bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors Associated with Severe Hypoglycemia among Patients with Type 2 Diabetes Treated with Insulin
Authors: PAWASKAR MANJIRI , LIU JINAN , RAVI SHANKAR R. , RAJPATHAK SWAPNIL 
Published: June 2018

We have previously reported that rates of severe hypoglycemic events (SHEs, defined as events that required hospitalization or an emergency department visit) are higher in patients with type 2 diabetes (T2D) on insulin alone (3.4%) or insulin+SU (2.5%) compared to those on insulin+other anti-hyperglycemic agents (AHA) (1.6%). The present analyses were conducted to further evaluate the independent risk factors of SHE after accounting for differences in two treatment groups based on propensity for SHE: Insulin±SU and Insulin+Other AHA. This retrospective analysis using MarketScan database included T2D adults (n=202,147; mean age: 54.0 years; 53% females) with a first prescription of insulin from 1/1/2013 to 12/31/2013 (index period). SHE was measured from the index date to the end of follow-up (12/31/2013). Multivariable Poisson regression was performed to compare the risk of SHE between insulin±SU vs. insulin+other AHA users and assess other predictors. The unadjusted SHE rate per 100 person years was 2.2% among all patients; 2.8% among those on insulin±SU and 1.3% among those on insulin+other AHA. After adjusting for patient’s baseline characteristics, the risk of SHE was 84% higher in patients on insulin±SU compared to those on insulin+other AHA [Hazard ratio (HR):1.84; 95% confidence interval (CI): 1.68- 2.01]. In addition to the treatment type, other factors predictive of SHE were previous history of SHE (HR: 4.73; 95% CI: 4.33- 5.17); and history of comorbidities including chronic kidney disease (HR: 1.75; 95% CI: 1.60-1.92), cardiovascular disease (HR: 1.60; 95% CI: 1.46-1.75), and neuropathy (HR: 1.55; 95% CI: 1.43-1.69). Our results suggest the risk of SHE is lower in patients on insulin with other AHA compared to patients on insulin alone or with SU. Healthcare professionals should take into account the risk of having SHE while making treatment choices especially for vulnerable populations such as patients with prior history of SHE, and other comorbidities.

Disclosure
M. Pawaskar: Employee; Self; Merck & Co., Inc. J. Liu: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; Anthem, Inc.. Employee; Self; Janssen Scientific Affairs, LLC. R. Shankar: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; NGM Biopharmaceuticals. S. Rajpathak: Employee; Self; Merck & Co., Inc..
Impact of Switching from Sulfonylureas to Dipeptidyl Peptidase-4 Inhibitors on Hypoglycemia Burden in the United States—A Predictive Modeling Approach
Authors: LIU JINAN , TANG YUEXIN , HANNACHI HAKIMA , ENGEL SAMUEL S. , RAJPATHAK SWAPNIL 
Published: June 2018

Hypoglycemia requiring medical care represents significant burden for patients with T2DM and health systems. Therefore, minimizing risk of hypoglycemia needs to be considered in treatment decision making, in addition to attaining glycemic goal. Using a predictive modeling approach, we conducted a study to estimate reduction in hypoglycemia event rates and costs that may result from switching from sulfonylureas (SU) to dipeptidyl peptidase-4 inhibitors (DPP-4i) in the United States.
A large commercial claims database was used to identify adult T2DM patients newly treated with SU or DPP-4i in 2014. Rates and costs of hypoglycemia were assessed within one year after drug initiation. A Poisson model, built and developed based on DPP-4i users, was applied in SU users to estimate hypoglycemia rate if they had been switched to DPP-4i adjusting for patient demographics, comorbidities and medication use at baseline. Using National Health and Nutrition Examination Survey, the observed and predicted hypoglycemia costs were then projected on the national level for SU users, and the cost difference represented the change of total hypoglycemia costs had they switched to DPP-4 instead on the national level.
Among patients who initiated SU (n=38,913) and DPP-4i (n=23,956), average age was 52 years; 44% were female. The observed hypoglycemia rates per 100-person years were 6.4 (95% CI: 6.0, 6.9) and 10.6 (95% CI: 10.1-11.1) in DPP-4i and SU groups, respectively. The predicted rate of hypoglycemia was 6.4 (95% CI: 6.1-6.8) in SU group had they switched to DPP-4i. At a national level, this switching could result in potential costs savings of $586 million (from $699 million to $113 million) within one year period.
Our study suggests that switching patients from SU to DPP-4i could reduce hypoglycemia event rates by almost 40% and also result in substantial cost savings associated with hypoglycemia in the United States.

