bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and Safety of Long-Term Administration of Dapagliflozin for Japanese Patients with Type 2 Diabetes Mellitus
Authors: YAMAZAKI MASAHIRO , SAKAI RYOSUKE , OKAMURA TAKURO , FUKUI MICHIAKI 
Published: June 2018

Background: There have been few studies yet on the efficacy and safety of SGLT2 inhibitor in Japanese people at 2 years and later. In this study, we administered dapagliflozin to Japanese patients with type 2 diabetes mellitus (DM) and studied its many effects and its safety.
Subjects and Methods: The subjects were 112 patients aged 20 years and older who were administered 5 mg/day of dapagliflozin after outpatient treatment with dapagliflozin between April 2014 and December 2015 at this hospital had been judged as useful by the primary physician. Body weight (BW), systolic blood pressure (sBP), HbA1c, liver enzymes, HDL-cholesterol (HDL-C), and uric acid (UA) were measured during hospital visits, and these values were analyzed by comparing them between before administration and at 104 weeks of administration. Inbody® was used in 44 patients to compare body composition before and after treatment.
Results: Dapagliflozin was administered over a period of 104 weeks, and a significant decrease in HbA1c, from 8.5±1.4% to 7.6±1.4% (week 0 vs. week 104, p&lt;0.001), and a significant decrease in BW, from 82.2±19.3 kg to 78.6±18.9 kg (week 0 vs. week 104, p&lt;0.001), were observed. sBP, UA, and liver enzymes also significantly decreased, and HDL-C significantly increased. When changes in body composition were checked with Inbody®, muscle mass and the amount of fat had both significantly decreased, but because of the large decrease in the amount of fat, the skeletal muscle index significantly increased. Also, the amount of the reduction in fat was significantly correlated with the amount of the decrease in HbA1c. Serious adverse drug reactions were not observed.
Conclusion: Dapagliflozin can be safely administered over a period of 104 weeks to Japanese patients with type 2 DM, and effects such as lower blood sugar, reduced body weight, and improved metabolism can be expected. Also, a reduction in the amount of fat was suggested to be related to a reduction in HbA1c.

Disclosure
M. Yamazaki: None. R. Sakai: None. T. Okamura: None. M. Fukui: Research Support; Self; Grant-in-Aid for Scientific Research (C), Ono Pharmaceutical Co., Ltd., AstraZeneca, Astellas Pharma US, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Kissei Pharmaceutical Co., Ltd., MSD K.K., Novo Nordisk Foundation.
HbA1c, Weight, and Blood Pressure Changes Associated with Early vs. Late Treatment Intensification with Dapagliflozin in U.K. Primary Care Patients with Type 2 Diabetes
Authors: WILDING JOHN P. , RIGNEY UNA , BLAK BETINA T. , NOLAN STEPHEN T. , FENICI PETER , MEDINA JESUS 
Published: June 2018

Early treatment intensification in patients with type 2 diabetes (T2D) is often required to achieve glycaemic control. Patients with T2D from the UK Clinical Practice Research Datalink, aged ≥18 years, initiating dapagliflozin between Nov 2012 and Aug 2016 and with prior oral T2D therapy (N=3,774) were included in this study. The relationship between early (2nd line) vs. later (≥3rd line) use of dapagliflozin and changes from baseline in HbA1c (≥1.0% absolute reduction), weight (kg) (≥5.0% relative loss) and systolic BP (≥2 mmHg absolute reduction) after 6-12 months were assessed with logistic regression models. Early use of dapagliflozin occurred in 25.2% patients (951/3774) vs. later use in 74.8% (2823/3774). Patients with later use were older [mean: 60.1 (SD 10.3) vs. 55.7 (SD 10.5) years], more likely to be male (61.6% vs. 55.3%), had T2D for longer [median 8.1 vs. 4.0 years] and higher CVD prevalence (13.9% vs. 11.2%). Patients with early and later use of dapagliflozin had similar baseline mean HbA1c levels [9.3% (SD 1.5) vs. 9.2% (SD 1.7)] and BP [134.2 (SD 14.2) vs. 135.0 (SD 14.6) mmHg]. Late users had lower BMI [mean 33.6 (SD 6.3) vs. 36.5 (SD 6.8) kg/m2] than early users. Early dapagliflozin users experienced mean (S.E) reductions of 1.6 (0.07)%, 3.8 (0.25)% and 3.0 (0.82) mmHg in HbA1c, weight and BP, respectively, vs. 1.0 (0.04)%, 4.6 (0.21)% and 3.1 (0.43) mmHg in later users. Compared to later dapagliflozin use, early initiation was associated with a greater likelihood of adjusted HbA1c reduction ≥1% (OR: 1.68, 95% CI: 1.15-2.45). Weight and BP reductions were observed with similar likelihood among early and late users (weight OR: 0.79, 95% CI: 0.54-1.14; BP OR: 0.87, 95% CI: 0.58-1.30).
In conclusion, glycaemic benefits of dapagliflozin were greater in patients receiving it earlier in their treatment pathway. Weight and BP reductions were achieved with similar likelihood among early and later users.

