bluuebunny/crossref_metadata_2025_split huggingface dataset:
442-P: Diabetic Foot Ulcer Amputation Is Associated with Two-Fold Increased Risk of Incident Cardiovascular Disease—A Korean National Health Information Database Study
Authors: YANG HYEWON , KIM BONGSEONG , JANG JINSUN , SON HEEJUN , SEUNG JUNG HYE , MIN CHO YOUNG , SOO PARK KYONG , HAN KYUNGDO , HEON KWAK SOO 
Published: June 2024

Diabetic Foot Ulcer (DFU), a critical complication of diabetes, impacts about 8% of individuals with diabetes and leads to a 20% risk of lower extremity amputation. People with DFU amputation are widely recognized to have an increased risk of cardiovascular disease (CVD) and mortality. However, previous studies have been limited by their small scale and cross-sectional design. The aim of this study was to quantify the risk of CVD and related mortality following DFU amputation, utilizing a large-scale prospective database.We included over 1.2 million individuals with diabetes who participated in nationwide health checkups from 2009 to 2012, with clams data linked through the Korean National Health Insurance Service. Incident CVD was defined as myocardial infarction (MI), stroke and cardiovascular mortality that occurred at least one year after a DFU amputation. Cox proportional hazard model was used to assess the risk of CVD in people with DFU amputation compared to those with diabetes but not amputated. Among 1,229,689 individuals with diabetes, 1,487 (0.12%) had a DFU amputation at baseline. Individuals with DFU tended to be older, predominantly male, and more often belong to the lower income 10%. During a median follow-up of 7.2 years (interquartile range 3.08), people with DFU amputation had a significantly higher incidence rate of CVD compared to those without DFU amputation (32.6 vs 11.0 per 1,000 person-years) with a hazard ratio (HR) of 1.8 (95% CI 1.6-2.1). Specifically, the HRs for MI and stroke were 2.2 (95% CI 1.9-2.6) and 1.6 (95% CI 1.4-1.8). Furthermore, CVD mortality significantly increased in people with DFU amputation compared to those without, with an HR of 2.11. (95% CI 1.9-2.3).Using a comprehensive nationwide health information database, we found that individuals with DFU amputation had up to a two-fold higher risk of CVD and associated mortality compared to those with diabetes but without DFU.

Disclosure
H. Yang: None. B. Kim: None. J. Jang: None. H. Son: None. H. Jung: Research Support; Novo Nordisk. Y. Cho: None. K. Park: None. K. Han: None. S. Kwak: Employee; SNUH Venture.

Funding
Funds of National Health Insurance Service and Korean Diabetes Association (2023-285)
446-P: Prognostic Role of Type 2 Diabetes Mellitus in Minor vs. Major Atherosclerosis
Authors: MADER ARTHUR , HAEBERLI DARIO , LARCHER BARBARA , DOPHEIDE JOERN F. , PLATTNER THOMAS , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , HEINZLE CHRISTINE , AMANN PETER , SCHINDEWOLF MARC , SAELY CHRISTOPH H. , DREXEL HEINZ 
Published: June 2024

The impact of diabetes on major cardiovascular events (MACE) in relation to the extent of pre-existing atherosclerotic disease remains unclear. In this study we compare the impact of T2DM on MACE in patients with two different states of atherosclerosis: minor coronary atherosclerosis (minAS) and peripheral artery disease, one of the most severe manifestations of major atherosclerosis (majAS). We included 1238 patients from two long-term prospective cohort studies. Patients underwent coronary angiography for the allocation to a control group without any lumen irregularities (n=332) or a minAS group with lumen irregularities but no significant coronary stenoses ≥50% at coronary angiography (n=425). Patients with sonographically proven peripheral artery disease were allocated to the majAS group (n= 481). Over a mean time-period of 7.7 years major cardiovascular events (MACE) were recorded. Overall, MACE were recorded in 681 (51%) patients. T2DM significantly increased the risk of MACE both among patients with minAS (22.0% vs. 32.4%; p=0.023) and majAS (50.6% vs. 67.1%; p&lt;0.001) but nut in the control group (12.0% vs. 12.1%; p=0.663). In majAS - patients who did not have T2DM, the risk of MACE was higher than that of T2DM patients with minAS (p&lt;0.001). Both T2DM (adjusted HR=1.78 [1.45-2.17], p&lt;0.001) and severity of atherosclerosis (adjusted HR=2.59 [2.18-3.10], p&lt;0.001) predicted MACE in a mutually independent manner. An interaction term severity of atherosclerosis x T2DM was not significant (p=0.364), indicating that the severity of pre-existing atherosclerosis did not impact the power of T2DM as a predictor of MACE. We conclude that T2DM confers an increased risk for MACE both in early and in advanced atherosclerotic states. The severity of pre-existing atherosclerosis does not impact the power of T2DM as a predictor of MACE.

