Clinical Sciences. Serum Soluble Corin Is Decreased in Stroke

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1 Clinical Sciences Serum Soluble Corin Is Decreased in Stroke Hao Peng, MD, PhD*; Fangfang Zhu, MD*; Jijun Shi, MD*; Xiujie Han, MD, PhD; Dan Zhou, MD; Yan Liu, MD; Zhongwen Zhi, MD; Fuding Zhang, MD; Yun Shen, MD; Juanjuan Ma, MD; Yulin Song, MD; Weidong Hu, MD, PhD Background and Purpose Soluble corin was decreased in coronary heart disease. Given the connections between cardiac dysfunction and stroke, circulating corin might be a candidate marker of stroke risk. However, the association between circulating corin and stroke has not yet been studied in humans. Here, we aimed to examine the association in patients wtith stroke and community-based healthy controls. Methods Four hundred eighty-one patients with ischemic stroke, 116 patients with hemorrhagic stroke, and 2498 healthy controls were studied. Serum soluble corin and some conventional risk factors of stroke were examined. Because circulating corin was reported to be varied between men and women, the association between serum soluble corin and stroke was evaluated in men and women, respectively. Results Patients with ischemic and hemorrhagic stroke had a significantly lower level of serum soluble corin than healthy controls in men and women (all P values, <0.05). In multivariate analysis, men in the lowest quartile of serum soluble corin were more likely to have ischemic (odds ratio [OR], 4.90; 95% confidence interval, ) and hemorrhagic (OR, 17.57; 95% confidence interval, ) stroke than men in the highest quartile. Women in the lowest quartile of serum soluble corin were also more likely to have ischemic (OR, 3.10; 95% confidence interval, ) and hemorrhagic (OR, 8.54; 95% confidence interval, ) stroke than women in the highest quartile. ORs of ischemic and hemorrhagic stroke were significantly increased with the decreasing levels of serum soluble corin in men and women (all P values for trend, <0.001). Conclusions Serum soluble corin was decreased in patients with stroke compared with healthy controls. Our findings raise the possibility that serum soluble corin may have a pathogenic role in stroke. (Stroke. 2015;46: DOI: /STROKEAHA ) See related article, p Stroke is the leading cause of long-term disability and mortality in China. 1 There are currently at least 7 million Chinese having stroke and 2 million new and recurrent strokes diagnosed each year. 2 Improved identification of those at risk of stroke might improve prevention. This has led to a search for new risk factors for stroke. Recently, increased natriuretic peptides were suggested to be risk factors for stroke, although the mechanism is not clear. 3,4 Human corin, a type II transmembrane serine protease highly expressed in the heart, 5,6 played a physiological role in the activation of natriuretic peptides. 7 This indicated a potential role of human corin in stroke. Key Words: CORIN protein, human stroke Human corin has been found to be decreased in the circulation among patients with heart failure 8 and acute coronary syndrome. 9 Given the connections between cardiac dysfunction and stroke, circulating corin might be a candidate marker of stroke risk. However, to date, the association between circulating corin and stroke has not yet been studied in humans. Here, we aimed to study the serum levels of corin in patients with stroke and community-based controls. Moreover, circulating corin was reported to be varied between men and women. 8 The association between serum soluble corin and stroke was studied in men and women individually. Because there is little information on the role of corin in stroke cause, Received December 3, 2014; final revision received February 15, 2015; accepted March 5, From the Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (H.P., J.S., Y.L., W.H.); Department of Emergency, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China (F.Z., Z.Z., J.M.); Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, China (J.S., Y.S., W.H.); and Department of Neurology, Anshan Changda Hospital, Anshan, China (X.H., D.Z., F.Z., Y.S.). *Drs Peng, Zhu, and Shi contributed equally and are joint first authors. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Yulin Song, MD, Department of Neurology, Anshan Changda Hospital, 69 Changda St, Tiedong District, Anshan, , China, yulinsong1969@sina.com or Weidong Hu, MD, PhD, Department of Neurology, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Rd, Gusu District, Suzhou, , China, weidonghu@aliyun.com 2015 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Peng et al Decreased Corin in Stroke 1759 we studied the levels of corin in ischemic and hemorrhagic stroke, respectively. Methods Participants Subjects were recruited after having provided their written informed consent and with approval from the Ethics Committee of Soochow University. This study consecutively recruited patients with first-ever ischemic or hemorrhagic stroke onset within 48 hours confirmed by brain computed tomography or magnetic resonance imaging from 3 hospitals between January 2014 and May 2014 (Table I in the onlineonly Data Supplement). The inclusion criteria were as follows: (1) age 22 years, (2) stroke onset within 48 hours confirmed by imaging, and (3) able and willing to sign informed consent by patients or their direct family members. Patients with one of the following were excluded: (1) recurrent stroke, (2) current pregnant women, and (3) unable to participate in the follow-up examination. Controls who never had cardiovascular diseases were recruited from a cohort of participants previously randomly recruited from communities in Suzhou city. 10 Data Collection For patients with stroke, information was recorded by means of a structured questionnaire about demographic characteristics (age and sex), lifestyle risk factors (cigarette smoking and alcohol consumption), medical history (hypertension, hyperlipidemia, diabetes mellitus, coronary heart disease, and other vascular diseases), and time from symptom onset to hospitalization at the time of enrollment. Coronary heart disease included angina pectoris, myocardial infarction, and coronary insufficiency. The medical history was defined as whether the participants were previously diagnosed or treated in hospitals and reported by the participants and their relatives. Stroke severity was assessed using the National Institutes of Health Stroke Scale by trained neurologists. 11 Computed tomography or magnetic resonance imaging of the brain was performed according to standard techniques to confirm the diagnosis of ischemic stroke or hemorrhagic stroke in all participants. Three consecutive blood pressure measurements were obtained at baseline by trained nurses according to a common protocol adapted from procedures recommended by the American Heart Association. 12 Blood pressure was measured with the participant in a supine position using a standard mercury sphygmomanometer and appropriate cuff size. Body weight and waist circumference were measured for each participant. Routine laboratory determinations (fasting plasma glucose, blood lipids, uric acid, etc.) were performed for all enrolled patients in each participating hospital at admission. Blood samples were collected immediately after hospitalization before receiving any drugs. After at least 30 minutes of spontaneous coagulation, blood samples were centrifuged at 4 C for 10 minutes and the serum were separated and frozen at 20 C for <2 months. The serum samples were then shipped to the Central Laboratory of School of Public Health in Soochow University and frozen at 80 C until the time of assay. For controls, the methods of data collection were detailed previously. 10 In brief, all participants were studied in the morning. Fasting blood samples were obtained by venipuncture and immediately centrifuged at 4 C and the serum frozen at 80 C until the time of assay. Serum Soluble Corin Measurement Serum soluble corin measurements were performed in the Central Laboratory of School of Public Health in Soochow University. The staff who performed the measurements were blind to the clinical characteristics of the study participants. Soluble corin was reported to be stable in blood samples frozen at 80 C after several cycles of freezing and thawing. 13 We used a quantikine human corin immunoassay (Catalog: DCRN00; R&D Systems, Inc, Minneapolis) to test soluble corin levels in serum. All the samples were processed in a duplicate assay. A standard curve was constructed and from which corin concentrations of unknown samples were determined. Intra- and interassay coefficients of variation were <2.7% and 6.3%, respectively. Statistical Analysis The statistical analysis was conducted using SAS statistical software (version 9.1, Cary, NC). Baseline characteristics in patients with ischemic stroke, patients with hemorrhagic stroke, and healthy controls were compared using a 1-way ANOVA test, Wilcoxon signed-rank test, or the χ 2 test as appropriate. The average level of serum corin was compared among the 3 groups using a Wilcoxon signed-rank test for lacking normal distribution. Circulating corin was reported to be varied between men and women. 