significantly increased if smoking and non-smoking patients were included in this study.CVA patients showed higher parameter values of baseline pulmonary function, lower airway reactivity and airway eosinophilic inflammation in contrast to CA, which may correlate with the pathogenesis of chronic cough in CVA.