Disclosure
J.P. Wilding: Other Relationship; Self; Astellas, AstraZeneca, Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Eli Lilly and Company, Orexigen Therapeutics, Inc., Merck & Co., Inc. U. Rigney: Employee; Self; AstraZeneca. B.T. Blak: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S.T. Nolan: Employee; Self; AstraZeneca. P. Fenici: Employee; Self; AstraZeneca. J. Medina: Employee; Self; AstraZeneca.
Dose-Response and Exposure-Response (HbA1c) of Dapagliflozin in T1DM Patients
Authors: PARKINSON JOANNA R. , MELIN JOHANNA , ÅSTRAND MAGNUS , HAMREN BENGT , BOULTON DAVID W. , TANG WEIFENG 
Published: June 2018

Dapagliflozin is an inhibitor of the human renal sodium glucose co-transporter type 2 (SGLT2), which lowers plasma glucose by promoting urinary glucose excretion. Dapagliflozin is approved for the treatment of type 2 diabetes mellitus in adults. The effect of dapagliflozin in type 1 diabetes mellitus (T1DM) has been evaluated in 2 clinical trials: DEPICT 1 and DEPICT 2 (NCT02268214 and NCT02460978). The aim of this analysis was to use pooled data from both studies and assess the dose-response (DR) and exposure-response (ER) relationship for dapagliflozin on HbA1c reduction in T1DM patients. In both studies, T1DM patients underwent double-blinded 24-week treatment with either placebo, 5 or 10 mg dapagliflozin doses—plus adjustable insulin. Mixed-Effect Model Repeated Measures including DR/ER functions was used to describe the longitudinal HbA1c data. The DR and ER models described the data from T1DM patients well. DR model predicted HbA1c mean (95% CI) reductions at week 24 (placebo-corrected change from baseline) in T1DM patients to: -0.38% (-0.46, -0.3) and -0.43% (-0.52, -0.35) for 5 mg and 10 mg doses, respectively, which was in good agreement with the actual observations (-0.42% and -0.37% for 5 mg and -0.45% and -0.42% for 10 mg in DEPICT 1 and DEPICT 2 studies, respectively). The estimated ED50 was 1.39 mg and AUC50 (exposure resulting in half maximal effect) was 35.56 ng/ml*h. The effect of several covariates was assessed and the method of insulin administration was found to have an impact on dapagliflozin efficacy in T1DM patients. According to the model, patients who were using insulin pump were predicted to have somewhat larger HbA1c reductions compared to patients who used multiple daily injections. For example, following 10 mg dapagliflozin treatment, patients using pump were predicted to have mean HbA1c reduction of -0.47%, compared to -0.39% in patients without the pump. The difference in the maximum HbA1c reductions was however only approximately 20% and was not deemed to be clinically relevant.