Disclosure
A. Mader: None. D. Haeberli: None. B. Larcher: None. J.F. Dopheide: None. T. Plattner: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. C. Heinzle: None. P. Amann: None. M. Schindewolf: None. C.H. Saely: None. H. Drexel: None.
453-P: Remnant Cholesterol Predicts Major Cardiovascular Events in Coronary Artery Disease Patients with NAFLD
Authors: PLATTNER THOMAS , LARCHER BARBARA , MADER ARTHUR , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2024

Remnant cholesterol has attracted interest as a marker of cardiovascular event risk. The power of remnant cholesterol to predict major cardiovascular events (MACE) in patients with non-alcoholic fatty liver disease (NAFLD) is unclear and is addressed in the present study. We enrolled a high-risk cohort of 913 patients with coronary artery disease (CAD). NAFLD was diagnosed using the validated fatty liver index (FLI). Prospectively, MACE including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke were recorded over a mean follow-up period of 9.5±5.2 years. At baseline, remnant cholesterol was significantly higher in patients with NAFLD (n=419) than in patients who did not have NAFLD (30±28 mg/dl vs. 18±17 mg/dl; p&lt;0.001). During follow-up, 379 of our patients suffered MACE. Remnant cholesterol in Cox regression models adjusting for age, sex, hypertension, smoking, diabetes mellitus, body mass index and LDL cholesterol independently predicted MACE in the total study population (standardized adjusted HR 1.18 [1.08-1.30], p&lt;0.001), and both in patients with NAFLD as well as in those who did not have NAFLD (standardized adjusted HRs 1.19 [1.05-1.35], p=0.006 and 1.24 [1.03-1.49], p=0.023, respectively). From our data we conclude that remnant cholesterol is a predictor of MACE in patients with CAD with and without NAFLD.

Disclosure
T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
46-PUB: A Quantitative Framework for Evaluating the Performance of Whole-Population Remote Patient Monitoring for Type 1 Diabetes Care
Authors: KURTZIG JAMIE , SCHEINKER DAVID 
Published: June 2024

Introduction: Care providers continue to adopt platforms that enable remote patient monitoring (RPM) for type 1 diabetes (T1D) care through the algorithmic analysis of continuous glucose monitor (CGM) data. No provider-facing quantitative framework is available to track how the use of such platforms impacts patient care and healthcare provider workload. We propose such a framework.
Methods: We used data from four sub-studies (n=127, 137, 136, 95) of whole-population algorithm-enabled RPM for T1D in Stanford’s pediatric Teamwork, Targets, Technology, and Tight Control (4T) Study. We used HbA1c measurements, CGM data, time studies of care providers, and secure messages sent by care providers to patients and families. We iteratively analyzed data and interviewed care providers to identify metrics relevant to whole-clinic and whole-population patient care and healthcare provider workloads. We developed an interactive dashboard to facilitate monitoring these metrics.
Results: The metrics identified were: the numbers of patients (1) in the overall program, (2) in each sub-study, (3) cared for by each care provider, (4) meeting criteria for review or care in each clinical category, (5) in each clinical category by care provider, (6) in each clinical review category by sub-study, and (7) each patient’s most recent date of being eligible for review by care providers.
Conclusion: We propose the first quantitative framework for healthcare organizations to supervise and enhance algorithm-enabled whole-population T1D care. As the role of digital care platforms continues to increase, this framework may help clinics manage and improve their programs.

Disclosure
J. Kurtzig: None. D. Scheinker: None.
462-P: Medication Documentation in Patients with Type 2 Diabetes Undergoing Coronary Angiography
Authors: ELSNER PASCAL , RATZ MAGDALENA , VOGEL JOHANNES , SAELY CHRISTOPH H. , PLATTNER THOMAS , MADER ARTHUR , LARCHER BARBARA , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ 
Published: June 2024

