bluuebunny/crossref_metadata_2025_split huggingface dataset:
135-OR: Mapping Cis-Regulatory Programs Affecting Diabetes Risk in Pancreatic Islet Cell Types Using Single-Cell Multimodal Profiling
Authors: MUMMEY HANNAH , ELISON WESTON , KORGAONKAR KATHA , LEE YUN S. , NEWSOME ASHMUS JACKLYN M. , BENAGLIO PAOLA , MILLER MICHAEL T. , MANNING FOX JOCELYN E. , GLOYN ANNA L. , MACDONALD PATRICK , PREISSL SEBASTIAN , GAULTON KYLE J. 
Published: June 2023

Genetic variants influencing type 1 diabetes (T1D) risk identified by genome-wide association studies (GWAS) are primarily non-coding and affect cis-regulatory element (cRE) activity in specific cell types. A more detailed understanding of cell type-specific cis-regulatory programs in the pancreas is therefore crucial for deciphering the functional impact of T1D risk. Recently developed assays that generate multimodal single nucleus RNA-seq (snRNA-seq) and ATAC-seq (snATAC-seq) profiles from the same cell enable high-resolution mapping of cis-regulatory programs in specific cell types. We generated deeply sequenced data from 28 nondiabetic pancreatic islet samples from the Alberta Diabetes Institute IsletCore using 10x multiome assays. After extensive quality control and filtering, we clustered multimodal profiles from 174,819 cells and identified ten major cell types. For several cell types we identified evidence of heterogeneous sub-populations; for example, in beta cells there were six sub-populations corresponding to cellular states associated with insulin secretion, stress response, and others. We identified 263,223 cREs across all cell types and developed a novel method to predict target genes of cREs based on the correlation of multimodal profiles across single cells. In beta cells, there were 122,352 cRE-target gene links involving 16,907 unique genes. We mapped chromatin accessibility quantitative trait loci (caQTLs) for cREs in each cell type and identified a total of 14,535 caQTLs at FDR&lt;.10. Finally, we annotated T1D risk variants from high-resolution fine-mapping of 136 T1D signals with cRE-target gene links and caQTLs. At 27 T1D signals including at the INS, MAPT, and DLK1 loci, variants affecting chromatin accessibility were linked to putative target genes in beta cells suggesting mechanisms of action at these loci. Experimental follow up of variant activity at these loci using genome editing in beta cell lines is ongoing.

Disclosure
H. Mummey: None. W. Elison: None. K. Korgaonkar: None. Y.S. Lee: None. J.M. Newsome Ashmus: None. P. Benaglio: Employee; Shoreline Biosciences. M.T. Miller: None. J.E. Manning Fox: None. A.L. Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. P. MacDonald: None. S. Preissl: None. K.J. Gaulton: Stock/Shareholder; Neurocrine Biosciences, Inc. Consultant; Genentech, Inc. Stock/Shareholder; Vertex Pharmaceuticals Incorporated.

Funding
National Institutes of Health (HG012059, DK105554, DK122607, DK114650)
1353-P: Glycemic Control and Longitudinal Brain MRI in Children Diagnosed with Diabetes before 3 Years of Age (CLARiFY Study)
Authors: MORAN CHRIS , GBADEYAN OYETUNDE , BROWN AMY , SAKOWSKI STACEY A. , SRIKANTH VELANDAI , CAMERON FERGUS , NORTHAM ELISABETH A. , FELDMAN EVA L. , BEARE RICHARD 
Published: June 2023

Though early childhood onset of type 1 diabetes (T1D) is associated with brain development alterations, the affected brain regions and role of glycemic control are unknown. We aimed to examine associations between of HbA1c mean and variability and brain structure in a cohort of children diagnosed with T1D before 3 years of age. We recruited children presenting to a tertiary hospital in Australia from 1990-1992 in the Cognition and Longitudinal Assessment of Risk Factors over 30 Years (CLARiFY) Study. HbA1c was serially measured over 30 years after T1D diagnosis. Brain MRI was performed at ~12- and 30-years post diagnosis. We used linear mixed effects modelling to examine associations between mean HbA1c and HbA1c coefficient of variation and brain MRI structural measures. Data were available for 10 subjects (6 female). The mean age of diabetes diagnosis was 1.9 years. The mean HbA1c at 12- and 30-years post diagnosis was 8.5%. We did not find an association between mean HbA1c and any of the brain structures. Greater HbA1c coefficient of variation was associated with less sub-cortical gray matter volume (β=-41537, p=0.006) and greater cortical thickness (β=0.47, p=0.02) but not other brain structure measures (Table 1). In these preliminary analyses, we found HbA1c variability associated with measures of gray matter. Work is ongoing to confirm and understand the implications of these results.

