bluuebunny/crossref_metadata_2025 huggingface dataset:
19-PUB: Improved Glycemic Control in People with Type 2 Diabetes (T2D) Initiating or Switching to Insulin Degludec/Insulin Aspart (IDegAsp) in a Real-World Setting in China
Authors: GUO LIXIN , CHEN LIMING , ZHAO FAN , LIU XIAO Y. , DING HONGCHENG , WANG KUN , XING ZHONG , BABU SHANKARAPPA VINAY , CHAUDHARY GAURAV
Published: June 2024

Introduction & Objective: This study investigated clinical parameters in a real-world population of Chinese individuals with T2D treated with IDegAsp in routine clinical practice.

Methods: This 20-week, prospective, single-arm, open-label, non-interventional study (NCT05221580) included adults with T2D receiving anti-hyperglycemic treatment (oral antidiabetic drugs [OADs] only, basal insulin [±OAD], basal-bolus insulin [±OAD], premixed insulin [±OAD] or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) ± insulin [±OAD]), initiating or switching to IDegAsp. Primary endpoint: change in HbA1c from baseline (BL) to end of study (EOS). Secondary endpoints: change in fasting plasma glucose (FPG) and hypoglycemic episode incidence.

Results: Of 878 adults (57.4% male; mean age 59.6 yrs), patients generally received IDegAsp once (47.2%) or twice (52.2%) daily. Initiating/switching to IDegAsp significantly lowered mean [95% CI] HbA1c (-1.27% [-1.36;-1.19], p<0.0001), with similar decreases in all prior treatment groups (Figure). Mean [95% CI] FPG fell significantly (-1.61 mmol/L [-1.81;-1.41], p<0.0001). Non-severe hypoglycemic episodes in last 20 wks were reduced at EOS vs BL (45 vs 115 patients).

Conclusion: Initiating/switching to IDegAsp improved glycemic control in a real-world population of Chinese adults with T2D.

Disclosure

L. Guo: Consultant; Abbott, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Eli Lilly and Company, Hengrui (USA) Ltd., Dreisamtech, Dongbao, Gan & Lee, Hansoh. L. Chen: None. F. Zhao: None. X.Y. Liu: None. H. Ding: None. K. Wang: None. Z. Xing: None. V. Shankarappa: Employee; Novo Nordisk A/S. G. Chaudhary: None.

Funding

Novo Nordisk
1903-LB: Real-World Bolus Dose Timing and Glycemic Impact Using the Tempo Platform
Authors: JOHNSON JENNAL , XUE JIE , DUKE DAVID L. , DAVIDSON MICHAEL B. , DASSAU EYAL
Published: June 2024

Background: Optimization of bolus dose timing is associated with better glycemic control and dose timing variability can be associated with negative glycemic impact. Use of the Tempo Platform in multiple daily insulin users allows visualization of bolus behavior. The objective for this analysis is to assess real-world bolus dose timing data and glycemic impact for users on CGM and the Tempo Platform.

Method: We performed a retrospective analysis of 31,140 bolus doses over 7,933 days from 120 MDI users (84 T1D and 36 T2D users) on the Tempo Platform. We analyzed glucose excursions using the GRID method and evaluated bolus timing and glycemia.

Results: There was no difference in bolus timing between T1D and T2D results by pooled mealtime excursions however, separately, breakfast showed the greatest differences by diabetes type. On average, those with T1D delayed boluses 22 minutes post glucose excursion and those with T2D delayed boluses 51 minutes post glucose excursions. The 4 hour glycemic analysis (post glucose excursion initiation and bolus) identified more hyperglycemia >180mg/dL than hypoglycemia (<70 mg/dL) post mealtime bolus dosing in both user groups with delayed boluses.

Conclusions: The Tempo Platform reveals critical insights on insulin utilization for MDI users. Our results indicate bolus dose timing differences by type of diabetes, predominately at breakfast. Late bolus timing can lead to dysglycemia.

Disclosure

J. Johnson: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Xue: Employee; Eli Lilly and Company. D.L. Duke: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.B. Davidson: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. E. Dassau: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.
191-OR: Symposium on the International Consensus Statement and Movement to End Diabetes Stigma
Authors: DE GROOT MARY , JOINER KEVIN , GARZA MATTHEW , GUZMAN SUSAN
Published: June 2024

Diabetes stigma is recognized as a highly prevalent experience for people living with diabetes across the lifespan. Diabetes stigma has been demonstrated to negatively impact health and quality of life for people living with diabetes. With the appreciation that many health practitioners have varying resources with which to implement suggestions to combat diabetes stigma, this symposium focuses on identifying strategies that practitioners and health care systems can put the recommendations of the International Consensus Statement for Ending Diabetes Stigma into practice within the context of their own training, practice patterns and access to resources. The session topics will also help practitioners and researchers to identify areas of need to better understand successful implementation of the recommendations of the End Diabetes Stigma campaign to improve diabetes health and quality of life outcomes. The proposed symposium will consist of the following sections:

I. International Consensus Statement for Ending Diabetes Stigma: Background, methodology of the Consensus Statement, and overview of recommendations for health professional and researchers - Dr. Mary de Groot

II. Prevalence and impact of diabetes stigma: Implications for health outcomes - Dr. Susan Guzman

III. Research in diabetes stigma: What's next? - Dr. Kevin Joiner

IV. Integration into care settings: Patient perspective and identifying resources - Matthew Garza, Diabtribe

Disclosure

M. de Groot: None. K. Joiner: None. M. Garza: Other Relationship; Sanofi. S. Guzman: Consultant; Abbott.
1915-LB: Impact of Glycemic Variability on the Relationship between TIR and GMI among Type 2 Diabetes Patients with TIR >70%
Authors: YANG YANLING , LIU ZHIGU , CHEN DANRUI , LIN BEISI , JIANG WEI , YAN JINHUA , ZENG LONGYI , XU WEN
Published: June 2024

Aim: Previous studies proved that glucose variability (GV) affected the relationship between TIR and glucose management indicator (GMI) in T2D patients with poor glycemic control. This study aimed to explore whether GV indexes affect the relationship between TIR and GMI in T2D patients with TIR > 70%.