8 The corin levels were also significantly higher in men compared with women in our study. We compared the median level of serum corin between men and women in patients with ischemic stroke, patients with hemorrhagic stroke, and healthy controls, respectively. As well, we evaluated the association between serum soluble corin and stroke risk in men and women, respectively. Participants were categorized into 4 groups according to the quartiles of serum corin in healthy men and women. With the highest quartile as a reference, we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) of ischemic stroke and hemorrhagic stroke for the other 3 quartiles using univariate and multivariate logistic regression models. Trends in the ORs across decreasing corin categories were determined, modeling corin category as an ordinal variable. The potential covariates, such as age, sex, cigarette smoking, alcohol consumption, family history of stroke, systolic blood pressure, waist circumference, total cholesterol, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, and serum uric acid, were included in the multivariate model. A 2-tailed P value <0.05 was considered statistically significant. Sensitivity Analysis To examine whether cardiac dysfunction affects the association between serum soluble corin and stroke, stroke patients with a history of coronary heart disease, heart failure, or atrial fibrillation were excluded. Results Baseline Characteristics We studied 481 patients with ischemic stroke, 116 patients with hemorrhagic stroke, and 2498 healthy controls (Table 1). Patients with ischemic stroke were more likely to be older, men, cigarette smokers, alcohol consumers, hypertensives, diabetic patients, individuals with a family history of stroke, and have higher waist circumference, systolic blood pressure, triglycerides, fasting plasma glucose, serum uric acid, and lower high-density lipoprotein cholesterol and total cholesterol than healthy controls (all P values, <0.05). Patients with hemorrhagic stroke were more likely to be older, men, cigarette smokers, alcohol consumers, hypertensives, diabetic patients, individuals with a family history of stroke, and have higher systolic blood pressure, diastolic blood pressure, fasting plasma glucose, serum uric acid, and lower high-density lipoprotein cholesterol and total cholesterol than healthy controls (all P values, <0.05). Compared with patients with ischemic stroke, patients with hemorrhagic stroke were more likely to be younger, have higher systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, fasting plasma glucose, National Institutes of Health Stroke Scale score, and lower triglycerides and serum uric acid (all P values <0.05). The median level of serum soluble corin was significantly lower in patients with hemorrhagic stroke ( pg/ml) than that in healthy controls ( pg/ml) and patients with ischemic stroke ( pg/ml; all P values, <0.05). There was no significant difference in the median level of serum soluble corin between patients with ischemic stroke and healthy controls.

3 1760 Stroke July 2015 Table 1. Characteristics of Study Participants Characteristics Healthy Controls, n=2498 Ischemic Stroke, n=481 Hemorrhagic Stroke, n=116 P Value Age, mean±sd 52.7± ±12.7* 58.7±12.2* <0.001 Men, n (%) 962 (38.5) 308 (64.0)* 76 (65.5)* <0.001 Cigarette smoking (%) 582 (23.3) 197 (41.0)* 48 (41.4)* <0.001 Alcohol consumption (%) 465 (18.6) 124 (25.8)* 41 (35.3)* <0.001 FHS (%) 227 (9.1) 94 (19.5)* 34 (29.3)* <0.001 History of CHD, n (%) 52 (10.8) 5 (4.3) <0.001 Hypertension, n (%) 1109 (44.4) 301 (62.6)* 76 (65.5)* <0.001 Diabetes mellitus, n (%) 109 (4.4) 116 (24.1)* 12 (10.3)* <0.001 BMI, mean±sd 24.77± ± ± WC, mean±sd 82.42± ±11.11* 83.64± SBP, mean±sd 130.1± ±21.0* 164.7±26.6* <0.001 DBP, mean±sd 84.8± ± ±17.1* <0.001 TC, mmol/l 5.09 ( ) 4.91 ( )* 4.88 ( )* <0.001 TG, mmol/l 1.10 ( ) 1.41 ( )* 1.23 ( ) <0.001 LDL-C, mmol/l 2.94 ( ) 3.06 ( ) 2.89 ( ) HDL-C, mmol/l 1.46 ( ) 1.09 ( )* 1.28 ( )* <0.001 FPG, mmol/l 5.2 ( ) 6.0 ( )* 6.8 ( )* <0.001 UA, mmol/l 268 ( ) 312 ( )* 283 ( )* <0.001 NIHSS score, points 4 (2 7) 6 (2 10) Corin, pg/ml ( ) ( ) ( )* All values are expressed with median (interquartile range) unless otherwise noted. BMI indicates body mass index; CHD, coronary heart disease; DBP, diastolic blood pressure; FHS, family history of stroke; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; UA, serum uric acid; and WC, waist circumference. *Compared with controls, P<0.05. Compared with patients with ischemic stroke, P<0.05. Distribution of Serum Soluble Corin As shown in Table 2, the median level of serum soluble corin was significantly higher in men than women regardless of stroke disease. Thus, we compared the median level of serum soluble corin among healthy controls, patients with ischemic stroke, and patients with hemorrhagic stroke