Disclosure
C.Moran: None. O.Gbadeyan: None. A.Brown: None. S.A.Sakowski: None. V.Srikanth: None. F.Cameron: None. E.A.Northam: None. E.L.Feldman: None. R.Beare: None.

Funding
National Institutes of Health (R01DK129320)
1356-P: Association of HbA1c with Diabetes Outcomes across Health Status Categories in Older Adults
Authors: LIPSKA KASIA J. , HUANG ELBERT , LIU JENNIFER , PARKER MELISSA M. , MOFFET HOWARD H. , GRANT RICHARD W. , LAITEERAPONG NEDA , KARTER ANDREW J. 
Published: June 2023

For older adults with type 2 diabetes (T2D) on insulin/sulfonylureas, Endocrine Society recommends HbA1c between 7-&lt;7.5% for those in good health, 7.5-&lt;8% for those in intermediate health, and 8-&lt;8.5% for those in poor health.
We evaluated associations between HbA1c levels and complications in adults age ≥65 yrs with T2D on insulin/sulfonylureas from an integrated healthcare delivery system. Complications included any microvascular or macrovascular events, severe hypoglycemia, or mortality during calendar year 2019. We categorized HbA1c (last result prior to 1/1/2019) as being below (overtreated), within (reference), or above (undertreated) recommended target range. Health status was adapted from the ADA Standards of Care. Cox proportional hazards models of complications were adjusted for sociodemographic and clinical variables.
Among 63429 eligible patients (mean age 74.2 yrs, 46.8% women), 8773 (13.8%) experienced a complication. Complication risk was significantly elevated for patients in good health who were overtreated or undertreated (Table). Among those with intermediate health, complication risk was elevated only for those who were undertreated. Among those with poor health, complication risk did not differ significantly by level of attained HbA1c.
Factors other than HbA1c level are likely to be more important predictors and/or drivers of complications in patients with T2D and poor health.

Disclosure
K.J.Lipska: Other Relationship; UpToDate. E.Huang: Advisory Panel; Twin Health, Stock/Shareholder; AbbVie Inc., Cardinal Health, Amgen Inc. J.Liu: None. M.M.Parker: Research Support; Dexcom, Inc. H.H.Moffet: Research Support; Dexcom, Inc. R.W.Grant: None. N.Laiteerapong: None. A.J.Karter: None.

Funding
National Institute on Aging (R01AG063391, R56AG074986); National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092924, P30DK092949)
1359-P: Gaps in the Use of Evidence-Based Diabetes Medications for NASH
Authors: ALEXOPOULOS ANASTASIA-STEFANIA , PARISH ALICE , OLSEN MAREN , BATCH BRYAN , MOYLAN CYNTHIA A. , CROWLEY MATTHEW J. 
Published: June 2023