Methods: Data were collected from T2D patients who received 6-day CGM between January 2018 and March 2023. TIR, GMI and GV indexes were obtained from CGM system. A linear regression equation was generated with values of TIR and GMI. Patients were then divided into three subgroups according to the tertile of different GV indexes. Predicted TIR in given GMI was calculated via the linear regression equations in different subgroups.

Results: A total of 216 T2D patients (age: 54.3±14.1 years old, median diabetes duration: 89.1 months, HbA1c: 8.1±2.2%, and TIR: 86.1±9.0%) were included. There was a strong negative correlation between TIR and GMI (r=-0.763, P<0.001). The slopes of regression lines fitted to TIR values as a function of GMI differed significantly for individuals with varying degrees of different GV indexes. For a given GMI, the predicted TIR values varied in different tertiles of GV indexes (Table 1).

Conclusions: Even in T2D patients with TIR > 70%, GV indexes mediated the relationship between TIR and GMI. Thus, GV indexes should be taken into consideration when setting an individualized target of TIR.

Disclosure

Y. Yang: None. Z. Liu: None. D. Chen: None. B. Lin: None. W. Jiang: None. J. Yan: None. L. Zeng: None. W. Xu: None.
1916-LB: Prevalence, Characteristic, and Chronic Complications of Patients with the Fast-Glycator Phenotype in Type 1 Diabetes
Authors: DENG CHAO , TAN KE , XU RUOYAO , FAN WENQI , LI XIA
Published: June 2024

Objective: To investigate the prevalence, characteristic and chronic complications of patients with the fast-glycator phenotype in type 1 diabetes (T1D), as well as the relationship between the fast-glycator phenotype and hemoglobin glycation index (HGI).

Methods: We enrolled individuals with T1D who utilized the continuous glucose monitoring system (CGM) for at least 10 days. Skin advanced glycation end products (AGEs) was measured by a spectroscopy device. Chronic complications were assessed through a standardized screening process. Glucose management indicator to HbA1c ratio < 0.9 was defined as a fast-glycator phenotype.

Results: We included 418 participants of T1D (59.3% female) with a median age of 17 years and a median duration of 28 months. 109 individuals (26.1%) were classified as having the fast-glycator phenotype. The prevalence of the fast-glycator phenotype was higher in patients who were adult-onset (38.6% vs. 14.9%, P<0.001), female (31.5% vs. 18.2%, P=0.003) and having a duration of 10 years or more (48.0% vs. 19.2%, P<0.001) than their counterparts. Fast-glycators had significantly higher HbA1c (8.3% vs. 6.9%, P < 0.001) with similar GMI (6.8% vs. 6.8%, P=0.663) compared with non-fast-glycators. Fast-glycators had notably higher skin AGEs (75.5 vs. 65.2, P < 0.001) and HGI (1.16% vs. 0.17%, P < 0.001), as well as increased prevalence of retinopathy (43.1% vs. 19.7%, P < 0.001), regardless of adjusting for age, duration of diabetes.

Conclusions: Fast-glycator phenotype is more prevalent in adults, females, and patients with longer disease duration in T1D, associated with higher risk of retinopathy, and increased skin AGEs and HGI.

Disclosure

C. Deng: None. R. Xu: None. W. Fan: None. X. Li: None.
1922-LB: CGM Use in People with Type 2 Diabetes Initiating GLP-1 or GIP/GLP-1RA Therapy—Real-World Data
Authors: WANG XIAOHAN , XU YING , NORMAN GREGORY J. , REID JENNIFER L. , SINGH HARSIMRAN , YANG LEI
Published: June 2024

Introduction & Objective: CGM use has been shown to improve glycemic outcomes in people with diabetes. We investigated CGM use pre- and post-initiation of GLP-1 or GIP/GLP-1 RA (incretin) therapy in a T2D cohort using real world data.

Methods: Retrospective analyses of electronic health records were conducted using Truveta data. People with T2D aged ≥30 years initiating incretin therapy were evaluated from 2018-2022 in 3 cohorts: intensive-insulin treated (IIT), basal-insulin treated (BIT) and non-insulin treated (NIT). CGM use was assessed 12-months pre- and post-incretin therapy initiation.

Results: Overall the cohort (n=299,157) was: 64.9-67.8% White, 52.1-53.8% female, mean (SD) 57.3 (11.7) to 59.5 (12.4) years of age. Over 5 years, individuals initiating incretin therapy approximately doubled in the insulin-treated cohorts (IIT=99%, BIT=85%) with a nearly 250% increase in the NIT cohort. CGM use increased each year pre- and post-incretin therapy initiation, with larger proportions observed in the insulin-treated cohorts vs NIT (Table).

Conclusion: These findings indicate that CGM use in people with T2D has increased substantially over 5 years, with a greater relative proportion of CGM use post- vs pre-incretin therapy initiation, independent of insulin use. Future research will evaluate the potential benefits of CGM use in conjunction with incretin therapy to optimize glycemic outcomes in people with T2D.

Disclosure

X. Wang: Employee; Dexcom, Inc. Y. Xu: Employee; Dexcom, Inc. G.J. Norman: Employee; Dexcom, Inc. J.L. Reid: Employee; Dexcom, Inc. H. Singh: Employee; Dexcom, Inc. L. Yang: Employee; Dexcom, Inc.
1933-LB: Innovative At-Home Kidney Health Testing Program for Diabetics
Authors: SPICER MORGAN J. , MILLER JUSTIN , WESTFIELD GERWIN , NORTHROP LESLEY , GAVIOLA GABRIEL
Published: June 2024

Introduction & Objective: Chronic kidney disease, or CKD, impacts approximately one in three of these diabetic patients. An estimated 37 million people in the US have CKD and 90% are unaware due to the lack of associated symptomatology. Routine monitoring of CKD-related biomarkers such as eGFR (estimated glomerular filtration rate) and UACR (urine albumin-creatinine ratio) help aid in early diagnosis, and can prevent progression into later stages where hemodialysis or transplants are needed. Advances in home-collected laboratory tests have now made it easier to perform this needed screening.

Methods: A retrospective analysis of eGFR and UACR home-collected, laboratory test results from January 1, 2020 through January 31, 2024 as part of Kidney Health program directed at diabetic individuals at high risk for CKD was conducted.

Results: Of 902,802 results available, 8.44% of eGFR (n = 73,788/873,617) results and 10.94% (n = 3,194/29,185) of UACR results were categorized as abnormal or critical. All patients with critical values received outreach and instructions on how to seek follow-up care.