separately by sex. The median level of serum soluble corin was pg/ ml and pg/ml in healthy men and women, respectively. Among men, the median level of serum soluble corin was lower in patients with hemorrhagic ( pg/ml) and ischemic ( pg/ml) stroke than healthy controls. Among women, the median level of serum soluble corin was also significantly lower in patients with hemorrhagic ( pg/ml) and ischemic ( pg/ml) stroke than healthy controls. Among patients with stroke, patients with hemorrhagic stroke had significantly lower level of serum soluble corin than patients with ischemic stroke (P<0.05). The median level of serum soluble corin was also compared among 3 subtypes of patients with ischemic stroke. We did not find a significant difference in the median level of serum soluble corin among the 3 subtypes in either men or women (Table II in the online-only Data Supplement). In men, patients with thrombotic (P<0.001) and lacunar (P=0.001) stroke had a significantly lower median level of serum soluble corin than controls. In women, patients with thrombotic stroke had a significantly lower median level of serum soluble corin than controls (P<0.001). Association Between Serum Soluble Corin and Stroke Participants were categorized into quartiles of serum soluble corin in healthy controls to evaluate the association between serum soluble corin levels and stroke in men and women, Table 2. Median Levels of Serum Soluble Corin in Patients With Stroke and Healthy Controls by Sex Participants Corin, Median (Interquartile Range) Men Women P Value Healthy controls ( ) ( ) <0.001 Ischemic stroke ( )* ( )* <0.001 Hemorrhagic stroke ( )* ( )* <0.001 *Compared with controls, P<0.05. Compared with patients with ischemic stroke, P<0.05.

4 Peng et al Decreased Corin in Stroke 1761 respectively. With the highest quartile as a reference, ORs of ischemic stroke and hemorrhagic stroke were calculated. The results are presented in Table 3. In men, both ischemic and hemorrhagic strokes were significantly associated with the decreasing levels of serum soluble corin even after multivariate adjustment (P for trend, <0.001). Participants in the lowest quartile had 4.90 (OR, 4.90; 95% CI, ) the OR of ischemic stroke and (OR, 17.57; 95% CI, ) the OR of hemorrhagic stroke for participants in the highest quartile. In women, both ischemic and hemorrhagic strokes were also significantly associated with the decreasing levels of serum soluble corin even after multivariate adjustment (P for trend, <0.001). Participants in the lowest quartile had 3.10 (OR, 3.10; 95% CI, ) the OR of ischemic stroke and 8.54 (OR, 8.54; 95% CI, ) the OR of hemorrhagic stroke for participants in the highest quartile. Results of Sensitivity Analysis Sensitivity analysis after excluding the stroke patients with a history of coronary heart disease, heart failure, or atrial fibrillation indicated that decreased serum soluble corin remained significantly associated with stroke (Table III in the onlineonly Data Supplement), suggesting that cardiac dysfunction did not affect the association between serum soluble corin and stroke. Discussion This is the first study performing to evaluate the association between serum soluble corin and stroke in humans. We found that serum soluble corin was significantly decreased in patients with ischemic and hemorrhagic stroke compared with healthy controls. ORs of both ischemic and hemorrhagic stroke were significantly increased with the decreasing levels of serum soluble corin even after multivariate adjustment. Our results indicated that serum soluble corin was significantly and inversely associated with ischemic stroke and hemorrhagic stroke. Soluble corin in the circulation was measured by the ELISA assays in most studies. 8,14 16 In this study, we also used commercially ELISA assays to measure the serum soluble corin for all participants. The range of serum corin ( pg/ml) detected in nonhypertensive individuals in our controls was similar to that ( pg/ml) in the previous report. 13 Recently, some small sampled case control studies have examined circulating soluble corin in some disease states, such as heart failure, 8 acute coronary syndrome, 9 osteoporosis, 17 and pregnant hypertension. 18 Corin concentration in the circulation was decreased in heart failure 8 and acute coronary syndrome. 9 Given the connections between cardiac dysfunction and stroke, circulating corin is a candidate marker of stroke risk. However, to date, the association between circulating corin and stroke has not yet been studied in humans. Although serum soluble corin has not been studied in stroke, the association between natriuretic peptides and stroke may give some information on the association between serum soluble corin and stroke because corin was suggested to be a physiological activator of atrial natriuretic peptides. 