bluuebunny/crossref_metadata_2025_split huggingface dataset:
817-P: Demographic, Clinical, and Treatment Characteristics of Patients with Timely vs. Delayed Basal Insulin Initiation
Authors: BILLINGS LIANA K. , SHETH SUNNY T. , BRADY BRENNA , RICHARDS MEGAN , RAJPURA JIGAR R. , MITRI JOANNA 
Published: June 2024

Introduction & Objective: Basal insulin is indicated for patients with uncontrolled type 2 diabetes (uT2D) after trials of glucose-lowering medications (GLMs). Despite its benefit, it remains underutilized and is often initiated after delay as a last resource. This study examined the demographic, clinical, and treatment characteristics of patients with timely vs delayed basal insulin initiation.
Methods: In the 2011-2018 MerativeTM Claims-EHR Database, adults with uT2D who were candidates for basal insulin (HbA1c&gt;7%, ≥2 GLMs totaling ≥180 days’ supply, no new GLM class in the next 90 days) and newly initiated treatment were selected (index date=first basal insulin fill). Timely and delayed initiators started treatment &lt;6 months and ≥6 months after meeting uT2D criteria, respectively. Patients had ≥12 months of pre- and post-enrollment, no claims for type 1 diabetes or pregnancy, and ≥1 claim for T2D. Demographic, clinical, and treatment characteristics were compared between cohorts.
Results: Among 1,054 (29.2%) timely and 2,561 (70.8%) delayed initiators, mean time from uT2D to basal insulin was 59±55 days and 741±504 days, respectively. Timely initiators were younger and more likely to be female. Delayed initiators used more GLM classes than timely initiators in both pre- and post-periods. Delayed initiators had more HbA1c results in the pre-period (2.1±1.5 vs 1.9±1.2), indicating possible increased monitoring prior to basal insulin initiation, while timely initiators had a significantly larger HbA1c decrease from the pre- to post-periods (-1.3±1.9 vs -1.0±1.8, p&lt;0.001).
Conclusion: Although basal insulin use led to reductions in HbA1c in both cohorts, greater benefits were observed with timely initiation. Patterns of GLM use and HbA1c monitoring suggested delayed basal insulin initiation was associated with more attempts to manage T2D with other GLMs, potentially prolonging exposure to hyperglycemia and increasing lifetime disease management costs.

Disclosure
L.K. Billings: Advisory Panel; Novo Nordisk, Pfizer Inc. S.T. Sheth: Employee; Novo Nordisk. B. Brady: None. M. Richards: None. J.R. Rajpura: Employee; Novo Nordisk. J. Mitri: Advisory Panel; MannKind Corporation. Consultant; Novo Nordisk. Research Support; Kowa Pharmaceuticals America, Inc. Consultant; Lilly Diabetes, Dianomi-. Employee; sequelmedtech. Consultant; AbbVie Inc., beigene-spouse, cellectar-spouse, kite-spouse, Janssen Pharmaceuticals, Inc., loxo-spouse, AstraZeneca.

Funding
Novo Nordisk Inc.
824-P: No Evidence of Increased Physical Activity–Related Hypoglycemia with Once-Weekly Insulin Icodec vs. Once-Daily Basal Insulin in Type 1 Diabetes—ONWARDS 6
Authors: SOURIJ HARALD , BRACKEN RICHARD M. , ASONG MARISSE , CARSTENSEN LISBETH , WATT SARA K. , PHILIS-TSIMIKAS ATHENA 
Published: June 2024

Introduction & Objective: ONWARDS 6 compared the efficacy and safety of once-weekly insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with T1D. This post hoc analysis examined physical activity-related hypoglycemia in ONWARDS 6.
Methods: During the trial, participants experiencing hypoglycemic episodes were asked to indicate any relationship to physical activity in a digital diary. Overall hypoglycemia rate was also assessed based on baseline physical activity level recorded using the International Physical Activity Questionnaire.
Results: The proportion of physical activity-related hypoglycemic episodes relative to overall hypoglycemic episodes was similar or lower for icodec vs degludec (Figure A); odds of having physical activity-related level 2 or level 3 hypoglycemia were similar between groups (OR: 1.04; 95% CI: 0.75-1.46; p = 0.8060). Most physical activity-related level 2 or level 3 hypoglycemic episodes did not lead to further hypoglycemic episodes within 24 hrs in either group (Figure B). Overall hypoglycemia rates (including those unrelated to physical activity) were comparable within each group regardless of baseline physical activity level (data not shown).
Conclusion: There was no evidence of increased risk of physical activity-related hypoglycemic episodes with icodec versus degludec in adults with T1D.

