bluuebunny/crossref_metadata_2025_split huggingface dataset:
318-OR: Ciliary GPCRs Regulate Glucose-Stimulated Insulin Secretion
Authors: WU CHIEN-TING , HILGENDORF KEREN , HANG YAN , BEVACQUA ROMINA J. , JOHNSON CARL T. , CHANG CHARLES A. , PARK SANGBIN , TELLEZ KRISSIE , KIM SEUNG , JACKSON PETER K. 
Published: June 2020

Defects in primary cilia result in syndromes collectively called “ciliopathies”, which often present with obesity and diabetes. Although glucose is the primary mediator of GSIS, circulating factors including free fatty acids, amino acids, and various hormones also play critical roles. At the interface between these circulating factors and GSIS, GPCR signaling is often central. The primary cilium is a membrane and microtubule-based sensory organelle and is highly enriched with specialized GPCRs. Cilia are present on pancreatic β-cells, but the role of cilia in β-cell function remains unclear. To discover ciliary GPCRs important for β-cell function, we compiled a list of candidate β-cell specific or highly expressed GPCRs based on human pancreatic gene expression profiles. We identified 66 β-cell specific GPCRs comparing with α-cells and acinar-cells. These 66 candidate GPCRs was expressed as C-terminally tagged GFP fusion proteins and screened for ciliary localization in a mouse pancreatic β-cell line, MIN6. To date, we have identified the following GPCRs localize to cilia in MIN6 cells: FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. To validate ciliary localization of GPCRs, we also used antibodies against the endogenous GPCRs. We have confirmed that the free fatty acid receptor 4 (Ffar4) and the prostaglandin E receptor 4 (Ptger4) are localized to the primary cilium of mouse and human β-cells. In addition, the treatment of each of agonists of these receptors promote glucose-stimulated insulin secretion (GSIS) in mouse and human islet. Tulp3 is required for transporting GPCRs into the primary cilium. We used shRNA targeting Tulp3 delivered by lentivirus to knock-down Tulp3 in mouse and human islet cells. Tulp3 depletion leaves ciliary structure intact but impairs the localization of Ffar4 and Ptger4 in cilia and disrupts agonist-stimulated GSIS in mouse and human pseudo-islets. Together, these data suggest that primary cilia and ciliary GPCRs are important for the circulating factors-regulated GSIS in β-cell.

Disclosure
C. Wu: None. K. Hilgendorf: None. Y. Hang: None. R.J. Bevacqua: None. C.T. Johnson: None. C.A. Chang: None. S. Park: None. K. Tellez: None. S. Kim: None. P.K. Jackson: None.

Funding
Stanford Diabetes Research Center
398-P: Hypoglycemia Requiring Paramedic Assistance in London, Canada
Authors: SPAIC TAMARA , LIU SELINA L. , CARTER DUSTIN R. , PEDDLE MICHAEL , MAHON JEFFREY 
Published: June 2020

Hypoglycemia requiring paramedic assistance places a large burden on the health care system (HCS), and negatively impacts quality of life and long-term outcomes in patients with diabetes. Prior studies have shown that only a small proportion of patients with paramedic-assist requiring hypoglycemia are subsequently brought to the Emergency Room; thus severe hypoglycemia (SHG) is often “invisible” to the HCS and is not adequately followed up on. We created an innovative, two-step hypoglycemia education program in London, Canada which consists of a direct electronic referral system by paramedics at the time they assess patients with SHG to the local Diabetes Education Center (DEC) for a standardized hypoglycemia education. There were a total of 446 SHG calls to the Middlesex-London Paramedic Service from September 2017- June 2018. Of those, 322 (72%) were eligible for our study, of whom 135 (42%) were referred to the DEC and only 79 patients agreed to attend. Of the 79 patients who were enrolled over 21 months, 49 (62%) were male; the mean age was 61±16 (range 18-88 yrs); and 40 (51%) had type 2, 32 (41%) type 1, and 7 (9%) were unknown diabetes type. Of those 48 (61%) were taking insulin, 8 (10%) oral hypoglycemic agents of which the most common was glyburide (5/8, 63%), and 19 (24%) were on both oral agents and insulin. Three (4%) patients were on an insulin pump. Mean HbA1c was 63±9 mmol/mol (7.9±1.3, range 4.8-10.6%) and the majority did not have an Endocrinologist (49, 62%). Only 50 (63%) completed the education program. There were no statistically significant differences between the characteristics of the patients who attended and did not attend DEC program. Patients experiencing SHG remain ’hidden’ from the HCS. Hence, the impact of SHG is underestimated and understudied. Despite an accessible referral system to a focused intervention, our program was not successful in engaging many patients with SHG requiring paramedic assistance in a program to decrease their risk for SHG. Further study to explore barriers is needed.