Conclusions: Critical UACR results were 3.6x more frequent than those for eGFR, highlighting the need for both tests to assess kidney health. Patients who receive abnormal or critical result values received outreach and were directed to follow up with in-person healthcare providers to receive treatment and/or lifestyle interventions to slow progression of CKD. At-home lab testing combined with counseling is effective for closing healthcare gaps in a diabetic population.

Disclosure

M.J. Spicer: Employee; Everly Health. J. Miller: None. G. Westfield: Employee; Everly Health. L. Northrop: None. G. Gaviola: None.
1942-LB: Detecting Unmet Psychosocial Needs in Adult Persons with Diabetes—First Data from Our National Danish Diabetes PROMS Questionnaire DiaProfil
Authors: NIKONTOVIC AMAR , TROELSEN LISE , MELLERGAARD NØRGAARD LISE , EJSKJAER NIELS
Published: June 2024

Introduction & Objectives: Persons with diabetes (PwD) and our VBS-PRO-DIA research team developed the national Danish Patient-Reported Outcome (PRO) fully digital questionnaire (#DiaProfil). It is now fully implemented in all 4 hospitals in our region (uptake 600.000 inhabitants). DiaProfil identifies unmet psycho-social needs addressing appropriate individual action plans. This study is the first to psychometrically describe the magnitudes of need for selected psycho-social domains in our hospital population in the North Denmark Region.

Methods: All PwD attending the outpatient clinic at Aalborg University Hospitals, completing the DiaProfil questionnaire (9 domains with 91 parameters) were included. The prevalence of each variable was determined using frequencies and percentages, while distributions were examined to clarify variable spread. T-tests were used to examine differences between variables.

Results: 1525 PwD (870 men and 655 women) with an average age of 50.9 years were included. Response rate 72 %. The average WHO-5 score was 63.7 points (national Danish non-diabetes score 68.5 points). We detected impacted sleep quality (40% disturbed sleep), sexual health (18% difficulty with intercourse), blood sugar regulation (39% report inadequate control), diabetes management (30% lacked confidence in their own diabetes management) and diabetes stress or depression (14,6 % in need of professional assistance).

Conclusion: This study describes the prevalence of specific psycho-social need domains in adult PwD enabling individualized action planning. Specific domains in need were poor sleep quality, sexual health challenges, self-management confidence and undetected diabetes stress, all excerting a substantial impact on diabetes management, individual well-being and quality of life.

Disclosure

A. Nikontovic: None. L. Troelsen: None. L. Nørgaard: None. N. Ejskjaer: None.
1958-LB: Overnight Glycemia’s Relevance to Insulin Resistance (IR) in Type 1 Diabetes (T1D)
Authors: CREE MELANIE G. , SIMON STACEY L. , BERNARD ANGEL , CHARTIER-LOGAN CATHERINE J. , BAUMGARTNER AMY , HINES ASHTON , BAILEY ALEXANDER , PTASZYNSKA SARA M. , BEST KYLA C. , CAREY GRAYSON , PYLE LAURA , SNELL-BERGEON JANET K. , NADEAU KRISTEN J.
Published: June 2024

IR is a key contributor to cardiovascular disease in T1D but is difficult to measure. The relevance of mean overnight glycemia (MOG) in IR assessments by gold-standard hyperinsulinemic-euglycemic clamps (HEC) in T1D is unclear. We assessed the relationship between pre-HEC MOG and HEC-assessed IR in pubertal adolescents ages 12-19 yrs with T1D.

Each youth underwent admission with variable overnight intravenous insulin infusion titrated with a standardized protocol to a goal blood glucose (BG) of 100-120 mg/dL, followed by an AM HEC with 80mU/m2/min insulin infusion paired with a variable glucose infusion rate (GIR, 20% dextrose infusion, goal BG 95-100 mg/dL). MOG and insulin infusion rates were assessed overnight. Achieved MOG was categorized as ≤100, 101-120, and 121-140 mg/dL. IR was assessed by end-HEC steady-state GIR and free fatty acids (FFA).

80 youth (42 girls, 38 boys) with T1D enrolled (mean age 16 ± 2.1 yrs, HbA1c 8.4 ± 1.6%, T1D duration 6.9 ± 4.0 yrs, BMI 24.0 ± 4.7 kg/m2). Mean BG at end-HEC was 99.0 ± 7.4 mg/dL. Results categorized by MOG category are shown in the Table. As MOG category increased, overnight insulin infusion requirements and end-HEC FFA’s increased and GIR decreased.

In T1D, more difficult to control overnight BG in a controlled setting likely reflects greater overnight IR and HEC whole-body and adipose IR. Future directions include home overnight pump/CGM-based simpler methods for assessing IR in T1D.

Disclosure

M.G. Cree: Consultant; Pollie, Inc. Research Support; Amino Co. A. Bernard: None. A. Baumgartner: None. A. Hines: None. A. Bailey: None. G. Carey: None. L. Pyle: None. J.K. Snell-Bergeon: None. K.J. Nadeau: None.

Funding

American Diabetes Association (7-11-CD-08); JDRF (2-SRA-2022-1144-M-B)
1959-LB: An Insulin-Modified Oral Glucose Tolerance Test (OGTT) to Assess Insulin Resistance (IR) in Type 1 Diabetes (T1D)
Authors: NADEAU KRISTEN J. , SIMON STACEY L. , BERNARD ANGEL , CHARTIER-LOGAN CATHERINE J. , BAUMGARTNER AMY , HINES ASHTON , BAILEY ALEXANDER , PTASZYNSKA SARA M. , BEST KYLA C. , CAREY GRAYSON , PYLE LAURA , DINIZ BEHN CECILIA , SNELL-BERGEON JANET K. , CREE MELANIE G.
Published: June 2024

IR is a key contributor to cardiovascular disease in T1D and increasingly so with increased rates of obesity in T1D. IR is difficult to measure in T1D due to absent insulin secretion. The hyperinsulinemic euglycemic clamp (HEC) is the gold-standard method for assessing IR in T1D, but is cumbersome, especially in youth. We thus adapted the simpler and more physiologic OGTT to T1D and assessed its performance vs. the HEC in T1D adolescents who use insulin pumps.

