bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-34a Aggravates Obesity-Induced Adipose Inflammation and Metabolic Dysfunction via Blocking Polarization of Anti-inflammatory M2 Macrophage
Authors: PAN YONG , HUI HANNAH , HOO RLC , FENG TIANSHI , LAM KAREN S. , XU AIMIN 
Published: June 2018

Adipose tissue-resident macrophages are an important contributor to systemic chronic inflammation and cardiometabolic abnormalities associated with obesity. However, the etiological factors that alter the number and polarization of adipose-resident macrophages remain poorly characterized. As our previous clinical study has identified microRNA (miR)-34a as one of the most significantly elevated genes in visceral fat of obese patients, we investigated the roles of miR-34a in obesity-related adipose tissue inflammation and metabolic disorders by generated adipose tissue-specific miR-34a knockout (KO) mice. After feeding with high fat diet (HFD), adipose miR-34a KO mice exhibited significant attenuation of HFD-induced glucose intolerance, insulin resistance, hyperlipidemia, steatohepatitis and systemic inflammation compared to HFD-fed wild type (WT) controls. These benefits of miR-34a deficiency were mainly attributed to the reduced number of total macrophages and polarization of adipose macrophages towards the pro-inflammatory M1 phenotype. Mechanistically, we found that miR-34a directly repressed the expression of the transcription factor Klf4, thereby enhancing macrophage polarization to the M1 phenotype. Silencing of Klf4 in the adipose-specific miR-34a KO mice suppressed M2 macrophage polarization. In visceral fat from obese patients, the expression of Klf4 was significantly decreased and negatively correlated with miR-34a level. These data demonstrated that increased miR-34a in adipose tissues exacerbates obesity-induced adipose tissue inflammation by suppressing the expression of Klf4, thereby leading to increased accumulation of pro-inflammatory M1 macrophages.

Disclosure
Y. Pan: None. H. Hui: None. R. Hoo: None. T. Feng: None. K.S. Lam: None. A. Xu: None.
A Systematic Review of Cases of Diabetes Mellitus following Immune Checkpoint Inhibitor Therapy for Cancer
Authors: MIZOKAMI-STOUT KARA R. , GIANCHANDANI ROMA , MACEACHERN MARK , IYENGAR RAVI M. , YENTZ SARAH , SHEN LIYAN , REDMAN BRUCE G. , TAN MENG 
Published: June 2018

Introduction: Immune checkpoint inhibitors (ICI) [anti-PD-1, anti-PD-L1, and anti-CTLA-4] are novel drugs increasingly used to treat solid tumor malignancies. Immune-related adverse events (irAE) occur with such therapy. We conducted a systematic review of case reports on endocrine irAE following ICI therapy. Here, we focus on the diabetes mellitus (DM) irAE case reports.
Method: In July 2017 we searched Medline, Embase, Cochrane Central Register and Web of Science for articles related to endocrine irAE and ICI. From 815 citations retrieved, 241 mentioned DM. From these, 32 articles reported 43 cases (had close temporal relationship of immunotherapy and development of DM IrAEs and clinical, biochemical, and/or treatment data). A hand-search in Jan 2018 found 8 more papers with 8 cases. These 51 cases were reviewed independently by 2 co-authors for quality of data, using a standardized form.
Results: Thirty-five patients presented in DKA (21 with fulminant T1DM), 15 with hyperglycemia, and 1 with lab data not reported (NR). The median age of the 31 males and 20 females was 63 years. Median time to onset of DM was 7 weeks after treatment initiation. Anti-GAD65, IA2, or ZnT8 were positive in 53% and negative or NR in 47%. Top 2 cancer treated were melanoma (n=23) and non-small cell lung cancer (n=11). The ICIs used were anti-PD-I (n=34); anti-PD-L1 (n=4); anti-PD-1 + CTLA-4 (n=7); and anti-CTLA-4 then anti-PD-1 (n=6). When DM occurred, ICI was stopped in 16, continued in 12, and NR in 23. At onset, 3 cases with known T2DM continued with oral meds, but all were treated with insulin and fluids. All patients recovered - 38 remained on insulin, 1 stopped insulin 81 days after ICI was stopped; and 12 NR.
Conclusion: Reported cases of T1DM irAE are rising - 9 in 2015, 13 in 2016 and 28 in 2017. Most (69%) presented in DKA. All were treated with anti-PD-1/PD-L1 drugs with the majority on monotherapy. All recovered and 38 were insulin-dependent. Endocrinologists and oncologists should collaborate in managing such patients.

Disclosure
K.R. Mizokami-Stout: None. R. Gianchandani: None. M. MacEachern: None. R.M. Iyengar: None. S. Yentz: None. L. Shen: None. B.G. Redman: None. M. Tan: Other Relationship; Self; Eli Lilly and Company.
Index60 Is More Strongly Associated with the Highest Type 1 Diabetes (T1D) Risk HLA DR3-DQ2/DR4-DQ8 (DQ2/DQ8) Genotype than Glucose Measures
Authors: REDONDO MARIA J. , GEYER SUSAN , ISMAIL HEBA M. , HEROLD KEVAN C. , PUGLIESE ALBERTO , PALMER JERRY P. , SOSENKO JAY ,   TYPE 1 DIABETES TRIALNET STUDY GROUP
Published: June 2018

Dysglycemia (i.e., fasting glucose=110-125 mg/dl; 30, 60, or 90-minutes glucose ≥200 mg/dl; and/or 2-h glucose=140-199 mg/dl, from oral glucose tolerance test [OGTT]) is used both as a predictive marker and pre-diagnostic endpoint in T1D prevention trials. However, recent evidence suggests that Index60 (based on fasting C-peptide, 60-minutes glucose and 60-minutes C-peptide, from OGTT) at a 1.00 threshold may be superior to dysglycemia. We thus hypothesized that Index60 is more strongly associated with T1D-linked genetic factors than glucose measures alone. We compared autoantibody-positive TrialNet Pathway to Prevention Study participants (n=1,098) with or without DQ2/DQ8 for associations with Index60, fasting glucose, 2-h glucose and dysglycemia. Participants with DQ2/DQ8 (n=159) compared to those without it (n=912) had higher Index60 values (median [interquartile range, IQR]=0.6 [-5.6 to 2.6] vs. 0.25 (-4.4 to 2.9]; p=0.001). In contrast, neither fasting glucose (p=0.51) nor 2-hour glucose p=0.07) were significantly different between the groups. The percentage with Index60≥1.00 was significantly higher in participants with (37.6%) than without (22.8%) DQ2/DQ8 (p=0.0001), whereas the percentages with dysglycemia were not significantly different (32.7% vs. 26.1%; p=0.11). Among those with normal OGTTs, Index60≥1.00 was more frequent among participants with DQ2/DQ8 (23.8%) than without it (12.0%; p=0.001), while among participants with Index60&lt;1.00, the frequency of dysglycemia was similar in those with and without DQ2/DQ8 (17.5% vs. 16.0%; p=0.70).
In conclusion, Index60, a metabolic marker based on glucose and C-peptide, is more strongly associated with the highest T1D risk HLA DQ2/DQ8 genotype than glucose measures, including dysglycemia. This suggests that Index60 has higher pathogenic specificity for T1D than glucose measures and should be considered for use in T1D prevention trials.

Disclosure
M.J. Redondo: None. S. Geyer: None. H.M. Ismail: None. K.C. Herold: None. A. Pugliese: None. J.P. Palmer: None. J. Sosenko: None.
Acute Caloric Restriction Leads to Loss of Hypoglycemic Counter-Regulation in Mice following Short-Term Refeeding
Authors: MCDOUGAL DAVID 
Published: June 2018

Background: Hypoglycemia-associated autonomic failure (HAAF) is a maladaptive failure in glucose counter-regulation known to be caused by recurrent exposure to insulin-induced hypoglycemia. Fasting or caloric restriction is the only natural physiological process which induces prolonged moderate-to-severe hypoglycemia similar to the antecedent of HAAF. In this study we tested the hypothesis that exposure to fasting-induced hypoglycemia can cause HAAF-like symptoms in mice.
Methods: Two groups of mice were used, an ad libitum (ad lib) fed group (n=6) and a caloric restriction (CR) group (n=6). CR mice were placed on 60% caloric restriction for 6 consecutive days. Ad lib mice were housed in an identical manner but fed ad libitum during this same period. Following 6 days of restriction, CR mice were given ad lib access to food for 16 h. After the 16 h period of refeeding, both CR and ad lib mice began a 6 h fast which was immediately followed by a hypoglycemic insulin tolerance test (ITT). ITTs consisted of a variable dose of insulin (1.4-1.75 U/kg, IP) which produced similar levels of hypoglycemia in each group (∼45 mg/dL).
Results: As expected, mice exposed to 6 days of 60% CR lost ≈30% of their initial body weight, and experienced a gradual fall in blood glucose to an average minimum of 67.9 mg/dL. CR mice displayed a significantly reduced fasting glucose level relative to ad lib mice (102.7 and 171.0 mg/dL respectively, p = 0.0002) as well as reduced serum glucagon levels in response to the ITT (6.0 and 30.4 pg/mL respectively, p = 0.0182).
Conclusions: Our results demonstrate that exposure to fasting-induced hypoglycemia produces HAAF-like symptoms in mice following refeeding. These results suggest that HAAF may be a result of an adaptive response to fasting which is inappropriately elicited during exposure to insulin-induced hypoglycemia. Further characterization of the effects of CR on the induction of deficits in glucose counterregulation warrants further investigation.

Disclosure
D. McDougal: None.
Duodeno-Jejunal Bypass Liner for the Treatment of Diabetes Mellitus in Obese Patients—Completeness of Duodenal Blinding as the Key Factor for Efficacy
Authors: BENES MAREK , DRASTICH PAVEL , HUCL TOMAS 
Published: June 2018

Introduction: The global increase in obesity incidence results in an increase of type 2 diabetes mellitus (T2DM). Surgical treatment has proven to be effective, however it carries a high risk of complications. The duodenal-jejunal bypass liner (EndoBarrier®, GI Dynamics, EB) is an endoscopic implant that mimics the intestinal bypass portion of the Roux-en-Y Gastric Bypass. It results in weight loss and improvements in glucose control in obese patients with T2 diabetes mellitus (T2DM).
Aims and Methods: This is a analysis of a prospective, controlled, multicentre study aimed to identify factors associated with an outcome of EB for T2DM.
Results: Seventy subjects (45 with an implant, 25 controls) were included in the study. The groups were comparable with respect to age, gender, BMI (mean 41.7 vs. 39.5 kg/m2), T2DM duration (7.8 vs. 8.3 years), HbA1c level (88 vs. 86 mmol/mol) and T2DM treatment. In the EB group, all devices were successfully implanted. Only 6 devices had to be explanted prior to the end of the 10 months study period (bleeding, dislocation and need for ERCP because of choledocholithiasis). At 10 months there was significantly greater weight loss and %EWL (19% vs. 7% and 43 vs. 12) and significantly improved long term compensation of T2DM marker HbA1c (decreased by 25 vs. 10 mmol/mol) in the EB group. T2DM medicinal treatment could be reduced in more device subjects than controls. There was no serious adverse event. Deepness of anchor ingrow, lower initial BMI and lower body height were identified as positive factors for efficacy of EB for T2DM compensation.
Conclusion: The EB is safe when implanted for 10 months, and results in significant weight loss and HbA1c reduction. Deepness of anchor ingrow, lower initial BMI and lower body height could be positive factors for efficacy.

Disclosure
M. Benes: None. P. Drastich: None. T. Hucl: None.
Elevated Insulin Clearance Contributes to the Reduced Peripheral Insulin Concentration Observed in Obese Young Asian with Type 2 Diabetes
Authors: PACINI GIOVANNI , TURA ANDREA , HOR CHEE PENG , LIM SHUEH LIN , TAN FLORENCE , TONG CHIN VOON , HONG JANET Y.H. , ZAIN FUZIAH MD , HOLST JENS J. , MOHAMUD WAN NAZAIMOON , YEOW TOH PENG 
Published: June 2018

Introduction: The importance of insulin clearance (CLins) on insulin dynamics and the role exerted in controlling glucose in type 2 subjects has recently been appreciated. Moreover, evidence in mice showed that CLins is reduced by incretin hormones at physiological levels.
Aim: To evaluate in 29 young (19±1 years) multi-ethnic Asian type 2 subjects (T2D) the contribution of CLins to insulin dynamics and if an association exists with GLP-1.
Methods: T2D (15F/14M; BMI=30.2±0.9 kg/m2; HbA1c=8.8±0.4% [73±4.4 mmol/mol]; mean duration of disease 2.5 years) had fasting glucose Gb=192±14 mg/mL and insulin Ib=19±3 µU/mL. They were compared to 17 (8F/9M) age-matched nondiabetic overweight (BMI=27.8±1.0, p=0.1) control subjects (CT, Gb=82±1, p&lt;0.0001; Ib=12±2, p=0.09). All underwent a 75g 2h OGTT with measurements of glucose, insulin, C-peptide and GLP-1. Insulin secretion (ISR) was assessed by deconvolution from peripheral C-peptide; CLins) by ISR/AUCinsulin; beta cell function (BCF) by AUCC-peptide/AUCglucose; insulin sensitivity by OGIS model. GLP-1 effect on BCF (GLPE) was empirically calculated as BCF/AUCGLP-1.
Results: T2D were insulin resistant (OGIS=277±16 mL/min m2 vs. 424±14) and had low BCF (82±11 pmolC-peptide/mmolglucose vs. 123±10), both p&lt;0.0001. Lower total AUCinsulin was observed in T2D (4.7±0.7 U/L 2h vs. 11.0±1.4, p&lt;0.0001), with higher CLins (2.06±0.19 L/min) than in CT (1.46±0.10, p=0.023). CLins directly correlated with OGIS in CT (R=0.55, p=0.02), but not in T2D (p=0.98). Despite no difference was observed in AUCGLP-1 (1.6±0.1 nmol/L 2h vs. 1.7±0.1 in CT, p=0.63), which did not correlate with CLins (p&gt;0.2), GLPE was lower in T2D (6.2±0.9 vs. 23.4±2.3, p&lt;0.0001).
Conclusion: Reduced peripheral insulin availability in obese young Asian T2D is due not only to a markedly impaired beta cell function and reduced GLP-1 effect, but also to an increased insulin clearance, which however shows no association to GLP-1 response.

Disclosure
G. Pacini: None. A. Tura: None. C. Hor: None. S. Lim: None. F. Tan: None. C. Tong: None. J.Y.H. Hong: None. F. Md Zain: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. W. Mohamud: None. T. Yeow: None.
Endobarrier (EB) in Type 2 Diabetes/Prediabetes with Obstructive Sleep Apnea Study—Preliminary Results
Authors: YADAGIRI MAHENDER , KINNEY FIONA Y. , ASHMAN NATALIE , LANG MICHAEL H. , FOGDEN EDWARD , ANDERSON MARK , BLEASDALE JOHN , WALTON CHRISTOPHER , GREENSTONE MICHAEL A. , RYDER ROBERT E. 
Published: June 2018

Aims: To assess the extent to which patients with type 2 diabetes or prediabetes, obesity (BMI 30-45kg/m²) and moderate OSA requiring continuous positive airway pressure ventilation (CPAP) are able to discontinue CPAP following EB-related weight loss (ISRCTN33788132).
Methods: We assessed Apnoea Hypopnoea Index (AHI), weight and HbA1c before and following EB. The full study involves 18 patients receiving EB for up to 1 year with 1 year follow-up.
Results: We report here the 1st 11 patients {9/11 (82%) female, 9/11 (82%) type 2 diabetes, 2/11 (18%) prediabetes, mean ± SD age 52.6 ± 9.7 years} to reach at least 3 months EB treatment. In 3 months, weight fell by 6.9 ± 3.3kg from 103.7 ± 14.8 to 96.8 ± 14.8kg (p&lt;0.001), mean BMI by 2.5 ± 1.3kg/m² from 37.1 ± 3.6 to 34.6 ± 3.7kg/m² (p&lt;0.001), mean HbA1c by 0.9±1.0% from 8.0±3.8 to 7.1±3.7% (p=0.025). OSA improved (Figure). Prior to EB, all 11 patients had AHI in moderate sleep apnoea range (15-29.9 events/hour). Following EB, the AHI of 7/11(64%) patients fell below the moderate sleep apnoea threshold of 15 events/hour, such that they no longer required CPAP. Of the remaining 4 patients, 1 came off CPAP at 6 months.
Conclusion: These preliminary results are encouraging in that EB has already allowed 8/11(73%) patients to discontinue CPAP, in addition to glycaemic and weight benefits. Discontinuing CPAP is beneficial to health services but especially to patients.

Disclosure
M. Yadagiri: None. F.Y. Kinney: None. N. Ashman: None. M.H. Lang: None. E. Fogden: None. M. Anderson: None. J. Bleasdale: None. C. Walton: None. M.A. Greenstone: None. R.E. Ryder: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; Bioquest, Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S.
Incretin and Cardiovascular Effects of Weight Loss and Remission of Prediabetes
Authors: STENTZ FRANKIE B. , AMMONS ANN 
Published: June 2018

Since the incretins GLP-1 and GIP have important roles in insulin sensitivity and have been shown to be effective in pharmacological treatment of type 2 Diabetes, we studied these incretin level changes with weight loss and remission of prediabetes in 24 obese women and men with prediabetes. Our studies have shown that prediabetes subjects on a 6 month HP diet (30% protein, 30% fat, 40% CHO) had 100% remission of prediabetes compared to only 33% on a HC diet (15% protein, 30%fat, 55% CHO). Subjects on the HP diet had increased satiety compared to the HC diet, therefore, we studied HP and HC diet effects on ghrelin levels. Additionally, since cardiovascular risk factors (CVRF) decreased more in the HP than the HC diet, we determined if the B-Type Natriuretic Peptide(BNP) released from the heart was affected by either diet. GLP-1, GIP, Ghrelin, and BNP levels were determined with a Meal Tolerance Test (MTT) at baseline and after 6 mo on HP and HC diets where all food was provided.
The active GLP-1 and total GIP area under the curves for the HP MTT increased significantly from baseline vs. 6 months (7860±31 vs. 8970±37 pmol/l/min, p=0.001) and (21,350±63 vs. 27,240±72 pg/ml/min, p=0.001) respectively. The ghrelin decreased significantly from baseline vs. 6 months on the HP MTT (338±21 vs. 78±14 pg/ml/min, p= 0.005). BNP decreased significantly from baseline (126±11pmol/l) to 6 months (78±9 pmol/l), p=0.01. HP diet had a significantly greater increase in GLP-1 and GIP than the HC diet. HP ghrelin results demonstrate that HP diet can induce satiety and is more effective than the HC diet. The BNP decrease in both groups demonstrates the improvement in heart tissue with the HP diet having a greater effect than the HC diet.
Although weight loss was similar (9.8% in HP vs. 11.3% in HC, p=0.692), this study demonstrates that the HP diet increases GLP-1 and GIP which may be responsible in part for the improved insulin sensitivity, and decreases BNP with greater improvement in CVRF with remission of prediabetes.

Disclosure
F.B. Stentz: None. A. Ammons: None.
Effects of Laparoscopic Sleeve Gastrectomy on Insulin Secretion Patterns in Young Obese Patients with Acanthosis Nigricans
Authors: QIAN CHUNHUA , QU SHEN , ZHU CUILING , GAO JINGYANG , MEI FANGYUN , BU LE 
Published: June 2018

Background: Acanthosis nigricans (AN) is a skin condition commonly often accompanied by insulin resistance and hyperinsulinemia. Patients with AN are prone to diabetes, especially in young obesity. Metformin were usually used to treat these patients. However, reports about the effectiveness of LSG surgery on young obese patients with AN are rare.
Objective: The aim of our study was to evaluate the efficacy of LSG surgery on insulin secretion patterns and anthropometric variables for obese patients with AN.
Methods: 30 young obese patients with AN were recruited for this study. Before and at 12 months after the LSG surgery, BMI and blood samples were collected. OGTT were used to evaluate the insulin level and its rhythm of secretion. AN extent and AN texture were determined according to the scale developed and validated.
Results: For these patients, BMI decreased from 40.98±4.93 kg/m2 to 27.27±4.13 kg/m2 at 12 months after surgery. Along with weight loss, triglycerides and total cholesterol decreased significantly, and high-density lipoprotein cholesterol (HDL-C) increased significantly as of 12 months after surgery. But the change of low-density lipoprotein cholesterol (LDL-C) is not obvious. A significant decrease in insulin resistant (HOMA-IR) was observed. The insulin release curves showed hyperinsulinemia and abnormal rhythm of secretion before surgery. At 12 months after surgery the fasting, 2h postprandial insulin levels and the rhythm of insulin secretion were restored to normal level. But the insulin levels at 30min and 60min were higher than before surgery. The extent of AN for most patients were improved. Only 23.4% patients still were severe (vs. 59.3% before surgery). More than 50% patients were remission.
Conclusion: In this study of LSG in obesity patients with AN, we found significant improvements in weight, dyslipidemia, hyperinsulinemia and AN extent. LSG will be a new effective therapeutic approach for young obesity patients with AN.

Disclosure
C. Qian: None. S. Qu: None. C. Zhu: None. J. Gao: None. F. Mei: None. L. Bu: None.
Influence of Race, Ethnicity, and Behavioral Factors on Childhood Obesity
Authors: AYINE PRISCILLA , PARRA EMILY P. , JEGANATHAN RAMESH B. , THANGIAH GEETHA 
Published: June 2018

Childhood obesity is a public health concern resulting from a variety of reasons. In the United States, approximately 12.7 million children and adolescents are classified as obese. 23.8% of African American children are obese compared with 13.1% of whites between ages 6 to 11 years. In Alabama, 35.5% children are overweight and obese; it is 6th highest ranked in United States. The most common causes of childhood obesity are behavioral, genetic factors, or a combination of both.
In this study we investigated the differences in some of the behavioral factors such as sleeping time, dinner time and television watching time in racial ethnic groups. 24 white/European American (EA) and 30 black/African American (AA) elementary school children aged between 6 to 10 years participated in this study. Height and weight were measured, without shoes and wearing only light clothing. Body mass index (BMI) percentile was calculated using Centers for Disease Control and Prevention growth reference. Parents reported child’s typical weekday bedtime, dinner time and television watching time of their children.
35% of EA children slept later than 8:30 pm during school days compared to 68% of AA children. Only 4% of EA children had late dinner (after 7 pm), whereas 50% of AA children had late dinner during week days. 21% of EA children watched television for more than 1 hour in comparison to 79% of AA children every day. Our findings suggest that insufficient sleep, late dinner schedule, and longer television exposure are some of the behavioral factors that contribute to greater percentage of childhood obesity in AA than EA children.

Disclosure
P. Ayine: None. E.P. Parra: None. R.B. Jeganathan: None. G. Thangiah: None.
Real-World Data from the MiniMed™ 670G System Commercial Launch—Patients Previously Using MDI Therapy
Authors: GOPALAKRISHNAN SHWETA , AGRAWAL PRATIK , STONE MICHAEL , FOGEL CATHERINE , LEE SCOTT W. 
Published: June 2018

The Medtronic MiniMed™ 670G hybrid closed-loop system with SmartGuard™ technology was released for commercial use in the U.S. in March 2017. Data from patients previously managing their diabetes with multiple daily insulin injections (MDI) therapy who transitioned to the MiniMed™ 670G system are reported. MiniMed™ 670G system data from patients who voluntarily uploaded to CareLink™ Personal software, from 3/17/17 to 12/14/17 (n=158), were de-identified and analyzed if there were ≥7 days of sensor wear. Comparisons were made of glycemic metrics between 4,529 patient-days in the initial open-loop Manual Mode and 14,1patient-days after initiating closed-loop Auto Mode features. The Table shows glycemic metrics during Manual Mode and after Auto Mode start and that time spent in target range increased, while time spent in low and high glucose levels decreased. Real-world findings from patients previously using MDI who transitioned to the MiniMed™ 670G system demonstrated increased TIR and reduced time in hypoglycemia and hyperglycemia, consistent with pivotal trial1 results in patients previously using pump therapy +/- CGM. Prior MDI patients also showed greater TIR the more time spent in Auto Mode.

Disclosure
S. Gopalakrishnan: Employee; Self; Medtronic. P. Agrawal: None. M. Stone: None. C. Fogel: Employee; Self; Medtronic. S.W. Lee: Employee; Self; Medtronic.