The utilization of multiple medications and the increasing complexity of medication regimens associated with chronic diseases such as type 2 diabetes (T2DM) necessitate the implementation of a medication documentation (MD). A complete medication plan serves to enhance medication safety and promotes adherence. The availability of MD in the clinically important population of T2DM patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD) remains unknown and is addressed in the present study. We analyzed MD, current medication status, and the Medication Regimen Complexity Index (MRCI) in 515 consecutive patients who underwent coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Our cohort included 177 patients (34%) with T2DM and 338 patients (66%) without diabetes. Patients with T2DM compared to those without diabetes had a significantly higher number of medications (7 [5-9] vs. 5 [3-6]; p&lt;0.001) and a significantly higher complexity in medication regimens (17 [11-24] vs. 12 [7-16]; p&lt;0.001). Specifically, out of 104 (59%) T2DM patients, MD was available, while 73 (41%) lacked MD. Further classification showed the following categories of MD in patients with diabetes: unstructured documentation in 28 (27%), physician’s letter in 17 (16%), medication plan in 58 (56%) and other categories in 1 (1%). We conclude that patients with T2DM who undergo coronary angiography for the evaluation of established or suspected stable CAD are affected by a high medication complexity and polypharmacy, which highlights the importance of an accurate MD in these patients. However, proper MD is not available in almost half of these patients.

Disclosure
P. Elsner: None. M. Ratz: None. J. Vogel: None. C.H. Saely: None. T. Plattner: None. A. Mader: None. B. Larcher: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
466-P: Therapeutic Efficacy of Monthly Semaglutide-Loaded Microsphere Injections in Zucker Diabetic Fatty Rats
Authors: PARK JIWON , KIM CHERNGJU , AN TAEKUN 
Published: June 2024

Introduction: This study aimed to develop semaglutide-loaded microsphere monthly injectables using a novel biodegradable microsphere manufacturing technology, and to compare its therapeutic efficacy with both semaglutide solution, administered weekly injectables, and semaglutide microsphere, administered monthly injectables, in male Zucker diabetic fatty (ZDF) rats and ZDF lean control rats.
Methods: Semaglutide microsphere was prepared by water-in-oil-in-water (w/o/w) emulsion solvent evaporation method using poly(D, L-lactide-co-glycolide) (PLGA). Therapeutic efficacy was evaluated by measuring blood glucose in both Zucker diabetic fatty (ZDF) and ZDF lean control rats. Subcutaneous administrations were performed once for the Semaglutide microsphere and vehicle control groups, while the Semaglutide solution was administered four times at weekly intervals.
Results: The Semaglutide microsphere significantly decreased blood glucose concentration compared to both the vehicle and semaglutide solution groups for four weeks, resembling levels in the lean control group (100 mg/dL) (Figure 1).
Conclusion: The Semaglutide microsphere injectables, administered monthly, showed the potential to substantially reduce the frequency of administrations compared to the commercial product, Ozempic® and Wegovy®, thereby potentially enhancing patient compliance.

Disclosure
J. Park: None. C. Kim: None. T. An: None.
467-P: Type 2 Diabetes and Chronic Kidney Disease as Predictors of Cardiovascular Events in Patients with Coronary Artery Disease
Authors: PLATTNER THOMAS , LARCHER BARBARA , MADER ARTHUR , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2024

This study aims to investigate the single and joint effects of T2DM and CKD on cardiovascular events in patients with coronary artery disease (CAD). We prospectively investigated 1044 patients with CAD over 8.5±5.0 years. Cardiovascular events occurred more frequently in T2DM patients (n=347) than in nondiabetic subjects (60.1% vs 50.6%, p=0.004) and in patients with CKD (eGFR&lt;60ml/min/1.73m2; n=192) than in those without CKD (64.7% vs 51.2%, p&lt;0.001). When both T2DM and CKD were considered, 586 subjects had neither T2DM nor CKD, 266 had T2DM but not CKD, 111 did not have diabetes but had CKD, and 81 had T2DM and CKD. Compared to the incidence of cardiovascular events among patients with neither T2DM nor CKD (49.6%), cardiovascular events were not significantly increased in patients with T2DM who did not have CKD (54.9%; p=0.121) or in nondiabetic patients with CKD (55.9%; p=0.298); however, the incidence of cardiovascular events was significantly increased in patients with the combination of T2DM and CKD (77.2%; p&lt;0.001), in whom it was higher than in those with T2DM but not CKD (p&lt;0.001) or those without T2DM but with CKD (p=0.001). In Cox regression analysis, T2DM (HR 1.31 [1.09-1.57]; p=0.004) and CKD (HR 1.32 [1.05-1.64]; p=0.016) proved to be mutually independent predictors of cardiovascular events after multivariate adjustment for age, sex, BMI, history of smoking, hypertension, LDL-C and HDL-C. We conclude that T2DM and CKD in patients with CAD are mutually independent predictors of cardiovascular events. CAD patients with both CKD and T2DM are at an extremely high risk for cardiovascular events.