Each youth underwent admission with variable overnight intravenous insulin infusion, followed by an AM HEC with 80mU/m2/min insulin infusion paired with a variable glucose infusion rate (GIR, 20% dextrose infusion). IR was assessed by end-HEC steady-state GIR. On a separate day, each youth underwent an OGTT. The participant’s insulin pump basal rate was left running with autocorrection mode suspended, and a subcutaneous injection of regular insulin given using the participant’s home insulin:carbohydrate ratio and blood glucose correction factor. 30 minutes later, a 75-gram Glucola was consumed (T=0). Blood samples were taken at T=-30, -20, -5, 0, +10, +20, +30, +45, +60, +75, +90, +120, and IR calculated via the Matsuda Index, which correlates well with HEC in non-T1D populations. Spearman correlations between GIR and Matsuda Index were performed. Descriptive statistics were examined for normality, then expressed as median (25th,75th) or mean ± SD.

17 pubertal youth (10 girls, 7 boys) 14-17 yrs of age (15.8 ± 0.9 yrs) were enrolled (BMI 20.0 [19.4, 24.8 kg/m2], HbA1c [7.6 ± 1.1%]). Mean HEC GIR was 10.0 ± 4.6 mg/kg/min; Matsuda was 4.9 ± 4.0 (unitless). GIR correlated with Matsuda Index (r=0.54, p=0.025).

In T1D youth, HEC-assessed IR correlated well with insulin-augmented OGTT Matsuda Index. Future work will compare different methods of calculating IR from an OGTT to determine the optimal method and incorporate isotope tracers to allow tissue-specific IR measures. An insulin-modified OGTT is a viable option to assess IR in T1D.

Disclosure

K.J. Nadeau: None. A. Bernard: None. A. Baumgartner: None. A. Hines: None. A. Bailey: None. G. Carey: None. L. Pyle: None. C. Diniz Behn: Research Support; Lumos Tech. J.K. Snell-Bergeon: None. M.G. Cree: Consultant; Pollie, Inc. Research Support; Amino Co.

Funding

JDRF (2-SRA-2022-1144-M-B)
1986-LB: Feasibility and Acceptability of an Intervention to Improve Metabolic Liver Disease in Latino/a and Black Patients with Diabetes
Authors: ALEXOPOULOS ANASTASIA-STEFANIA , DANUS SUSANNE , PARISH ALICE , OLSEN MAREN , BATCH BRYAN , MOYLAN CYNTHIA A. , CROWLEY MATTHEW J.
Published: June 2024

Patients with type 2 diabetes (T2D), and particularly those from historically marginalized racial/ethnic groups, are at high risk of poor outcomes from metabolic dysfunction-associated steatotic liver disease (MASLD). In this 3-month feasibility pilot, we proactively delivered evidence-based care for MASLD in Latino/a and/or Black patients with T2D and elevated liver enzymes, with a goal of reducing risk of MASLD progression. We recruited 10 patients (5 Latino/a and 5 Black) with T2D and alanine aminotransferase level (ALT) >40 U/L; exclusions for non-MASLD liver disease were applied. The intervention was entirely remote and included: a) MASLD education; b) monthly diet/lifestyle counseling sessions; c) T2D medication management, with prioritization of glucagon-like peptide-1 receptor agonists and pioglitazone as appropriate; and d) clinically-indicated ordering of liver tests and referrals. Primary outcomes were feasibility and acceptability as measured by the Treatment Acceptability and Preferences (TAP) measure and participant interviews. Mean patient age was 51.1 (SD 9.6) and 5/10 participants were female. Mean BMI was 36 (SD 5.6), HbA1c was 6.9% (SD 1.2) and ALT was 58 U/L (SD 17.6). At 3 months, retention rate was 100% and all 30 study visits were completed. Mean TAP was 3.98 (SD 0.13) with a maximum score of 4, indicating high intervention acceptability. All participants felt the intervention was helpful in improving their awareness of MASLD and motivating behavioral change to reduce MASLD risk. Of the 10 participants, 5 had their T2D medications adjusted, 2 underwent liver ultrasound (both had steatosis) and 1 was referred to Hepatology. This study demonstrates feasibility and acceptability of an intervention that delivers evidence-based care for MASLD in Latino/a and Black patients with T2D.

Disclosure

A. Alexopoulos: None. S. Danus: Other Relationship; Novo Nordisk, Fractyl Health, Inc., Lilly Diabetes. A. Parish: None. M. Olsen: None. B. Batch: Advisory Panel; LLENA (AI). C.A. Moylan: Research Support; Madrigal Pharmaceuticals, Inc. Consultant; Novo Nordisk. Research Support; GlaxoSmithKline plc, Exact Sciences. Consultant; Sirtex. M.J. Crowley: None.

Funding

The Duke Clinical and Translational Science Award (CTSA) program funded by the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), award number KL2 TR002554.
1993-LB: Subgroups of Type 2 Diabetes (T2D) by Clinical Features and Islet Autoimmunity
Authors: PILLA SCOTT J. , KNOWLER WILLIAM C. , BALASUBRAMANYAM ASHOK , HAMPE CHRISTIANE S. , PIETROPAOLO SUSAN , LIN DARREN , ANDERSON ANDREA M. , ZHAO NI , LERNMARK ÅKE , MATHIOUDAKIS NESTORAS N. , BANCKS MICHAEL , CLARK JEANNE , MARUTHUR NISA M.
Published: June 2024

Introduction: Adults with T2D may have phenotypic subgroups; prior clustering analyses had limited measures of beta-cell function, islet autoimmunity, or both. We aimed to characterize T2D subgroups in Look AHEAD (Action for Health in Diabetes), a randomized trial of adults with clinically-diagnosed T2D and overweight/obesity.

Methods: In 3,952 participants, we measured islet autoantibodies (GADA, ZnT8A) and performed homeostatic model assessment v2 of beta cell function (HOMA2-B) and insulin resistance (HOMA2-IR) using fasting C-peptide. We applied k-means clustering using these measures plus age at T2D diagnosis, BMI, and HbA1c.

