Korea Health Industry Development Institute Research Articles

4-OR: Oxidative Phosphorylation in Kidney-Resident Macrophages Aggravates the Progression of Diabetic Kidney Disease

Introduction and Objective: Oxidative phosphorylation (OXPHOS) is a hallmark alteration in the diabetic kidney. However, it remains unclear whether this change occurs in kidney-resident macrophages (KRMs) and how this condition contributes to the progression of diabetic kidney disease (DKD). Methods: We investigated OXPHOS-related transcriptomic changes in KRMs within diabetic kidneys using single-cell RNA sequencing data derived from human kidneys. We assessed OXPHOS expression in KRMs and its associated renal immunological alterations in DKD mouse models induced by high-fat diet, streptozotocin, and adenine-mixed diet, particularly under conditions of augmented inflammation. Results: Single-cell RNA sequencing analysis revealed increased OXPHOS alteration in KRMs of diabetic kidneys compared to nondiabetic controls. These findings were validated through the examination of OXPHOS-related protein expression in biopsy-proven diabetic nephropathy samples, where enhanced OXPHOS expression correlated with accelerated DKD progression. In DKD mouse models, elevated OXPHOS expression in diabetic KRMs promoted T cell infiltration into the kidneys through the overexpression of chemokine ligands and proinflammatory cytokines. Inhibition of OXPHOS reduced T cell infiltration and mitigated the decline in renal function. Conclusion: Elevated OXPHOS expression in KRMs is a defining feature of diabetic kidneys, fostering a proinflammatory milieu through T cell infiltration. Targeting OXPHOS in KRMs may serve as a potential therapeutic strategy for DKD. Disclosure H. Yoon: None. P. Park: None. J. Hwang: None. M. Hong: None. B. Jang: None. C. Kang: None. D. Yun: None. S. Han: None. Funding Korea Health Industry Development Institute (HI23C1531)

0591 Application of Decentralized Clinical Trial to Validate the Efficacy of Digital Therapeutics for Insomnia

Abstract Introduction Cognitive behavioral therapy for insomnia (CBT-I) has proven to be an effective treatment, however, its accessibility is limited. To address this issue, digital therapeutics for insomnia (DTx-I) have emerged as potential solution to enhance access. We have opted to conduct a decentralized clinical trial (DCT) which can minimize the necessity for participants to in-person hospital visits. This study aimed to evaluate the clinical efficacy of a proprietary DTx-I, “WELT-I”, and assess the feasibility and utility of DCTs for validating DTx-I. Methods A double-blind, sham-controlled randomized DCT was conducted with 68 participants meeting DSM-5 criteria for insomnia (n=33 for WELT-I group, n=35 for control group). Sleep metrics and self-reported psychiatric questionnaires, including dysfunctional beliefs and attitudes about sleep (DBAS-16), were measured over 7 weeks. All trial procedures except one on-site visit for written consent were conducted remotely. The primary outcome for efficacy was sleep efficiency. For the utility of DCTs, time to reach recruitment goal, retention rates, and participants’ satisfaction were evaluated. Results WELT-I significantly improved sleep efficiency compared to the sham app (least square difference=8.28, p value=0.04) and DBAS-16 score (least square difference=-1.03, p value=0.01). Recruitment was completed within 73 days, with a retention rate of 82.14% and a mean satisfaction score of 7.21 out of 10. Conclusion This study provides evidence that WELT-I, a CBT-I-based digital therapeutics, is a safe and effective approach to managing insomnia disorder. The DCT approach enabled rapid recruitment, high retention, and strong participant satisfaction, highlighting its potential as a scalable and efficient method for validating DTx-I. Support (if any) The present study was supported by the National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning, Republic of Korea, under grant number 2022R1A2B5B03002611 (Eun Lee); the Daegu-Gyeongbuk Medical Innovation Foundation under grant number B0081115000708 (Eun Lee); the Korea Health Industry Development Institute under grant number RS-2023-00266002 (Eun Lee); and Korea Medical Device Development fund, under grant number RS-2023-00255005 (Kyung Mee Park). The funding sources were not involved in study design, data collection, analysis, decision to publish, or manuscript preparation.