Disclosure
H. Sourij: Advisory Panel; Amarin Corporation. Speaker's Bureau; Amgen Inc., Amarin Corporation, Bayer Inc. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Novartis AG. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Sanofi. Speaker's Bureau; Sanofi. Consultant; K:Businesscom. R.M. Bracken: None. M. Asong: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. L. Carstensen: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. S.K. Watt: Employee; Novo Nordisk. A. Philis-Tsimikas: Advisory Panel; Dexcom, Inc., Lilly Diabetes, Novo Nordisk, Sanofi, Medtronic, Bayer Inc.

Funding
Novo Nordisk A/S
829-P: iGlarLixi vs. Basal-Bolus (BB) or Premixed Insulin in Older Adult Ethnic Minorities with Type 2 Diabetes (T2D)
Authors: UMPIERREZ GUILLERMO , GILL JASVINDER , HOOD DAVID , LI XUAN , NÚÑEZ ANA 
Published: June 2024

Introduction & Objective: Ethnic minorities and older adults, who are disproportionately affected by T2D, are underrepresented in studies. This retrospective study assessed whether the fixed-ratio combination iGlarLixi improved outcomes vs complex insulin therapies in these populations.
Methods: Medicare claims data were used from African American, Asian, and Hispanic beneficiaries with T2D aged ≥65 years receiving basal insulin who newly initiated iGlarLixi, BB, or premixed insulin from Jan 1, 2019-Dec 31, 2021. Groups were propensity score matched (PSM) at baseline and followed for up to 12 months. The primary endpoint was treatment persistence. Secondary endpoints included treatment adherence and hypoglycemia event rates.
Results: PSM generated 1162 participants/group for iGlarLixi vs BB and 1160 vs premix. For iGlarLixi, persistence was statistically significantly higher, and adherence was numerically higher than BB or premixed insulin in the overall cohort. Hypoglycemia event rates were numerically lower for iGlarLixi vs BB or premixed insulin in the overall cohort. Similar findings were observed in African-American, Asian, and Hispanic groups (Table).
Conclusion: In minority populations with Medicare, iGlarLixi led to higher treatment persistence, numerically higher adherence, and lower hypoglycemia event rates compared to BB or premixed insulin.

Disclosure
G. Umpierrez: Research Support; Abbott, Bayer Inc., Dexcom, Inc., AstraZeneca. Advisory Panel; Dexcom, Inc. J. Gill: Employee; Sanofi-Aventis U.S. D. Hood: Employee; Pfizer Inc. X. Li: Employee; Sanofi. A. Núñez: None.

Funding
Sanofi US
839-P: Treatment Satisfaction and Time in Range (TIR) after 16 Weeks of iGlarLixi in Insulin-Naive Adults with Suboptimally Controlled Type 2 Diabetes
Authors: SHAH VIRAL N. , DEX TERRY A. , MENEGHINI LUIGI , RODRIGUES AMÉLIE , POLONSKY WILLIAM H. 
Published: June 2024

