bluuebunny/crossref_metadata_2025_split huggingface dataset:
25-OR: Two Weeks of Exercise Alters Neuronal Extracellular Vesicle Insulin Signaling in Adults with Prediabetes
Authors: MALIN STEVEN K. , BATTILLO DANIEL J. , CHAUDHRY BILAL A. , BEERI MICHAL S. , DELGADO-PERAZA FRANCHESKA , KAPOGIANNIS DIMITRIOS 
Published: June 2024

Introduction & Objective: Prediabetes raises Alzheimer’s Disease and Related Dementia (ADRD) risk. While exercise may lower ADRD risk, it is unclear if it does so by raising brain insulin sensitivity and/or brain derived neurotrophic growth factor (BDNF). We hypothesized that short-term exercise would raise brain insulin signaling and BDNF from neuronal extracellular vesicles (nEVs) in adults with prediabetes.
Methods: Twenty-one adults (18F, 60.0±8.6 y; 33.5±1.1 kg/m2) with prediabetes (75g OGTT, ADA criteria) were randomized to 12 supervised work-matched continuous (n=13, 70% HRpeak) or interval (n=8, 90% and 50% HRpeak for 3 min each) sessions over 2-wks for 60 min/d. Aerobic fitness (VO2peak) and body weight were assessed. After an overnight fast, whole-body glucose tolerance (total area under the curve, tAUC) and insulin resistance (glucose x insulin tAUC) were determined from a 120min 75g OGTT. nEVs were measured at 0- and 60min of the OGTT to depict phosphorylated insulin signaling (i.e. p-IRS-1, total/pAkt, pERK1/2, pJNK1/2 and pp38) and pro-BNDF. OGTT stimulated effects were calculated from protein differences (i.e. 60-0min).
Results: Adults were collapsed into a single group as exercise intensity did not affect measures. Exercise raised VO2peak (+1.4±2.0 ml/kg/min, P&lt;0.01) and decreased weight (-0.4±0.9 kg, P=0.04) as well as whole-body glucose tAUC120min (P=0.02) and insulin resistance (P=0.01). Training lowered fasting pro-BDNF (704.1±1019.0 vs. 414.5±533.5 pg/ml, P=0.04), and increased OGTT-stimulated tAkt (-51.8±147.2 vs. 95±204.5 a.u., P=0.01), which was paralleled by reduced pAkt/total-Akt at 60min of the OGTT (1.3±0.2 vs. 1.2±0.1 a.u., P=0.04). No other insulin protein was impacted by exercise.
Conclusion: Two weeks of exercise altered brain insulin signaling responses to the OGTT and lowered pro-BNDF in adults with prediabetes. Further work is needed to assess if exercise-induced brain insulin sensitivity contributes to ADRD risk reduction.

Disclosure
S.K. Malin: None. D.J. Battillo: None. B.A. Chaudhry: None. M.S. Beeri: None. F. Delgado-Peraza: None. D. Kapogiannis: None.

Funding
National Institutes of Health (RO1-HL130296)
253-OR: Exploring Incorporation of Type 1 Diabetes into Identity and Perceptions of Diabetes Technologies in Adolescents and Young Adults (AYAs)
Authors: COMMISSARIAT PERSIS V. , SCHNEIDER-UTAKA AIKA K. , MORRISSEY BRENDEN , TINSLEY LIANE J. , HANES SARAH , HOOD KOREY K. , LAFFEL LORI M. 
Published: June 2024

Objective: AYAs with T1D have endorsed physical, emotional, and social barriers to device use that suggest devices may negatively impact one’s identity. We examined associations between AYAs’ incorporation of T1D into identity and perceptions of diabetes technologies.
Methods: AYAs with T1D (ages 14-25 yrs, T1D ≥1 yr, eligibility A1c 7-13%) were recruited at 2 sites. AYAs completed the ADAPT (Accepting Diabetes and Personal Treatment) survey with 3 factors measuring incorporation of T1D into identity as well as validated surveys of diabetes technology attitudes and glucose monitoring satisfaction. See table for survey information.
Results: Participants were 191 AYAs (age 19.8±3.4 yrs, T1D duration 11.4±5.4 yrs, 49% male, 89% White, 86% on pump, 98% on CGM, 77% on AID, A1c 8.0±1.2%). Greater overall identity incorporation was related to lower A1c and higher % TIR (p’s &lt;0.01). Greater overall incorporation was also related to more positive attitudes toward technology, less behavioral and emotional burden of glucose monitoring, greater feelings of freedom and device trust, and greater satisfaction with glucose monitoring (p’s &lt;0.01). See table for details on ADAPT factors.
Conclusion: Greater incorporation of T1D into identity was associated with better glycemia and more positive perceptions of diabetes technologies reducing burden and increasing flexibility in daily life.