0681 It’s the Heart: Novel Subtype of Obstructive Sleep Apnea Syndrome Using Oxygen Saturation and Heart Rate

Abstract Introduction Studies predicting survival using the apnea-hypopnea index (AHI) have not produced consistent results in Obstructive sleep apnea syndrome (OSAS) patients. Authors conducted this study to subtype OSAS using heart rate and oxygen saturation, which reflect cardiac health that has a significant impact on survival. Methods We conducted the study using the PSG and clinical information of the sleep heart health study dataset (Quan SF, et al., 1997). Only subjects with an AHI ≥ 5/hour on the first PSG were included in the analysis. K-means clustering was performed using the variance of oxygen saturation and heart rate during sleep after the uniform manifold approximation projection (UMAP). We also calculated a brain age index using electroencephalography channel (C3A2) (Sun H, et al., 2019). Cox proportional hazard analysis was performed using the cluster revealed along with the other variables (gender, age, body mass index [BMI], AHI, and brain age index). Results 4803 subjects (male 52.3%, 64.2 [standard deviation, SD 11.1] year-old at the first visit) were included in the analysis. We revealed distinctive 2 clusters (average silhouette score = 0.44, Calinski-Harabasz score = 6837.92). Cluster 2 (n=2688, male 56.2%, 64.9 [SD 10.8] year-old) showed lower BMI, AHI, average heart rate, and higher average oxygen saturation compared to cluster 1 (n=2089, male 47.4%, 63.4 [SD 11.3] year-old). In the cox proportional hazard model, each variable showed the following hazard ratio (HR) and 95% confidence interval (95% CI): cluster 2 (0.70 [95% CI 0.62, 0.79]), male gender (1.43 [95% CI 1.27, 1.62]), age (1.13 [95% CI 1.12, 1.13]), BMI (0.99 [95% CI 0.98, 1.00]), AHI (1.00 [95% CI 1.00, 1.01]), brain age index (1.02 [95% CI 1.01, 1.03]). Conclusion Authors identified the novel subtype of OSAS using variance of heart rate and oxygen saturation in PSG. And that have a greater impact on survival prognosis than AHI and brain age index reported in previous studies. Support (if any) A grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-00267049)

Multicenter validation of a machine learning model to predict intensive care unit readmission within 48 hours after discharge.

Multicenter validation of a machine learning model to predict intensive care unit readmission within 48 hours after discharge.

Optimising efficiency and patient-centredness in general hospitals: insights from data envelopment and matrix analysis.

Medical institutions face management challenges from intense competition and an unclear link between patient-centredness and profitability. This study examined the association between efficiency and patient-centredness in general hospitals and identified management strategies to optimise both. Data from the 2021 patient experience evaluation by the Health Insurance Review and Assessment Service and financial statements from the Korea Health Industry Development Institute for general hospitals in South Korea were used. Efficiency scores and patient-centredness were determined for 256 general hospitals using data envelopment analysis (DEA), and their relationships were analysed through matrix analysis. The Kruskal-Wallis and Mann-Whitney tests assessed group differences identified through matrix analysis. Efficiency and patient-centredness can be improved concurrently. Hospitals in the highest efficiency group reported significantly higher average inpatient revenue per 100 beds (179.67) and net profit (158.84) than those in lower-performing groups (p<0.001). Optimal management of hospital beds and specialised diagnostic equipment per 100 beds was associated with higher efficiency scores, while a greater number of doctors and nurses positively influenced patient-centredness metrics. Therefore, general hospitals should invest in personnel and resources to enhance efficiency and patient-centredness, achieving optimal financial and operational outcomes. This study combines DEA and matrix analysis to explore the link between hospital efficiency and patient-centredness, using recent data on patient experience and financials from South Korean hospitals. It identifies strategies to enhance both dimensions.