Results: We identified four subgroups (Figure): lower adiposity with good glycemic control (LA/GC, 42% of the sample), high adiposity with good glycemic control (HA/GC, 26%), poor glycemic control (PC, 30%) and islet autoimmunity (IA, 3%). The LA/GC subgroup had high HOMA2-B (median 73%) and low HOMA2-IR (median 2.4). HA/GC had the highest HOMA2-B (median 113%) and HOMA2-IR (median 3.8). The PC subgroup had low HOMA2-B (median 46%) and youngest T2D diagnosis. Only the IA subgroup had frequent islet autoimmunity (95% GADA+, 18% ZnT8A+) and had low HOMA2-B (median 55%). Insulin use was infrequent in LA/GC (9%) and HA/GC (4%), and common in PC (32%) and IA (41%).

Conclusions: Using clinically-available measures, we identified four distinct T2D subgroups with important physiologic differences.

Disclosure

S.J. Pilla: None. W.C. Knowler: None. A. Balasubramanyam: None. C.S. Hampe: None. S. Pietropaolo: None. D. Lin: None. A.M. Anderson: None. N. Zhao: None. Å. Lernmark: Advisory Panel; DiaMyd Medical AB, Stockholm, Sweden. M. Bancks: None. J. Clark: Advisory Panel; Boehringer-Ingelheim. N.M. Maruthur: Other Relationship; Johns Hopkins Health Care Solutions.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126825, K23DK128572)
1997-LB: Curation of an AI-Ready Dataset Using Domain-Informed Features Derived from Type 1 Diabetes TrialNet Studies
Authors: TALLON ERIN M. , SHAPIRO MELANIE R. , SHRIKRISHNA WAGHMODE AMEY , MERRITT RYAN , WASSERFALL CLIVE , BACHER RHONDA , LOCKEE BRENT , VANDERVELDEN CRAIG , PANFIL KELSEY , MOORE WAYNE V. , ATKINSON MARK A. , BRUSKO TODD M. , CLEMENTS MARK A.
Published: June 2024

Introduction: Machine learning and artificial intelligence (ML/AI) will increasingly have pivotal roles in advancing scientific discoveries related to diabetes. The NIDDK Central Repository (NIDDK-CR) hosted a “Data Centric Challenge” (DCC) between December 2023 and February 2024 to enhance the potential for using its data resources in innovative ML/AI research that aligns with the FAIR (Findable, Accessible, Interoperable, Reusable) principles.

Objective: As DCC participants, we describe our experience transforming data from multiple Type 1 Diabetes (T1D) TrialNet (TN) studies into a single AI-ready dataset for ML/AI applications.

Methods: For its intermediate/advanced Challenge, the NIDDK-CR provided fully deidentified data from four studies: TN01 (TN participant screening and monitoring), TN16 (long-term TN participant follow-up), TN19 (immunotherapy in new-onset T1D), and TN20 (antigen-specific immunotherapy). We first generated a single “raw” dataset comprising all data from the four studies by joining on participant ID. We then transformed structured data from TN01 and TN20 to create an AI-ready dataset.

Results: Our raw dataset contained data for 237,324 TN participants (TN01 [n=237,048]; TN16 [n=561]; TN19 [n=119]; TN20 [n=115]). Since few individuals participated in ≥3 of these studies, we curated an AI-ready dataset comprised of fully harmonized, longitudinal immunologic, genetic, phenotypic, and demographic data - including numerous new, AI-ready data features (e.g., normalized fold change in autoantibody titers and CyTOF tetramers, genetic risk score, T1D stage) - from individuals who completed participation in TN01 and TN20 (n=75). All data handling processes are repeatable and thoroughly documented.

Conclusion: Data from multiple TN studies can be transformed into domain-informed, AI-ready data. Future efforts will entail analyses of newly engineered data variables to inform ML modeling efforts for predicting progression to Stage 2 and Stage 3 T1D.

Disclosure

E.M. Tallon: None. M.R. Shapiro: None. A. Waghmode: None. R. Merritt: None. C. Wasserfall: None. R. Bacher: None. B. Lockee: None. C. Vandervelden: None. K. Panfil: None. W.V. Moore: None. M.A. Atkinson: None. T.M. Brusko: None. M.A. Clements: Research Support; Abbott. Consultant; Glooko, Inc. Research Support; Dexcom, Inc.

Funding

Emilie Rosebud Diabetes Research Foundation; Orlando Brown Jr.
2005-LB: Optimization of Single Nuclei Isolation from Frozen Human Skeletal Muscle and Pancreatic Tissue Samples for Single Nuclei Multiome ATAC + Gene Expression
Authors: DOLGACHEV VLADISLAV , VARSHNEY ARUSHI , MOO KEAGAN G. , WANG XIAOOU , ORCHARD PETER , SAUNDERS DIANE C. , BRISSOVA MARCELA , PARKER STEPHEN C.
Published: June 2024

Background: Dysfunctional pancreatic islets beta cells are a well established hallmark of type 2 diabetes. Despite intense research, we still lack understanding of the underlying gene dysregulation mechanisms, including gene regulatory pathways driving the shift between normal and diabetic cells. Single-nucleus (sn) multiome (joint RNA and ATAC profiling on the same nucleus) sequencing is a powerful technique to acquire multi-modal data from the same nucleus. sn-multiome quality depends on the quality of the input material. Increasing the quality of single nuclei isolated from previously frozen human skeletal muscle and pancreas samples can enhance sn-multiome output.

Goal of the study: Reduce noise in sn-multiome data by isolating high quality nuclei from human samples.

Methods: We compared data from nuclei isolated with citric acid and sucrose gradient protocols to nuclei sorted with the MACS Quant Tyto flow cytometer. The quality of isolated nuclei was visually determined by light microscopy, quantified by ATAC library trace, and RNA integrity number (RIN) score.

Results: We optimized isolation of nuclei from frozen human skeletal muscle samples. Quality controls checks revealed intact nuclei microscopically, all expected peaks on ATAC library traces, and 9.2 RNA RIN. Optimization of nuclei isolation from frozen pancreatic human tissues was more challenging due to the high amount of RNases, which quickly degrade RNA quality and compromise subsequent library preps, even with high-quality nuclei. We optimized nuclei isolation protocol by fine tuning experimental procedures along with adjustment of concentrations of RNase inhibitors.

Conclusions: Optimization of nuclei isolation from frozen human skeletal muscle and pancreatic tissue with MACS Quant Tyto cell sorter demonstrated high quality of sorted nuclei by visual integrity, ATAC trace and high RNA RIN and high sn-multiome data quality.

