bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Outcomes and Mortality among Patients Hospitalized with Hypoglycemia and End-Stage Renal Disease in the U.S.
Authors: GALINDO RODOLFO J. , HURTADO CAROLINA R. , PASQUEL FRANCISCO J. , VELLANKI PRIYATHAMA , UMPIERREZ GUILLERMO E.
Published: June 2018

Patients with diabetes and end stage renal disease (ESRD) are at high risk of hypoglycemia. The prevalence and outcomes among hospitalized patients with hypoglycemia and ESRD in the U.S. is not known. Accordingly, we compared the outcomes of patients hospitalized for hypoglycemia with and without ESRD in a U.S. nationwide cohort. We searched the National Inpatient Sample (largest public inpatient database in the U.S.), for adult patients (>18 years) in 2014. We used ICD9 codes to identify admissions for hypoglycemia (primary diagnosis) and ESRD (secondary diagnosis), defined as stage 5 chronic kidney disease, with or without dialysis. Among 97,445 patients admitted for hypoglycemia, 11,285 (11.6%) had ESRD. Patients with ESRD were more likely of African-American and Hispanic race, and had a higher mortality rate, longer length-of-stay (LOS) and higher hospitalization costs compared to those without ESRD (Table). In multivariate analysis, ESRD was significantly associated with an increased odds for mortality (OR 2.92, 95% CI 1.98, 4.29, p<0.01), longer LOS (p<0.001) and higher hospitalization costs (p<0.001). Among patients with hypoglycemia, ESRD is common (11.5%) and is associated with a 3-fold increase in mortality, longer LOS and higher hospitalization costs. Further research on treatment strategies to decrease the burden of hypoglycemia in this population is needed.

CharacteristicsHypoglycemia with ESRD n: 11,285 (11.6%)Hypoglycemia without ESRD n: 89,160 (88.4%)p-valueAge, mean years (±SD)60.5 (30.8)63.4 (41.8)<0.001Female, n (%)4,695 (41.6)35,940 (40.3)0.9Race, Caucasian, n (%)4,294 (39)51,000 (57)<0.001Race, African-American, n (%)4,090 (38)18,000 (20)<0.001Ethnicity, Hispanics, n (%)1,725 (16)10,000 (11)<0.001Hospital Mortality, n (%)220 (1.95)590 (0.67)<0.001LOS, mean days (±SD)6.4 (18.5)5.1 (11.9)<0.001Costs, mean US$ (±SD)13,810 (43,448)9,859 (34,040)<0.001

Disclosure

R.J. Galindo: None. C.R. Hurtado: None. F.J. Pasquel: Consultant; Self; Merck Sharp & Dohme Corp., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. G.E. Umpierrez: Research Support; Self; Sanofi US, Merck & Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc..
Intensive Hypoglycemia Avoidance and Improved Awareness of Hypoglycemia Associated with Partial Recovery Activation Lost in Hypoglycemia Unaware Patients with Type 1 Diabetes
Authors: CHOUDHARY PRATIK , NWOKOLO MUNACHISO , O'DALY OWEN , AMIEL STEPHANIE A. , ZELAYA FERNANDO O.
Published: June 2018

Aim: The brain senses hypoglycemia and governs symptomatic, hormonal and behavioral responses to it. This study aimed to understand the differences in regional brain responses to experimental hypoglycemia between adults with type 1 diabetes (T1D) with intact hypoglycemia awareness [HA] and impaired awareness of hypoglycemia [IAH] and evaluate the impact of intensive hypoglycemia avoidance on these responses.

Methods: We performed ASL fMRI scans to measure global and regional cerebral blood flow [CBF and rCBF] and measured symptomatic and hormonal responses to experimental hypoglycemia [47 mg/dl] in 15 HA T1D subjects and 22 subjects with IAH matched for age, HbA1c and duration of diabetes. Those with IAH underwent a hypoglycemia avoidance program including education, frequent contact and additional technology where required, including sensor augmented pump therapy with predictive low glucose suspend before being restudied with ASL FMRI at hypoglycemia.

Results: Baseline scans: Global CBF increased in response to hypoglycemia in HA and IAH [HA 6.3% p=0.01; IAH 8.0%, p=0.03; HA vs. IAH p=NS]. There was greater increase in rCBF in thalamus, prefrontal cortex and orbitofrontal cortex in HA vs. IAH and greater reduction in rCBF in the hippocampus. Repeat scans: The hypoglycemia avoidance program improved subjective awareness [Gold score 6 ±1 vs. 4.2±1.9; p = 0.001] in the 12 completers. Compared to baseline scans, there was a trend to greater increase in rCBF in the anterior cingulate cortex in response to hypoglycemia [p=0.058], but no changes in the thalamus, prefrontal or orbitofrontal cortices.

Conclusion: Intensive education and support can improve hypoglycemia awareness with some restoration of activation in the anterior cingulate cortex, but frontal changes are not restored suggesting cognitive responses to hypoglycemia may not be changed by these interventions.

Disclosure

P. Choudhary: Speaker's Bureau; Self; Medtronic MiniMed, Inc., Novo Nordisk Inc.. Advisory Panel; Self; Becton, Dickinson and Company, Sanofi-Aventis, Roche Diabetes Care Health and Digital Solutions, Lilly. M. Nwokolo: None. O. O'Daly: None. S.A. Amiel: Advisory Panel; Self; Medtronic MiniMed, Inc., Novo Nordisk A/S, Roche Diabetes Care Health and Digital Solutions. F.O. Zelaya: None.
A Risk Prediction Model for Heart Failure Hospitalization among Patients with Type 2 Diabetes
Authors: WILLIAMS BRENT , GANDHI PRANAV
Published: June 2018

Type 2 diabetes mellitus (T2DM) is strongly associated with future cardiovascular (CV) events, including heart failure (HF) and its sequelae such as hospitalization (HFH) and death. Identifying T2DM patients at highest risk of HFH may be clinically valuable so therapeutic regimens can be optimized.