Disclosure
J.R. Parkinson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Melin: Employee; Self; AstraZeneca. M. Åstrand: Employee; Self; AstraZeneca. B. Hamren: Employee; Self; AstraZeneca. Employee; Spouse/Partner; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. W. Tang: Employee; Self; AstraZeneca.
ZYDG2, a Potent, Selective, and Safe GPR40 Agonist for Treatment of Type 2 Diabetes
Authors: JAIN MUKUL R. , GIRI SURESH R. , TRIVEDI CHITRANG J. , BHOI BIBHUTI B. , RATH AKSHYAYA CHANDAN. , RATHOD ROHAN MANUBHAI. , SUNDAR RAJESH , BANDYOPADHYAY DEBDUTTA , RAMDHAVE RASHMI , PATEL GAUTAM D. , SRIVASTAVA BRIJESH KUMAR. , DESAI RANJIT C. 
Published: June 2018

GPR40 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. Agonists of GPR40 are known to stimulate insulin secretion and reduces circulating glucose levels in a glucose-dependent manner. TAK-875, a GPR40 small molecule agonist developed by Takeda Pharmaceuticals showed antidiabetic efficacy in animals and humans, but its development was terminated in phase 3 due to adverse liver effects. ZYDG2 is a safer GPR40 agonist that has shown desirable profile in preclinical studies. ZYDG2 was identified as a potent and selective agonist for GPR40, exhibiting EC50 of 13 nM and 41 nM for hGPR40, in HEK-293 cell-based Ca2+ mobilization assay and IP1 ELISA assays respectively. It increased insulin secretion and showed dose-dependent improvement in glucose tolerance test in n-STZ Wistar rats, DIO mice and db/db mice. It also showed anti-hyperglycemic effects in rats unresponsive to sulfonylureas. No tachyphylaxis was observed after repeated administration for 15 weeks in n-STZ rats. ZYDG2 showed glucose-stimulated insulin secretion as revealed by significant increase in glucose infusion rate in hyperglycemic clamp study using SD rats. ZYDG2 treatment was associated with significant rise in plasma total GLP1 levels in nondiabetic and diabetic animal models which was not observed in case of TAK-875. Since TAK-875 was terminated due to hepatotoxicity associated with bile acid transporter inhibition, this aspect was studied in details. TAK-875 inhibited the hBSEP and hMRP2 at efficacy concentrations whereas ZYDG2 does not show any inhibition (up to 300 µM) for hBSEP and hMRP2. TAK-875 also showed significantly increased cholic acid levels in Sprague Dawley rat which was not shown by ZYDG2. The maximum tolerated dose for ZYDG2 was 2000 mg/kg and 28 days NOAEL was 300 mg/kg. This clearly demonstrates that ZYDG2 has a great potential to become a safe and effective candidate for treatment of type 2 diabetes.

Disclosure
M.R. Jain: None. S.R. Giri: None. C.J. Trivedi: None. B.B. Bhoi: None. A.C. Rath: None. R.M. Rathod: None. R. Sundar: None. D. Bandyopadhyay: None. R. Ramdhave: None. G.D. Patel: None. B.K. Srivastava: None. R.C. Desai: None.
The Impact of Metformin Exposure on Lactate Level in Tibetan Type 2 Diabetes Living at High-Altitude Area
Authors: LUO YINGYING , GENG YANYAN , REN QIAN , ZHOU LINGLI , LV XUEMEI , MENG SHUYOU , YANG LIHUI 
Published: June 2018

Objective: To investigate the impact of Metformin exposure on lactate level in Tibetan type 2 diabetics living at high-altitude area.
Methods: Our hospital sits 3600 meters above sea level. We retrospectively reviewed the in-patients’ documents since Nov. 2016 to Dec. 2017 in our department. We selected those who did not receive Metformin previously and initiated Metformin treatment during their stay in the hospital with their lactate level assayed. Firstly, we compared the lactate level before and after Metformin treatment. We then did the subgroup analysis according to the participants’ age, baseline lactate level and baseline oxygen saturation degree. Finally, we analyzed the associated factors which may influence the lactate level after Metformin exposure by logistic regression test.
Results: There were 132 patients recruited into our study, including 98 male patients. The mean age of all the participants were 52±12 years old. There was no significant difference between the lactate level before and after Metformin exposure (3.15±1.82mmol/L vs. 3.29±1.96mmol/L, t=-0.784, P=0.435). For the subgroup analysis, we found that in the normal lactate level (&lt;2.0mmol/L) and hyperlactatemia group (2.0-3.9mmol/L), there was a significant elevation of the lactate level after the exposure of Metformin. Reversely, a significant decrease of the lactate level was seen in the severe hyperlactatemia group (≥4.0mmol/L) after Metformin exposure. There were 73 patients (55.3%) who had an elevated lactate level after the Metformin treatment. We also found that baseline lactate level (P&lt;0.001, OR =0.019, 95% CI 0.002-0.159) and baseline oxygen saturation (P=0.04, OR =1.092, 95% CI 1.004-1.187) were two associated factors leading to the elevation of the lactate level after Metformin treatment.
Conclusion: Metformin treatment does not lead to the elevation of lactate level in Tibetan type 2 diabetics living at high-altitude area. Metformin can be safely used in high-altitude residents.