Disclosure
P.V. Commissariat: None. A.K. Schneider-Utaka: None. B. Morrissey: None. L.J. Tinsley: None. S. Hanes: None. K.K. Hood: Consultant; Cecelia Health, Sanofi. L.M. Laffel: Consultant; Dexcom, Inc. Advisory Panel; Medscape, Medtronic, Vertex Pharmaceuticals Incorporated. Consultant; Novo Nordisk. Advisory Panel; Lilly Diabetes, Provention Bio, Inc., Sanofi-Aventis U.S., Janssen Pharmaceuticals, Inc., MannKind Corporation.

Funding
National Institutes of Health (R01DK129479)
256-OR: Understanding Parent and Youth Diabetes Device Satisfaction
Authors: WONG JESSIE J. , FLORES HALEY M. , HANES SARAH , NGO JESSICA , HOOD KOREY K. 
Published: June 2024

Aim: As youth increasingly adopt diabetes technologies, little is known about device satisfaction. This study sought to understand factors associated with youth and parent diabetes device satisfaction.
Methods: A sample of 157 youth ages 12-19 (Mage=14.7, SD=1.89; 46% female) and their parents enrolled in an RCT provided glycemic and survey data, including single-item ratings of diabetes device satisfaction. Chi-square and t-tests evaluated baseline correlates of satisfaction.
Results: Most youth (57%) endorsed being “very satisfied” with their devices compared to 35% of parents. Only 25% of parent-youth dyads were both “very satisfied.” Most very satisfied youth were male. While youth satisfaction was unrelated to glycemic outcomes, high satisfaction was related to less diabetes distress, better diabetes-related quality of life, better parent-child relationships, and less non-supportive diabetes involvement by parents. Parent satisfaction was related to lower A1c, lower youth diabetes distress, and higher parent diabetes-related quality of life.
Conclusions: Our results highlight key similarities and differences between youth and parents’ device satisfaction. While both parent and youth satisfaction were correlated with youth diabetes distress, parent satisfaction was linked with A1c while youth satisfaction correlated with parent-youth diabetes dynamics. Addressing these areas may promote ongoing device use.

Disclosure
J.J. Wong: None. H.M. Flores: None. S. Hanes: None. J. Ngo: None. K.K. Hood: Consultant; Cecelia Health, Sanofi.

Funding
National Institute of Health (K23-DK121771)
266-OR: Retatrutide, an Agonist of GIP, GLP-1, and Glucagon Receptors, Improves Markers of Pancreatic Beta-Cell Function and Insulin Sensitivity
Authors: ROSENSTOCK JULIO , COSKUN TAMER , HARTMAN MARK L. , LOU JITONG , WU QIWEI , DU YU , GURBUZ SIREL , MATHER KIEREN J. , MILICEVIC ZVONKO , THOMAS MELISSA K. 
Published: June 2024

Retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, significantly reduced HbA1c up to 2.2% in T2D and body weight up to 17% in T2D at wk 36 and 24% in obesity without T2D (OB) at wk 48 in Ph2 trials. To explore mechanisms by which RETA improved glycemic control, we assessed markers of beta-cell function and insulin sensitivity. Mixed models for repeated measures evaluated fasting biomarkers from two Ph2 double-blind randomized placebo-controlled trials: in T2D (281 subjects, 36-wks) and in OB (338 subjects, 48-wks). Homeostatic model assessment (HOMA2)-IR index (insulin), a measure of insulin resistance, decreased over time from baseline with RETA 12 mg reaching reductions of 39% in T2D at 36 wks and 52% in OB at 48 wks. Adiponectin, a marker of insulin sensitivity, increased with RETA from baseline up to 52% in T2D and up to 70% in OB, (p&lt;0.001). HOMA2-B index (C-peptide), a marker of beta-cell function, rapidly increased with RETA up to 88% from baseline in T2D but did not significantly increase in OB. Proinsulin and proinsulin/C-peptide ratios, measures of beta-cell stress and dysfunction, decreased from baseline with RETA, by up to 71% and 62%, respectively, in T2D (p&lt;0.001). In conclusion, RETA improved markers of beta-cell function in T2D and markers of insulin sensitivity in T2D and OB.