Accordingly, this study aimed to develop and validate a risk prediction model for HFH among patients with T2DM. This electronic medical record- (EMR-) based, retrospective cohort study included patients with new or preexisting diagnoses of T2DM receiving health care services longitudinally through the Geisinger Health System. Study patients were assigned an index date at an office visit at least two years following their first EMR-documented encounter between 1/1/03 and 11/10/15. Candidate predictors of HFH were defined according to EMR documentation in the 2-year period prior to the index date from demographics, vital signs, medical history including diagnoses and procedures, CV-related symptoms, and laboratory tests. Cox proportional hazards regression with stepwise variable selection identified the strongest predictors of HFH. Internal validation was performed by randomly splitting the sample 1:1. Among 77,385 T2DM patients meeting study criteria, median (IQR) age of patients at the index date was 62 (52, 72) years and 49% were male. Over a mean (SD) follow-up of 5.8 (4.2) years, 2903 (3.8%) HFH occurred, and estimated HFH incidence rates at 1, 3, and 5 years after the index date were 0.5%, 1.8%, and 3.0%. The development set model containing the 15 strongest HFH predictors had a c-statistic of 0.833, and the validation set c-statistic was 0.824. The five strongest predictors were age, a history of HF, coronary artery disease, blood urea nitrogen, and HbA1c. The patients with 10% highest risk based on the model had ≥2.0% annual risk of HFH. This proposed model for HFH among T2DM demonstrated strong predictive capability and may be valuable in guiding therapeutic decision making.

Disclosure

B. Williams: None. P. Gandhi: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Electrophysiological Assessment of Cardiac Complication in Chronic Diabetic Minipigs
Authors: STRICKER-KRONGRAD ALAIN , LIU JASON , BOUCHARD GUY
Published: June 2018

Abundant evidence shows that patients with type 1 diabetes are at high risk for several cardiovascular disorders. Our objective was to assess cardiac electro-pathophysiology changes linked to chronic insulin-dependent diabetes in the Yucatan miniature swine (total N = 22). Diabetic animals were divided into different groups based on duration of diabetes (Group 1: normal; Groups 2, 3, 4 and 5: diabetes duration of 3-4, 4-5, 5-6 and >6 years). Cardiac electrophysiological parameters were acquired in conscious diabetic and normal control animals using a standard lead II configuration. Routine measurements of electrocardiograms, including HR (bpm), RR, PR, QRS, QT and QTc, were done (all in msec). A heart rate correction for the QT interval (QTc) was calculated using the Fridericia method [QTc=QT/(cubed root of RR)]. Mean heart rate was decreased for the diabetic Groups 2, 4, and 5 compared to the mean heart rate for normal animals (52, 54 and 54 vs. 75 bpm, respectively). The mean PR interval was increased in all diabetic animals compared to normal animals and the effect increase with the duration of diabetes (132 vs. 138, 140, 152 and 172 msec for Groups 1, 2, 3, 4 and 5, respectively). The mean QRS interval was increased for all of the diabetic animals compared to normal animals (47 vs. 56, 66, 52 and 64 msec for Groups 1, 2, 3, 4 and 5, respectively). There were no pronounced QTc abnormalities in this study when comparing diabetic to the normal animals although one animal in Group 3 did have a QTc prolongation of 43 msec. In addition, one animal in Group 5 had a prolonged PR segment (224 msec) associated with frequent ventricular escape complexes.

In conclusion, chronic diabetes in Yucatan miniature swine manifests with progressive effects on heart rate, PR interval, and QRS duration. This indicates that the diabetic minipig could provide a good model to test preventative approaches for progressive cardiac therapies in diabetes, using electrocardiography segments as markers of early heart damage.

Disclosure

A. Stricker-Krongrad: None. J. Liu: None. G. Bouchard: None.
Update in Cardiovascular Safety of Glucagon-Like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes—A Mixed Treatment Comparison Meta-analysis of Randomized Controlled Trials
Authors: ALFAYEZ OSAMAH , YAMI MAJED S. AL , ALSHEIKH RAZAN
Published: June 2018

Background: The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) was recently published. Thus, we here present a mixed treatment comparison meta-analysis (MTC) of major randomized clinical trials to determine Glucagon like peptide 1 (GLP-1) receptor agonists’ effects on CV outcomes in patients with T2DM.

Methods: A comprehensive, systematic review was conducted using Embase and MEDLINE databases. Studies were included in the MTC meta-analysis if they were (1) RCTs and (2) evaluated the effects of one of the GLP-1 agonists vs. placebo on CV outcomes as their primary endpoint. The primary outcomes were CV death, nonfatal MI, and nonfatal stroke. Hospitalization for HF was evaluated as a secondary endpoint.

Results: A total of 202 publications were identified and reviewed, of which 198 were excluded based on study design or relevance to the research question. A total of 4 trials, including 33,457 patients, met the eligibility criteria and were retained analysis. The pairwise meta-analysis showed a 13% reduction in death from cardiovascular causes in patients who received GLP-1 agonists vs. those who received placebo (RR 0.87, 95% CI: 0.78-0.96, I2=0%, P=0.592). The NMA showed no differences among all the interventions, with liraglutide the preferred agent (53%) followed by semaglutide (18%). The pairwise meta-analysis showed no significant reduction in non-fatal MI events between the two groups (RR 0.95, 95% CI: 0.86-1.04, I2=19.5%, P=0.293). Like the pairwise meta-analysis, the NMA results showed no reduction in non-fatal MI events with semaglutide as the preferred agent (66%), followed by liraglutide (19%).

Conclusion: GLP-1 therapy was associated with a significant reduction in CV death. However, GLP-1 agonists seem to have a safety profile comparable to placebo in terms of reducing non-fatal MI, non-fatal stroke events, and rates of HF hospitalization.