Disclosure
J. Liu: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; Anthem, Inc.. Employee; Self; Janssen Scientific Affairs, LLC. Y. Tang: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc.. Employee; Spouse/Partner; GlaxoSmithKline plc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc. H. Hannachi: Employee; Self; Merck & Co., Inc. S.S. Engel: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. S. Rajpathak: Employee; Self; Merck & Co., Inc..
Limited Availability of Glucagon by Emergency Personnel
Authors: KAHN PETER , WAGNER NICOLE , GABBAY ROBERT A. 
Published: June 2018

Hypoglycemia causes more than 100,000 emergency department visits per year costing over $120 million. Glucagon can reduce the number and severity of hypoglycemic episodes requiring emergency medical attention and hospital admission. However, EMS personnel are often unable to administer glucagon.
U.S. EMS offices were queried for glucagon administration and blood glucose testing protocols. Only paramedics are able to administer glucagon in most states, whereas the 198,200 EMT-Basics personnel nationally cannot. The average response time to calls was 15.34 minutes. Dispatchers correctly coded 44.67% of these calls as a “diabetic problem,” increasing the likelihood of dispatching providers who cannot administer glucagon. The National Emergency Management Information System (NEMIS) (2013- 2015) indicates 89, 263 cases in which glucagon was administered with only 3,944 events with side effects.
Despite its’ favorable safety profile, glucagon cannot be administered by EMT-basics in most states, even though family members can often with minimal training. 3 out of 4 emergency personnel are unable to use glucagon. The likelihood of the correct personnel being dispatched based on dispatcher information alone is poor. Increasing the availability of glucagon in the prehospital setting will likely result in reduced cost burden and adverse consequences of severe hypoglycemia.
EMS Policies Regarding Use of Glucagon and Blood Glucose Testing.

Disclosure
P. Kahn: None. N. Wagner: None. R.A. Gabbay: Consultant; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Onduo, health reveal.
Insulin Acts in Ventromedial Hypothalamus to Regulate the Sympathoadrenal Response to Hypoglycemia in Rats
Authors: AGRAWAL RAHUL , ABREU ADRIANA VIEIRA DE , DURUPT GRIFFIN T. , FISHER SIMON J. 
Published: June 2018

We tested the hypothesis that the correction of ventromedial hypothalamus (VMH) insulin deficiency was sufficient to restore the impaired sympathoadrenal response to hypoglycemia in diabetic rats. Sprague-Dawley rats were injected with either vehicle (nondiabetic controls; CON) or streptozotocin (STZ; 65 mg/kg IP). STZ diabetic rats received osmotic mini-pumps to infuse either artificial cerebrospinal fluid (DIAB) or insulin (3mU/day; DIAB+InsVMH) into the VMH bilaterally. Two weeks later, all three groups underwent hyperinsulinemic (50 mU.kg-1.min-1) hypoglycemic (∼50 mg/dl) clamps. As expected, STZ-diabetic rats showed blunted epinephrine response to hypoglycemia as compared to nondiabetic controls. Chronic infusion of insulin into VMH of diabetic rats normalized the epinephrine response to hypoglycemia and lowered the glucose infusion rate required to maintain hypoglycemia. Examining brain insulin action, it was noted that STZ diabetic rats had decreased Akt phosphorylation and decreased expression of insulin dependent glucose transporter 4 (GLUT4) in VMH by 44 and 40% respectively as compared to the nondiabetic controls. Notably, chronic infusion of insulin to the VMH normalized Akt phosphorylation and GLUT4 expression.
In summary, insulin acts chronically in the VMH to preserve the sympathoadrenal response to hypoglycemia, possibly by regulating GLUT4 expression.