Disclosure
J. Rosenstock: Research Support; Biomea Fusion, Inc. Other Relationship; Lilly Diabetes. Research Support; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Corcept Therapeutics. Other Relationship; Novo Nordisk. Research Support; Pfizer Inc. Other Relationship; Sanofi, Boehringer-Ingelheim. Research Support; Shionogi & Co., Ltd. Other Relationship; Structure Therapeutics, Inc. Advisory Panel; Terns Pharmaceuticals, Zealand Pharma A/S. Other Relationship; Applied Therapeutics, Hanmi Pharm. Co., Ltd., Oramed Pharmaceuticals. Advisory Panel; Scholar Rock. T. Coskun: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.L. Hartman: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Lou: None. Q. Wu: None. Y. Du: None. S. Gurbuz: Employee; Eli Lilly and Company. K.J. Mather: Employee; Eli Lilly and Company. Z. Milicevic: Employee; Eli Lilly and Company. M.K. Thomas: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding
Eli Lilly and Company
269-OR: Glucose Control in Free-Life under Hybrid Closed-Loop 6 and 12 Months after Initiation from a Nationwide Survey
Authors: RIVELINE JEAN-PIERRE , JULLA JEAN-BAPTISTE , JOUBERT MICHAEL , LABLANCHE SANDRINE , RENARD ERIC , GAUTIER JEAN-FRANÇOIS 
Published: June 2024

The effectiveness of the Hybrid Closed Loop (HCL) system has been demonstrated in randomized controlled studies. This extensive national study was conducted to assess the initiation process, follow-up modalities, and the metabolic effectiveness of HCL during real-life use, following six and twelve months of continuous usage.
Methods: All adult patients who began HCL therapy between January 1st and December 31st, 2022, were included from 48 centers, irrespective of the specific HCL model employed. Clinical, continuous glucose monitoring (CGM), and HbA1c data were gathered at the initiation of HCL therapy and subsequently every 6 months. We also documented the approach healthcare professionals took when educating patients during follow-up. In this report, we present the 6-month and 12-month follow-up results for adult patients in the study.
Results: A total of 2156 adults patients were included; baseline characteristics are presented in Table 1. Metabolic evolution at 6 months ((n=1993) and at 12 months (n=1143) are presented in Table 2. At 12 months, 3.2% have stopped the HCL.
Conclusions: HCL has shown remarkable effectiveness in real-life scenarios, enabling the achievement of time in range goals and a significant reduction in severe hypoglycemic events after a 12-month follow-up. Only a small number of patients discontinued the use of HCL.

Disclosure
J. Riveline: Board Member; Abbott, Novo Nordisk A/S, Sanofi, Eli Lilly and Company, Medtronic, Dexcom, Inc., Insulet Corporation, Air Liquide, AstraZeneca. J. Julla: Speaker's Bureau; Lilly Diabetes, Novo Nordisk. Board Member; Sanofi. M. Joubert: Consultant; Abbott, Medtronic, Dexcom, Inc. S. Lablanche: None. E. Renard: None. J. Gautier: Board Member; Sanofi. Other Relationship; Sanofi. Speaker's Bureau; AstraZeneca, Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Pfizer Inc.
279-OR: FBLN7 in Pre-adipocytes Promotes Adipose Tissue Fibrosis and Disrupts Metabolic Homeostasis in Obesity
Authors: YU HAIRONG , YAN JING , HU CHENG 
Published: June 2024