Disclosure

O. Alfayez: None. M.S. Al Yami: None. R. Alsheikh: None.
A Novel Therapeutic Approach to Intensive Statin Therapy–Resistant Vulnerable Plaque of Coronary Artery in Diabetic Patients by Use of Anti-PCSK9 Antibody and Coronary CT Angiography (CCTA)
Authors: HIRAI AIZAN , FUJIMURA KOJI , KONDO SEIYA , SAKAI TAKENORI , IKEJIMA SHIN , TANIAI HISANORI , HIRAI KEIJI , MURATA KAZUYA , SHIRAKAMI ATSUSHI , OKUZAKI KAZUTOSHI , KAGEYAMA TAKAHIRO
Published: June 2018

Purpose: Coronary plaque progression despite very low levels of LDL-C has been reported in the patients with coronary artery disease (CAD) who received intensive statin therapy (IST). CCTA has been applied to detect vulnerable coronary plaques having low attenuation of CT value. The best characterized function of PCSK9 is the binding to hepatic LDL receptors, leading to their degradation. PCSK9 is produced also in vascular smooth muscle cells constituting the atheriosclerotic lesion in addition to hepatocytes. PCSK9 promotes foam cell formation by suppressing the excretion of cholesterol from macrophages. Recently, statin is demonstrated to promote PCSK9 production. PCSK9 has been proposed to play a crucial role in the pathogenesis of IST resistance. The present study was performed to establish a novel therapeutic approach to IST resistant vulnerable plaque of coronary artery in diabetic patients.

Methods: The present study included 1T2DM patients with non-FHC asymptomatic CAD who developed vulnerable plaques in coronary artery despite IST over 1 year. CCTA by use of 320-slice CT was applied to evaluate vulnerable plaques in coronary artery. During the administration of anti-PCSK9 antibody, changes in serum lipids and CT value of vulnerable coronary plaques were determined.

Results: After the administration of anti-PCSK9 antibody, 72% decrease in serum LDL-C was observed. Also, improvement of vulnerable coronary plaque e.g., rise in the CT value of plaque (from 45.2 ± 12.0 HU to 107.5 ± 42.3 HU, p<0.0001) was observed in 6 months after administration of the drug.

Conclusion: A significant improvement in vulnerable coronary plaques was observed in the patients with asymptomatic CAD who are resistant to IST after 6 months administration of anti-PCSK9 antibody. An analysis of the plaque quality by CCTA is useful method for the evaluation of the effect of the drug on vulnerable coronary plaques.

Disclosure

A. Hirai: None. K. Fujimura: None. S. Kondo: None. T. Sakai: None. S. Ikejima: None. H. Taniai: None. K. Hirai: None. K. Murata: None. A. Shirakami: None. K. Okuzaki: None. T. Kageyama: None.
Specific Deletion of PKC Delta in Endothelial Cells Restores VEGF Action in Diabetes
Authors: GERALDES PEDRO
Published: June 2018

Introduction: Ischemia due to narrowing of the femoral artery and distal vessels is also a major cause of peripheral arterial disease and morbidity affecting patients with diabetes. Our laboratory has previously shown that hyperglycemia reduced vascular endothelial growth factor receptor (VEGFR2) activity in ischemic muscle of diabetic mice, which was not observed in protein kinase C (PKC)-Δ deficient mice. The objective of this study is to evaluate the impact of a specific deletion of PKC-Δ in endothelial cells in diabetic mice.

Methods: Nondiabetic (NDM) and 3 months diabetic (DM) mice with deletion of PKC-Δ specifically in endothelial cells (PrckdEC-) were used. Ligation of the femoral artery was performed and blood flow reperfusion was measured by laser Doppler for 4 weeks. Primary lung endothelial cells (EC) isolated from each group of mice were exposed to normal (5.6mM; NG) or high glucose concentrations (25mM; HG) for 48 hours, in normoxia (20% oxygen) or hypoxia (1%) for the last 24 hour in presence of VEGF, a pro-angiogenic factor.

Results: Blood flow was recovered to 43% in DM mice compared to 78% in NDM mice. Specific EC deletion of PKC-Δ enhanced reperfusion in NDM and DM mice up to 88% and 71%, respectively. Expression of VEGFR2 was decreased in ischemic muscle of DM mice, but not in DM-PrkcdEC- mice. In vitro, VEGF-induced Akt phosphorylation was reduced by 40% in EC isolated from DM mice compared to NDM mice, which was prevented in EC isolated from DM-PrkcdEC- exposed to HG+hypoxia.

Conclusion: Diabetes induced PKC-Δ activity and caused inhibition of VEGF actions in EC, whereas the deletion of PKC-Δ specifically in EC restored VEGF action, VEGFR2 expression and blood flow reperfusion in diabetic mice.

Disclosure

P. Geraldes: None.
Prevalence of Preexisting Dysglycaemia among Inpatients with Acute Coronary Syndrome and Associations with Outcomes
Authors: MAHENDRAN DINESH , HAMILTON GARRY , WEISS JEREMY , LEW JEREMY , KHOO KAYLYN , EKINCI ELIF I.
Published: June 2018

Objective: We aimed to determine the prevalence of preexisting dysglycaemia in inpatients admitted with acute coronary syndrome (ACS), their characteristics and, association with acute and 12-month clinical outcomes.

Research Design and Methods: In this prospective observational cohort study, admission HbA1c testing was undertaken on consecutive inpatients aged ≥54 years admitted with ACS. Patients were categorised into those with diabetes (prior diagnosis or HbA1c ≥ 6.5%, ≥48mmol/mol), prediabetes (HbA1c 5.7-6.4%, 39-46mmol/mol) and no diabetes (HbA1c <5.6%, <38mmol/mol).

Results: Between July 2013 and July 2015, 847 consecutive inpatients aged ≥54 years were admitted with ACS. 313 (37%) inpatients had diabetes, 312(37%) had prediabetes and 222(25%) had no diabetes. After adjusting for age, sex, smoking status and previous myocardial infarction, diabetes, as opposed to no diabetes, was associated with higher odds of Acute Pulmonary Oedema (APO) (OR 2.60, P<0.01), longer length of stay (LOS) (IRR 1.18, P=0.02) and, higher odds of 12-month ACS recurrence (OR 1.86, P<0.05). Prediabetes was not a statistically significant marker of adverse clinical outcomes. However, analysed as a continuous variable, every 1% (11 mmol/mol) increase in HbA1c was associated with increased odds of APO (OR 1.28, P=0.002) and, longer LOS (IRR 1.05, P=0.03).