Patients with type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH) are at exceedingly high risk of NASH progression to cirrhosis and end-stage liver disease. T2D medications shown to improve histologic features of NASH, such as GLP-1 receptor agonists and pioglitazone, should be considered for use in all patients with T2D and NASH, unless contraindications exist. However, utilization of T2D medications that benefit NASH are poorly understood. Our objective was to address this gap by examining their use in patients with T2D and NASH engaged with Primary and/or Endocrinology care in the Duke University Healthcare System between 1/1/2019 and 1/1/2021. T2D and NASH were defined by ICD-10 codes, E11.xx and K75.81, respectively and 848 patients were included in the analyses. Mean age of our cohort was 60 (SD 12) years, 62% were female (n=525), 13% (n=110) were Black race and 4.7% (n=40) were Hispanic ethnicity. The mean HbA1c was 7.5% (SD 1.5), and the majority followed with Endocrinology (58.5%, n=496) and used insulin (62.4%, n=529). Only 26.3% (n=223) had an appointment with Duke Hepatology during the study period (either new consultation or follow-up visit). The use of evidence-based T2D medications for NASH was low (34.8%, n=295), with only 31.3% (n=265) and 6.5% (n=55) of patients having been prescribed a GLP-1 receptor agonist or pioglitazone during the study period, respectively. Prescriptions of these medications did not significantly vary by race (Black vs. White unadjusted OR 1.08, 95% CI 0.71, 1.64) or Hispanic ethnicity (unadjusted OR, 1.46, 95% CI 0.77, 2.79).
In summary, we observed a large gap between recommended and current use of evidence-based medications for NASH in patients with T2D. Use of pioglitazone was particularly low, despite its low cost and longstanding evidence for use in NASH. Future studies should explore reasons for underuse of these evidence-based T2D medications in NASH, and whether this is changing over time with growing evidence supporting their use in NASH.

Disclosure
A. Alexopoulos: None. A. Parish: None. M. Olsen: None. B. Batch: Advisory Panel; LLENA (AI). C.A. Moylan: Advisory Panel; Boehringer Ingelheim Inc. Research Support; GlaxoSmithKline plc. M.J. Crowley: None.

Funding
National Institutes of Health (KL2TR002554)
136-LB: The Implication of Glycemic Risk Index Varies with Different Levels of Glycosylation A1c (HbA1c) in Type 1 Diabetes
Authors: HE BINBIN , XIE YUTING , LI XIA , ZHOU ZHIGUANG 
Published: June 2023

Objective: Type 1 diabetes (T1D) is characterized by significant fluctuations in blood glucose, necessitating comprehensive assessment of glycemic control. The Glucose Risk Index (GRI) is a new glucose assessment metric derived from continuous glucose monitoring (CGM) that can simultaneously indicate hyperglycemic and hypoglycemic risks. This study explored the implications of GRI for T1D with different HbA1c levels.
Methods: We obtained 507 CGM and clinical data points from 281 patients with T1D, some of whom had follow-up data with intervals of over 3 months. The included patients aged 4-72 years with duration greater than 3 months and wore a CGM for at least 14 days. The hypoglycemic index and hyperglycemic index were calculated by time below range (TBR) &lt;54 mg/dL + 0.8 × TBR &lt;70-54 mg/dL and time above range (TAR) &gt;250 mg/dL) + 0.5 × TAR &gt;180-250 mg/dL, respectively. GRI is the sum of 3 times hypoglycemic index and 1.6 times hyperglycemic index. Relationships between GRI and HbA1c, each CGM metrics were explored and compared in patients with HbA1c &lt;7% and ≥7%.
Results: The mean GRI and HbA1c were 57.6 ± 20.6 and 7.3 ± 1.1%, respectively, and HbA1c of 7% approximately corresponded to GRI of 55. GRI was correlated with HbA1c (R = 0.536), hypoglycemic index (R = 0.466) and hyperglycemic index (R = 0.654), but the correlation between GRI and HbA1c disappeared in subgroup with HbA1c &lt;7%. Compared with the HbA1c ≥7% group, GRI in the HbA1c &lt;7% group had a stronger correlation with hypoglycemic index and a weaker correlation with hyperglycemic index. Further analysis showed the combination of dichotomous HbA1c (&lt;7% or ≥7%) and GRI (&lt;55 or ≥55) conferred best evaluation of glycemic control.
Conclusions: The implication of GRI varies with different levels of HbA1c in T1D, with GRI mainly representing hypoglycemic risk when HbA1c &lt;7%, and hyperglycemic risk when HbA1c ≥7%. A more comprehensive assessment of glycemic control in T1D should be the combination of dichotomous HbA1c and GRI.

Disclosure
B. He: None. Y. Xie: None. X. Li: None. Z. Zhou: None.