7 Largescale prospective cohort studies found that increased natriuretic peptides were significantly associated with increased risks for incident stroke, 3,4 although the mechanism is not clear. Clinical studies reported that natriuretic peptides were increased in patients with stroke and associated with infarct size. 19 As an animal experiment 20 found that the activation of atrial natriuretic peptides was abolished after corin gene knockout in mice, increased atrial natriuretic peptides need Table 3. Odds Ratios and 95% Confidence Interval of Stroke Associated With Serum Soluble Corin Quartiles in Men and Women Corin (Quartiles) No. of Controls No. of Cases Ischemic Stroke Hemorrhagic Stroke Stroke Adjusted OR (95% CI) No. of Cases Adjusted OR (95% CI) No. of Cases Adjusted OR (95% CI) Men (reference) (reference) (reference) ( ) ( ) ( ) ( ) ( ) ( ) < ( ) ( ) ( ) P for trend <0.001 <0.001 <0.001 Women (reference) (reference) (reference) ( ) ( ) ( ) ( ) ( ) ( ) < ( ) ( ) ( ) P for trend <0.001 <0.001 <0.001 Adjusted for age, cigarette smoking, alcohol consumption, waist circumference, systolic blood pressure, total cholesterol, triglycerides, highdensity lipoprotein cholesterol, fasting plasma glucose, uric acid, and family history of stroke. CI indicates confidence interval; and OR, odds ratio.

5 1762 Stroke July 2015 more corin to activate them. In light of these findings, serum corin would be increased corresponding to the increased natriuretic peptides in stroke. In stark contrast, serum corin was decreased in patients with stroke compared with healthy controls in our study, and serum corin level varied in ischemic and hemorrhagic stroke. Our results were consistent with other studies that found that plasma corin was decreased in heart failure 8 and acute coronary syndrome. 9 However, the underlined mechanism was not clear. Also, it is not clear yet whether there is a causal relationship between the decreased serum levels of corin and stroke. In addition to the functional role of corin in the activation of natriuretic peptides, other potential roles of corin should be understood for answering this question. We found that serum soluble corin was significantly associated with some preindexes of stroke, such as age, sex, cigarette smoking, alcohol consumption, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and fasting plasma glucose. In our study, the significant association between serum soluble corin and stroke persisted after adjustment for these preindexes of stroke. The results indicated that serum soluble corin was significantly associated with stroke and the association was independent of these preindexes of stroke. Our findings increased the probability that serum soluble corin could be a marker or risk factor for stroke. Several previous studies reported a sex difference in circulating corin. In this study, women had a lower level of serum soluble corin than men in healthy controls, ischemic stroke, and hemorrhagic stroke. To eliminate the influence of sex on the association between serum soluble corin and stroke, we examined the association in men and women, respectively. We found that the association was significant in both men and women. Nevertheless, the estimated effect of the association between serum corin and hemorrhagic stroke was stronger in men than women (OR in the fourth quartile, versus 8.54). The reason is not clear and the sample size of patients with hemorrhagic stroke is not large enough in our study. The association between serum soluble corin and hemorrhagic stroke still needs further study in humans with a larger sample size. In addition, we compared the median level of serum soluble corin among 3 subtypes of patients with ischemic stroke. We did not find a significant difference in the median level of serum soluble corin among the 3 subtypes in either men or women (Table II in the online-only Data Supplement). Interestingly, we found a significantly lower median level of serum soluble corin in patients with thrombotic stroke than controls. This finding indicated a potential role of corin in atherosclerosis. The pathogenic role of serum soluble corin in stroke is warranted to be studied. Stroke and cardiovascular diseases shared some pathological mechanisms, such as atherosclerosis, and cardiac dysfunction was suggested to be a risk factor for stroke. 