Conclusions: In our study, three-quarters of all inpatients aged ≥54 years admitted with ACS had preexisting dysglycaemia. Inpatients with diabetes had increased odds of APO, longer LOS and higher 12-month ACS recurrence. Higher HbA1c, was associated with increased odds of APO and longer LOS. Randomised studies with cardioprotective anti-hyperglycaemic agents are necessary in determining if improving dysglycaemia in ACS patients improves clinical outcomes.

Disclosure

D. Mahendran: None. G. Hamilton: None. J. Weiss: None. J. Lew: None. K. Khoo: None. E.I. Ekinci: None.
Early Vascular Parameters in the Micro- and Macrocirculation in Type 2 Diabetes
Authors: SCHMIEDER ROLAND E. , KANNENKERIL DENNIS , KARG MARINA V. , BOSCH AGNES , HARAZNY JOANNA M. , OTT CHRISTIAN
Published: June 2018

Background: In a large cross-sectional analysis we analyzed various vascular parameters in the renal, retinal and systemic circulation, with the goal to identify which vascular parameter of early organ damage is the earliest that can be clinically detected.

Methods: In 111 patients with type 2 diabetes (T2DM) and 54 subjects without T2DM we assessed urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), retinal capillary flow (RCF), intercapillary distance (ICD) as parameters of capillary rarefaction, wall-to-lumen ratio (WLR) of the retinal arterioles [all assessed by Scanning Laser Doppler Flowmetry], and central systolic pressure(cSBP) and central pulse pressure (cPP) [measured by pulse wave analysis, Syphygmocor].

Results: Compared to subjects without T2DM, patients with type 2 diabetes (duration: mean 63.9 ± 56.4, range 1-271 months) were older (59.8 ± 7.3 vs. 43.4 ± 12.9 years, p<0.001), more females (33.3 vs. 20.4 %, p<0.001) but 24-hour systolic and diastolic blood pressure did not differ between the two groups (129±11/79±8 vs. 130±11/77±6 mmHg).

Non-T2DM-subjects (n=54)Patients with T2DM (n= 111)Unadjusted p-valueAge- gender- adjusted p-valueAdjusted p-value (potential confounders)ICD (µm)20.8 ± 3.523.9 ± 5.1<0.001<0.0010.001RCF (AU)310.4 ± 55.1297.8 ± 72.90.150.350.72WLR (-)0.35 ± 0.080.38 ± 0.110.040.670.90eGFR (ml/min/1.73m²)95.9 ± 17.391.7 ± 9.90.10<0.001<0.0017.9 ± 7.521.3 ± 86.6<0.0010.550.91cPP (mmHg)34.8 ± 10.641.8 ± 11.70.0010.31<0.001RCF (AU)310.4 ± 55.1297.8 ± 72.90.150.350.72

Conclusion: These data suggest that at similar blood pressure capillary rarefication in the retinal circulation (ICD), eGFR in the renal circulation and central pulse pressure (cPP) of large arteries are earlier detectable than vascular remodeling of the micro- (WLR, RCF, UACR) and macrocirculation (cSPB) in patients with T2DM.

Disclosure

R.E. Schmieder: Consultant; Self; AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; Novartis AG. Consultant; Self; Novartis AG. Speaker's Bureau; Self; Servier. D. Kannenkeril: None. M.V. Karg: None. A. Bosch: None. J.M. Harazny: None. C. Ott: None.
Comparative Cardiovascular Efficacy of SGLT2 Inhibitors, DPP-4 Inhibitors, and GLP-1 Agonists—A Network Meta-analysis
Authors: RODDICK ALISTAIR J. , ZHENG SEAN
Published: June 2018

Background: Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i), Dipeptyl Peptidase-4 inhibitors (DPP-4i) and Glucagon-Like Peptide-1 agonists (GLP-1a) effectively reduce HbA1c levels. Their long-term cardiovascular effects have been tested against placebo, but the comparative efficacy of individual drug types is unclear.

Aim: To compare the efficacy of SGLT2i, DPP-4i and GLP-1a for reducing cardiovascular outcomes by network meta-analysis.

Methods: Medline, Embase and the Cochrane Library Central Register of Controlled Trials were searched for randomised controlled trials (RCTs) of >12 weeks’ duration enrolling patients with type 2 diabetes and comparing drugs of SGLT2i, DPP-4i or GLP-1a classes with another included class or control. Comparative point estimates were synthesised by random effects frequentist network meta-analysis.

Results: In all, 236 RCTs were included, accounting for 176,310 patients across 20 interventions (DPP-4i: 6; GLP-1a: 7; SGLT2i: 7). Empagliflozin and liraglutide reduced cardiovascular mortality compared to control (RR 0.63; 95% CI 0.51-0.79; P<0.001; and RR 0.79, 95% CI 0.66-0.93, P=0.006, respectively). Empagliflozin was the highest-ranking drug for cardiovascular mortality (P-score=0.89) and significantly reduced fatal cardiovascular events compared to 5 other drug types in addition to control (DPP-4i: 2; GLP-1a: 2; SGLT2i: 1). Empagliflozin and canagliflozin reduced heart failure events compared to control (RR 0.66; 95% CI 0.51-0.86 and RR 0.70; 95% CI 0.54-0.90 respectively), while saxagliptin increased heart failure events (RR 1.23; 95% CI 1.04-1.46). Myocardial infarction and stroke were not affected by any drug of any class.

Conclusions: Empagliflozin and liraglutide demonstrate the greatest efficacy for cardiovascular mortality, while SGLT2i may exert additional benefits in heart failure. This study provides evidence to support clinical decisions in treatment of type 2 diabetes.