Disclosure

V. Dolgachev: None. A. Varshney: None. X. Wang: None. P. Orchard: None. D.C. Saunders: None. M. Brissova: None. S.C. Parker: Research Support; Pfizer Inc.
2010-LB: Glycemic Responses to Metformin Montherapy by SNP Clusters in Patients with Type 2 Diabetes
Authors: SHEU WAYNE H.H. , LEE CHUN-YI , LIAO CAI-SIAN , HSIAO TZU-HUNG , ROTTER JEROME I.
Published: June 2024

Introduction and Objective: Glycemic responses to metformin based on 8 SNP clusters in diabetes individuals, published by Suzuki (Nature, 2024), are unknown. Employing dataset from part of Taiwan Precision Medicine Initiative (TPMI), we explored the glycemic responses to metformin by quintile SNP cluster scores.

Methods: Tracking EMR from a medical center in Taiwan, we analyzed changes of fasting glucose and HbA1c, based on SNP clusters, in newly diagnosed type 2 diabetes who received metformin monotherapy for 6 months. (Fig. 1). GEE was used to compare the glycemic responses in those with Q1 vs. Q5 in each or two SNP clusters.

Results: Significant reduction of fasting glucose (FG) (p=0.007) and HbA1c (p<0.001) in those carrying Q1 vs. Q5 in beta cell dysfunction with negative proinsulin (BDNP). Greater lowering of FG (p=0.008) and marginally lowering of HbA1c (p=0.079) in those carrying Q1 vs. Q5 in beta cell dysfunction with positive proinsulin (BDPP). When considering both clusters together, diabetes subjects having clusters of both BDNP and BDPP showed better FG reduction in Q1 as compared to Q5 (p=0.015). Diabetes subjects carrying clusters of both metabolic syndrome and BDNP had greater HbA1c reduction in Q1 compared to Q5 (p=0.013).

Conclusion: We identified that SNP clusters with BDNP and BDPP, and metabolic syndrome, contributed to glycemic responses to metformin monotherapy in patients with type 2 diabetes.

Disclosure

C. Liao: None. T. Hsiao: None. J.I. Rotter: None.

Funding

National Health Research Institutes, Taiwan (MG-112-PP-18, MG-113-PP-18)
2013-LB: Population-Scale Skeletal Muscle Single-Nucleus Multiomic Profiling Reveals Extensive Context-Specific Genetic Regulation
Authors: VARSHNEY ARUSHI , MANICKAM NANDINI , ORCHARD PETER , TOVAR ADELAIDE , ZHANG ZHENHAO , FENG FAN , LAKKA TIMO A. , LAAKSO MARKKU , TUOMILEHTO JAAKKO , MOHLKE KAREN L. , KITZMAN JACOB , KOISTINEN HEIKKI A. , LIU JIE , BOEHNKE MICHAEL , COLLINS FRANCIS S. , SCOTT LAURA , PARKER STEPHEN C.
Published: June 2024

Skeletal muscle, the largest human organ by weight, is relevant to several polygenic metabolic traits and diseases including type 2 diabetes (T2D). Identifying genetic mechanisms underlying these traits requires pinpointing the relevant cell types, regulatory elements, target genes, and causal variants. Here, we used genetic multiplexing to generate population-scale single nucleus (sn) chromatin accessibility (snATAC-seq) and transcriptome (snRNA-seq) maps across 287 frozen human skeletal muscle biopsies representing 456,880 nuclei. We identified 13 cell types that collectively represented 983,155 ATAC summits, cataloging caQTL peaks that atlas-level snATAC maps often miss. We integrated genetic variation to discover 6,866 expression quantitative trait loci (eQTL) and 100,928 chromatin accessibility QTL (caQTL) (5% FDR) across the five cell types. We identified 1,973 eGenes colocalized with caQTL and used mediation analyses to construct causal directional maps for chromatin accessibility and gene expression. 3,378 genome-wide association study (GWAS) signals across 43 relevant traits colocalized with sn-e/caQTL, 52% in a cell-specific manner. 77% of GWAS signals colocalized with caQTL and not eQTL, highlighting the critical importance of population-scale chromatin profiling for GWAS functional studies. A C2CD4A/B T2D GWAS signal colocalized with caQTL in muscle fibers and multiple chromatin loop models nominated VPS13C, a glucose uptake gene. Sequence of the caQTL peak overlapping caSNP rs7163757 showed allelic regulatory activity differences in a human myocyte cell line massively parallel reporter assay. These results illuminate the genetic regulatory architecture of human skeletal muscle at high-resolution epigenomic, transcriptomic, and cell state scales and serve as a template for population-scale multi-omic mapping in complex tissues and traits.

Disclosure

A. Varshney: None. N. Manickam: Employee; 10x Genomics. P. Orchard: None. A. Tovar: None. Z. Zhang: None. F. Feng: None. T.A. Lakka: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. K.L. Mohlke: None. J. Kitzman: Advisory Panel; Myome Inc. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. J. Liu: None. M. Boehnke: None. F.S. Collins: None. L. Scott: None. S.C. Parker: Research Support; Pfizer Inc.

Funding

R01DK072193UM1DK126185R01DK117960P30AR069620
2034-LB: Drug Screening Identifies Dicoumarol as a Novel IRE1α Inhibitor That Protects Mice from ER Stress-Induced Liver Damage
Authors: YANG JIFENG , WEN SHIYI , CHEN YANMING , SHI GUOJUN
Published: June 2024

Excessive nutrition intake leads to endoplasmic reticulum (ER) stress and activate unfolded protein response (UPR) in the liver. Depending on the level and duration of ER stress, IRE1α, the most conserved branch of UPR, a dual-functional ER transmembrane protein promotes either adaptation or apoptosis. Transient activation of IRE1α induces trans auto-phosphorylation and binds an ATP to its kinase domain, subsequently driving homo-oligomerization and exposure of its RNase domain, which catalyzes an unconventional splicing of XBP1 mRNA and generates an adaptive transcription factor XBP1s to restore ER homeostasis. However, under excess and chronic ER stress, hyperactivation of IRE1α expands RNase substrate repertoire to many other mRNA species, known as regulated IRE1-dependent decay (RIDD), which leads to apoptosis. To modulate the activity and effects of IRE1α, we performed a virtual screening targeting the kinase domain of IRE1α which contains a natural pocket structure to identify ATP-competitive small molecules. To validate the effects of those small molecules, an IRE1α-XBP1s activity reporter cell line was employed to further discriminate the candidates that inhibit IRE1α activity using fluorescence-activated cell sorting. Based on these strategies, we identified dicoumarol as a novel IRE1α inhibitor, which inhibits ER stress agonist-induced activation of IRE1α both in vitro and in vivo. Particularly, dicoumarol ameliorates tunicamycin- and tetrachloromethane-induced acute hepatic ER stress consequently protecting the liver from damage. Thus, dicoumarol shows a powerful hepatic protective effect, however, the potency of dicoumarol in the application of chronic ER stress, such as obesity and type 2 diabetes, needs further determination.