Funding
National Natural Science Foundation of China (81600649)
1360-P: Health Disparities in Clinical Research among Those Living with Diabetes-Related Retinopathy
Authors: COOPER LILLIAN H. , AINLEY LEXIE , STEVENS HENRY , QUINN KEVIN , COOPER BLAKE A. 
Published: June 2023

Background: Despite the higher rates of diabetes among the Black, Indigenous, and People of Color (BIPOC) population, there is a significant underrepresentation of this population in diabetes-related clinical trials which compromises the generalizability of results and further exacerbates health disparities.
Objective: To identify barriers and solutions to BIPOC enrollment in diabetes-related clinical trials.
Methods: We reviewed 18 diabetes-related clinical trials at Retina Associates LLC in Kansas City and interviewed recruiting physicians from practices across the US. Results: Fewer BIPOC population (15.6%) and women (40%) were enrolled in the analyzed trials. Men were 1.6 times more likely to be screened despite having a 20% higher screen fail rate than women. The fail rate was lower among Caucasian participants than among Hispanic participants (29.6% vs 37.5%). Based on zip codes, the fail rate was 1.25 times higher for those with an estimated average household income below $70,000 compared to those with an income above $100,000. The interviewed physicians valued a potential clinical trial patient’s ability to understand, commitment to health, reliability, and overall interest. They stressed the immense difficulty of time and travel commitments that clinical trials can pose for patients and agreed that increasing diversity in the staff could prove to be beneficial, especially regarding the language barrier many patients face.
Conclusions: Several recommendations from the reviewed trials and interviews to improve BIPOC enrollment. Clinical trial sponsors should provide Informed Consent Forms (ICFs) in multiple languages. There needs to be a level of diversity when hiring healthcare providers and study coordinators. Clinical trials should be designed to be less burdensome and include geographic locations with a higher population percentage of minorities, as well as locations within the neighborhoods where these populations receive their healthcare care.

Disclosure
L.H.Cooper: None. L.Ainley: None. H.Stevens: None. K.Quinn: None. B.A.Cooper: Advisory Panel; Genentech, Inc., Speaker's Bureau; Regeneron, Optomed.
1363-P: Clinical Profile and Outcome of Diabetic Ketoacidosis in an Emergency Department Non-COVID ICU
Authors: R CHANDNI , JAMI BIPENTHUNG N. , SURESH ANJANA , MANGALY AUSTIN J. 
Published: June 2023

The clinical profile of DKA in a 4-bedded ED ICU of a single tertiary care centre from 12 April 2022 to 4 January 2023 is presented. A total of 11 DKA events were managed, with a mean age of 45.5 ± 19.2 y with M: F ratio of 1:2.7. Type 1 in 36%, type 2 in 45% and 18% were unclassified. 55% had no comorbidities, and 45% had Hypertension, CAD, CKD, and hypothyroidism. Presented with nausea & vomiting in 6 (55 %), shortness of breath in 5 (45%), dysuria in 4 (36 %), fever & fatiguability in 3 (27%), abdominal pain, chest pain, loose stools in 2 (18%), cough, haematemesis and loss of consciousness in 1 (9%). Of the total patients, 36 % were only on OADs, 18 % on Insulin and OADs and 18 % on Insulin alone. Duration of diabetes ranged from 2 to 13 years, and 2 were first diagnosed. Reasons for DKA were Non-adherence to medication (18%), the first presentation of DM (18%), Infections (73%), CAD-ACS (18%) and Pancreatitis (9%). One patient was on Dapagliflozin 10 mg daily with blood glucose 240 mg/dL at presentation. Lab parameters are shown in Table 1. Course in ICU: All patients received the standard treatment of DKA. 27 % had AKI and 27% had Acute on CKD. ICU mortality was 36 % with definite alternative causes identified for death. Conclusions: Infections are the most important cause of precipitating events for DKA. Co-morbidities and Complications decide the outcome and early recognition and standard treatment and ICU care are important in critically ill.