Disclosure

A.J. Roddick: None.S. Zheng: None.
High Prevalence of Asymptomatic Coronary Artery Disease (CAD) Evaluated by Intravascular Ultrasound (IVUS) in a Norwegian Cohort with Type 2 Diabetes (T2D) as Compared with Asymptomatic Controls without T2D—A Cross-Sectional Study
Authors: OFSTAD ANNE P. , ARORA SATISH , ULIMOEN GEIR R. , BIRKELAND KARE I. , ENDRESEN KNUT , GULLESTAD LARS L. , JOHANSEN ODD ERIK
Published: June 2018

The prevalence of asymptomatic CAD in T2D is unclear. We investigated the CAD burden using the gold standard IVUS in an asymptomatic T2D-cohort compared to a reference population without T2D. Patients with T2D and ≥ 1 cardiovascular (CV) risk factor (n=56, 21% women, mean age/diabetes duration 65.2±7.8/13.1±5.8 years, HbA1c 7.2±1.1%, systolic BP 136±17 mmHg, LDL-cholesterol 2.3±0.8 mmol/L) underwent invasive coronary angiography with IVUS. Reference population comprised heart transplant donors free from T2D and CAD who had IVUS performed 7-11 weeks post-transplant (n=76). IVUS was described by maximal intimal thickness (MIT), percent atheroma volume (PAV) and normalized total atheroma volume (TAV). All indices of atherosclerosis were significantly increased in T2D (T2D cohort: MIT 0.75±0.27 mm, PAV 33.7±9.8%, TAV 277.0±137.2 mm3 vs. reference population: MIT 0.44±0.18 mm, PAV 20.1±7.4%, TAV 139.0±110.0 mm3, [p-values<0.001]) and the proportion with CAD defined by MIT was significantly higher in the T2D population (Figure). Our data suggest that asymptomatic T2D patients have extensively diseased coronary arteries suggesting a need for more aggressive residual CV risk management.

Disclosure

A.P. Ofstad: Employee; Self; Boehringer Ingelheim GmbH. S. Arora: None. G.R. Ulimoen: None. K.I. Birkeland: Research Support; Self; AstraZeneca, Novo Nordisk A/S, Eli Lilly and Company, Sanofi, Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp.. K. Endresen: None. L.L. Gullestad: None. O. Johansen: Employee; Self; Boehringer Ingelheim GmbH.
Impact of Human vs. Analog Insulins on Occurrence of Death and Major Cardiovascular Events
Authors: SCHROEDER EMILY B. , O'CONNOR PATRICK J. , SCHMITTDIEL JULIE , REYNOLDS KRISTI , DESAI JAY R. , HO MICHAEL , BENITEZ GABRIELA VAZQUEZ , ANDERSON JEFFREY P. , PIMENTEL NOEL , LOES LINDA M. , NEUGEBAUER ROMAIN
Published: June 2018

Background: This observational study uses rigorous causal inference methods of comparative effectiveness research to emulate a trial evaluating the cardiovascular safety of analog (AI) vs. human insulins (HI).

Methods:On date of first insulin use, 127,600 adults with type 2 diabetes were classified as using: AI with or without HI, or HI only. Separate analyses assessed occurrence of: myocardial infarction (MI), stroke (CVA), congestive heart failure hospitalization (CHF), cardiovascular (CV) death, or death, censored at disenrollment, start of pregnancy, or 12/31/2013. Marginal structural modeling (MSM) with Inverse Probability Weighting (IPW) was used to compare event free survival in per-protocol analyses in which follow-up data was right-censored for cross-over or interrupted insulin therapy. Adjusted and unadjusted effect estimates were based on two logistic MSM parameterizations for counterfactual hazards. To address potential residual confounding, we conducted four sensitivity analyses with three nested covariate adjustment sets and machine learning for data-adaptive selection of covariates.

Results:Mean follow-up time was 21 months. The Table shows hazard ratios (95% CI) of AI vs. HI users for events of interest.

Conclusions: We observed no statistically significant differences in 5 major clinical outcomes between users of AI and HI.

Disclosure

E.B. Schroeder: None. P.J. O'Connor: None. J. Schmittdiel: None. K. Reynolds: Research Support; Self; Amarin Corporation, Novartis Pharmaceuticals Corporation, Amgen Inc., CSL Behring. J.R. Desai: None. M. Ho: None. G. Vazquez Benitez: None. J.P. Anderson: None. N. Pimentel: None. L.M. Loes: None. R. Neugebauer: None.
Effect of Glucagon on Nocturnal Rates of Endogenous Glucose Production in Type 2 Diabetes
Authors: BASU ANANDA , ZHAI HUALING , CARTER RICKEY , BASU RITA
Published: June 2018

The role of nocturnal glucagon on regulation of overnight endogenous glucose production (EGP) in T2D is unknown. We studied 13 T2D and 13 age, BMI matched nondiabetic subjects (ND) on two occasions at the Clinical Research Unit at Mayo Clinic. Deuterated water was provided to measure gluconeogenesis (GNG) and glycogenolysis (GGL) using the HMT (hexamethylenetetramine) method. A somatostatin pancreatic clamp was initiated at 10 PM with 0.25 mU/kg/min insulin infusion until 7 AM along with [3-3H] glucose to measure turnover in the presence of glucagon infusions at 0.65 ng/kg/min (basal) or 1.5 ng/kg/min (high) in random order. Blood was sampled periodically for the measurements of plasma glucose, [3-3H] glucose, hormones; EGP rates were measured at 7AM. Results are presented in the Table. Fasting glucose, insulin and c-peptide concentrations were not different in either group during either visit. Glucose infusion rates (GIR) required to maintain euglycemia were lower during high glucagon in both groups and lower in T2D vs. ND regardless of visit indicating insulin resistance. Rates of EGP at 7AM were higher in both groups with the high vs. basal glucagon (matched data shown for calculation). Partial GNG data that are available indicate increased rates of GGL at 7 AM in the presence of high glucagon. In T2D higher glucagon overnight could contribute to higher rates of GGL and EGP. Therapies to reduce GGL may help lower overnight EGP.{F280D615-E887-4E30-8C76-ED88282D5E23}All data are Mean +/- SD. Statistical analyses was not performed on EGP and HMT data as it is preliminary.Diabetes StatusBasal Glucagon 7 AMHigh Glucagon 7 AM7 AM p-value Basal vs HighGlucose (mmol/L)ND T2D5.4 ± 0.6 8.2 ± 4.0 (p < 0.001)5.2 ± 0.6 8.2 ± 4.0 (p < 0.001)0.4 0.9Glucagon (pg/ml)ND T2D82.0 ± 14.0 90.5 ± 12.5 (p = 0.56)138.3 ± 15.4 151.5 µ 17.2 (p = 0.20)p < 0.01 p < 0.01GIR (µmol/kgFFM/min)ND T2D23.0 ± 12.8 6.7 ± 8.4 (p <0.001)21.0 ± 11.4 4.0 ± 6.8 (p <0.001)p < 0.01 p < 0.01EGP (µmol/kgFFM/min)ND n=13 T2D n=138.0 ± 4.2 13.3 ± 4.710.3 ± 6.6 15.8 ± 4.3HMT data (EGP) (µmol/kgFFM/min)ND n=4 T2D n=710.3 ± 4.8 15.2 ± 5.615.1 ± 8.7 22.0 ± 5.0GluconeogenesisND n=4 T2D n=73.8 ± 1.3 5.6 ± 2.24.7 ± 3.4 9.4 ± 1.6GlycogenolysisND n=4 T2D n=76.5 ± 3.4 9.6 ± 3.310.4 ± 1.2 12.6 ± 3.5