Fibrosis, resulting from excess extracellular matrix deposition, is a feature of adipose tissue (AT) dysfunction and obesity-related insulin resistance. However, the precise mechanisms underlying AT fibrosis in obesity remain unclear. In this study, through scRNA-seq data we discovered Fibulin7 (FBLN7), a recently identified member of fibulin family, as a promoter of AT fibrosis. The precise role of FBLN7 in AT remains unknown. We showed that the loss and gain of function of FBLN7 in pre-adipocytes inhibits and promotes, respectively, TGFβ-induced fibrogenic responses. In vivo, genetic ablation of FBLN7 in adipocyte precursors, and treatment with FBLN7-neutralizing antibody dramatically alleviated AT fibrosis-inflammation state and improved systemic metabolic health. Mechanically, FBLN7 bound to thrombospondin-1 (TSP1) through its EGF-like calcium-binding domain, activated TGFBR1/TGFβ/Smad signaling via TSP1. Furthermore, in obese humans, FBLN7 levels were upregulated in both visceral fat and systemic circulation and correlated with clinical metabolic traits. And we also revealed that variant p.V99E was associated with improved metabolic performance in humans and inhibited TSP1/TGFBR1/TGFβ/Smad axis in cells. Conclusively, our findings imply that FBLN7 produced by pre-adipocytes is a potential biomarker of AT fibrosis and may represent a therapeutic target for AT fibrosis.

Disclosure
H. Yu: None. J. Yan: None. C. Hu: None.
281-OR: Pyruvate Carboxylase Flux Is Increased in the Type 1 Diabetic Exocrine Pancreas
Authors: RUSHIN ANNA , GRAHAM DALTON S. , HARDIN CALLIE , MERRITT MATTHEW 
Published: June 2024

The exocrine pancreas displays structural and functional abnormalities in type 1 diabetes, such as acinar atrophy and fibrosis. Metabolic dysfunction may occur alongside these changes. Real-time exocrine pancreatic metabolism was investigated using nuclear magnetic resonance (NMR) and hyperpolarized (HP) pyruvate. This work used the hyperglycemic NOD.Rag1-/-.AI4α/β mouse model of T1D (n=4), normoglycemic NOD.Rag1-/-.AI4α/β mice (n=3) to model the pre-T1D state, and the NOD.Rag1-/- control (n=3). NMR spectra were collected at 14 T after injection of 4 mM HP [1-13C] pyruvate into the common bile duct, and 13C signals from several central carbon metabolites were detected. Pancreata from diabetic mice produced significantly more (p&lt;0.05) fumarate and aspartate compared to control mice, indicating increased pyruvate carboxylase flux. Alanine to lactate and bicarbonate to lactate ratios were significantly altered in pre-diabetic and diabetic mice compared to the control, indicating a detectable shift in tissue redox balance prior to altered glycemia. Separately, immunofluorescence imaging of pancreas slices revealed pyruvate carboxylase levels were increased in T1D mice. Ultimately, these results indicate that the diabetic pancreas displays increased pyruvate carboxylase (PC) flux and altered redox balance, thus providing unique insights into uncharacterized metabolic shifts in the exocrine pancreas in T1D.

Disclosure
A. Rushin: None. D.S. Graham: None. C. Hardin: None. M. Merritt: None.

Funding
National Institutes of Health (T32 DK10876); National Science Foundation (DMR-1644779)
289-OR: Autophagy Promotes Islet α-Cell Function by Maintaining ER Proteostasis and Glucagon Production
Authors: ZHU WENZHEN , PAN LINXIU , CHIARA RUSSO ANNA , RAY ROHIT , PEDERSON BRENT , SHRESTHA NEHA , QI LING , REINERT RACHEL B. 
Published: June 2024