Disclosure
T. Spaic: Research Support; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Dexcom, Inc., Sanofi. S.L. Liu: Consultant; Self; Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Novo Nordisk Inc., Sanofi. D.R. Carter: None. M. Peddle: None. J. Mahon: None.

Funding
Academic Medical Organization of Southwestern Ontario
404-P: Cardiovascular Risk Scoring and Stratification in Patients with Type 2 Diabetes Enrolled in a Medicare Advantage Plan
Authors: HAYDEN JENNIFER D. , PIMPLE PRATIK , LUTHRA RAKESH , PREWITT TODD G. , CHIGULURI VINAY , KATTAN MICHAEL , HARVEY RAYMOND , GOSS ASHLEY M. , CAPLAN ELEANOR O. 
Published: June 2020

Current tools to identify patients at risk for cardiovascular (CV) disease or events are variable, limiting their utility and generalizability. The purpose of this study was to develop a predictive model to identify patients with type 2 diabetes (T2D) who are ≥65 years of age, enrolled in a Medicare Advantage Prescription Drug (MAPD) plan and at risk for future CV events. This retrospective cohort study used administrative claims, laboratory and enrollment data from 1/2011-12/2018. Patients with T2D were identified from 1/2012-12/2013 using diagnosis codes and/or claims for antihyperglycemic medications. The dependent variable was the first composite CV event defined as ≥1 inpatient hospitalization for myocardial infarction, ischemic stroke, unstable angina, or heart failure or any evidence of revascularization. Independent variables for the prediction survival model included baseline demographic and clinical characteristics prognostic for the dependent variable. C-statistic, accuracy, sensitivity, and specificity were used to assess model performance. Risk ranking was conducted, whereby patients were classified as low, medium or at high risk of an event based on probability distribution derived cut-points. A total of 362,791 patients with T2D were identified. The proportion of patients with ≥1 CV event was 18.0% up to 5 years after T2D identification. The final model included 42 demographic and clinical variables. The C-statistic was 0.68, and accuracy, sensitivity and specificity were 0.63. Results were consistent across the training, test and holdout datasets suggesting internal validity. Up to 5 years after identification, 11% of patients classified as low, 27% as medium, and 51% as high risk had a future CV event. A predictive model for composite CV events utilizing administrative claims to identify and risk stratify patients may be used to scale focused interventions to high-risk T2D patients in a MAPD population to prevent future CVD events.

Disclosure
J.D. Hayden: Employee; Self; Humana. P. Pimple: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Employee; Spouse/Partner; CVS Caremark. R. Luthra: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. T.G. Prewitt: None. V. Chiguluri: None. M. Kattan: Consultant; Self; GlaxoSmithKline plc. Research Support; Self; Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Inc. R. Harvey: None. A.M. Goss: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. E.O. Caplan: Employee; Self; Humana.