Tumor-Primed CD3+CD56+ natural Killer T-like Cells As an Efficient Novel Cell Therapy for Relapsed/Refractory Multiple Myeloma

Tumor-Primed CD3+CD56+ natural Killer T-like Cells As an Efficient Novel Cell Therapy for Relapsed/Refractory Multiple Myeloma

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

위치 상황 기반 보완대체의사소통의 자원 계층 구조와 상황 전환 사용자 인터페이스 개발

Background and Objectives: For people who have difficulties in language, locationbased Augmentative and Alternative Communication (AAC) mobile applications recommend AAC symbols based on their location to assist communication in daily life. Using AAC symbols available at a specific location with smart devices having small screens requires additional actions like swiping, which can be burden for [This research was supported by a grant of the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (grant number : HJ21C0007). This research extends the poster presentation of ‘An AAC Board Hierarchy and User Interface for Communication Situation Switching in Location-Based AAC’ in ‘The 3rd East Asian Regional Conference on Augmentative and Alternative Communication: AAC Beyond Pandemic’ of Korean Society of Augmentative and Alternative Communication (KSAAC). Correspondence to Ki-Hyung Hong, Ph.D., Department of Service Design Engineering, Sungshin Women’s University, Seoul, Korea, e-mail: khhong@sungshin.ac.kr, tel: + 82 2 920 7525] AAC users. This study aims to make it easier for AAC users to explore symbols and improve efficiency of facilitation by reusing AAC resources. Method: We define AAC situation boards as collections of AAC symbols specifically needed for certain communication situations. Group AAC boards, on the other hand, are collections of AAC symbols that belong to the same categories. We designed a hierarchy to allow these situation and group AAC boards to be included as sub-boards in general and location AAC boards. We also developed a user interface that allows facilitators to manage AAC resources based on the hierarchy. The interface makes it easy for AAC users to select appropriate AAC symbols for the current situation through a situation-based symbol circulation and switching method. Result &amp; Conclusion: We enhanced and expanded location and situation-based AAC mobile applications by utilizing a hierarchy of AAC resources and integrating a user interface for efficient management and utilization of these resources. To assess its usability, we conducted a user evaluation involving 44 facilitators. The results of the evaluation indicate that the location and situation-based AAC mobile application, with its ability to switch situations based on the AAC resource hierarchy, received high ratings in terms of satisfaction, convenience, and stability.

위치 상황 기반 보완대체의사소통의 자원 계층 구조와 상황 전환 사용자 인터페이스 개발

Background and Objectives: For people who have difficulties in language, locationbased Augmentative and Alternative Communication (AAC) mobile applications recommend AAC symbols based on their location to assist communication in daily life. Using AAC symbols available at a specific location with smart devices having small screens requires additional actions like swiping, which can be burden for [This research was supported by a grant of the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (grant number : HJ21C0007). This research extends the poster presentation of ‘An AAC Board Hierarchy and User Interface for Communication Situation Switching in Location-Based AAC’ in ‘The 3rd East Asian Regional Conference on Augmentative and Alternative Communication: AAC Beyond Pandemic’ of Korean Society of Augmentative and Alternative Communication (KSAAC). Correspondence to Ki-Hyung Hong, Ph.D., Department of Service Design Engineering, Sungshin Women’s University, Seoul, Korea, e-mail: khhong@sungshin.ac.kr, tel: + 82 2 920 7525] AAC users. This study aims to make it easier for AAC users to explore symbols and improve efficiency of facilitation by reusing AAC resources. Method: We define AAC situation boards as collections of AAC symbols specifically needed for certain communication situations. Group AAC boards, on the other hand, are collections of AAC symbols that belong to the same categories. We designed a hierarchy to allow these situation and group AAC boards to be included as sub-boards in general and location AAC boards. We also developed a user interface that allows facilitators to manage AAC resources based on the hierarchy. The interface makes it easy for AAC users to select appropriate AAC symbols for the current situation through a situation-based symbol circulation and switching method. Result &amp; Conclusion: We enhanced and expanded location and situation-based AAC mobile applications by utilizing a hierarchy of AAC resources and integrating a user interface for efficient management and utilization of these resources. To assess its usability, we conducted a user evaluation involving 44 facilitators. The results of the evaluation indicate that the location and situation-based AAC mobile application, with its ability to switch situations based on the AAC resource hierarchy, received high ratings in terms of satisfaction, convenience, and stability.