Disclosure
R. Agrawal: None. A. Vieira de Abreu: None. G.T. Durupt: None. S.J. Fisher: None.
Sustainability of a Real-Time Informatics Alert to Prevent Inpatient Severe Hypoglycemia
Authors: ELLIOTT MICHAEL , BLACKBURN MARY C. , HEARD KEVIN M. , MILLIGAN PAUL E. , BRAVO PAULINA CRUZ , TOBIN GARRY S. 
Published: June 2018

Inpatient severe hypoglycemia (SH), blood glucose (BG) &lt;40 mgs/dl, is associated with morbidity. We previously piloted a predictive model to identify and intervene in inpatients at risk for SH that decreased the rate of SH by 68%. Expanding the alert system-wide to 9 hospitals, succeeded in reducing the occurrence of severe hypoglycemia from 2.9% to 1.7% per 1000 at risk patient days during all visits, and from 4.4% to 2.5% during visits where an alert occurred across all hospitals (both p-values&lt;.001). There were 4142 alerts in 2013; number increased to 5171 in 2014, and stayed steady in 2015 (5161), 2016 (5649), and 2017 (4964).
This study reflects a retrospective analysis of system-wide data from 2011 to 2017. Results show BG levels post alert are higher on average (mean 92.83) than pre-alert (mean 74.43). This magnitude of difference occurs in each year (pre-post differences range from 14.7 to 19.3), suggesting that the alert system led to a sustained beneficial effect over time. A decreasing trend in SH rate over time was observed, which differed by hospital (Figure). System-wide electronic surveillance and alerts improve safety in patients with diabetes across a range of clinical settings. This study proves ongoing efficacy of the alert process and variables.

Disclosure
M. Elliott: None. M.C. Blackburn: None. K.M. Heard: None. P.E. Milligan: None. P. Cruz Bravo: None. G.S. Tobin: Speaker's Bureau; Self; Novo Nordisk Inc., MannKind Corporation. Advisory Panel; Self; Novo Nordisk Inc..
C-Peptide Levels Are Associated with Glycemic Variability and Hypoglycemia in Insulin-Treated Type 2 Diabetes
Authors: CHRISTENSEN MERETE B. , GOTFREDSEN ANDERS , NØRGAARD KIRSTEN 
Published: June 2018

Objective: Emerging evidence has suggested that glycemic variability plays an important role in the development of diabetes complications. We aimed to evaluate the influence of c-peptide levels on glycemic variability and hypoglycemia in patients with GAD-antibody negative, insulin-treated type 2 diabetes.
Methods: We enrolled 80 patients with insulin-treated type 2 diabetes (mean age 62.6 ± 9.4 years, mean HbA1C 71.9 ± 11.9 mmol/mol, mean BMI 33.1 ± 5.7 kg/m2). All patients were GAD-antibody negative, had long diabetes duration (18.9 ± 7.4 years) and were treated with basal-bolus insulin. Glycemic variability and hypoglycemia duration were assessed from continuous glucose monitoring data recorded over 6 consecutive days. Glycemic variability was assessed by calculating mean Coefficient of Variation (CV). Hypoglycemia was defined as BG ≤70 mg/dl (3.9 mmol/L) or BG &lt;54 mg/dl (3.0 mmol/L). Fasting c-peptide and fasting glucose were measured on day 1.
Results: Mean fasting c-peptide was 647 ± 493 pmol/L. Low levels of fasting c-peptide were correlated to higher CV (r = -0.44, P=0.001). In a multivariate regression model with HbA1C, BMI, diabetes duration and total daily insulin dose only c-peptide was significantly associated with CV. 47,5% of the patients had at least one episode of hypoglycemia (BG ≤70 mg/dl) and 23.7% had at least one episode of BG &lt;54 mg/dl. Patients with at least one episode of hypoglycemia had significant lower c-peptide than patients without hypoglycemia (494 ± 460 pmol/L vs. 821 ± 479 pmol/L, P=0.004). There was no significant difference in c-peptide between patients with BG ≤70mg/dl and patients with BG &lt;54mg/dl.
Conclusion: Low levels of c-peptide are associated with higher glycemic variability and risk of hypoglycemia in GAD-antibody negative patients with insulin treated type 2 diabetes, suggesting a role for c-peptide in optimizing treatment and prevention of hypoglycemia in insulin-treated type 2 diabetes.