Disclosure
C.R: None. B.N.Jami: None. A.Suresh: None. A.J.Mangaly: None.
1364-P: Cinicoradiological and Microbial Spectrum of Skull Base Osteomyelitis and Its relation to Diabetes Mellitus
Authors: RADHAKRISHNAN SUMA , C DINSHA , DAHIYA VIJEYTA , R CHANDNI 
Published: June 2023

Skull base osteomyelitis (SBO) is a rare life-threatening disease, which is on the increase specifically the incidence of fungal skull base osteomyelitis.
Objectives: To describe the demographic, and clinicoradiological profile, and to assess the outcome of skull base osteomyelitis.
Methodology: A prospective study from a tertiary care centre, in Kerala from 1st February 2018 to 31st August 2019 with a minimum follow-up of 6 months. All patients diagnosed with skull base osteomyelitis were included. The demographic profile and relevant investigations, radiological correlations and treatment outcomes were analysed.
Results and Discussions: 30 patients (23 males and 7 females) were studied. Incidence was found to be high in the age group 51-60 years. The mean (SD) of Age (Years) was 62.02 (14.21), ranging from 1.5-78 years. The most common presentation was a nocturnal earache (86.7%).13.3% of patients presented with headache alone, these cases were diagnosed to be central skull base osteomyelitis and had a significant association with clival erosion. All the patients were having diabetes mellitus except 1.5 yrs old who had congenital cyclic neutropenia. We could see an association between uncontrolled blood glucose and the severity of the disease (P value &lt;0.001). 63.3% of the participants had Cranial Nerve Palsy at the presentation. The culture yielded Pseudomonas followed by staphylococcus aureus, MRSA & Aspergillus. The ESR and CRP levels were reliable for the detection, progression and resolution of disease status in SBO. All patients were treated with third-generation cephalosporins and fluoroquinolones for a minimum of 6 weeks and of which, 12 patients with fungal SBO were given antifungals also.
Conclusions: Skull base osteomyelitis is an entity that requires a lifelong commitment. A high index of suspicion, early diagnosis, and prompt and aggressive management are critical for a positive outcome. Uncontrolled diabetes mellitus was the risk factor recognised.

Disclosure
S.Radhakrishnan: None. D.C: None. V.Dahiya: None. C.R: None.
1365-P: Recurrent Diabetic Ketoacidosis—Patient Characteristics and Clinical Outcomes in Qatar
Authors: ELEDRISI MOHSEN , ALABDULRAZZAK IMAD , ALKABBANI HAIFAA M. , ABOAWON MALK K. , ALI AYA A. , ELHAJ MAAB F. , AHMED ASHRAF O.E. , ALQAHWACHI HAZIM , MALIK RAYAZ A. 
Published: June 2023

Background: Recurrent diabetic ketoacidosis (DKA) is associated with poor clinical outcomes.
Objective: We aimed to examine patients’ characteristics and clinical outcomes for patients hospitalized with recurrent DKA in Qatar.
Methods: The hospital database was interrogated for patients admitted with DKA to government hospitals in Qatar between 2015 to 2020. Precipitating cause, clinical characteristics, laboratory data, severity of DKA, complications, need for admission to the intensive care unit, length of hospital stay, time to resolution of DKA, and mortality rates were evaluated in patients with recurrent (&gt;1 admission) compared to a single admission.
Results: A total of 1612 episodes of DKA, of which 434 patients (26.9%) had recurrent DKA, were evaluated. Compared to patients who had a single admission for DKA, those with recurrent DKA were younger [35.0 (24.0-53.0) vs 39.0 (28.0-54.0) years, p&lt;0.001], more likely to be females (50.6% vs 37.1%, p&lt;0.001), more likely to have type 1 diabetes (47.9% vs. 33.4%, p&lt;0.001), a longer duration of diabetes [12.0 (5.0-19.0 vs 5.0 (0.0-13.0) years, p&lt;0.001], more likely to have severe DKA (48.6% vs 38%, p&lt;0.001), with a shorter time to resolution of DKA [12.5 (9.0-24.0) vs 23.0 (10.0-33.0) hours, p&lt;0.001]. There was no difference in the precipitating cause of DKA, need for admission to the intensive care unit, hospital stay or inpatient mortality. On multivariable logistic regression analysis, significant predictors of occurrence of recurrent DKA were younger age (OR, 0.96; 95% CI, 0.95-0.98; p= 0.0001), female gender (OR, 0.63; 95% CI, 0.46-0.85; p= 0.003) and longer duration of diabetes (OR, 1.07; 95% CI, 1.04-1.09, p= 0.0001).
Conclusion: In this cohort study, recurrent DKA was associated with younger age, female predominance and longer duration of diabetes. However, hospital course and inpatient mortality rates did not differ from those with a single admission for DKA.