920-P: Sodium–Glucose Cotransporter 2 Inhibitor Use and Risk of Dementia and Parkinson’s disease among Patients with Type 2 Diabetes—A Longitudinal, Nationwide, Population-Based Cohort Study

The efficacy of sodium-glucose cotransporter 2 inhibitor (SGLT2i) in neurologic disorders is not well-established. This study aimed to investigate the association of SGLT2i use with risks of incident dementia and Parkinson’s disease (PD) in patient with type 2 diabetes. Subjects aged ≥ 40 years, diagnosed with type 2 diabetes, and who started antidiabetic drugs from 1 September 2014 and 31 December 2019 were evaluated, using the National Health Insurance Service Database. Propensity score matching (1:1; SGLT2i to other oral antidiabetic drugs [OAD]) produced a cohort of 358,862. Primary outcomes were a composite of dementia from any cause (Alzheimer’s disease [AD], vascular dementia [VaD], and other dementia) and PD. From the 358,862 participants analyzed (mean age, 57.8 years; 57.9% male), 6,837 incident dementia or PD events occurred. Overall, use of SGLT2i was associated with a 22% lower risk for the composite of dementia from any cause and PD than use of other OADs (adjusted HR [aHR], 0.78 [95% CI 0.73─0.83]) with a 6-month lag period. Regarding the individual endpoints, SGLT2i use was associated with reduced risks for AD (aHR, 0.81 [95% CI 0.76─0.87]), VaD (aHR, 0.69 [95% CI 0.60─0.78]), and PD (aHR, 0.80 [95% CI 0.69─0.91]). In this nationwide population-based cohort study, SGLT2i use significantly reduced the risks for dementia and PD in patients with type 2 diabetes independent of various factors including comorbidities and bioclinical parameters. Disclosure H. Kim: None. G.J. Biessels: None. M. Yu: None. J. Bae: None. A. Choi: None. M. Lee: Other Relationship; JW Pharmaceutical Corporation, Boryung Corporation, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., HK inno.N, Servier Korea, Handok Inc., Daewoong Pharmaceutical, KUKJE PHARM CO., LTD, GC Biopharma Corporation. Funding Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (HR22C141104)2); 'SENTINEL (Severance Endocrinology daTa scIeNcE pLatform)’ program funded by the 2020 Research fund of Department of Internal Medicine, Severance Hospital; Sung-Kil Lim Research Award (4-2018-1215; DUCD000002); Yonsei University College of Medicine (6-2020-0155)

426-P: Association of Succinate and Adenosine Nucleotide Metabolic Pathways with the Progression of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus

Introduction &amp; Objective: The prevalence of diabetic kidney disease (DKD) is increasing, and biomarkers that can enhance prognosis beyond renal function and albuminuria are rare. This study aimed to evaluate the potential of adenosine, succinate, and their related pathways, including hyaluronic acid (HA), as predictors of DKD progression. Methods: We examined 230 participants categorized as healthy controls, DKD non-progressors, and rapid progressors. Eligible patients with diabetes had at least five prior urine creatinine measurements during a median of 5.8 years of follow-up. Using previously collected eGFR data, rapid progressors were identified based on a decline in eGFR (ΔeGFR/year ≤−3 mL/min/1.73 m2/year or annual rate of eGFR decline ≥ 3.3%) before enrollment. At the end of the cohort, we measured the concentrations of urinary adenosine, succinate, HA, and serum cluster of differentiation 39 (CD39) and CD73, which are involved in adenosine generation. Associations between eGFR, ΔeGFR, and albuminuria were analyzed after adjusting for DKD progression risk factors. Results: Urinary succinate and serum CD39 levels were more elevated in rapid progressors compared to controls and non-progressors. This trend persisted when using the percentage criterion (≥40% decline in eGFR) for renal disease progression. Correlation analysis consistently linked urinary succinate and serum CD39 concentrations with eGFR at enrollment, ΔeGFR and albuminuria. However, among the various metabolites studied, multivariate regression analysis identified urinary succinate as an independent metabolite of rapid DKD progression and albuminuria. Conclusion: Among several potential metabolites, only urinary succinate exhibited associations with rapid DKD progression. Disclosure I. Jung: None. S. Nam: Consultant; HieraBio Inc., Korea, Republic of. S. Park: None. D. Lee: None. J. Yu: None. J. Seo: None. D. Lee: None. N. Kim: None. Funding This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2023R1A2C2003479) and the Bio &amp; Medical Technology Development Program of the NRF funded by MSIT (NRF-2019M3E5D3073102). This study was also supported by a National IT Industry Promotion Agency (NIPA) grant funded by the MSIT (No. S0252-21-1001, Development of AI Precision Medical Solution (Doctor Answer 2.0)) and a Korea Health Industry Development Institute (KHIDI) grant funded by the Ministry of Health &amp; Welfare of Korea (No. HI16C1997 and No. HI23C0679).