Disclosure
Y. Luo: None. Y. Geng: None. Q. Ren: None. L. Zhou: None. X. Lv: None. S. Meng: None. L. Yang: None.
Novel Analysis of Bionic Pancreas Trial Data Emphasizing Benefit to Individuals Rather than the Group as a Whole
Authors: SLOANE JASON 
Published: June 2018

We previously showed in a multicenter, outpatient, random-order crossover trial (n=39, 11 days each arm) that the bionic pancreas (BP) reduced group mean CGM glucose (141±10 vs. 162±29 mg/dl, p&lt;0.0001) and percent of time spent &lt;60 mg/dl (0.6±0.6% vs. 1.9±1.7%, p&lt;0.0001) relative to usual care (UC) with pump ± CGM (El-Khatib FH, et al. Lancet. 2017; 389:369-80). We applied a new statistical approach to these data to determine how many individuals saw benefit for each outcome. We compared the average CGM glucose and average time &lt;60 mg/dl between the BP and UC arms for each patient using autoregressive time series models to determine significance of differences. We found that 72% of subjects had a statistically significant reduction in mean CGM glucose, 51% had significant reduction in time &lt;60 mg/dl, 44% had a significant reduction in both, and 97% had a significant reduction in at least one outcome. For every subject with mean CGM glucose that was nominally higher in the BP arm, the mean glucose in the BP arm was &lt;154 mg/dl (predicted A1c &lt;7%) and the average time &lt;60 mg/dl was less than in the UC arm (significantly less in 2/6 cases). These analyses provide a new prospective on the efficacy of the BP emphasizing the benefit to individuals rather than the group as a whole. Subjects least likely to benefit were those who had extremely tight glycemic control and minimal hypoglycemia under UC.

Disclosure
J. Sloane: None.
HD-6277, a Novel GPR40 Agonist, Improves Glucose Homeostasis and Enhanced Glucose-Dependent Insulin Secretion in Beta Cells and Type 2 Diabetic Rats
Authors: KIM DAEHOON , KIM CHUN HWA , CHOI HYO SUN , YANG GOEUN , KANG SEUNG JUN , LEE SUN HEE , LIM KWAN SOO , PARK MIN AH , KIM DOO YOUNG , RHEE JAE KEOL 
Published: June 2018

GPR40 is known as free fatty acid receptor 1. Currently, HD-6277, a novel GPR40 agonist, is being developed by Hyundai Pharm in first in human study. The aim of this study was to determine the effects of the novel GPR40 agonist. HD-6277 is a highly potent, selective and orally available small molecule agonist. The potency was measured in vitro and in vivo studies. In vitro potency was determined by HD-6277, TAK-875 and GW95(EC50, &lt;10 nM, 27 nM and 14 nM) in stably hGPR40 expressed CHO cells. Selective GPR40 activity of HD-6277 was evaluated by GPCR panel assay.In vivo glucose lowering effect was determined by oral glucose tolerance test (OGTT) and HbA1c in Sprague-Dawley (SD) rats and various type 2 diabetes rats, respectively. Oral administration of HD-6277 (0.1∼10 mg/kg) once daily reduced plasma glucose excursion and enhanced insulin secretion in GK, DIO, OLETF and ZDF rats. Antidiabetic efficacy compared with Metformin, Glimepiride, Linagliptin, Empagliflozin, Rosiglitazone and Fasiglifam respectively. HD-6277 treatment showed potent anti-hyperglycemic effects than commercially available antidiabetic drugs. GSIS was assessed in INS-1 cells and rats with sulfonylurea and glinides. HD-6277 enhanced insulin excursion in high glucose condition, whereas in low glucose circumstance was not, thus hypoglycemic risk was low. Repeat dosing for 7day in SD rats, glibenclamide (10 mg/kg) and nateglinide (50 mg/kg) caused hypoglycemia but HD-6277 (100 mg/kg) was not.
In conclusion, HD-6277 shows a promising new drug candidates to treat type 2 diabetes mellitus.