Introduction & Objective: Islet α cells have traditionally been maligned for contributing to hyperglycemia in diabetes but are increasingly recognized for their potential to promote β cell mass and function. The cellular mechanisms regulating proglucagon production and its subsequent processing into glucagon and/or glucagon-like peptide 1 (GLP-1) in α cells are incompletely understood. Autophagy, the process of recycling cellular components by lysosomal degradation, is essential for insulin production and β cell survival.
Methods: To investigate the role of autophagy in α cells, we deleted the key autophagosome protein Atg7 using the Cre-lox system in mice or CRISPR in αTC cells.
Results: Atg7 Δ Gcg mice showed normal growth and oral glucose tolerance into adulthood but had impaired glucagon secretion following hypoglycemia by two months of age. Islet α cells in Atg7 Δ Gcg mice became hypertrophic and vacuolated with age, but survived without a substantial decline in mass. Instead, pancreatic glucagon content was reduced in Atg7 Δ Gcg mice (42.2 +/- 7.3 vs. 75.3 +/- 9.1 ng/g). Electron microscopy revealed α cells with fewer glucagon granules and dilated endoplasmic reticulum (ER), and increased expression of the ER chaperone BiP was confirmed in αTCΔAtg7 cells. This was associated with a decrease in the proglucagon processing hormone PC2, possibly limiting production of mature glucagon. Interestingly, total pancreatic GLP-1 content was increased in Atg7 Δ Gcg mice (1351 +/- 114 vs. 891 +/- 75 pg/g) without changes in serum GLP-1 levels. Using the GLP-1 receptor antagonist exendin(9-39), we observed a similar impairment in oral glucose tolerance in Atg7 Δ Gcg mice and littermate controls.
Conclusion: These data show that autophagy promotes classic α cell function by maintaining ER proteostasis and glucagon production. However, defective α cell autophagy does not entirely disrupt proglucagon-mediated signaling in vivo and may promote α cell GLP-1 production.

Disclosure
W. Zhu: None. L. Pan: None. A. Russo: None. R. Ray: None. B. Pederson: None. N. Shrestha: Employee; Regeneron Pharmaceuticals Inc. L. Qi: None. R.B. Reinert: None.

Funding
National Institutes of Health (K08DK129719, T32DK007245)
29-OR: Analysis of Fib-4 Index Changes in Adults with Type 2 Diabetes in an Effective Comprehensive Diabetes Care Program
Authors: SILVA-TINOCO RUBÉN , RIVAS-ALARCÓN ALINNE , DELATORRE-SALDAÑA VIRIDIANA , GALINDEZ-FUENTES ANA , MÁRQUEZ-GUILLÉN ERNESTO , SANTOS-LÓPEZ FRANCISCO , AMAYA DAVID , CASTRO ELIZABETH , MUNGUÍA BERENICE , LÓPEZ NARAI , GUZMAN-OLVERA EILEEN B. , CUATECONTZI-XOCHITIOTZI TERESA 
Published: June 2024

Introduction: The Fib-4 index (FIB4) is recommended for screening liver fibrosis (LF) risk in adults with T2D. Recent evidence suggests that dynamic changes (increases/decreases) in FIB4 overtime may be linked to subsequent risk of liver events and diabetes-related complications. We explored the change in FIB4 among adults with T2D engaged in a quality improvement initiative within primary care-the DIABEMPIC program.
Methods: This quasi-experimental, single group pre/post-intervention design encompassed participants undergoing a 5-month multicomponent comprehensive care program. Designed to improve diabetes care goals, the program featured therapeutic diabetes education and interdisciplinary care, emphasizing intensive lifestyle modification and treatment intensification. No liver fibrosis-modifying drugs were used.
Results: The observed prevalence of indeterminate/high risk (FIB4 ≥ 1.3; IHR) for LF was 27%. Baseline characteristics and changes (Δ) in participants, stratified by baseline LF risk status, are detailed in Table 1. The Δ in FIB4 in the overall participants was -0.11 ± 0.5 (p = 0.004), while in the IHR group the Δ observed was -0.5 ± 0.77 (p &lt; 0.001). At follow-up, 35 subjects (46%) moved from the IHR to the low-risk status.
Conclusions: This study underscore that intensive comprehensive care schemes within adults with T2D can mitigate the risk of LF, as measured through FIB4.