Disclosure
T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
468-P: Association between Sudomotor Function and Coronary Atherosclerosis in Patients with Type 2 Diabetes
Authors: XU HUAN , CHEN XUEYAN , PENG JIE , TANG XIAOYUN , SHUI XING , YAN JINHUA , XU WEN , YAO BIN , DENG HONGRONG , YANG XUBIN 
Published: June 2024

Object: This study aims to investigate the relationship between sudomotor function and coronary atherosclerosis in patients with type 2 diabetes.
Methods: A total of 147 patients with type 2 diabetes were enrolled (64.60% male, 59.58±10.20 years). Using sudoscan detector to assess the mean electrochemical skin conductance (ESC). Patients were divided into three groups according to the mean hands and feet ESC: sudomotor severe dysfunction group (SDF: ESC &lt; 40μS), sudomotor moderate dysfunction group (MDF: 40μS ≤ ESC ≤60μS) and normal sudomotor function group (NSF: ESC &gt; 60μS). The severity of coronary atherosclerosis was determined according to Gensini score.
Results: Gensini score was significantly different among the three groups, with an increasing trend from NSF to MDF and SDF[3.50(0.00, 12.00) vs. 6.50(2.13, 12.25) vs. 10.50(4.86, 22.75), P=0.010]. Spearman correlation analysis revealed a negative correlation between the Gensini score and hand ESC (r=-0.2, P=0.013). After adjusting for confounding factors, multiple linear regression analysis indicated that ESC was significantly associated with coronary atherosclerosis (OR=0.100, 95% CI: 0.012-0.875, P=0.038).
Conclusions: In patients with type 2 diabetes, the severity of coronary atherosclerosis increased with impaired sudomotor function, and sudomotor dysfunction is independently associated with coronary atherosclerosis.

Disclosure
H. Xu: None. X. Chen: None. J. Peng: None. X. Tang: None. X. Shui: None. J. Yan: None. W. Xu: None. B. Yao: None. H. Deng: None. X. Yang: None.

Funding
Natural Science Foundation of Guangdong Province (2018A030313915); Medical Scientific Research Foundation of Guangdong Province of China (A2018286).
474-P: Novel Changes in Chromatin 3D Architecture under Diabetic Conditions in Human Macrophages
Authors: REDDY MARPADGA A. , BHATTACHARYA SUPRIYO , TANWAR VINAY S. , MALEK VAJIR , ZHANG LINGXIAO , LANTING LINDA L. , PANDEY PRIYATAMA , CHEN ZHUO , WU XIWEI , NATARAJAN RAMA 
Published: June 2024

Aberrant activation of monocytes and macrophages in diabetes increases chemokines and cytokines associated with chronic inflammation and diabetic vascular complications like atherosclerosis and nephropathy. Epigenetic mechanisms are implicated; however, the chromatin 3D reorganization during macrophage activation in diabetes is unclear. We examined chromatin architecture in human CD14+ monocytes (from healthy volunteers) differentiated into macrophages and treated with High glucose +TNF-α (HT, 72 h) versus normal glucose using HiChIP and ChIP-seq with H3K27ac antibody (enhancer mark) and integrated these datasets with gene expression (RNA-seq) and chromatin-accessibility (ATAC-seq) data. We found HT induced dramatic changes in transcriptional programs that regulate inflammatory pathways similar to CD14+ monocytes from diabetic volunteers. HT promoted extensive changes in open chromatin (OC) and chromatin loops between enhancers and other regulatory elements and disrupted transcriptionally active/inactive (A/B) genomic compartments and topologically associating domains. Upregulated inflammatory genes were associated with increased OC and promoter-enhancer loops, which were reduced at downregulated cell cycle genes. We identified key pro-inflammatory transcription factor motifs enriched in OC/chromatin loops, and interactions between distal enhancers and promoters of chemokine, cytokine, and upstream signaling genes. ChIP and 3C assays confirmed HT-induced H3K27ac at distal enhancers and enhancer interactions with the CCL2 and IRAK2 promoters. Moreover, HT-induced enhancers harbored SNPs linked with type 2 diabetes. These results reveal unique rewiring of the epigenome and chromatin 3D architecture by HT, which likely promotes macrophage activation in diabetes. They can reveal potential targets for epigenetic therapies to mitigate chronic inflammatory diabetes complications.

Disclosure
M.A. Reddy: None. S. Bhattacharya: None. V.S. Tanwar: None. V. Malek: None. L. Zhang: None. L.L. Lanting: None. P. Pandey: None. Z. Chen: None. X. Wu: None. R. Natarajan: None.