Funding
Boehringer Ingelheim; Humana
42-LB: Factors Associated with Use of Diabetes Self-Management Education and Support Programs in Newly Diagnosed Type 2 Diabetes Patients in Louisiana
Authors: YOSHIDA YILIN , SHI LIZHENG , HONG DONGZHE , NAUMAN ELIZABETH , HU GANG , KATZMARZYK PETER T. , PRICE-HAYWOOD EBONI G. , BAZZANO ALESSANDRA N. , SHEN YUN , FONSECA VIVIAN 
Published: June 2020

Background: Prevalence of and factors associated with use of diabetes self-management education and support (DSME/S) programs in newly diagnosed type 2 diabetes (T2D) patients in Louisiana (LA) have not been fully evaluated.
Methods: We used EHRs from 3 hospital systems in LA (01/01/2013 to 10/31/2019). Eligible patients were 35-94 y-old with T2D based on ICD-codes, an antidiabetic drug prescription, an HbA1c ≥6.5%, an FPG ≥126, a 2-hr OGT ≥200, or random plasma glucose ≥200 mg/dL. New T2D was defined as entry of T2D diagnosis in the condition list occurring ≥1 y after first recorded office visit. DSME/S were searched by HCPCS codes G0108 and G0109. Logistic regressions compared differences between DSME/S vs. non-DSME/S group ≥180 days before the first recorded DSME/S.
Results: The prevalence of DSME/S use in T2D patients was 5.6% (18,139/313,242). In newly diagnosed T2D patients, the prevalence was 6.2% (8,918/137,629). Comparing to gender-, age- and race-matched non-DSME/S group, DSME/S group had worse clinical profiles, e.g., higher mean A1c and triglycerides, lower mean HDL, and higher obesity rate. Adjusted models showed self-pay patients were 70% less likely (OR 0.3, 95% CI 0.2-0.6) to use DMSE/S than Medicare beneficiaries. Current smokers were 2.6 times more likely (2.6, 1.8-3.7), but former smokers were 40% less likely (0.6, 0.5-0.7) to use DMSE/S than never smokers. Patients with hypolipidemic or antihypertensive drugs were 50% (1.5, 1.4-1.8) or 60% (1.6, 1.4-1.8) more likely to use DSME/S than those without the medications. Patients with A1c &gt;6.5% were 3.9 times more likely (3.9, 3.4-4.6) to use DSMES/S than those with normal A1c. Obese patients were 60% more likely (1.6, 1.4-1.9), but hypertensive patients (SBP&gt;130/DBP&gt;80 mmHg) were 60% less likely to use DSME/S (0.4, 0.3-0.5).
Conclusion: Use of DSME/S is low in LA, and there are marked differences in using the service by insurance type, smoking status and diabetes risk control.

Disclosure
Y. Yoshida: None. L. Shi: None. D. Hong: None. E. Nauman: None. G. Hu: None. P.T. Katzmarzyk: None. E.G. Price-Haywood: None. A.N. Bazzano: None. Y. Shen: None. V. Fonseca: Consultant; Self; Abbott, Asahi Kasei Corporation, AstraZeneca, Bayer Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Stock/Shareholder; Self; Amgen, Bravo4health.
422-P: Association between Nonalcoholic Fatty Liver Disease and Diastolic Myocardial Dysfunction and Myocardial Insulin Resistance in Patients with Type 2 Diabetes
Authors: KIM YOUNG-EUN , LEE MINYOUNG , LEE SEJEONG , CHA BONG-SOO , KANG EUN SEOK 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes and associated with cardiovascular risks. We investigated whether degree of NAFLD was associated with myocardial dysfunction in relation to myocardial glucose uptake in patients with type 2 diabetes. A total of 131 patients with type 2 diabetes were included from a tertiary care hospital. Myocardial glucose uptake was assessed using [18F]-FDG-PET scan. Hepatic steatosis and fibrosis were determined using transient liver elastography (Fibroscan). Echocardiogram was performed to evaluate cardiac structure and function. Patients with NAFLD revealed cardiac diastolic dysfunction with increased left ventricular filling pressure (E/e’ ratio) and left atrial volume index (LAVI) compared with patients without NAFLD (all p&lt;0.05). Hepatic steatosis was correlated with E/e’ ratio and LAVI, and hepatic fibrosis was also correlated with E/e’ ratio (all p &lt; 0.05). In linear regression analyses, degree of hepatic steatosis and fibrosis were independent determinant factors for a higher E/e’ ratio even after adjusting for confounding factors (r2=0.409, p=0.041 for steatosis and r2=0.423, p=0.009 for fibrosis). Higher degree of steatosis and fibrosis were associated with decreased myocardial glucose uptake (p for trends=0.084 and 0.012 for steatosis and fibrosis, respectively). Furthermore, decreased myocardial glucose uptake was an independent determinant factor for a higher E/e’ ratio (r2=0.409, p=0.04).
In conclusion, hepatic steatosis and fibrosis are significantly associated with diastolic heart dysfunction in patients with type 2 diabetes coupled with decreased myocardial glucose uptake.