Disclosure

A. Basu: Research Support; Spouse/Partner; AstraZeneca. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Voluntis France. H. Zhai: None. R. Carter: None. R. Basu: Research Support; Self; AstraZeneca.
Effect of Number of Achieved Targets for Risk Factors on Coronary Artery Disease (CAD) in Those With and Without Diabetes Mellitus (DM)
Authors: FUJIHARA KAZUYA , MATSUBAYASHI YASUHIRO , KITAZAWA MASARU , YAMAMOTO MASAHIKO , OSAWA TAEKO , KANEKO MASANORI , YAMANAKA NAUTA , SEIDA HIROYASU , KATO KIMINORI , KODAMA SATORU , SONE HIROHITO
Published: June 2018

Although control of multiple risk factors is essential to prevent CAD in persons with and without DM, longitudinal studies are scarce that directly and quantitatively compared effects of such control in DM and non-DM. Thus, we investigated effects on subsequent CAD of the number of controlled risk factors among blood pressure, LDL cholesterol and HbA1c using a nationwide claim-based database (median follow-up 4.8 y) in Japan. Targets were based on ADA and Japanese guidelines. Of 207,029 non-DM persons, 42.8% and 37.9% were at target for 1 and 2 factors, respectively. Of 13,471 persons with DM, 39.5%, 32.1%, and 10.0% were at target for 1, 2, and 3 factors, respectively. Multivariate Cox analysis showed reduced CAD risk with increased numbers of risk factor targets reached in DM compared to non-DM (Table, upper). However, in DM, although fulfillment of the target for only 1 risk factor significantly elevated the hazard ratio (HR) (i.e., 1.98 (1.28-3.07)) to non-significance (i.e., 1.03 (0.68-1.66)), no further significant HR reduction below reference (i.e., non-DM with no target achieved) was found (Table, lower). These findings show that composite control of modifiable risk factors has a larger effect in DM compared to non-DM, but the effect was not sufficient to bring CAD risk in DM below that for non-DM persons with none of 3 risk factors being at target based on current target levels.

Disclosure

K. Fujihara: None. Y. Matsubayashi: None. M. Kitazawa: None. M. Yamamoto: None. T. Osawa: None. M. Kaneko: None. N. Yamanaka: None. H. Seida: None. K. Kato: None. S. Kodama: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..
Effects of Treatment-Achieved HbA1c on Incidence of Micro-/Macrovascular Complications in Patients with Diabetes Mellitus
Authors: HARADA MAYUKO , FUJIHARA KAZUYA , OSAWA TAEKO , YAMAMOTO MASAHIKO , KANEKO MASANORI , MATSUBAYASHI YASUHIRO , MATSUNAGA SATOSHI , YAMADA TAKAHO , YAMANAKA NAUTA , SEIDA HIROYASU , KODAMA SATORU , SONE HIROHITO
Published: June 2018

Although a so-called “J”- or “U”-shaped relationship between treatment-achieved HbA1c values and risk of coronary artery disease (CAD) has often been reported, it is not yet clarified whether the association is maintained across various treatment modalities including diet only (D) for macro/microvascular complications of diabetes. Thus, we investigated effects of treatment-achieved HbA1c on CAD events and treatment-required diabetic eye disease (TRDED) in 4 treatment subgroups: D, insulin (I), sulfonylurea (S) and antihyperglycemic agents other than glinides, S or I. We utilized a nationwide claims database of 14,633 patients with diabetes in Japan (mean age 50.3 y, HbA1c 7.2%). Cox regression examined CAD and TRDED risk over a 5.1 y follow-up. A significant linear trend in the association between HbA1c and CAD events was only seen in the D group. Significantly higher risks for CAD were observed in the I and S groups whose HbA1c was ≤7.0% or S compared to D group patients with HbA1c ≤7.0%. Conversely, risk for TRDED was strongly dependent on achieved HbA1c regardless of treatment modalities. However, risks of TRDED did not differ significantly between categories of ≤7.0% and 7.1-8.0% among S and I groups. These results implied the necessity of setting different target HbA1c goals according to treatment modalities for prevention of micro-/macrovascular complications.