21 Plasma corin was decreased in coronary heart disease 9 and heart failure, 8 indicating a probable influence caused by coronary heart disease or heart failure on the decreased serum soluble corin in patients with stroke. So that we applied a sensitivity analysis after excluding the stroke patients with a previous coronary heart disease, atrial fibrillation, or heart failure, and we found that the associations between serum soluble corin and ischemic and hemorrhagic strokes were persistent in men and women. This indicated that cardiovascular diseases did not affect the association between serum soluble corin and stroke. To our knowledge, this is the first study examining the association between circulating soluble corin and stroke in humans. There were some strengths to be mentioned. The major strength was that we evaluated the association of serum soluble corin with ischemic and hemorrhagic strokes separately, although these 2 stroke types shared some risk factors. In addition, we compared the median level of serum soluble corin between the 2 stroke subtypes and found that the median level of serum soluble corin was significantly decreased in hemorrhagic stroke than ischemic stroke. This may help us better understand the role of corin in stroke cause. In our study, we obtained the blood samples before any medications because we are not clear about whether medications would influence corin levels. We use an unelected community-based population without any cardiovascular diseases as healthy controls ensuring the representation of the population from which the stroke cases arose. Nevertheless, some limitations should be acknowledged. A causal relationship between serum soluble corin and stroke cannot be inferred because of the case control nature of the study design. Prospective cohort study is needed to confirm the causal relationship between soluble corin and stroke. The patients with stroke were recruited from 3 hospitals, which may cause selection bias. Nevertheless, we did not find any differences in the median level of serum soluble corin among the 3 groups of patients with stroke (Table IV in the online-only Data Supplement). Some data that may influence the results of the study, such as those on renal dysfunction and preindex stroke medications, were not taken into account. We did not obtain electrocardiographic and echocardiographic morphological and functional data on atria and ventricles. These variables might influence the association between serum soluble corin and stroke, although we did sensitivity analysis after excluding the participants with coronary heart disease, atrial fibrillation, or heart failure. We did not evaluate possible associations between serum soluble corin and infarct or hematoma volume. We did not evaluate the possibility of serial measurements of serum levels of corin in patients with stroke to detect possible changes over time of these molecular biomarkers. We did not examine atrial natriuretic peptide level, which can reflect the activity of corin. Patients included in our study had a lower median National Institutes of Health Stroke Scale score of 4 (interquartile range, 2 8) compared with 7 (interquartile range, 2 10) in Chinese national registry data. 22 We did not find a significant correlation between serum soluble corin and National Institutes of Health Stroke Scale score (Spearman correlation coefficient, 0.04; P=0.289). Our results may not be generalized to patients with more severe stroke, elder patients with stroke, or other ethnicity populations. Further study is needed in populations other than Han ethnicity. Finally, the sample of patients with hemorrhagic stroke was not large enough so that the 95% CIs of the point estimates were wide. The point estimates of OR of hemorrhagic stroke were high, indicating a strong association between serum soluble corin and hemorrhagic stroke.

6 Peng et al Decreased Corin in Stroke 1763 In summary, we found that the level of serum soluble corin was decreased in patients with stroke compared with healthy controls. Our findings raise the possibility that serum soluble corin may have a pathogenic role in stroke. Further research into the relationship between stroke and circulating soluble corin is warranted. Acknowledgments We are deeply appreciative of the participants in this study and thank all staffs for their support and assistance. Especially, we thank Center for Disease Prevention and Control of Gusu District for their support in the recruitment of controls. Sources of Funding This study was supported by the Suzhou Science and Technology Project (no. SS0910 and no. SS201333), the Innovation of Graduate Student Training Project in Jiangsu Province (no. CXZZ13_0839), and Kunshan City and Social Development of Science and Technology Plan Project (no. KS1360). None. Disclosures References 1. 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