Disclosure
Y. Kim: None. M. Lee: None. S. Lee: None. B. Cha: None. E. Kang: None.
451-P: Proteome Profiling in Rat Cardiomyoblasts: Understanding Diabetic Cardiomyopathy
Authors: STRATMANN BERND , EGGERS BRITTA , MATTERN YVONNE , MARCUS KATRIN , TSCHOEPE DIETHELM 
Published: June 2020

Introduction: Diabetic cardiomyopathy is characterized by oversupply of nutrients with concurrent loss of metabolic flexibility. Even in excess substrate availability the heart suffers energy depletion as metabolic fluxes are diminished. We established a stably GLUT4 overexpressing cell line derived from H9C2 that presents a diabetic cardiomyopathy like phenotype. Protein expression patterns are analyzed by proteomic approaches.
Material and Methods: Rat cardiomyoblasts stably overexpressing GLUT4 (H9C2-GLUT4) were cultured under hyperglycemic conditions (30mM glucose) either short time (3 days) or long time (more than 3 months). Expression profile was compared to non-transfected H9C2 cells (H9C2), using same culture conditions. Cell culture samples were prepared for mass spectrometric analysis by sample lysis followed by tryptic digestion. Peptides were analyzed on an Orbitrap Elite (ThermoFisher, Scientific) and resulting files were taken for the identification and quantification of proteins using MaxQuant and Perseus. DAVID Bioinformatics Resources 6.8 functioned as Pathway and GO term enrichment tool for further in depth analysis of the data set.
Results: We were able to quantify 2,841 proteins of whose 881 were found to be significantly regulated (5% FDR; ANOVA corrected p-value). Further analysis of long time and short time exposure of either WT or GLUT4 overexpressing cells lead to the identification of 135 significantly expressed proteins in the WT and 112 significantly expressed proteins in the H9C2-GLUT4 model (5% FDR; ANOVA corrected p-value). In depth pathway and GO term enrichment analysis support effects on metabolism, protein biosynthesis and handling, and ECM composition.
Discussion: Chronic glucose overload in cardiomyoblasts induced by GLUT4 overexpression and hyperglycemia resulted in a metabolic induced proteome profile change. These models may thus increase our knowledge of biological effects of chronic hyperglycemia on the diabetic heart.

Disclosure
B. Stratmann: Speaker’s Bureau; Self; AstraZeneca, Neoplas Tools GmbH. B. Eggers: None. Y. Mattern: None. K. Marcus: None. D. Tschoepe: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Neoplas tools GmbH.
479-P: Inhibition of the NLRP3 Inflammasome by MCC950 Accelerates Renal Injury in Diabetes Model
Authors: ØSTERGAARD JAKOB A. , JHA JAY C. , SHARMA ARPEETA , DAI AOZHI , COOPER MARK E. , DE HAAN JUDY B. , JANDELEIT-DAHM KARIN 
Published: June 2020