Introduction & Objective: A 16-week open-label study (NCT05114590) using blinded continuous glucose monitoring in insulin-naive adults with type 2 diabetes suboptimally controlled on ≥2 oral antihyperglycemic drugs (OADs) ± glucagon-like peptide-1 agonist (GLP-1 RA) showed that once daily iGlarLixi significantly increased TIR (26.2%; P&lt;0.001). We describe patient-reported treatment satisfaction.
Methods: Treatment satisfaction was assessed with the Diabetes Medication Treatment Satisfaction Tool (DM-SAT), a 16-item survey scored from 0 (not at all) to 10 (extremely satisfied) in 4 domains. Association of TIR and overall satisfaction (sum of all items) was also assessed.
Results: In total, 124 people (58.9% males; 70.2% Hispanic/Latino; mean age 55.6 y, A1C 10.2%) were enrolled. At Week 16, there was improvement in overall and all subdomain scores (Table). For individual items, improvement was high for glucose control (+2.9), avoiding glucose highs (+2.7), and feeling in control of diabetes (+2.7). Treatment satisfaction was positively correlated with TIR (r 0.142; 95% CI -0.057, 0.328).
Conclusion: In people with type 2 diabetes suboptimally controlled on ≥2 OADs ± GLP-1 RA, 16 weeks’ treatment with iGlarLixi significantly improved treatment satisfaction, which may be associated with increased TIR.

Disclosure
V.N. Shah: Consultant; Dexcom, Inc., Insulet Corporation. Research Support; Insulet Corporation. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Sanofi, Medscape. Consultant; embecta, Tandem Diabetes Care, Inc. T.A. Dex: Stock/Shareholder; Pfizer Inc. Employee; Sanofi. Stock/Shareholder; Viatris Inc., Teva Pharmaceutical Industries Ltd. L. Meneghini: Employee; Sanofi. A. Rodrigues: Consultant; Sanofi. W.H. Polonsky: Research Support; Abbott Diagnostics, Dexcom, Inc. Consultant; Eli Lilly and Company, Sanofi. Advisory Panel; embecta. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; 9am Health.

Funding
Sanofi US
840-P: Efficacy and Safety of Once-Weekly Insulin Icodec vs. Once-Daily Basal Insulin in Type 2 Diabetes according to Baseline Glucagon-Like Peptide 1 Receptor Agonist Use—ONWARDS 1–5
Authors: VILSBØLL TINA , BANGSGAARD KATRINE O. , FU ARIEL , KELLERER MONIKA , SØGAARD STINNE B. , GOLDENBERG RONALD 
Published: June 2024

Introduction & Objective: To assess the treatment effects of once-weekly (OW) insulin icodec (icodec) vs once-daily (OD) basal insulin comparators ± concomitant glucagon-like peptide-1 receptor agonist (GLP-1 RA) use in ONWARDS 1-5.
Methods: A post hoc analysis by trial of insulin-naïve (ONWARDS 1, 3, 5) and insulin-experienced (ONWARDS 2, 4) adults with type 2 diabetes (T2D).
Results: Participants on icodec vs OD comparators had larger or similar A1C reductions from baseline (BL) to end of treatment (EOT) irrespective of GLP-1 RA use; there was no statistically significant treatment by subgroup interaction in A1C changes (Table). Overall rates of clinically significant or severe hypoglycemia were low (&lt;1 event/patient-year of exposure) across arms among ONWARDS 1-3 and 5 subgroups, with numerically lower rates among GLP-1 RA users vs non-users; in ONWARDS 4 (basal-bolus trial), the hypoglycemia rate was similar among GLP-1 RA users vs non-users in the icodec arm (Table). There was no statistically significant treatment by subgroup interaction in any trial for the attainment of A1C &lt;7% without clinically significant or severe hypoglycemia, nor body weight change from BL to EOT.
Conclusion: The efficacy and safety of icodec vs OD comparators was generally consistent among adults with T2D, irrespective of baseline GLP-1 RA use.

Disclosure
T. Vilsbøll: Consultant; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Mundipharma. Advisory Panel; Novo Nordisk, Lilly Diabetes, Sanofi. Speaker's Bureau; Bayer Inc., Gilead Sciences, Inc. Advisory Panel; Sun Pharmaceutical Industries Ltd. Research Support; Lilly Diabetes. K.O. Bangsgaard: Employee; Novo Nordisk A/S. A. Fu: Employee; Novo Nordisk A/S, Novo Nordisk. M. Kellerer: Advisory Panel; Abbott. Speaker's Bureau; Daiichi Sankyo. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Advisory Panel; Sanofi, GlaxoSmithKline plc, AstraZeneca, Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Novo Nordisk. S.B. Søgaard: Employee; Novo Nordisk A/S. R. Goldenberg: Speaker's Bureau; Bayer Inc., Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company, HLS Therapeutics Inc., Novo Nordisk, Sanofi.

Funding
Novo Nordisk A/S
845-P: The Menin Inhibitor Ziftomenib Induces Insulin Production and Improves Insulin Sensitivity in a Rat Model of Type 2 Diabetes Mellitus (T2DM)
Authors: MCCLOSKEY ASAKO , LIU YAHU A. , WANG XINGJUAN , BURROWS FRANCIS 
Published: June 2024

Menin is an epigenetic scaffold protein known to regulate pathogenic gene expression in several cell types. Genetic menin loss (MEN1 Syndrome) is associated with insulinemia due to upregulated pancreatic β-cell proliferation. Ziftomenib is a potent and selective menin inhibitor currently in clinical trials for the treatment of acute leukemias. Zucker Diabetic Fatty rats were used to assess the antidiabetic activity of ziftomenib dosed orally once daily for 27 days. Ziftomenib treatment was well tolerated and rapidly reduced fasting blood glucose (FBG) levels, with normalization of FBG levels observed in most animals within 2 weeks. Ziftomenib also progressively reduced %HbA1C by an average of 1.49% by week 4 (FIG). Oral glucose tolerance tests demonstrated that ziftomenib-treated animals achieved significantly improved postprandial glucose control (P&lt;0.0001). Ziftomenib induced a reduction in HOMA-IR within 1 week, suggesting that one of the effects of menin inhibition is acute sensitization of the animals to insulin. In addition, fasting insulin and c-peptide levels demonstrated that ziftomenib significantly stimulated insulin production at week 3-4 (FIG). These observations suggest that pharmacological targeting of menin may be a viable option to treat both insulin resistance and insulin insufficiency, the two main pathological features of T2DM.

Disclosure
A. McCloskey: None. Y.A. Liu: None. X. Wang: None. F. Burrows: None.
847-P: Berberine Ursodeoxycholate (HTD1801) Improves Key Glycemic and Cardiometabolic Parameters across the Type 2 Diabetes Mellitus Disease Spectrum
Authors: JI LINONG , MA JIANHUA , MA YUJIN , CHENG ZHIFENG , GAN SHENGLIAN , YUAN GUOYUE , LIU DEXUE , LI SHELI , LIU YU , XUE XIA , BAI JIE , WANG KUN , CAI HANQING , LI SHU , LIU KUI , YU MENG , LIU LIPING 
Published: June 2024

Introduction: HTD1801 is a gut-liver anti-inflammatory metabolic modulator shown to improve key glycemic and cardiometabolic parameters. The aim of this study was to evaluate the effectiveness of HTD1801 across the T2DM disease spectrum.
Method: In a Ph2 study of treatment-naïve patients with T2DM 113 patients were randomized 1:1:1 to placebo (n=38), HTD1801 500 mg BID (n=37), and 1000 mg BID (n=38) for 12 weeks. Key inclusion criteria included T2DM (WHO criteria), HbA1c 7%-10.5% and FPG &lt;13.9 mmol/L. The primary endpoint was change from baseline (BL) in HbA1c at Week 12. For this analysis, patients were assigned to high/low risk groups by BL HbA1c above/below 8.5%.
Result: At BL, 35% of patients had HbA1c ≥8.5%. BL characteristics were balanced between treatment groups and subgroups. Patients with elevated HbA1c had elevated glycemic and cardiometabolic parameters at BL. Treatment with HTD1801 for 12 weeks resulted in a dose dependent reduction across both subgroups (Table). Improvements with 1000 mg BID were significant vs placebo at Week 12. HTD1801 patients with higher HbA1c had more substantial reductions across all parameters compared to patients with lower HbA1c.
Conclusion: Regardless of BL disease severity, HTD1801 treatment resulted in significant improvements in key glycemic and cardiometabolic parameters. HTD1801 continues to be evaluated for T2DM in Ph3 studies.

Disclosure
L. Ji: None. J. Ma: None. Y. Ma: None. Z. Cheng: None. S. Gan: None. G. Yuan: None. D. Liu: None. S. Li: None. Y. Liu: None. X. Xue: None. J. Bai: None. K. Wang: None. H. Cai: None. S. Li: None. K. Liu: Employee; Shenzhen HighTide Biopharmaceutical Ltd. Stock/Shareholder; Shenzhen HighTide Biopharmaceutical Ltd. M. Yu: Employee; Shenzhen HighTide Biopharmaceutical Ltd. Stock/Shareholder; Shenzhen HighTide Biopharmaceutical Ltd. L. Liu: Employee; Shenzhen HighTide Biopharmaceutical Ltd. Stock/Shareholder; Shenzhen HighTide Biopharmaceutical Ltd.
861-P: Efficacy of Digital Intervention vs. Metformin for Women with Polycystic Ovary Syndrome—A Randomized Clinical Trial
Authors: QU SHEN , DILIMULATI DILIQINGNA , CAI MEILI , ZHANG YUQIN , ZHANG MANNA 
Published: June 2024

Objective: To evaluate the efficacy of digital intervention versus metformin treatment for women with polycystic ovary syndrome (PCOS) with insulin resistance (IR).
Methods: A total of 80 women with PCOS with IR were randomly assigned to receive either digital intervention (n = 40) or metformin (n = 40) for 12 weeks. The primary outcomes were the changes in the homeostatic model assessment for insulin resistance (HOMA-IR). Anthropometric parameters, menstruation frequency, sex hormone levels, metabolic factors, body fat distribution, and questionnaires on diet, exercise, sleep, anxiety and depression were obtained.
Results: A total of 72 participants completed the follow-up (90% follow-up rate), including 35 and 37 from the digital intervention and metformin groups, respectively. The HOMA-IR of the digital intervention group was significantly improved after a 12-week of treatment, but no statistical difference was observed between the groups. Both digital intervention and metformin significantly improved menstruation, and reduced body weight and total fat mass. Furthermore, the digital intervention had a significant advantage over metformin in improving waist circumference (WC), waist-hip ratio (WHR), total fat mass, and dehydroepiandrosterone sulfate (DHEAS). In terms of safety, the main adverse events in the digital intervention and metformin groups were sensations of hunger (5%) and gastrointestinal adverse events (30%), respectively.
Conclusion: Our data suggest that digital intervention is an effective treatment option for patients with PCOS, with an efficacy comparable to that of metformin, which can also alleviate the negative effects of medications and make it easier and more efficient to adhere to lifestyle treatments.

Disclosure
S. Qu: None. D. Dilimulati: None. M. Cai: None. Y. Zhang: None. M. Zhang: None.
877-P: Effect of Lobeglitazone, a Novel Thiazolidinedione, on Liver Fat in Patients with Type 2 Diabetes and Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD)—A Randomized Controlled Trial (Lobe-MASLD Trial)
Authors: GADVE SHARVIL S. , GADVE SNEHA S. , GADVE SHRIYA , CHAVANDA KETKI S. , HANAMSHETTI SATISH 
Published: June 2024

Objective: Thiazolidinediones reduce liver fat. Older thiazolidinediones including pioglitazone have concerns in use like impact on bone health. Data regarding the effect of lobeglitazone, a novel thiazolidinedione on human liver fat are limited. This study examined effect of lobeglitazone on liver fat in patients with T2DM & metabolic dysfunction-associated steatotic liver disease (MASLD) by using MRI-derived proton density fat fraction (MRI-PDFF).
Research Design & Methods: 80 patients with T2DM & MASLD were randomly assigned to either the lobeglitazone group (standard treatment for T2DM plus lobeglitazone 0.5 mg daily) or the control group (standard treatment without lobeglitazone) for 24 weeks. Patients using sglt2 inhibitors, glucagon-like peptide 1 receptor agonists were excluded. Change in liver fat was measured by MRI-PDFF. Secondary outcome measures were change in alanine transaminase (ALT), aspartate transaminase (AST), and γ-glutamyl transferase (GGT) levels, FIB-4 score.
Results: Lobeglitazone was significantly better at reducing liver fat (mean MRI-PDFF difference between the lobeglitazone and control groups -3.9 %; P = 0.004). Significant reduction was found in the end-of-treatment MRI-PDFF for the lobeglitazone group (15.9% to 12.1%; P = 0.002) and a nonsignificant change was found in the control group (16.0% to 15.4%; P = 0.091). Lobeglitazone group showed significant difference for change in serum ALT level (P = 0.004) and both groups showed nonsignificant differences for AST (P = 0.517) and GGT (P = 0.098) levels and FIB-4 score (P=0.62).
Conclusions: Lobeglitazone reduces liver fat and improves ALT levels in patients with T2DM and MASLD. This benefit was seen even in absence of concurrent use of sglt2 inhibitors or glucagon-like peptide 1 receptor agonists.

Disclosure
S.S. Gadve: None. S.S. Gadve: None. S. Gadve: None. K.S. Chavanda: None. S. Hanamshetti: None.
880-P: Gene Therapy for MODY3 Moving from Mice to Large Animals
Authors: CASANA ESTEFANIA , JIMENEZ VERONICA , GARCIA MIQUEL , LUISA JAÉN MARIA , CASELLAS ALBA , MORRÓ MERITXELL , PUJOL ANNA , FERRE TURA , SACRISTAN VICTOR , JAMBRINA CLAUDIA , LEON XAVIER , FRANCKHAUSER SYLVIE , BOSCH FATIMA 
Published: June 2024

Introduction & Objective: Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcription factor hepatocyte nuclear factor 1A (Hnf1α) gene. We have developed a pancreas-directed adeno-associated viral vectors (AAV)-Hnf1α gene therapy, which counteracted hyperglycemia, improved glucose tolerance and enhanced insulin secretion in MODY3 mice. Here, we further explore the benefits of the AAV-Hnf1α treatment in MODY3 mice and the feasibility of the pancreas-mediated gene transfer in large animals for the future translation of this approach.
Methods: AAV-Hnf1α vectors were administered intraductally to MODY3 mice. Biodistribution of vector genomes and Hnf1α expression, and key metabolic parameters were analyzed in these mice. Transcriptomic analysis of islets was also performed. Moreover, healthy beagle dogs were also administered intraductally with AAV vectors, and the AAV biodistribution in the pancreas and other key tissues examined.
Results: Treatment of MODY3 mice with AAV-Hnf1α resulted in vector genome copy number in the pancreas but restricted Hnf1α expression to islets. Moreover, comparative transcriptomic analysis in isolated islets revealed the restoration of the MODY3 pathway genes in treated mice. As a first step towards translation, intraductal delivery of AAV vectors to Beagle dog resulted in efficient transduction of pancreas, including endocrine cells, in the absence of adverse events or toxicities.
Conclusion: These results provide strong evidence of the efficacy of AAV-Hnf1α to treat MODY3 in mice and pave the way moving to the clinic this approach to treat MODY3 patients in the future.

Disclosure
E. Casana: None. V. Jimenez: None. M. Garcia: None. M. Jaén: None. A. Casellas: None. M. Morró: None. A. Pujol: None. T. Ferre: None. V. Sacristan: None. C. Jambrina: None. X. Leon: None. S. Franckhauser: None. F. Bosch: None.

Funding
This work was performed with the support of the Fundació La Marató de TV3 (Project 201603-31-32-33) and by grants SAF2017-86266R funded by Ministerio de Economía, Industria y Competitividad (MINECO), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional(FEDER, EU), Programa Estatal de I+D+i Orientada a los Retos de la Sociedad; grant PID2020-113864RB-I00 funded by MCIN/AEI/10.13039/501100011033, and 2017 SGR 1508, ICREA Academia Award to F.B. from Generalitat de Catalunya, Spain