Disclosure
M.B. Christensen: None. A. Gotfredsen: None. K. Nørgaard: Research Support; Self; Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic, Zealand Pharma A/S, Novo Nordisk A/S. Research Support; Self; Zealand Pharma A/S.
Incidence of Hypoglycemia Events in a Large, Real-World Diabetes Population
Authors: BOLLYKY JENNIFER , LU WEI , SCHNEIDER JENNIFER 
Published: June 2018

Background: It is difficult to accurately determine the frequency of hypoglycemic events in a clinical setting. Remotely captured glucose data from connected meters offers an opportunity to understand real-world treatment effects outside of a clinical trial setting. The Livongo for Diabetes Program provides over 50,000 commercially-insured people with diabetes a cellular-enabled, two-way messaging device that measures and records blood glucose. Free, unlimited blood glucose test strips are also provided.
Methods: We obtained blood glucose (BG) values directly from 35,436 individuals who had been using Livongo connected meters over 3 months. Frequency of BG checking, hypoglycemia event rates (BG&lt;70 mg/dL) and clinically significant hypoglycemia event rates (BG&lt;54mg/dL) were characterized by age, gender, race, diabetes type, estimated HbA1c and medication use.
Results: The mean percentage of total BG checks &lt;70mg/dL and &lt;54mg/dL by medication use and diabetes type are reported in Table below.
Conclusions: In a heterogeneous population with type 1 and type 2 diabetes we captured many hypoglycemic episodes, the frequency of which was associated with medication use and diabetes type. The Livongo platform provides an opportunity to understand real-world treatment effects outside of a clinical trial setting.
No meds (N=3181)Oral Meds Only (N=19,135)Insulin Once Daily (N=5,315)insulin &gt; Once Daily - T2D (N=4,606)insulin &gt; Once Daily - T1D (N=2834)MeanSDMeanSDMeanSDMeanSDMeanSDBG&lt;70 mg/dL1.08%3.95%1.14%4.16%3.21%7.34%3.59%6.44%10.45%10.80%BG&lt;54 mg/dL0.20%1.24%0.26%1.85%0.89%2.83%1.19%3.92%4.36%5.88%

Disclosure
J. Bollyky: Employee; Self; Livongo Health. Stock/Shareholder; Self; Livongo Health. W. Lu: None. J. Schneider: Employee; Self; Livongo Health. Stock/Shareholder; Self; Livongo Health.
Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose Tolerant Subjects–Role of Glucagon and Gluconeogenic Substrates
Authors: TRIPATHY DEVJIT , MEROVCI AURORA , CORCHADO ENRIQUE R. MALDONADO , RITA BASU , DEFRONZO RALPH A. 
Published: June 2018