Disclosure
D. Kim: Employee; Self; Hyundai Pharm. Corp. C. Kim: Employee; Self; Hyundai Pharm. corp.. H. Choi: None. G. Yang: Employee; Self; Hyundai Pharm. CORP. S. Kang: Employee; Self; Hyundai Pharm. corp. S. Lee: Employee; Self; Hyundai Pharm. CORP. K. Lim: Employee; Self; Hyundai Pharm. corp. M. Park: Employee; Self; Hyundai Pharm.corp. D. Kim: Employee; Self; Hyundai Pharm. CORP. J. Rhee: Employee; Self; Hyundai Pharm. corp..
Saroglitazar Delays and Prevents Type 2 Diabetes in db/db Mice
Authors: GIRI SURESH R. , BHOI BIBHUTI B. , TRIVEDI CHITRANG J. , RATH AKSHYAYA C. , RATHOD ROHAN M. , JAIN MUKUL R. 
Published: June 2018

Saroglitazar is a novel dual PPARα/γ agonist that shows significant triglyceride-lowering and insulin-sensitizing effects in animal models and humans. Saroglitazar causes insulin sensitization and increases flux of lipids in adipocytes thereby preventing the glucotoxicity and lipotoxicity. It also improves mitochondrial bioenergetics potential and increased the ATP production rate and reduces the expression of pro-inflammatory (TNFα, IL1β and IL6) genes. In this study, we have evaluated the potential of saroglitazar to delay the onset or prevent development of T2DM in db/db mice. The db/db mouse is a widely used model for T2DM and shows progressive changes starting with development of obese phenotype at the age of 4 weeks followed by hyperglycemia and hyperinsulimenic condition between 4-8 weeks of age and hypoinsulinemia accompanied by hyperglycemia at 12-16 weeks of age. Group of male db/db mice were treated with saroglitazar (0.8 and 2.5 mg/kg, p.o.) or metformin (250 mg/kg, p.o.) starting at the age of 4 weeks (prediabetes condition) and continued the treatment for 12 weeks (till animals become 16 weeks old and develop frank T2DM). Saroglitazar treatment for 12 weeks completely prevented diabetes onset as reflected by normal fed and fasting blood glucose levels during 6-16th week, whereas metformin treated animals showed elevated fasting blood glucose levels after 8 weeks. Saroglitazar also caused almost 100% improvement in glucose tolerance and insulin sensitivity which was not shown by metformin. Furthermore, as compared to placebo and metformin treated db/db mice, saroglitazar-treated showed HbA1c levels similar to normal C57 mice indicating total protection from development of diabetes. It appears that by unique engagement of PPARα and PPARγ, saroglitazar not only normalizes lipids and glucose, but it also preserves the pancreatic β cell function and prevents development of T2DM by a combination of mechanisms involving anti-inflammatory, anti-oxidant, lipid regulating and glucose regulatory pathways.

Disclosure
S.R. Giri: None. B.B. Bhoi: None. C.J. Trivedi: None. A.C. Rath: None. R.M. Rathod: None. M.R. Jain: None.
Prevalence and Trends in Gestational Diabetes Mellitus among Women in the United States, 2006–2016
Authors: ZHOU TAO , SUN DIANJIANYI , LI XIANG , HEIANZA YORIKO , NISA HOIRUN , HU GANG , PEI XIAOFANG , SHANG XIAOYUN , QI LU 
Published: June 2018