Funding
NIH RO1 DK065073, Arthur Riggs Diabetes and Metabolism Research Institute Endowment
48-OR: Novel Lipidated Interleukin-22 Reduces Body Weight and Improves Glucose Homeostasis in Mice
Authors: VAN DE BUNT MARTIJN , LOUISE KJØLBYE ANNE , JORGENSEN RASMUS 
Published: June 2024

Introduction & Objective: Developing novel therapeutics is critical to provide additional treatment options and improve long‑term outcomes for patients with obesity and diabetes. The atypical cytokine interleukin-22 (IL-22) which acts on epithelial cells has shown a range of metabolic benefits. Here we demonstrate efficacy of a novel long-acting lipidated IL-22 agonist on reducing body weight and improving key metabolic parameters in mice.
Methods: The effect of lipidated IL-22 on obesity at 2 dose levels was investigated in two diet-induced obese (DIO) models - one at standard conditions and one at thermoneutrality including energy expenditure measurements while diabetic db/db mice were used to determine the effect of 3 dose levels on glucose homeostasis.
Results: Lipidated IL-22 dosed for 5 weeks resulted in a dose-dependent reduction in body weight (-7.7%, and -20.2%) compared to vehicle (-1.1%) in DIO mice accompanied by a dose-dependent reduction in food intake. However, the effect of IL-22 was partly food intake independent as weight-matched control animals consumed 16% less food than the lipidated IL-22 comparator group. EchoMRI showed more fat mass loss and less lean mass loss in the lipidated IL-22 group compared to its weight-matched control. Lipidated IL-22 did not increase energy expenditure compared to vehicle at week 1 and 4 in the DIO study at thermoneutrality. In db/db mice, IL-22 dose dependently reduced plasma glucose and %HbA1c at termination (-1.0, -1.3 and -1.7 compared to vehicle). This was accompanied by a dose-dependent improvement in HOMA-IR, in line with the significant reduction in fasting insulin observed in the DIO mice.
Conclusion: A novel long-acting lipidated IL-22 significantly reduced body weight and improved glucose homeostasis through a novel mode-of-action in a variety of mouse models. Safety and tolerability of lipidated IL-22 in humans is currently being investigated in a Phase 1 trial.

Disclosure
M. van de Bunt: Employee; Cytoki Pharma. A. Kjølbye: Employee; Cytoki Pharma. R. Jorgensen: Employee; Cytoki Pharma. Stock/Shareholder; Cytoki Pharma.
482-P: SCS for Painful DPN—Consistent Outcomes from Multiple RCTs and Real-World Data
Authors: BODE BRUCE W. , MURPHY MELISSA , VIGERSKY ROBERT A. , JOHANEK LISA , MARTINEZ MARLON , MARQUEZ ADRIAN , COLETTI FILIPPO , LARUE MADDIE 
Published: June 2024

Painful diabetic peripheral neuropathy (DPN) is treated medically with antineuralgics, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors which are often not satisfactory long-term. Spinal Cord Stimulation (SCS) is an effective treatment alternative per 3 randomized controlled trials (RCTs) which consistently demonstrate that SCS is more effective than conventional medical management for painful DPN treatment. To assess “real-world” SCS efficacy for painful DPN, we qualitatively looked for consistency in outcomes between published RCT results and patient-reported outcomes collected using a digital health platform. We retrospectively analyzed demographics and characterized pain profiles using PROMIS-29 (Patient-Reported Outcomes Measurement Information System®) surveys at baseline to 3-month follow-up. Between Oct-2022 and Jul-2023, 295 DPN patients underwent SCS device trials while using the digital health platform, with 69.2% receiving a permanent implant. At the time of submission, paired data at baseline and 3-mo was available for 20 patients. The data shows significant improvement in 6 of the 7 functional domains of the PROMIS-29 survey (Table 1). These findings suggest SCS can provide significant improvement in DPN pain-related symptoms. Collectively, robust published outcomes from 3 RCTs in combination with real-world data support the efficacy of SCS for painful DPN.

Disclosure
B.W. Bode: Research Support; Omnipod. Speaker's Bureau; Omnipod. Research Support; Medtronic. Advisory Panel; Medtronic. M. Murphy: Advisory Panel; Medtronic. Consultant; Relievant. R.A. Vigersky: Employee; Medtronic. L. Johanek: Employee; Medtronic. M. Martinez: Employee; Medtronic. A. Marquez: Employee; Medtronic. F. Coletti: Employee; Medtronic. M. LaRue: Employee; Medtronic.

Funding
This study was sponsored by Medtronic.