Disclosure

J. Yang: None. Y. Chen: None.

Funding

National Natural Science Foundation of China (82070811); National Natural Science Foundation of China (81770826); Key Area Research & Development Program of Guangdong Province (2019B020227003)
2057-LB: Amino Acids Plasma Levels Do Not Correlate with Lean Mass Loss in Weight-Matched DIO Mice Treated with Survodutide or Semaglutide
Authors: KLEPAC-BARTL KATARINA , PEREIRA MAFALDA , ZIMMERMANN TINA , RIST WOLFGANG , BAJRAMI BESNIK , KLOECKENER TIM , KLEIN THOMAS
Published: June 2024

Concomitant with beneficial fat mass loss, anti-obesity therapies lead to detrimental lean mass loss. It is known that amino acids are essential for muscle mass maintenance, growth, and repair. Moreover, it is recognized that glucagon promotes skeletal muscle wasting to supply amino acids for gluconeogenesis. Given that survodutide is a dual glucagon/glucagon like peptide 1 (GLP1) receptor agonist, and semaglutide acts solely as GLP1 receptor agonist, it could be hypothesized that survodutide leads to greater lean mass loss. Hence, we investigated plasma amino acids levels, body composition and energy expenditure (EE) of DIO (diet induced obesity) mice (8 mice/group) treated with either survodutide or semaglutide (both at 20 nmol/kg s.c. q.d. 3 weeks). Similar weight loss was achieved with survodutide (17.7±3.3%) and semaglutide (15.6±3.7%) vs. baseline, mean±SD, p<0.0001. While the weight loss for semaglutide was due to its anorexigenic effect, survodutide additionally increased EE (p=0.0081, d21) due to its glucagon component. Both compounds showed ~40% decrease in fat mass (40.4±1.7% and 40.8±3.7%, mean±SD, survodutide and semaglutide respectively, p=0.0006 vs. vehicle). Importantly, lean mass loss was not significantly different when comparing survodutide (8.3±0.8%) and semaglutide (5.3±0.9%), mean±SD, p=0.9071. Interestingly, both essential and non-essential plasma amino acids were decreased when comparing semaglutide with survodutide: L-lysine decreased from 180.5±32.7 µmol/L to 90.3±16.6 µmol/L and L-alanine from 336.4±121.4 µmol/L to 117.8±32.2 µmol/L when comparing semaglutide and survodutide respectively, mean±SD. In summary, we showed that the glucagon component of survodutide increased EE and reduced plasma amino acids levels when compared to semaglutide. However, these results did not translate into a different lean mass loss, indicating that the reduction in plasma amino acids did not correlate with lean mass loss.

Disclosure

K. Klepac-Bartl: Employee; Boehringer-Ingelheim. M. Pereira: Employee; Boehringer-Ingelheim. T. Zimmermann: Employee; Boehringer-Ingelheim. W. Rist: Employee; Boehringer-Ingelheim. B. Bajrami: Employee; Boehringer-Ingelheim. T. Kloeckener: Employee; Boehringer-Ingelheim. T. Klein: Employee; Boehringer-Ingelheim.

Funding

Boehringer Ingelheim
2058-LB: DA-1726, a GLP1R/GCGR Dual Agonist, a Promising Approach in Obesity Treatment and Lipid Management
Authors: CHAE YUNA , JUNG IL-HUN , KIM TAE-HYOUNG , KIM MI-KYUNG , JIN LEE SU , HEON KIM HYUNG
Published: June 2024

DA-1726 is being prepared for obesity Phase 1 clinical trials following IND approval. Our study focuses on the pharmacological effects of this novel oxyntomodulin analogue, which has been effective at improving lipid profiles and reducing weight in rodent models. In a prior study, DA-1726 showed a difference in improving lipid levels, despite similar weight loss to tirzepatide. Therefore, the direct lipid-regulating effect of DA-1726 was assessed in a hypercholesterolemia rat model compared with tirzepatide. As a result, DA-1726 was more effective than tirzepatide in suppressing the elevation of T-CHO ( -33.5%, -25.5% vs. control; P<0.05) and LDL-C (-53.2%, -41.5% vs. control; P<0.05). This differentiated impact is thought to arise from DA-1726's glucagon action, alongside its GLP-1 effect. We evaluated whether these differential effects could also be distinguished from drugs of the same class. In an obese mouse model, DA-1726 significantly lowered T-CHO (-67.7%, -49.6%; P<0.05 vs. control) and TG (-49.5%, -41.2%; P<0.05 vs. control) levels under conditions that resulted in similar weight loss effects (-31.9%, -25.4%; P<0.05 vs. control) as survodutide. Besides, DA-1726 exhibited superior glucose lowering compared to survodutide (-54.7%, -30.4% vs. control; P<0.05). Interestingly, despite the same mechanism of action, DA-1726-treated mice maintained similar levels of weight loss while consuming more food due to less dietary restriction in terms of appetite suppression. This effect might stem from DA-1726's GLP-1 and glucagon receptor activity ratio. DA-1726's glucagon action could further enhance energy expenditure (EE), and it is believed to have significantly increased the expression of EE-related genes in brown adipose tissue. In summary, it was confirmed that DA-1726 has differentiating characteristics in the competition of obesity treatment drugs with similar or identical mechanisms in its effect on improving cholesterol metabolism through glucagon action.