Disclosure

M. Harada: None. K. Fujihara: None. T. Osawa: None. M. Yamamoto: None. M. Kaneko: None. Y. Matsubayashi: None. S. Matsunaga: None. T. Yamada: None. N. Yamanaka: None. H. Seida: None. S. Kodama: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..
Treatment for Diabetes and Cardiovascular Risk Factors in a Predominantly Minority Urban Cohort of Kidney Transplant Recipients
Authors: TSOMOS EFFIE , ALEKSIC SANDRA , ANARAKI SARA ZAHEDPOUR , JAPP EMILY , UPADHYAY LAXMI , AJAIMY MARIA , ZONSZEIN JOEL , AKALIN ENVER
Published: June 2018

Background: Given the increased incidence of post-transplant diabetes and the high cardiovascular burden in transplant recipients, glycemic control and other cardiovascular risk factors such as blood pressure and cholesterol should be targeted aggressively. We aimed to analyze management of predominantly Hispanic and non-Hispanic black kidney transplant recipients with type 2 diabetes (T2D) and new onset diabetes after transplant (NODAT).

Methods: We performed a retrospective chart review of all recipients of kidney transplant from June 01, 2012 until December 31, 2014 in a large university center. Recipients with type 1 diabetes or pancreas transplant were excluded. NODAT was defined by the ADA criteria.

Results: The study included 304 individuals. Fifty percent had T2D and another 36% developed NODAT during a follow-up of 37 (22-52) months. Individuals with T2D, compared to NODAT and non-DM, were more frequently treated with statins (76% vs. 65% vs. 39%, respectively, p<0.001). At 6, 12, and 24 months posttransplant individuals with T2D, compared to NODAT, had higher levels of A1c (7.9 ± 1.8 vs. 6.5 ± 1.2%, 8.1 ± 1.8 vs. 6.6 ± 1.3%, 8.6 ± 2.1 vs. 6.6 ± 1.1%, respectively, p<0.0001 for all comparisons) and less frequently reached goal of <7% (33 vs. 80%, 26 vs. 71%, 14 vs. 79%, respectively, p<0.0001 for all comparisons). Most frequent glucose-lowering treatment in T2D was insulin (92%), followed by metformin (20%), DPP-4 inhibitors (19%) and sulfonylurea (11%), while NODAT was treated most frequently with diet only (43%), followed by metformin (20%) and DPP-4 inhibitors (20%).

Conclusions: While metabolic control was better in NODAT than T2D, both groups were predominantly treated with older glucose-lowering medications and had a significant number of individuals with suboptimal glucose and lipid management. Earlier and more aggressive treatment with cardio-protective and newer glucose-lowering agents is warranted in this high-risk population.

Disclosure

E. Tsomos: None. S. Aleksic: None. S. Zahedpour Anaraki: None. E. Japp: None. L. Upadhyay: None. M. Ajaimy: None. J. Zonszein: Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. E. Akalin: None.
Effects of Hyperglycemia and Hyperinsulinemia on Glucose Turnover during Exercise in Type 1 Diabetes
Authors: ROMERES DAVIDE , BASU ANANDA , SCHIAVON MICHELE , COBELLI CLAUDIO , DALLA MAN CHIARA , BASU RITA
Published: June 2018

Exercise (E) induced increase in glucose uptake (Rd) is offset by compensatory increase in endogenous glucose production (EGP) in health. To determine the extent to which this occurs in type 1 diabetes (T1D) and to assess the effects of hyperglycemia and hyperinsulinemia, we studied six T1D subjects (age 29±7 years, BMI 28.3±4.8 kg/m2, VO2 max 28.7±10 ml/kg/min) on three visits (V1: euglycemia, low insulin; V2: euglycemia, high insulin; V3: hyperglycemia, low insulin) in random order. Glucose fluxes were measured with tracer-tracee clamp using [6,6-2H2] glucose before, during and after, 60 min of E at 65% VO2 max. By design, plasma glucose concentrations were higher in V3 than V1 and V2 (9.7±0.5, 5.2±0.1, 5.2±.0.1 mM respectively, p<0.05), while plasma insulin concentrations were higher in V2 than V1 and V3 (324.3±19.4, 129.3±9.3, 111.6±5.9 pM, p<0.05). Rd increased with E in all visits (p<0.05) and returned to pre-E values thereafter. EGP during E increased (p<0.05) in V1 and to a lesser extent in V3, but was unchanged in V2. To summarize, hyperinsulinemia, but not hyperglycemia inhibits E induced compensatory increase in EGP; both hyperinsulinemia and hyperglycemia augments increase in Rd with E albeit to different extents; Rd returns to pre-E values when E stops. Taken together, euglycemia coupled with low insulin appear to be the most favorable milieu for T1D during E.

Disclosure

D. Romeres: None. A. Basu: Research Support; Spouse/Partner; AstraZeneca. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Voluntis France. M. Schiavon: None. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. C. Dalla Man: None. R. Basu: Research Support; Self; AstraZeneca.
Skin Autofluorescence Predicts Macrovascular Events in Type 1 Diabetes
Authors: BLANC-BISSON CHRISTELE , CEPHISE FRITZ-LINE VELAYOUDOM , HELMER CATHERINE , BLANCO LAURENCE , MOHAMMEDI KAMEL , MONLUN MARIE , RIGALLEAU VINCENT
Published: June 2018

Advanced Glycation end-products play a role in diabetic vascular complications. Their optical properties allow to non invasively evaluate their accumulation in tissue by measuring skin autofluorescence (SAF). SAF predicts macrovascular complications in type 2 diabetes mellitus but it was not demonstrated in type 1 diabetes. The aim of our study was to search for an association between SAF and macrovascular event (MVE) incidence: myocardial infarction, stroke, gangrene or artery revascularization procedures during a 7 years follow-up. In 2009, 246 subjects with type 1 diabetes patients were included. SAF measurement, clinical (age, sex, BMI, comorbidities) and biological data (glycemia, HbA1C, renal parameters, blood lipids) were recorded. MVE were registered at visit in the center or phone call to medical practitioner until 2016. They were mainly men 58.8% (n=143), mean age 51.2 years (±16.7) with BMI 24.9 kg/m2 (± 4.1), diabetes duration 21.4 years (±13.8), HbA1C 7.6% (± 1.1). Among these DT1 patients, 25.7% (n=59) were smokers, 44.9% (n=109) had arterial hypertension, LDL cholesterol was 1.04 (± 0.29) g/L. Estimated Glomerular Filtration Rates (CKD-EPI) was 86.3 ml/min/1.73m2 (±26.6) and albumin excretion rates was 54.9mg/24H (± 220.0). Twenty-four subjects had a history of previous MVE (9.9%). From 2009 to 2016, 18 patients had new MVE: 4 myocardial infarctions, 2 gangrene, 17 artery revascularizations. Their SAF was 2.46 (±0.71) UA vs. 2.10 (±0.55) for others patients (p=0.02). After adjustment for cardiovascular risk factors (age, sex, diabetes duration, BMI, hypertension, smoking status, blood lipids, albumin excretion rates, statins treatment and MVE previous to 2009), the association between high level SAF in 2009 and MVE incidence during seven years was still significant(OR=9.7 p=0.004). A high SAF is predictive of MVE incidence in patients with type 1 diabetes.