1615-P: Adrenal Gland Volume and Development of Type 2 Diabetes Using Deep Learning Techniques

Objectives: Current insights into the dynamic between adrenal gland volume (AGV) and changes in blood glucose levels are insufficiently explored. This research aims to establish an association between AGV, evaluated through a deep learning-based method, and the risk of developing type 2 diabetes (T2D). Research Design and Methods: Our study included an analysis of 9,708 adults who underwent abdominopelvic CT scans during health examinations between 2011 and 2012. Eligibility for the study was contingent on the absence of adrenal nodules in participants. We obtained AGV measurements from CT scans using a three-dimensional nnU-Net deep learning framework. The research approach to understanding the AGV-T2D relationship was designed to be both cross-sectional and longitudinal. Results: The AI model demonstrated notable precision in segmenting the adrenal gland, with a correlation coefficient of 0.71 (standard deviation [SD], 0.11) and an average volume discrepancy of 0.6 mL (SD 0.9) in an external dataset. At the outset, individuals with T2D showed higher AGV compared to those without T2D (7.3 vs. 6.7 cm³ in males and 6.3 vs. 5.5 cm³ in females, all P &amp;lt;0.05). Furthermore, AGV was positively correlated with various metabolic factors, including waist size, area of abdominal visceral fat, triglyceride-glucose index, and levels of glycated hemoglobin. We determined optimal AGV cutoffs for T2D prediction to be 7.2 cm³ for males and 5.5 cm³ for females. Following a median 7-year observation period, 938 subjects were diagnosed with T2D. A significant observation was that individuals with higher AGV faced a greater cumulative risk of developing T2D, this finding remained significant after controlling for other known risk factors (hazard ratio [95% confidence interval], 1.268 [1.105-1.455]). Conclusions: In summary, AGV evaluated using deep learning techniques demonstrated a significant association with current diabetes status and can be considered a reliable predictor for T2D. Disclosure E. Ku: None. S. Yoon: Stock/Shareholder; MEDICAL IP. S. Park: None. J. Kim: None. J. Yoon: None. Funding This study was supported by the National Research Foundation of the Ministry of Science and ICT of Korea (Project No. NRF-2020R1C1C1010723) and a grant from the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare of the Republic of Korea (Project No. HI21C0032 and HI22C0049).

913-P: Risk of Dementia in Diabetes Patients Aged Less than 70 Years Initiating Sodium–Glucose Cotransporter-2 Inhibitor vs. Dipeptidyl-Peptidase-4 Inhibitor

Objective: To compare the risk of dementia associated with sodium glucose co-transporter 2 inhibitor (SGLT2i) versus dipeptidyl peptidase 4 inhibitor (DPP4i) among relatively young patients with type 2 diabetes (T2DM) patients. Methods: We conducted a population-based cohort study using 2010-2021 Korea National Health Insurance Service database on T2DM patients aged ≥40 and ≤70 years initiating SGLT2i versus DPP4i. The primary outcome was new onset dementia based on diagnosis codes. Secondary outcomes were dementia requiring medications, individual types of dementia, genital infection (positive control), and osteoarthritis encounter (negative control). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Fine-Gray models adjusting for competing risk of death, after a 1:1 ratio propensity-score (PS) matching for &amp;gt;110 potential baseline confounders. Subgroup analyses were done by age, sex, concurrent metformin use, and baseline cardiovascular risk. Results: 110,885 PS-matched pairs of SGLT2i and DPP4i initiators were included. The mean follow-up time (standard deviation) were 670 days (650) with 1,172 new cases of dementia. The incidence rate was 0.22 in SGLT2i initiators and 0.35 in DPP4i initiators per 100 person-years, with the corresponding HR (95% CI) of 0.65 (0.57-0.73) for dementia, 0.57 (0.49-0.67) for dementia with medications, 0.63 (95% CI 0.55-0.72) for Alzheimer dementia, and 0.53 (95% CI 0.36-0.77) for vascular dementia. We observed a 2.45 times risk of genital infection with SGLT2i and near-null association for osteoarthritis encounter. The benefits were consistent across subgroups, and after accounting for lag times, but greater beyond than within 2 years of treatment. Conclusion: Among patients with T2DM, SGLT2i may reduce the risk of dementia. Disclosure A. Shin: None. B. Koo: None. J. Lee: None. E. Kang: None. Funding This study was supported by the grant from the Korea Health Industry Development Institute (KHIDI)-AZ Diabetes Research Program (#08-2022-0261).