Gestational diabetes mellitus (GDM) is a common medical complication in pregnancy, carries adverse health outcomes for both mothers and offspring. However, national data on the prevalence and secular trends of GDM during the past 10 years in the U.S. is lacking. This study included 26,340 ever-pregnant women aged ≥ 18 years from the National Health Interview Survey in 20and 2016. We examined GDM prevalence in 20and 2016. The prevalence of GDM increased from 4.6% in 20to 8.2% in 2016 (P&lt;0.001). non-Hispanic white women showed less increase in the prevalence (2.8%) than non-Hispanic black women (3.8%), Hispanic women (4.1%), and women with other race/ethnicity (8.4%). The prevalence of GDM in non-Hispanic white women was higher than in non-Hispanic black (P=0.01) and women with other race/ethnicity (P=0.01) in 2006; but similar with in non-Hispanic black and lower than in women with other race/ethnicity (p=0.02) in 2016. The prevalence of GDM in non-Hispanic white and Hispanic women was similar in 20and 2016. In addition, the increase of GDM was more evident among women who were overweight, had low income, aged between 45-64 years, and had insufficient physical activity.
In conclusion, the prevalence of GDM increased by 3.6% from 20to 2016; and the rise was more marked among non-white, overweight, low income, age 45-64 years, and insufficient activity groups.

Disclosure
T. Zhou: None. D. Sun: None. X. Li: None. Y. Heianza: None. H. Nisa: None. G. Hu: None. X. Pei: None. X. Shang: None. L. Qi: None.
Cardiometabolic Management—Success of Online CME at Expanding Diabetes Management Past Glycemic Control
Authors: LARKIN AMY , LACOUTURE MICHAEL , LE ANNE 
Published: June 2018

We sought to determine if an online continuing medical education (CME) curriculum could improve the clinical knowledge and competence of primary care physicians (PCPs) and diabetologists/endocrinologists (diabs/endos) regarding cardiometabolic management of T2D incorporating recent cardiovascular outcomes trial (CVOT) data.
The online CME activities consisted of a 2 faculty, 15-minute video consultation and an interactive, case-based text activity. A 4-question repeated pairs pre-/post-assessment study design and McNemar’s chi-squared test were used to determine the efficacy of online education. P values &lt; .are considered statistically significant. Activities were launched online on June 26, 2017 and August 28, 2017, with data collected until July 27, 2017 and September 28, 2017, respectively.PCPs baseline knowledge seen to be significantly lower than that of diabs/endosTopicPCP Baseline Correct ResponsesDiab/endo Baseline Correct ResponsesP valueAvoidance of TZDs in patent with T2D and HF36% (N=344)71% (N=41)P &lt; 0.001Optimizing T2D therapy to meet cardiac-related goals47% (N=344)78% (N-41)P &lt; 0.001T2D treatment intensification in patient with CVD25% (N=344)54% (N=41)P &lt; 0.001Identification of blood pressure lowering as an extraglycemic effect of SGLT2 inhibitors49% (N=200)81% (N=78)P &lt; 0.001Significant overall improvements were seen post educationTopicPCP Change pre-to-postP valueDiab/endo Change pre-to-postP valueSelection of liraglutide to treat a patient with T2D, CVD, and renal disease51% (N=344)P&lt;.000139% (N=41)P&lt;.0001Recognition of TZDs as a bad therapeutic option in a patient with T2D and HF27% (N=344)P&lt;.000114% (N=41)P=.114Identification of antihyperglycemic agents that have been shown to have positive CV effects16% (N=200)P&lt;.00118% (N=78)P=.006Recognized blood pressure lowering as an extraglycemic effect of SGLT2 inhibitors13% (N=200)P&lt;.00114% (N=78)P=.003Persistent knowledge/competence gapsTopicPCP Gap (Percent incorrect)Diab/endo Gap (Percent incorrect)Knowledge of CVOT data40% (N=344)37% (N=41)Therapeutic intensification strategy for T2D and CVD39% (N=344)15% (N=41)Utilization of TZDs in patent with T2D and HF37% (N=344)15% (N=41)Knowledge of CVOT data40% (n=200)37% (N=78)Efficacy of antihyperglycemia therapies24% (n=200)14% (N=78)
This study demonstrates the success of an online curriculum with multiple educational components consisting of both video discussions and interactive text-based cases improving knowledge and competence of PCPs and diab/endos. Additional and persistent gaps were identified for future educational targets.

Disclosure
A. Larkin: None. M. LaCouture: None. A. Le: None.