Background: Previous studies suggest that NLRP3 inflammasome activation could have pathological relevance in diabetic kidney disease (DKD). A recent study demonstrated that NLRP3 inhibition in a preventional approach in db/db mice provided reno-protection, potentially via a ROS dependent mechanism. We aimed to examine the therapeutical potential of the NLRP3 inflammasome inhibitor, MCC950 in a more clinically relevant interventional approach in a model of DKD and its impact on renal pathology.
Methods: Diabetes was induced by streptozotocin in ApoE-/- mice. A subgroup of control and diabetic mice was treated with MCC950 (5mg/kg/3 times/week). Treatment was commenced after 5 or 9 weeks of diabetes and continued for another 5 or 9 weeks for the assessment of renal gene expression as well its impact on albuminuria and renal morphology, respectively.
Results: Diabetes-induced mesangial expansion was further increased in MCC950 treated diabetic mice when compared to untreated diabetic group (18.9±0.6% vs. 16.3±0.7%, respectively). MCC950 treated diabetic mice showed a trend of increased albuminuria when compared to untreated diabetic mice (43±9 vs. 31±5 ug/24hrs, respectively). Gene expression of markers of fibrosis (fibronectin, collagen IV, α-smooth muscle actin and PCNA) and pro-oxidant enzymes (Nox2 and Nox4) were upregulated in diabetic mice compared to nondiabetic controls. These changes were further upregulated in MCC950-treated diabetic mice when compared to untreated diabetic mice. In addition, mRNA expression of pro-inflammatory markers (MCP-1 and IL-6) were increased in untreated diabetic animals as compared to controls and MCC950 treatment did not show additional upregulation of these parameters.
Conclusions: The present study indicates that inhibition of the NLRP3 inflammasome by MCC950 after establishment of disease, may not have a reno-protective effect. Our data rather shows an adverse effect of this drug at least in this model of DKD.

Disclosure
J.A. Østergaard: None. J.C. Jha: None. A. Sharma: None. A. Dai: None. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novartis AG, Sanofi-Aventis, Servier. J.B. de Haan: Research Support; Self; Bayer Inc., Reata Pharmaceuticals. K. Jandeleit-Dahm: None.
48-LB: The Effect of Acute Psychosocial Stress in Adults with Type 1 Diabetes
Authors: PARK MINSUN , SONG YOUNGKWAN , CHU MINSEUNG , SEVIL MERT , HOBBS NICOLE , SHARP LISA , CINAR ALI , QUINN LAURIE T. 
Published: June 2020

The effects of acute psychological stress, heart rate variability (HRV), an indicator of autonomic function and glycemic variability (GV) have not been extensively researched in type 1 diabetes (T1D). The aim of this study is to explore the effect of acute psychosocial stress on HRV and GV in people with T1D. Methods: Eleven participants with T1D (33.00 ± 11.25 years) participated in the study. To assess acute mental stress, the subjects 1) participated in the Trier Social Stress Test (TSST); and 2) played competitive video games (Nintendo Switch™). The TSST followed standardized procedures whereby stress was induced asking participants to provide a job talk and arithmetic in front of two judges. Participants played the Mario Kart to go-kart races (10 minutes) and rotated their controllers to untangle the Treasure Chest (10 minutes). Resting HRV and GV were obtained. The subjects wore a continuous glucose monitor and a Zephyr Bioharness™ to record GV and HRV, respectively. Nonparametric, paired samples T-tests were conducted using SPSS 24.
Results: During TSST, there were significant differences between the resting and TSST testing period in the sympathetic nervous sympathetic nervous system index (.57 ± 1.33 vs. 1.36 ± 1.40; z = -2.845, respectively; p &lt;.01; and stress index (8.17 ± 3.69 vs. 10.27 ± 5.69; z = -2.578, respectively; p &lt;.05). When subjects were playing video games, there were significant differences in the parasympathetic nervous sympathetic nervous system index (-.09 ± 1.75 vs. -.87 ± 1.05; z = -2.134, respectively; p &lt;.05) compared to a resting period. However, there were no significant differences in GV compared to a resting period in during TSST and playing video game.
Conclusion: This study suggests that the TSST induced stress in people with T1D, increased sympathetic activity; however, the TSST did not change glycemic variability. Playing competitive video game did not appear to neither induces stress nor affected glycemic variability. The competitive video game did not cause stress compared to TSST.

Disclosure
M. Park: None. Y. Song: None. M. Chu: None. M. Sevil: None. N. Hobbs: None. L. Sharp: None. A. Cinar: Research Support; Self; Dexcom, Inc., JDRF. Stock/Shareholder; Self; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S, Tandem Diabetes Care. L.T. Quinn: None.