1400-P: Hepatic Effectiveness of SGLT2 Inhibitors in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated promising effects on liver outcomes. However, comprehensive evidence regarding liver outcomes in direct comparison with thiazolidinediones (TZD) and glucagon-like peptide-1 receptor agonists (GLP1RA), which are recommended in guidelines for patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), is still lacking. Using health insurance claims data from South Korea, we established two pairwise 1:1 propensity score (PS)-matched cohorts who initiated SGLT2i, GLP1 RA (cohort #1, median age=57 years, 60% male), or TZD (cohort #2, median age=57 years, 72% male) between January 2014 and December 2022. The primary outcome was a composite of hepatic decompensation events, including ascites, esophageal varices with bleeding, hepatic failure, or liver transplant. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. In cohort #1, compared to GLP1RA, SGLT2i showed a similar risk of hepatic decompensation events (HR 0.92, 95% CI 0.76-1.12). In cohort #2, compared to TZD, SGLT2i demonstrated a reduced risk of hepatic decompensation events (HR 0.77, 95% CI 0.72-0.82). In this nationwide cohort study, SGLT2i was associated with a reduced risk of hepatic decompensation events in patients with NAFLD and T2D compared to TZDs, showing similar effectiveness to GLP1RA. Disclosure S. Bea: None. H. Ko: None. J. Shin: Research Support; Pfizer Inc., Celltrion, SK Bioscience, GlaxoSmithKline plc. Funding This research was supported by a grant of the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (grant number: RS-2023-00273553)

Endurance training and essential amino acid intervention synergize to ameliorate fructose-induced metabolic dysfunction in mice

Purpose: Excessive fructose (FRU) consumption can rapidly produce multiple features of metabolic syndrome, including dysregulation of systemic metabolism, insulin resistance, and diabetes. Essential amino acids (EAAs) and endurance exercise training (ET) improve abnormal metabolism in various disease conditions, yet their combined effect and metabolic mechanism remain unclear. Thus, the current study aimed to investigate metabolic kinetic mechanism and the combined effect of EAA and ET on fructose-induced metabolic dysfunction. Materials and methods: Mice were randomly divided into 5 groups with an 8-week intervention: normal chow (CON), FRU, FRU+ET, FRU+EAA or FRU+ET+ EAA, followed by stable isotope tracer infusions ([U-13C16]palmitate, [D2]glucose, and [D5]glycerol) or D2O administration to determine substrate metabolic flux rates and their contribution to TCA cycle flux and protein synthesis rates of various organs, respectively. Summary of results: FRU-induced adverse changes in body weight and physical function were reversed by ET, EAA, or ET+EAA. In stable isotope tracing analysis, ET and ET+EAA alleviated hyperglycemia by suppressing hepatic glucose production rate, while EAA and ET+EAA normalized palmitate turnover and contribution to TCA cycle in various organs. Additionally, the altered protein synthesis measured using a D2O labeling method was normalized by ET and ET+EAA. Conclusion:These findings suggest that the combined treatment of dietary EAAs and ET more effectively mitigates fructose-induced metabolic dysfunction by normalizing hepatic glucose production rate, protein synthesis rates, and fatty acid metabolism. This research was supported by a grant of the Korea Health Technology R&amp;D Project through the Korea Health industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (HI22C2208), and the National Research Foundation of Korea (NRF), funded by the Korea government (MSIT) (No. 2021R1A2C3005801), and partially funded by MYOCARE INC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