Disclosure
R. Silva-Tinoco: None. A. Rivas-Alarcón: None. V. delaTorre-Saldaña: None. A. Galindez-Fuentes: None. E. Márquez-Guillén: None. F. Santos-López: None. D. Amaya: None. E. Castro: None. B. Munguía: None. N. López: None. E.B. Guzman-Olvera: None. T. Cuatecontzi-Xochitiotzi: None.
290-OR: Acetylation Induces a SUMOylation–Phosphorylation Switch to Enhance MafA Transactivation
Authors: CHIRIKJIAN MARGOT , LIANG JIANI Z. , BARTOLOMÉ ALBERTO , SONI RAJESH , STEIN ROLAND , PAJVANI UPTAL 
Published: June 2024

MAF bZIP transcription factor A (MafA) transactivates multiple genes involved in β-cell maturity function. MafA transactivation is increased by recruitment and binding of multiple lysine acetyltransferases, Kat2b and CBP, but mechanisms underlying this phenomenon are unclear. We performed a LC-MS/MS screen and validation experiments that revealed that Kat2b and CBP increased MafA acetylation at lysines (K) 32, 33 and 255. To understand functional consequences of MafA acetylation, we mutated all three to glutamine (3KQ) or arginine (3KR) to mimic constitutively acetylated and deacetylated MafA, respectively, and performed luciferase assays with these mimetics that showed increased transactivation ability at the insulin promoter by 3KQ, independent of stability, DNA binding or MafA localization. Intriguingly, 3KQ MafA also showed retarded mobility on SDS-PAGE, suggesting that acetylation induced another post-translational modification (PTM). In a second LC-MS/MS screen followed by alanine scanning, we identified that acetylation increased MafA phosphorylation at serine (S) 14. Thus, S14A mutation attenuated the effects of acetylation. Simultaneously, MafA acetylation at K32 prevents SUMOylation at the same site; thus, inhibition of SUMOylation increased MafA acetylation and activity. Overall, our findings suggest that acetylation induces a novel PTM switch in MafA - enhancing S14 phosphorylation and blocking K32 SUMOylation, to potentiate transactivation at target promoters.

Disclosure
M. Chirikjian: None. J.Z. Liang: None. A. Bartolomé: None. R. Soni: None. R. Stein: None. U. Pajvani: None.
30-PUB: Difference in Glycemic Control between Ipragliflozin (Ipra) and Sitagliptin (Sita) according to Fatty Liver Index (FLI)—Post Hoc Analysis of the Results of the Niigata Ipragliflozin and Sitagliptin with Metformin (NISM) Study
Authors: KITAZAWA MASARU , SONE HIROHITO , FUJIHARA KAZUYA , YAMADA TAKAHO , MATSUBAYASHI YASUHIRO , ISHIZAWA MASAHIRO , SUZUKI HIROSHI , YAMAMOTO MASAHIKO , YAMADA MAYUKO H. , HATTA MARIKO 
Published: June 2024

Fatty liver (FL) is a major complication of type 2 diabetes mellitus and has adverse effects on glycemic control. Although there are many reports on drug selection to improve FL (e.g., SGLT2 inhibitors), reports on drug selection considering the effects of the presence or degree of FL on glycemic control are scarce. To address this issue, we performed a post-hoc analysis of the results of the NISM study, a 52-week randomized controlled trial comparing the efficacy of Ipra and Sita. Included were 90 participants (58.9% male; 44 using Ipra; 46 using Sita). Mean age was 59.3 y and mean HbA1c 7.5%, BMI 26.6 kg/m2, ALT 30.7 U/L and FLI 51.1. Participants were stratified into low FLI (n=44, FLI &lt;51.0) and high FLI (n=46, FLI ≥51.0) groups. In the low FLI group, HbA1c improved significantly with Sita compared with Ipra (Ipra 0.37 vs. Sita -0.68, p = 0.04). On the other hand, in the high FLI group, HbA1c improved significantly with Ipra compared with Sita (Ipra -0.63 vs. Sita -0.14, p = 0.04). There was no difference in changes in the FLI in the low FLI group (-8.1 vs. -2.7, p = 0.051), but in the high FLI group, FLI improved significantly (-13.5 vs. -0.8, p &lt;0.001) with Ipra compared with Sita. The FLI is effective in drug selection for type 2 diabetes.

Disclosure
M. Kitazawa: None. H. Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Eisai Inc., Sumitomo Dainippon Pharma Co., Ltd. K. Fujihara: None. T. Yamada: None. Y. Matsubayashi: None. M. Ishizawa: None. H. Suzuki: None. M. Yamamoto: None. M.H. Yamada: None. M. Hatta: None.

Funding
This study was funded by Astellas Pharma Inc. The company was not involved in study design, patient selection, data aggregation/analysis, interpretation of results, or preparation of the manuscript.