Funding
JDRF
50-LB: Behavior and Learning Challenges in ABCC8-Related Neonatal Diabetes
Authors: BROWN NAIRI , BERRY SHAGUN , HARRIS ANASTASIA , LETOURNEAU-FREIBERG LISA R. , GREELEY SIRI ATMA W. 
Published: June 2020

Background: Activating mutations in KCNJ11 or ABCC8 cause neonatal diabetes (NDM) as well as neurodevelopmental difficulties, related to expression of mutated KATP channels in pancreatic beta cells as well as brain. Even individuals with more mildly activating KCNJ11 mutations underperform on many neurodevelopmental measures compared to sibling controls; however, very little information has been available about those with ABCC8 mutations.
Methods: Surveys were used to assess attention-deficit hyperactivity disorder (ADHD), learning and behavioral challenges, sleep disturbances, and other related medical conditions in participants with ABCC8-related NDM from the University of Chicago Monogenic Diabetes Registry.
Results: Baseline data including diagnosis and treatment information, and relevant medical records, were available for 19 of 20 participants with ABCC8-NDM (10 permanent, 9 transient), while 10 completed the ADHD/behavior/sleep survey. Participants with ABCC8-related NDM showed a range of neurodevelopmental and behavioral challenges (Table 1).
Conclusions: Our results suggest that individuals with ABCC8-NDM have a high prevalence of neurodevelopmental, behavioral and sleep challenges and should therefore receive relevant ongoing evaluation and support to address these challenges.

Disclosure
N. Brown: None. S. Berry: None. A. Harris: None. L.R. Letourneau-Freiberg: None. S.W. Greeley: None.

Funding
American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)
501-P: Urinary C-Peptide Creatinine Ratio: A New Marker of Insulin Resistance and Diabetic Kidney Disease
Authors: WANG YANAI , CAI XIAOLING , JI LINONG 
Published: June 2020

Introduction: Urinary C-peptide creatinine ratio (UCPCR) is used to access β cell function, but rare study had explored UCPCR in conditions with insulin resistance (IR). Some studies indicated the positive correlation between diabetic kidney disease (DKD) and IR. This study aims to explore the correlation among UCPCR,IR and DKD.
Methods: Chinese hospitalized patients with type 2 diabetes were included (n=1299). Fasting UCPCR was collected in the morning. We divided patients into three groups by the tertile of UCPCR, the characteristics of three groups were compared.
Results: In patients with the highest tertile of UCPCR, they had the lowest percentage of male (223 [51.6%] vs.294 [68.1%] vs. 302 [70.1%], P&lt;0.001), highest homoeostasis model assessment 2 estimates of insulin resistance (HOMA2-IR) (2.0 [1.5,2.6] vs. 1.6 [1.2,2.2] vs. 1.5 [1.0,2.0], P&lt;0.001), urinary albumin creatinine ratio (9.58 [4.67,36.42] vs. 7.14 [4.10,22.43] vs. 6.87 [3.60,22.94]mg/g, P=0.003) level,highest percentage of diabetic kidney disease (DKD) (121 [27.9%] vs. 95 [21.9%] vs. 98 [22.7%], P=0.078), coronary heart disease (CHD) (75 [17.4%] vs. 61 [14.1%] vs. 36 [8.4%], P&lt;0.001) and stroke (77 [17.8%] vs. 55 [12.7%] vs. 46 [10.7%], P=0.007). After the adjustment for sex, age, duration, SBP, DBP, BMI, UA,TG, LDL-c, HbA1c, the history of smoke, hypertension and hyperlipidemia, UCPCR level had a positive correlation with the risk of DKD (OR=1.207,95%CI [1.026,1.419], P=0.023) and CHD (OR=1.302, 95%CI [1.069,1.587], P=0.009).
Conclusions: UCPCR is a practical and non-invasive marker of insulin resistance and associated with increased risk of DKD and CHD.

Disclosure
Y. Wang: None. X. Cai: None. L. Ji: None.