HepScope: CNN-based single-cell discrimination of malignant hepatocytes

Background: Hepatocellular carcinoma (HCC) poses a significant global health challenge. This study aims to identify robust single-cell biomarkers specifically designed to distinguish between malignant and non-malignant hepatocytes, thereby advancing precision medicine strategies for HCC. Methods: At the single-cell level, we investigated the reliability of established marker genes for malignant hepatocytes in distinguishing them from their non-malignant counterparts. Leveraging one of the largest integrated single-cell transcriptomics (scRNA-seq) datasets of healthy and diseased liver tissues, alongside independent scRNA-seq, spatial transcriptomics (stRNA-seq), bulk RNA-seq, and bulk proteome datasets, we defined a signature gene set, denoted as HepScope. Five other publicly available gene sets related to HCC were used for comparison with HepScope. The development of machine learning (ML) and 1-dimensional convolutional neural network (1D-CNN) models involved utilizing normalized expression of signature genes from scRNA-seq datasets. The HepScope-1D-CNN model was developed to assess differentiation performance by considering the expression values of each signature gene across different tissues and within the same tissue. Finally, we calculated a risk score based on the signature genes to evaluate its prognostic capability. Result: We demonstrated the lack of specificity and consistency among current HCC marker genes in distinguishing malignant hepatocytes from non-malignant hepatocytes. The differential expression (DEG) analysis identified 113 genes upregulated in malignant hepatocytes, forming the HepScope. In contrast to HepScope, the expression values of the five other publicly available gene sets did not exhibit the ability to discriminate between malignant and non-malignant hepatocytes. Utilizing the genes from HepScope, the Gaussian Naive Bayes ML model proficiently distinguished between malignant and non-malignant hepatocytes. The HepScope-CNN model showed the highest performance and effciency compared to other 1D-CNN models trained with different gene sets. Conclusion: In conclusion, our study reveals a novel gene set designed to precisely identify malignant hepatocytes at the single-cell level. This research holds promise for advancing precision medicine in HCC, providing valuable insights into the development of targeted therapies and personalized treatment strategies. We acknowledge support provided by the National Research Foundation (NRF) of Korea (2020R1A6A1A03043539, 2020M3A9D8037604, and 2022R1C1C1004756) and the Korea Health Technology R&amp;D Project of the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (HR22C1734). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comprehensive analysis of transcription factor-based molecular subtypes and their correlation to clinical outcomes in small-cell lung cancer

Comprehensive analysis of transcription factor-based molecular subtypes and their correlation to clinical outcomes in small-cell lung cancer

Distributed leadership in inter-organisational public research and development teams

PurposeThe authors contribute to the literature on leadership by investigating how characteristics of principal investigators (PIs) affect innovation performance, and how collaborative and non-collaborative projects moderate this relationship within the context of inter-organisational research projects.Design/methodology/approachThe authors analysed panel data from the National Science and Technology Information Service on 171 research projects within a biomedical and regenerative medicines programme overseen by the Korea Health Industry Development Institute. The authors used a hierarchical regression model, based on the ordinary least squares method, to examine the relationship between PI characteristics and performance, considering both quantity and quality.FindingsThe results show that the characteristics of PIs have diverse effects on the quantity and quality of innovation performance. Gender diversity within PIs negatively affects the quality of innovation performance, while the capacity of PIs positively influences it. Moreover, the degree of PI’s engagement is positively associated with the quantity of innovation performance but does not have a significant relationship with the quality of performance. In terms of moderating effects, collaborative projects with multiple leaders seem less reliant on PI capacity than non-collaborative projects led by a single leader, in terms of innovation performance.Originality/valueThe results contribute significantly to the literature on innovation management by examining the role of leadership in collaborative environments to enhance innovation performance, addressing the need for empirical evidence in this area. Analyses of PI characteristics in government R&D management can lead to improved team performance, more efficient processes and effective resource allocation, ultimately fostering innovation.