Disclosure

Y. Chae: None. I. Jung: None. T. Kim: None. M. Kim: None. S. Lee: None. H. Kim: Employee; NeuroBo Pharamceuticals Inc., Dong-A ST Co., Ltd.
2059-LB: NA-931, a Novel Triple IGF-1/GLP-1/GIP Incretin Receptor Agonist Reduces Body Weight and Improves Metabolic Profile in DIO Mice
Authors: TRAN LLOYD L.
Published: June 2024

Background: Insulin-like Growth Factor 1 (IGF-1) plays a major part in fuel metabolism and regulation of body composition. GIP and GLP-1 have been shown to be effective for weight loss in non-diabetic patients with obesity when given as adjunctive therapy to diet and exercise. IGF-1 contributes to modulate glucagon secretion in which IGF-1 inhibits the ability of low glucose concentration to stimulate glucagon expression and secretion. NA-931 and its analogs, NA-932 and NA-933 (“NA-931 Compounds”) are metabolites of IGF-1. Acting as a receptor agonists targeting IGF-1, GLP-1 and GIP, NA-931 Compounds may provide enhanced therapeutic benefits.

Methods: Male diet-induced obese (DIO) mice were treated with daily subcutaneous injections of vehicle or one of novel triple IGF-1/GLP-1/GIP receptor agonists, NA-931, NA-932 and NA-933 (10 nmol/kg), for 14 days. Tirzepatide (10 nmol/ kg) as used as positive controls. Cohorts were then assessed for changes in BW, glucose, and lipids.

Results: Treatment with NA-931 Compounds resulted in reductions to BW (up to 26%, p<0.0001), plasma glucose, plasma triglycerides, (up to 23% and 34%, respectively, p<0.003 for each), and liver triglycerides (up to 46%, p<0.05) compared to vehicle treatment. Weight loss effects in cohorts treated with NA-931 Compounds were comparable to those observed in tirzepatide-treated animals. In addition, liver lipid reductions were numerically greater among animals treated with the NA-931Compounds.

Conclusions: NA-931 and its analogs produced significant reductions in BW in DIO mice. Effect sizes were comparable to those observed in the tirzepatide control group. The NA-931 Compounds have been shown to produce desirable changes to lipid profile, suggesting global cardiometabolic benefit, represent a promising therapeutic approach to metabolic disorders such as obesity, type 2 diabetes, and non-alcoholic steatohepatitis. Additional research on these drug candidates is ongoing.
2081-LB: Efficacy and Safety of Semaglutide and Tirzepatide—A Comparative Analysis of Clinical Trials
Authors: TRAN LLOYD L. , TRAN ZUNG V.
Published: June 2024

Introduction & Objective: In the past years, many obesity drugs were approved by the FDA and withdrawn. Semaglutide and tirzepatide are dominating the obesity market. We analyzed published phase 2/3 clinical trials to evaluate their efficacy and safety.

Methods: We selected 17 randomized phase 2/3 trials. Participants had obesity, diabetes, or both. Outcomes were baseline - post treatment differences: efficacy [body wt (kg/%), fasting glucose (mg/dL), HbA1c (%)]; safety [nausea, diarrhea, vomiting, constipation]; also age, %women, %white, sample size, and duration, To estimate pooled differences, we used bootstrapping, a machine learning/AI methodology to resample a dataset, generating a sampling distribution for statistical calculations. We estimated means, 95%CI of the differences by performing 10,000 resamples.

Results: Table 1: Across the 17 trials, semaglutide and tirzepatide lowered body by 8.5 and 10.7 %; fasting glucose by 29.8 and 51.8 mg/dL; HbA1c by 1.1 and 1.8%, respectively.

Conclusion: Semaglutide and tirzepatide are comparable in their efficacy and safety profile. Tirzepatide is better at reducing fasting glucose. Dual agonism at GIP and GLP-1R may contribute to the weight control effects of tirzepatide. At the ADA conference, Biomed introduces NA-931, a new oral drug with triple agonism at GIP/ GLP-1 and IGF-1 as an alternative treatment with less AEs for those with obesity and diabetes.

Disclosure

Z.V. Tran: Employee; Biomed Industries, Inc.
2086-LB: Islet Surface Modification with Bissulfosuccinimidyl Suberate Prevents the Instant Blood-Mediated Inflammatory Reaction—A Novel Approach
Authors: KALIVARATHAN JAGAN , BALAJI SARAVANAN PRATHAB , FUGLESTAD BRIAN A. , DHAKAL SOMA , MOHAMMED SHUJAUDDIN , LEVY MARLON F. , KANAK MAZHAR A.
Published: June 2024

Introduction and Objectives: In pancreatic islet cell transplantation, the early graft loss is due to the instant blood-mediated reaction (IBMIR). Control of early inflammatory events could improve the efficacy of islet cell transplantation and may enhance the long-term function of transplanted islets. Nanoencapsulation of islets is an attractive method for masking cell features that can trigger inflammatory cascades. Bissulfosuccinimidyl suberate (BS3) is a homobifunctional crosslinker with NHS ester on each side to bind to amine groups. Herein, we investigated the effects of BS3-modified human islets in terms of viability, function, longevity of modification, and inflammatory properties.

Methods: The surface of the human islets was modified with BS3 in different concentrations (0.5, 1, and 5 mM). Visual coverage and efficiency of surface conjugation were determined by incorporating an Amine-PEG-Biotin conjugate. Surface-conjugated islets were then cultured for 7 days. Visualization of conjugation and viability determination was performed days 0, 1, 4, and 7 of culture. The impact of BS3 conjugation on islet function was determined by measuring the oxygen consumption rates and glucose-stimulated insulin secretion.

Results: BS3 modification was found to be exceptionally biocompatible. The viability and functional integrity of islets were not altered at 0.5 mM and 1 mM BS3, but viability showed a mild decline at 5 mM BS3. However, improved conjugation of the islet surface and good coverage were noted in the 5 mM BS3 group. The surface modification was maintained for all 7 days tested with minimal loss of coverage. The markers of inflammation were examined using qPCR analysis. BS3 treated group showed higher inhibition of all pro-inflammatory genes under strong cytokine cocktail exposure.

Conclusion: Surface modification of islets with BS3 is a safe and tolerable approach that may be used for localized drug delivery strategies.

Disclosure

J. Kalivarathan: None. P. Saravanan: None. B.A. Fuglestad: None. S. Dhakal: None. S. Mohammed: None. M.F. Levy: None. M.A. Kanak: None.

Funding

Department of Defense (W81XWH2210102)