Disclosure
M.Eledrisi: None. I.Alabdulrazzak: None. H.M.Alkabbani: None. M.K.Aboawon: None. A.A.Ali: None. M.F.Elhaj: None. A.O.E.Ahmed: None. H.Alqahwachi: None. R.A.Malik: None.
1366-P: Nonalcoholic Fatty Liver Disease in Young-Onset Type 2 Diabetes Mellitus—A New Epidemic?
Authors: SHARMA ANU , GODINEZ LEIVA EDDISON , LOMONACO ROMINA , VALDEZ SAENZ ENRIQUE , ORTIZ ROCHA ANDREA , MARANGI STEPHEN A. , GONZALEZ MARIA A. , SHRESTHA SULAV , SHETTY SHWETHA S. , BUDD JEFFREY T. , BARB DIANA , KALAVALAPALLI SRILAXMI , CUSI KENNETH 
Published: June 2023

The prevalence of young-onset type 2 diabetes mellitus (YOT2DM), defined as T2DM diagnosed in adults &lt;45 years old, is steadily increasing. Nonalcoholic fatty liver disease (NAFLD) is common in people with T2DM but its prevalence in YOT2DM is unknown. We therefore hypothesized that NAFLD is an emerging health concern in this population. A total of 161 adults aged 35-44 years with and without T2DM, underwent screening for NAFLD with laboratory tests and imaging by elastography (steatosis by controlled attenuation parameter [CAP]; fibrosis by liver stiffness measurement [LSM]). Of these, 25 (16%) had YOT2DM and 136 (84%) did not have diabetes mellitus (noDM). While obesity was very prevalent in the cohort (53%), those with YOT2DM had a higher BMI (35±7 vs. 31±7 kg/m2, p&lt;0.01), and reported comorbidities more frequently: hypertension (48% vs. 24%, p=0.02) and atherogenic dyslipidemia (76% vs. 54%, p=0.04). Hepatic (HOMA-IR 4.6±2.8 vs 2.6±1.9, P&lt;0.01) and adipose tissue (6.5±5.1 vs 3.9±3.5, p=0.01) insulin resistance were worse in people with YOT2DM. Adiponectin, a reflection of proper adipose tissue function, was lower in YOT2DM (4.2±2.3 vs 6.2±3.5 μg/mL, p=0.02). Hepatic steatosis (CAP ≥274 dB/m) was prevalent in both groups but higher in people with YOT2DM (64% vs. 47%), but much lower in people without obesity or diabetes (27%; p&lt;0.01). Male sex was associated with a significantly higher risk of hepatic steatosis (OR 3.7, 95% CI 1.5-9.2). The frequency of any fibrosis as measured by LSM (≥7.0 kPa) was 3-fold higher in YOT2DM compared to people without diabetes (12% vs. 4%, p=0.08). Every 1 unit increase in BMI elevated the risk of both steatosis and fibrosis by 20% (OR 1.2, 95% CI 1.03-1.3).
Conclusion: Hepatic steatosis is highly prevalent in young-onset type 2 diabetes (YOT2DM) and is strongly influenced by obesity. Hepatic fibrosis is relatively common and affects 1 in 8 people with YOT2DM. These results warrant the need for larger and longer follow-up studies in this population.

Disclosure
A. Sharma: None. E. Godinez Leiva: None. R. Lomonaco: None. E. Valdez Saenz: None. A. Ortiz Rocha: None. S.A. Marangi: None. M.A. Gonzalez: None. S. Shrestha: None. S.S. Shetty: None. J.T. Budd: None. D. Barb: None. S. Kalavalapalli: None. K. Cusi: Research Support; Echosens, Inventiva. Consultant; Poxel SA. Research Support; LabCorp, Zydus. Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns.