bluuebunny/crossref_metadata_2025_split huggingface dataset:
208-OR: Posttranslational Truncation of Apolipoproteins C1 and C2 and Plasma Lipids in Multiethnic Study of Atherosclerosis (MESA)
Authors: KOSKA JURAJ , FURTADO JEREMY , SINARI SHRIPAD , MCCLELLAND ROBYN , BILLHEIMER DEAN , REAVEN PETER 
Published: May 2022

Apolipoproteins (apo) C1 and C2 are small interchangeable molecules that regulate lipoprotein metabolism. ApoC1 inhibits lipoprotein lipase (LPL) and stimulates reverse cholesterol transport while apoC2 activates LPL. Both exist as full-size native and minor truncated proteoforms; however, whether distribution of these apoC1 and C2 proteoforms may influence plasma lipids is largely unknown. Baseline plasma from 5,791 MESA participants was tested for truncated to native apoC1 and apoC2 ratios (apoC1’/C1; apoC2’/C2) . Total apoC1 and C2 concentrations were measured in a subset of 3,851 participants. Plasma lipids were measured for up to 6 times over 15 years. In adjusted models (Table) , higher apoC1’/C1 was associated with lower triglycerides (TG) and higher total (TC) and LDL cholesterol both at baseline and follow-up, and higher HDL at follow-up. Higher apoC2’/C2 was associated with lower TG and higher LDL at baseline, and higher baseline and follow-up TC and HDL. In contrast, the associations of total apoC1 and apoC2 concentrations with TG and HDL were largely in opposite directions of their proteoform ratios. For example, plasma TG were inversely associated with apoC1 and apoC2 truncation but positively associated with total apoC1 and apoC2 concentrations. Our data indicate a possible role of posttranslational apoC1 and apoC2 modification in regulating lipid metabolism.

Disclosure
J.Koska: None. J.Furtado: Research Support; Eli Lilly and Company, Pfizer Inc. S.Sinari: None. R.Mcclelland: None. D.Billheimer: None. P.Reaven: Research Support; AstraZeneca, Dexcom, Inc.

Funding
National Institutes of Health (R01-HL138969
210-OR: Presence of Type 2 Diabetes (T2D) Affects HDL Particle Proteomic Composition Independently of Obesity or Fatty Liver
Authors: BRIL FERNANDO , PEARCE RYAN , COLLIER TIMOTHY S. , KALAVALAPALLI SRILAXMI , MCPHAUL MICHAEL J. , CUSI KENNETH 
Published: May 2022

Patients with T2D remain at high risk of cardiovascular (CV) events despite adequate glycemic and LDL-C control. Changes in HDL particle composition and function may explain part of this increased CV risk. The aim of this study was to determine the proteomic composition of isolated HDL particles in T2D patients, and establish which factors contribute to these abnormalities. Patients (n=213) with and without T2D were included in the study and underwent an OGTT, liver MRS, and routine blood chemistries. Advanced lipid testing and lipoprotein subfractions were measured by ion mobility. ApoA-I containing particles (i.e., HDL) were isolated and a novel targeted proteomic approach using multiple reaction monitoring (MRM) by liquid chromatography and tandem mass spectrometry (LC-MS/MS) was undertaken to measure HDL-bound proteins. Patients with (n=146) vs. without (n=67) T2D were older (56±9 vs. 47±12) , more obese (34.2±4.7 vs. 32.6±5.3 kg/m2) , but had no significant differences in other important clinical characteristics, such as gender or race. Patients with T2D had lower HDL-C (38±9 vs. 43±13 mg/dl, p&lt;0.001) , but no difference in the number of HDL particles. A panel of 28 HDL-bound proteins were targeted and quantified by MRM LC-MS/MS. After correction for multiple comparisons (false discovery rate set at 5%) and adjustment for obesity and NAFLD, 4 proteins were found to be decreased in T2D patients (ApoA-I, ApoC-I, ApoM, and PON3; all p&lt;0.0015) . The pCAD index (well-validated score for coronary artery disease and CV mortality based on HDL-bound proteins) was increased in patients with T2D, irrespectively of obesity or NAFLD (93±15 vs. 61±38, p&lt;0.0001) .
In conclusion, patients with T2D showed significant differences in the apolipoproteomic composition of HDL particles, and this translated into increased CV risk based on pCAD index. Different HDL composition and function may explain the residual CV risk of patients with T2D optimally treated for hyperglycemia and LDL-C.

Disclosure
F.Bril: None. R.Pearce: Employee; Quest Diagnostics. T.S.Collier: Employee; Quest Diagnostics, Stock/Shareholder; Quest Diagnostics. S.Kalavalapalli: None. M.J.Mcphaul: Employee; Quest Diagnostics. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk.

Funding
American Diabetes Association (1-08-CR-08) ; The Obesity Society (Early-Career Research Grant) Veterans Affairs (1 I01 CX000167-01) . UF CTSI (UL1TR001427)
211-OR: Plasma Insulin Is Required for the Increase in Plasma ANGPTL8 Concentration following Glucose Ingestion
Authors: ABU-FARHA MOHAMED , ABUBAKER JEHAD , KHAIRI IRINA AL , CHERIAN PREETHI T. , AGYIN CHRISTINA , ABDELGANI SIHAM , ALOZAIRI EBAA S. , ADAMS JOHN M. , ALMULLA FAHD , DEFRONZO RALPH A. , ABDUL-GHANI MUHAMMAD 
Published: May 2022

Aim: ANGPTL8 plays an important role in regulating lipoprotein lipase activity. Its plasma level is increased following nutrient ingestion. Its not well characterized whether insulin or glucose drive the increased ANGPTL8 after food uptake. To address this, we examined the dynamic relationship between plasma insulin level, ANGPTL8 concentration and glucose following glucose ingestion.
Methods: 30 healthy subjects with impaired fasting glucose (IFG) (n=14) and normal glucose tolerance (NGT) (n=16) received 75-glucose OGTT, multistep euglycemic hyperinsulinemic clamp and pancreatic clamp. ANGPTL8 level was measured during the fasting state, OGTT and the clamp studies.
Results: Subjects with IFG had significantly higher ANGPTL8 during the fasting state (80±5.6 pmol/L VS 68±4.9 pmol/L respectively, p&lt;0.05) . During the OGTT, plasma ANGPTL8 level increased by 62% above the fasting level (from 81±8 pmol/L to 131±pmol/L, p&lt;0.0001) . During the insulin clamp, insulin infusion caused a dose-dependent increase in ANGPTL8 level (figure 1) . Conversely, during the pancreatic clamp and in the absence of an increase in plasma insulin, the increase in plasma glucose concentration failed to cause a significant increase in plasma ANGPTL8 concentration.
Conclusion: The increased ANGPTL8 expression in circulation after glucose ingestion was driven by increased insulin and not glucose.

Disclosure
M.Abu-farha: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. M.Abdul-ghani: None. J.Abubaker: None. I.Al khairi: None. P.T.Cherian: None. C.Agyin: None. S.Abdelgani: None. E.S.Alozairi: None. J.M.Adams: None. F.Almulla: None.

Funding
Kuwait Foundation for the Advancement of Sciences
216-LB: Hepatocyte N6-Methyladenosine mRNA Modification in Hepatic Gluconeogenesis and Diabetes
Authors: ZHENG QIANTAO , ZHONG XIAO , REN DECHENG , RUI LIANGYOU 
Published: May 2022

The liver produces endogenous glucose to support life during fasting. Counterregulatory hormones, including glucagon, catecholamines, and glucocorticoids, stimulate the expression of gluconeogenic enzymes in the liver, thus driving liver glucose production. In contrast, insulin suppresses hepatic gluconeogenesis, thereby restraining postprandial glucose levels. Hepatic gluconeogenesis aberrantly increases in type 2 diabetes due to an imbalance between insulin and counterregulatory hormone actions, contributing to hyperglycemia and glucose intolerance. N6-methyladenosine (m6A) RNA methylation has emerged as a critical paradigm shaping cell identities and functions. The Mettl3/Mettl14 complex catalyzes m6A on RNA and RNA-binding proteins bind to the m6A motifs and determine the fate of client mRNAs (splicing, trafficking, stability, and/or translation) . However, m6A RNA modification has not been explored in liver gluconeogenesis. Here, we identified Mettl14 as an important positive regulator of hepatic gluconeogenesis. Liver Mettl14 levels were increased in db/db mice and mice with high fat diet (HFD) -induced obesity. Hepatocyte-specific deletion of Mettl14 decreased hepatic glucose production and ameliorated HFD-induced glucose intolerance; conversely, liver-specific overexpression of Mettl14 increased liver glucose production and HFD-induced glucose intolerance. Of note, Mettl14 did not alter liver insulin actions under our experimental conditions. Remarkably, hepatic deficiency of Mettl14 profoundly blunted the ability of glucagon to stimulate gluconeogenesis in mice. Consistently, deletion of Mettl14 largely blocked glucagon-stimulated gluconeogenesis ex vivo in liver slices as well as in primary hepatocyte cultures. In contrast, overexpression of Mettl14 had the opposite effects. Collectively, these data unravel a previously unrecognized glucagon/Mettl14/gluconeogenesis axis that is involved in hyperglycemia and glucose intolerance in diabetes.

Disclosure
Q. Zheng: None. X. Zhong: None. D. Ren: None. L. Rui: None.

Funding
National Institutes of Health (RO1DK127568) , American Heart Association (831585)
225-LB: Impaired Microvascular Responses May Explain Health Disparities and Impaired Metabolic Flexibility in Hispanic Residents of the Rio Grande Valley
Authors: RUSSELL RYAN D. , LUN TAI YU , MARUPUDI SMARAN 
Published: May 2022

Purpose: Impaired skeletal muscle microvascular blood flow (MBF) is one of the earliest pathophysiologies of type 2 diabetes (T2D) . People with a family history of T2D (FH+ are at greater risk for developing T2D than those with no family history (FH-) . Further, we have shown that normoglycemic Caucasian FH+ individuals have impaired skeletal muscle microvascular responses and metabolic flexibility (MF - ability to switch substrate oxidation upon stimulation) to a mixed meal challenge (MMC) when compared with matched FH- (p&lt;0.01) , suggesting early vascular insulin resistance. Mexican Hispanic individuals have the highest prevalence of T2D in the US and make up ∼95% of Hispanic residents of the Rio Grande Valley (HRGV) where T2D diagnosis rates are ∼3x the national average. Therefore, we sought to determine if impaired MBF responses are present in healthy HRGV.
Methods: 15 FH- and 13 FH+ HRGV were recruited to assess MF and MBF responses to a MMC. MF was measured via indirect calorimetry and MBF via contrast-enhanced ultrasound while fasting and again 60-min post MMC.
Results: No changes in skeletal MBF were noted in FH- (1.21 ± 0.53 SEM and 0.86 ± 0.23 SEM fasting and postprandial MBF respectively) or FH+ (2.17 ± 0.98 SEM and 1.49 ± 0.66 SEM fasting and postprandial MBF respectively) groups. Abdominal adipose MBF responses increased in FH+ (-2.3 ± 0.71 SEM, p=0.004) , but not in FH- (-0.49 ± 0.39 SEM p=0.39) . FH+ display impaired postprandial metabolic flexibility (MF) responses during 60-min of testing post-MMC. Neither blood glucose responses (99.3 ± 1.3 SEM and 102.27 ± 2.1 SEM fasting and post-prandial respectively, p=0.2) nor body composition differed between FH groups.
Conclusions: HRGV display impaired skeletal muscle MBF responses, indicating early vascular insulin resistance. Further, the impairment in MF in FH+ may be partially explained by increased adipose MBF responses, as adipose is less metabolically active than skeletal muscle.

Disclosure
R. D. Russell: None. Y. Tai: None. S. Marupudi: None.
229-OR: Role of Insulin Signaling in the Regulation of Proteostasis in Astrocytes
Authors: GEFFKEN SHAWN , SMITH CATHERINE , LEE HIU HAM , CAI WEIKANG 
Published: May 2022

Insulin is a principal metabolic hormone. It regulates a plethora of metabolic pathways in sensitive peripheral tissues. Recent studies show insulin signaling plays fundamental roles in the brain. Loss of insulin action in different neuronal and glial cells contributes to a variety of metabolic and behavioral abnormalities in mice. In particular, loss of astrocytic insulin signaling leads to impaired brain glucose sensing and increased depressive-like behavior in mice. How insulin signaling modulates astrocytic cellular functions and neural circuits is not completely known. Using next-generation RNA sequencing, we show that insulin triggers a robust transcriptional regulation on multiple metabolic pathways in primary astrocytes. As expected, insulin increased expression of genes involved in cholesterol biosynthesis, important for supporting synaptic integrity and remodeling. Further, autophagy is a quintessential pathway subjected to insulin regulation, indicating the role of insulin action on proteostasis in astrocytes. Thus, insulin suppresses the expression of most critical genes involved in autophagy, including p62, Ulk1/2, several Atg genes. The inhibitory effect is potent, as 1 nM is sufficient to suppress gene expression. To determine whether insulin receptors (IR) are required for such regulation, we examined the insulin response in astrocytes without endogenous IR. IR loss only partially reverses insulin-dependent suppression of autophagic genes, indicating that insulin may act through closely related IGF-1 receptors in astrocytes.
In summary, insulin potently suppresses autophagy in astrocytes through transcriptional regulation, indicating a potential important role of astrocytic insulin signaling on regulating proteostasis in accordance with systemic nutritional status. Impairment of this regulation in insulin resistance and diabetes may affect the modulation of neural circuits by astrocytes and contribute to neurological complications linked to diabetes.

Disclosure
S.Geffken: None. C.Smith: None. H.Lee: None. W.Cai: None.

Funding
KDK120740
232-OR: Alterations in Decision-Making Neurocircuits during Hypoglycemia in Patients with T1DM
Authors: DEAJON-JACKSON JELANI , RANGEL ELIZABETH SANCHEZ , LACADIE CHERYL , GREENE ABIGAIL S. , BELFORT-DEAGUIAR RENATA , CONSTABLE TODD , ROTHMAN DOUGLAS L. , HWANG JANICE J. 
Published: May 2022

Prior work by our group and others have shown that, in response to hypoglycemia, individuals with T1DM have altered regional brain activity and resting state functional connectivity (FC) in reward and decision-making regions such as the orbitofrontal cortex (OFC) and insula. Recently, fMRI studies have found that performing trait-relevant tasks while measuring FC can provide a more accurate representation of cognitive function. Thus, we tested whether individuals with T1DM have different patterns of “task-amplified” FC in response to hypoglycemia compared to non-diabetic control subjects. Twenty-five individuals (17 T1DM, 7F/10M, age 36±3 years, BMI 26±1 kg/m2, HbA1c 7.2±0.2%, duration of DM 19±2 years and 8 healthy controls (HC) , 5F/3M, age 31±2 years, BMI 25±1 kg/m2, HbA1c 5.3±0.1%) underwent BOLD fMRI scanning for FC at rest and during the performance of a Card-Guessing Task to assess reward-based decision making. During scanning, glucose levels were controlled using a 2-step hyperinsulinemic euglycemic (90 mg/dl) -hypoglycemic (60 mg/dl) clamp. Seed-based analysis using a predefined region of interest in the OFC was performed. During resting state, there were no significant Group (HC, T1DM) X Session (euglycemia, hypoglycemia) interactions. In contrast, during the Card Guess task, there was a significant Group X Session interaction (P&lt;0.001) in the dorsal anterior cingulate cortex (dACC) . Specifically, during the task, hypoglycemia elicited connectivity changes between the OFC and the dACC in healthy control subjects but not T1DM subjects. These findings suggest that task-amplified FC may be a more sensitive method to assess neurological differences in T1DM patients that are not apparent at rest. Moreover, because the OFC and dACC have direct neuronal connections and encode a variety of decision-making processes, these data highlight the need for better understanding of not only neurocognitive changes in patients with T1DM but also the factors contributing to these changes.

Disclosure
J.Deajon-jackson: None. E.Sanchez rangel: None. C.Lacadie: None. A.S.Greene: None. R.Belfort-deaguiar: Research Support; Fractyl Health, Inc. T.Constable: None. D.L.Rothman: None. J.J.Hwang: None.

Funding
National Institute of Health (DK020495)
241-OR: Increased Time in Range on Days with Structured Aerobic, Interval, or Resistance Exercise as Compared with Sedentary Days, in Adults with Type 1 Diabetes (T1D)
Authors: LI ZOEY , RIDDELL MICHAEL , RICKELS MICHAEL R. , BECK ROY , CASTLE JESSICA R. , CLEMENTS MARK A. , DOYLE FRANCIS J. , GAL ROBIN L. , GILLINGHAM MELANIE B. , JACOBS PETER G. , MARTIN CORBY K. , PATTON SUSANA R. , CALHOUN PETER 
Published: May 2022

Different types of exercise (i.e., aerobic vs. interval vs. resistance) may have different immediate glycemic effects in adults with T1D, but the impact of exercise type on percent time in range 70-180 mg/dL (TIR) on physically active and inactive days is unknown. The Type 1 Diabetes Exercise Initiative (T1DEXI) study examined CGM data on active vs. sedentary days to assess the effect of exercise type on TIR. Adults (N=497) with T1D ([mean ± SD] age= 37 ± 14 years; HbA1C= 6.6 ± 0.8%) , completed six aerobic, interval, or resistance study-designed exercise videos at home over a 4-week period. TIR was higher and mean glucose concentration lower on days when the study-designed exercise video was completed, as compared with sedentary days (Table) . Time below range was low in general in this cohort, although slightly higher on exercise days. Results were remarkably similar for each exercise type, with marginally less increase in hypoglycemia with resistance exercise.
In summary, adults with type 1 diabetes have clinically significant improvements in TIR on active days as compared to inactive days, regardless of the exercise type.

Disclosure
Z.Li: None. P.G.Jacobs: Other Relationship; Pacific Diabetes Technologies, Research Support; Dexcom, Inc. C.K.Martin: Advisory Panel; Wondr Health, Board Member; EHE Health, Other Relationship; ABGIL, ABGIL, Academy of Nutrition and Dietetics. S.R.Patton: None. P.Calhoun: None. M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Consultant; Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. R.Beck: Consultant; Diasome, Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Research Support; Ascensia Diabetes Care, Beta Bionics, Inc., Bigfoot Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Roche Diabetes Care, Tandem Diabetes Care, Inc. J.R.Castle: Advisory Panel; Insulet Corporation, Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Pacific Diabetes Technologies. M.A.Clements: Consultant; Glooko, Inc., Research Support; Abbott Diabetes, Dexcom, Inc. F.J.Doyle: Other Relationship; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care, Stock/Shareholder; Mode AGC. R.L.Gal: None. M.B.Gillingham: None.
256-OR: Five-Year Simulation of Diabetes-Related Complications in Individuals Treated with Once-Weekly Tirzepatide and Semaglutide vs. Once-Daily Insulin Glargine
Authors: NIU SHU , JIAO TIANZE , GUO YI , BIAN JIANG , SHI LIZHENG , FONSECA VIVIAN , SHAO HUI 
Published: May 2022

This study compared the 5-year risk of diabetes complications of tirzepatide (TZP) and semaglutide with insulin glargine in individuals with type 2 diabetes (T2Ds) , using the BRAVO diabetes model, which has been validated to have a high degree of accuracy. We used the BRAVO model to predict 5-year complications among users of TZP (5 mg, mg, or 15 mg) , semaglutide (1 mg) , and insulin glargine, based on short-tern efficacy data from the SURPASS-2 trial and SUSTAIN-4 trial, under two scenarios: the short-term drug efficacy lasted for 5 years (optimistic) , and the drug efficacy diminished in 5 years (conservative) . We found a 5-year risk reduction in major adverse cardiovascular events (MACE) (relative risk [RR] 63.7%, 95% CI: 61.4%-66.2%) with 15 mg TZP under an optimistic scenario, and MACE (RR 87.6%, 95% CI: 86.8%-88.6%) risk reduction with 15 mg TZP under a conservative scenario, when compared with insulin glargine (Figure) . Lower doses of TZP also had similar, albeit slightly smaller, benefits. The long-term use of TZP and semaglutide may lead to a substantial reduction in diabetes-related complications among individuals with T2Ds, compared to insulin. A high dose of TZP was also superior to semaglutide in this respect.

Disclosure
S.Niu: None. T.Jiao: None. Y.Guo: None. J.Bian: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. H.Shao: Board Member; BRAVO4HEALTH, LLC.
259-OR: Stem Cell–Derived, Fully Differentiated Islet Cells for Type 1 Diabetes
Authors: MARKMANN JAMES F. , NAJI ALI , RICKELS MICHAEL R. , ALBA MARIA , MARIGOWDA GAUTHAM , ROSS LEORAH , WANG CHENKUN , PAGLIUCA FELICIA , SANNA BASTIANO , KEAN LESLIE S. , PETERS ANNE L. , WITKOWSKI PIOTR , RICORDI CAMILLO 
Published: May 2022

Cadaveric islet transplantation can achieve glycemic control in T1D, but cadaveric islet quantity and quality are limiting. We report the first patient-administered VX-880, an investigational allogeneic stem cell–derived, fully differentiated, pancreatic islet cell replacement therapy.
A 64-year-old male with a 40-year history of T1D complicated by impaired awareness of hypoglycemia with 5 severe hypoglycemic events (SHEs) the year before VX-880 was receiving 34U insulin/day at baseline (HbA1c 8.6%; undetectable fasting and stimulated C-peptide) . After a single VX-880 infusion at half target dose, fasting C-peptide was detected by Day 29 and increased rapidly; HbA1c and daily insulin decreased in parallel. At Day 90, robust increases in fasting and stimulated C-peptide, improved glycemic control, and a substantial reduction in exogenous insulin administration were observed and continued to improve through last time point assessed (Table) .
VX-880 was generally safe and well tolerated; most AEs were mild or moderate and consistent with immunosuppression. The most common AEs were SHEs (not serious or related to VX-880) , which occurred in the perioperative period. There was 1 serious AE of rash (mild, unrelated to VX-880) , which resolved.
These unprecedented results are the first evidence that stem cell–derived islets can restore insulin production and glucose control in T1D. The study continues to enroll and dose patients.

Disclosure
J.F.Markmann: Consultant; Vertex Pharmaceuticals Incorporated. L.S.Kean: Advisory Panel; HiFiBio, Mammoth Biosciences, Other Relationship; Bristol-Myers Squibb Company, Research Support; Bluebird Bio, Gilead Sciences, Inc., Magenta Therapeutics, Merck & Co., Inc., Novartis AG, Regeneron Therapeutics. A.L.Peters: Advisory Panel; Abbott Diabetes, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Shouti, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Other Relationship; Omada Health, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Leona M. and Harry B. Helmsley Charitable Trust, Stock/Shareholder; Teladoc Health. P.Witkowski: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated. C.Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. A.Naji: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. M.Alba: None. G.Marigowda: None. L.Ross: Employee; Vertex Pharmaceuticals Incorporated. C.Wang: Employee; Vertex Pharmaceuticals Incorporated. F.Pagliuca: Employee; Vertex Pharmaceuticals Incorporated, Other Relationship; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. B.Sanna: Employee; Vertex Pharmaceuticals Incorporated.