The aim of the present study was to evaluate the effect of a physiologic increase in plasma glucose concentration on endogenous glucose production (EGP) in healthy NGT individuals. 16 NGT subjects [8 with and 8 without family history of T2DM (9M/7F, age = 44± 3 years, BMI = 26 ± 1 kg/m2)] participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m2 min) euglycemic clamp before and after a 48 hour glucose infusion to increase plasma glucose conc by ∼45 mg/dl above baseline (89±4 to 136±4.9 mg/dl). EGP was measured with [3-3H] glucose and gluconeogenic rate was measured following administration of deuterated water. Plasma FFA, glucagon, lactate, glycerol and alanine concentrations also were measured. Following 48 hours of glucose infusion basal EGP increased from 2.05±0.09 to 3.06±0. mg/kg min (p=0.003) and hepatic insulin resistance index (EGP X Fasting Plasma Insulin) increased markedly and similarly (25.1±1.0 vs. 48.3± 3.2, p&lt;0.005). The baseline plasma glucagon concentration tended to be higher following 48 hours of glucose infusion (64±3 vs. 77± 8 pg/ml, p=0.2) while the product of the plasma glucagon and insulin concentrations was markedly increased (540 ± 56 vs. 1336 ± 262, p=0.004). Although the baseline plasma FFA concentration was markedly reduced following 48 hours of glucose infusion (0.482 ±0.to 0.055± 0.01mM), there was no difference in plasma glycerol concentration (13.4±1.2 vs. 13.3 ± 2.2 mg/L p=ns). There were small increases in both the plasma lactate and alanine concentrations. Total body insulin sensitivity declined from 8.75±2.1 to 6.92± 6 mg.kg/min (p&lt;0.05).
Conclusion: Chronic (48 hr) physiologic hyperglycemia to levels seen in T2DM increases basal hepatic glucose production and induces hepatic and skeletal muscle insulin resistance in healthy NGT subjects. These results demonstrate, for the first time that glucotoxicity causes resistance to the suppressive effect of insulin on hepatic glucose production.

Disclosure
D. Tripathy: None. A. Merovci: None. E.R. Maldonado Corchado: None. R. Basu: Research Support; Self; AstraZeneca. R.A. DeFronzo: Speaker-s Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..
The Effect of Bariatric Surgery on Neprilysin and Vasoactive Factors
Authors: DANDONA PARESH , GHANIM HUSAM , MONTE SCOTT , GREEN KELLY , CARUANA JOSEPH A. 
Published: June 2018

Objective: Since morbid obesity is associated with congestive cardiac failure and hypertension, and gastric bypass surgery is followed by a reduction in blood pressure and a reduction in the risk of congestive cardiac failure, we hypothesized that weight loss following bariatric surgery in morbidly obese patients is associated with a decrease in plasma concentrations of neprilysin, mediators of renin angiotensin system, catecholamines and endothelin-1 with an increase in the concentrations of vasodilators.
Method: Fasting blood samples were obtained from fourteen patients with morbid obesity and diabetes prior to and 6 months after Roux-en-Y gastric bypass (RYGB) surgery. Plasma and serum were separated for the measurement of neprilysin; vasoconstrictors, angiotensinogen, renin, angiotensin II, endothelin-1, epinephrine and norepinephrine; and vasodilators, ANP, BNP, cGMP, and cAMP. The mRNA expression of angiotensin converting enzyme (ACE) and adenylate and guanylate cyclases in circulating mononuclear cells (MNC) was also measured.
Results: Six months after RYGB, BMI fell from 52.1±4.8 to 40.4±4.0 kg/m2 and there were significant improvements in the HbA1c. Plasma concentrations of neprilysin, angiotensinogen, angiotensin II, renin and endothelin-1 fell significantly by 27±16%, 22±10% 22±8%, 35±13% and 17±6% (p&lt;0.for all) respectively, while ANP concentrations increased significantly by 24±13% at 6 month following surgery. There was no significant change in aldosterone, BNP, cAMP or cGMP concentrations and ACE mRNA expression.
Conclusion: RYGB suppressed neprilysin concentrations, which may contribute the observed increase in plasma ANP concentrations. In addition, RYGB resulted in a reduction in plasma angiotensinogen, angiotensin II, renin and endothelin-1 concentrations. These changes may contribute to the reduction in the risk of congestive cardiac failure and blood pressure after RYGB.

Disclosure
P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. H. Ghanim: None. S. Monte: Stock/Shareholder; Self; Mobile Pharmacy Solutions (Community Pharmacy). Employee; Self; Synergy Bariatrics, a Department of ECMC. K. Green: None. J.A. Caruana: None.
Contribution of Serum FGF-21 Level to the Identification of Left Ventricular Systolic Dysfunction and Cardiac Death
Authors: BAO YUQIAN , SHEN YUN , ZHANG XUELI , PAN XIAOPING , XU YITING , XIONG QIN , LU ZHIGANG , MA XIAOJING 
Published: June 2018

Aim: This study aimed to investigate the relationship between fibroblast growth factor 21 (FGF-21) and left ventricular systolic dysfunction and cardiac death.
Methods: The optimal cutoff of FGF-21 for identifying left ventricular systolic dysfunction at baseline was analyzed via receiver operating characteristic (ROC) curves. The identification of different serum levels of FGF-21 and their association with cardiac death was analyzed via Kaplan-Meier survival curves.
Results: A total of 253 patients were recruited for this study at baseline. Patients were excluded if they lacked echocardiography or laboratory measurement data, and there were 218 patients enrolled in the final analysis. The average age was 66.32±10.10 years. The optimal cutoff values of FGF-21 and NT-pro-BNP for identifying left ventricular systolic dysfunction at baseline were 321.5 pg/ml and 131.3 ng/l, respectively, determined separately via ROC analysis. The areas under the curves were non-significant among FGF-21, NT-pro-BNP and FGF-21+NT-pro-BNP as determined by pairwise comparisons. Both a higher serum level of FGF-21 and a higher serum level of NT-pro-BNP were independent risk factors for left ventricular systolic dysfunction at baseline (odd ratio (OR) 3.138 [1.037-9.500], P=0.043, OR 9.207 [2.036-41.643], P=0.004, separately). Further Kaplan-Meier survival analysis indicated an association between both a higher serum level of FGF-21 and a higher serum level of NT-pro-BNP with cardiac death in 5 years (RR5.000 (1.326-18.861), P=0.026; RR 9.643 (2.596-35.825), P=0.009, respectively).
Conclusion: Serum FGF-21 level was significantly correlated with left ventricular systolic dysfunction at baseline. Patients with higher serum levels of FGF-21 tended to suffer greater risks of cardiac death than patients with lower serum levels of FGF-21. The identification of FGF-21 and its relationship with left ventricular systolic function and cardiac death were non-inferior to NT-pro-BNP.

Disclosure
Y. Bao: None. Y. Shen: None. X. Zhang: None. X. Pan: None. Y. Xu: None. Q. Xiong: None. Z. Lu: None. X. Ma: None.
Serum FGF-21 Is Associated with Future Cardiovascular Events in Patients with Coronary Artery Disease—Results from a Median Follow-Up of 4.8 Years Study
Authors: BAO YUQIAN , SHEN YUN , ZHANG XUELI , XU YITING , XIONG QIN , LU ZHIGANG , MA XIAOJING 
Published: June 2018

Objectives: To investigate whether the serum fibroblast growth factor (FGF) 21 levels can be used to predict the future development of major adverse cardiovascular events (MACEs).
Methods: 253 patients at baseline received subsequent follow-up, 234 of whom finished the data collection. Independent predictors of MACEs were identified using Cox proportional hazards regression analysis. The prognostic value of FGF-21 levels for MACEs was evaluated by Kaplan-Meier survival analysis.
Results: Of 229 patients finally enrolled in the analysis, 27 of 60 without coronary artery disease (CAD) at baseline experienced a MACE, and 132 of 169 patients with CAD at baseline experienced a MACE. Among patients with CAD at baseline, serum FGF-21 levels were significantly higher in patients with MACEs (P&lt;0.05) than in patients without MACEs. Kaplan-Meier survival analysis showed a significantly lower event-free survival (P=0.001) among patients with a higher serum FGF-21 level than in those with a lower serum FGF-21 level. Further Cox proportional hazards regression analysis, including the traditional risk factors for cardiovascular disease, showed that serum FGF-21 was one of the independent predictors of the occurrence of MACEs.
Conclusions: In patients with CAD at baseline, an elevated serum FGF-21 level was associated with the development of a MACE in the future.

Disclosure
Y. Bao: None. Y. Shen: None. X. Zhang: None. Y. Xu: None. Q. Xiong: None. Z. Lu: None. X. Ma: None.