740-P: Six Subclasses with Glucose and Insulin Curves during OGTTs Capture Distinct Metabolic Characteristics and the Most Common Pathway to T2D in a Cohort of Koreans

Heterogeneity of glucose abnormalities makes prevention and treatment of diabetes challenging. Subclasses of people at high risk have been identified based on glucose profiles during OGTTs. However, previous work on subclasses lacks longitudinal confirmation. Here, we used glucose and insulin during OGTTs and k-means clustering to classify subclasses of people without diabetes and then determined the model-derived beta-cell function (BCF) and insulin sensitivity (IS) within each subclass. We identified metabolic risk and the most common pathway to T2D by tracking transitions of subclasses over the 16-year Korean Genome Epi. Study. Participants underwent OGTTs every 2 years for up to 16 years or until diabetes (N=2682, BMI=24.4±2.9 kg/m2, age 49.8±7.6 y). 1) 6 subclasses: Cluster A: Normal BCF, Normal IS, B: Mildly impaired BCF and IS, C: Impaired BCF, mildly impaired IS, D: Strong BCF, impaired IS, E: Mildly impaired BCF, impaired IS, F: Strong BCF, severely impaired IS; 2) Cluster C had the highest risk for T2D, HR: 10.7 (8.0, 14.1), compared to cluster A, followed by Clusters E, B, F, and D; Transition from A to B and C was the most common pathway; A, B, and C together comprised 86% of the cohort. Clustering using glucose and insulin classified 6 subgroups showing distinct metabolic parameters and identified the most common pathway to T2D in Koreans. Disclosure J.Kim: None. H.Kang: None. S.T.Chung: None. A.Sherman: None. S.Kim: None. J.Ha: None. W.Yi: None. D.Kim: None. M.Im: None. S.Ryang: None. M.Kim: None. Y.Kim: None. I.Kim: None. Y.Kim: None. Funding Busan Economic Promotion Agency; National Research Foundation of Korea (2022H1D3A2A01063552); Korea Health Industry Development Institute (HI18C2383); dkNET New Investigator Pilot Program in Bioinformatics; National Institute of Diabetes and Digestive and Kidney Diseases

177-OR: Worsening Insulin Resistance Is Key Pathological Contributor to Dysglycemia in Lean Koreans—A Longitudinal Validation Study in the Korean Genome and Epidemiology Study (KoGES)

Insulin resistance (IR) is a modest but important pathophysiological factor in the development of type 2 diabetes (T2D) in East Asians and manageable through lifestyle intervention. The degree to which worsening insulin resistance independent of beta cell dysfunction, contributes to diabetes progression in lean Koreans is unknown. With a 10-year longitudinal study from a Korean cohort, we investigated whether worsening insulin resistance contributes to disease progression in individuals who had normal glucose tolerance at baseline (N=3700, Age=50.1±8.3 y, BMI= 24.1±2.9 kg/m2). We identified metabolic characteristics of progressors and non-progressors to prediabetes (PreDM) or T2D at baseline and 10 year-longitudinal changes in IR and BMI. To assess whether longitudinal changes of IR, independent of beta-cell function (BCF), contributed to progression, the cohort was divided into low and high BCF groups, using group median at baseline. Progressors to PreDM or T2D had weaker BCF and more insulin resistance, compared to non-progressors (Panel A) at baseline. Insulin sensitivity declined more, 30.7 vs 46.5 vs 16.7% and BMI increased in progressors to PreDM or T2D, but not in nonprogressor (Panels A and B). Conclusion: Worsening insulin resistance even for lean people is a key pathological factor to PreDM and T2D progression. Disclosure D.Kim: None. H.Kang: None. A.Sherman: None. S.T.Chung: None. S.Kim: None. J.Ha: None. J.Kim: None. M.Im: None. S.Ryang: None. W.Yi: None. M.Kim: None. Y.Kim: None. I.Kim: None. Y.Kim: None. Funding Busan Economic Promotion Agency; National Research Foundation of Korea (2022H1D3A2A01063552); Korea Health Industry Development Institute (HI18C2383); dkNET New Investigator Pilot Program in Bioinformatics; National Institute of Diabetes and Digestive and Kidney Diseases