Disclosure

C. Blanc-Bisson: None. F. Velayoudom Cephise: None. C. Helmer: None. L. Blanco: None. K. Mohammedi: Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi, Takeda Development Centre Europe Ltd., Boehringer Ingelheim Pharmaceuticals, Inc.. M. Monlun: None. V. Rigalleau: None.
Insulin Rescues Diabetes-Induced Pulmonary Complications
Authors: CAMPOLO ALLISON , MARIA ZAHRA , HINSDALE MYRON , LIU LIN , LACOMBE VERONIQUE
Published: June 2018

Hyperglycemia is an independent risk factor for the development of respiratory diseases, including influenza infections. Although the lung is a major organ to utilize glucose, the regulation of glucose transport in the healthy and diabetic lung has received little attention. We hypothesized that hyperglycemia would predispose diabetic mice to alterations in pulmonary glucose transport and pulmonary complications during Influenza A infection. To test this hypothesis, we used a streptozotocin-induced type 1 diabetic mouse model (n=8-12/group). A subset of diabetic mice was treated with insulin via a subcutaneous insulin pump to restore euglycemia. After 8 weeks, an additional subset of mice was intranasally infected with influenza A H1N1 (A/PR/8/34; 250 PFU). Viral titer was determined from bronchoalveolar lavage (BAL) fluid by plaque assay. Glucose concentration in BAL fluid was measured spectrophotometrically. Glucose transporter (GLUT) protein content was quantified in whole lung homogenates by Western blotting. Both infected and uninfected diabetic mice had higher glucose concentrations in BAL fluid than their control or insulin-treated counterparts (p<0.05). There was a trend towards a decrease in protein content of GLUT4 (the major insulin-sensitive isoform) and GLUT1 (a basal isoform) in the diabetic lung (p<0.1). Total protein content of GLUT12 (a novel isoform) was increased in the diabetic lung (p<0.05). Diabetic mice possessed a significantly higher percentage of lymphocytes in their BAL fluid (p<0.05). GLUT protein content and lymphocyte alterations were rescued when mice were treated with insulin. Influenza-infected diabetic mice also had a higher percentage of lymphocytes (p<0.05), and a trend toward an increase in viral load in BAL fluid vs. infected control mice. These novel findings suggest that 1) the regulation of glucose transport is altered in the lung during hyperglycemia, and 2) diabetic mice are predisposed to pulmonary inflammation and viral replication during influenza infection.

Disclosure

A. Campolo: None. Z. Maria: None. M. Hinsdale: None. L. Liu: None. V. Lacombe: None.
Type 2 Diabetes Mellitus Is Not Associated with the Incidence or the Outcome of Pneumonia in Patients with Acute Ischemic Stroke
Authors: PAPAGIANNI MARIANTHI , TZIOMALOS KONSTANTINOS , KOSTAKI STAVROULA , ANGELOPOULOU STELLA-MARIA , CHRISTOU KONSTANTINOS , SOFOGIANNI ARETI , ALKAGIET STELINA , DIDANGELOS TRIANTAFYLLOS , SAVOPOULOS CHRISTOS , HATZITOLIOS APOSTOLOS I.
Published: June 2018

Background/Aims: The association between T2DM and the incidence and outcome of pneumonia in patients with acute ischemic stroke is unclear. The aim of the present study was to evaluate this association.

Patients and Methods: We prospectively studied 922 consecutive patients admitted with acute ischemic stroke (42.2% males, age 79.6±6.9 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed with dependency rates at discharge (modified Rankin scale 2-5) and in-hospital mortality.

Results: During hospitalization, 113 patients developed pneumonia. Patients who developed pneumonia had higher fasting plasma glucose (FPG) levels at the second day of hospitalization than patients who did not develop pneumonia (7.4±3.4 and 6.3±2.6 mmol/l, respectively; p<0.005) whereas the prevalence of T2DM and HbA1c levels did not differ between the two groups. Independent risk factors for pneumonia were obesity (relative risk (RR) 2.05, 95% confidence interval (CI) 1.10-3.79, p<0.05) and NIHSS at admission (RR 1.13, 95% CI 1.09-1.16, p<0.001). Among patients who developed pneumonia, 50.4% were dependent at discharge and 43.4% died during hospitalization. Patients who were dependent at discharge had similar prevalence of T2DM and similar FPG and HbA1c levels with patients who were independent at discharge. Patients who died during hospitalization had higher FPG levels than patients who were discharged (8.3±4.4 and 6.7±2.3 mmol/l, respectively; p<0.05) whereas the prevalence of T2DM and HbA1c levels did not differ between the two groups. Independent risk factors for in-hospital mortality were diastolic blood pressure at admission (RR 1.05, 95% CI 1.01-1.09, p<0.05) and NIHSS at admission (RR 1.16, 95% CI 1.09-1.23, p<0.001).

Conclusions: T2DM does not appear to be associated with the incidence or the outcome of pneumonia in patients admitted with acute ischemic stroke.

Disclosure

M. Papagianni: None. K. Tziomalos: None. S. Kostaki: None. S. Angelopoulou: None. K. Christou: None. A. Sofogianni: None. S. Alkagiet: None. T. Didangelos: None. C. Savopoulos: None. A.I. Hatzitolios: None.