bluuebunny/crossref_metadata_2025_split huggingface dataset:
153-LB: Type 1 Diabetes (T1D) Onset and COVID-19—Effect of the Second Wave on Diabetes Ketoacidosis and ICU Admission Rates in Newly Diagnosed Children with T1D in Kuwait
Authors: OTHMAN FOUZEYAH , AL-ABDULRAZZAQ DALIA , ALKANDARI HESSA 
Published: May 2022

Introduction: The COVID-19 pandemic had affected access to healthcare services around the globe. On February 24th, 2020, the first wave of the pandemic was announced. The government of Kuwait had implemented public health measures including curfews, nationwide lockdowns, and limited access to healthcare services. The second wave was declared on March 7, 2021; virtual visits, availability of diabetes clinics, and easier access to healthcare facilities may change the frequency of diabetes ketoacidosis (DKA) and the requirement for ICU admission for children with type 1 diabetes (T1D) onset in the second wave.
Aims: To evaluate DKA at presentation and ICU admission among children with T1D onset during the first and second waves using data from Childhood Onset Diabetes electronic Registry (CODeR) .
Methods: Data were extracted from CODeR. Included patients were aged less than 14 years at the time of T1D diagnosis in the period (February 24th - December 31st, 2021) , and in the same period in 2020.
Results: Between February and December 2021, 253 children were identified to have T1D onset, compared with 282 during the same period in 2020. There were no significant differences between HbA1c levels (11.41% vs. 11.56%;p value=0.21) and frequency of DKA in both groups (56.4% vs. 54%, p value=0.51) . Mild/moderate DKA rates didn't differ in both periods (66.1% vs. 60.7%, p value=0.42) , and Severe DKA as well (33.9% vs. 39.3%, p value=0.42) . No significant difference in ICU admission rates was observed in both periods (25.5% vs. 23.9%,p value=0.74) .
Conclusion: The second wave of the COVID-19 pandemic didn't change DKA frequency or the requirement of ICU admission compared to the first wave. Further studies investigating the frequency of DKA, ICU admission, and other factors are needed over longer periods to evaluate how the COVID-19 pandemic affects DKA changes as the pandemic continues.

Disclosure
F. Othman: None. D. Al-abdulrazzaq: None. H. Alkandari: None.

Funding
Dasman Diabetes Institute (RA MoH 2021-017)
154-LB: Population-Based Optimization of Metabolic Monitoring for Autoantibody-Positive Individuals at Risk for Type 1 Diabetes
Authors: OROURKE COLIN , SPEAKE CATE , YLESCUPIDEZ ALYSSA , BENDER CHRISTINE , LORD SANDRA 
Published: May 2022

Diabetic ketoacidosis (DKA) is often the sentinel event to a diagnosis of clinical type 1 diabetes. Research studies involving antibody positive (AAB+) individuals at risk for developing type 1 diabetes have demonstrated that metabolic monitoring every 6 months with oral glucose tolerance testing can dramatically reduce the incidence of DKA at diagnosis. It is unknown whether other schedules can reduce the population level burden of metabolic monitoring in AAB+ individuals while retaining the potential benefit of reducing DKA.
We reasoned that the shorter the time time-period during which clinical type 1 diabetes (T1D) remains undetected, the lower the likelihood of DKA. We aimed to develop models of optimized monitoring visit schedules to limit undiagnosed (UnDx) time for the population. Using OGTT data from 6193 islet AAB+ relatives identified in TrialNet’s Pathway to Prevention study, we developed models and an algorithm to optimize visit schedules to limit population-based UnDx time. The results of modeling were presented using estimated hazard rate as a function of age. An "optimal" visit schedule was determined for each model to achieve a minimum average level of UnDx time for the population. This was applied for risk patterns identified by each model thus producing optimal schedules for pediatric and adult populations with single or multiple antibodies.
Modeling an optimized visit schedule to keep UnDx time ≤ 6 months at a population level, we find that conducting half the number of metabolic monitoring visits usually done in research studies is likely to be effective in significantly impacting the population incidence of DKA at diagnosis of T1D. Our approach has implications for public health screening and monitoring for T1D risk.

Disclosure
C. Orourke: None. C. Speake: Advisory Panel; Vertex Pharmaceuticals Incorporated. A. Ylescupidez: None. C. Bender: None. S. Lord: Other Relationship; Pfizer Inc.

Funding
Helmsley Charitable Trust (2103-05008) ; Helmsley Charitable Trust (2210-05590)
155-LB: Evaluating Community COVID-19 Vaccination Status and Diabetes Visit Frequency during the Pandemic
Authors: OJUKWU SANDO , ADAM ATIF , KAUSHAL TARA , CHEN CHARLOTTE , TINSLEY LIANE J. , VOLKENING LISA K. , LAFFEL LORI M. 
Published: May 2022

Aim: The COVID-19 pandemic highlighted potential healthcare misalignment as seen by vaccine rates. We investigated pediatric diabetes visit frequency in patients living in lower vs. higher COVID 19 vaccination areas.
Method: We obtained EHR-extracted visit data for youth with T1D, ≤18 years old, with ≥1 visit in both the pre-pandemic (9/15/18-3/15/20) and pandemic (4/1/20-12/31/21) period. Residential addresses were geocoded and linked with CDC county level COVID vaccination data from 2/2/2022. High vaccine counties were defined as those in which ≥75% of the population ages 12 and older were fully vaccinated. We performed paired t-tests and logistic regression. Models were adjusted for age, gender, pre-pandemic A1c, and diabetes duration.
Results: There were 1,029 youth (49% female, pre-pandemic age 13.7±3.8 yrs, T1D duration 6.7±4.3 yrs) who had clinical encounters in both periods. 541 youth were from high vaccine counties. There was no difference in age, gender, T1D duration, CGM or pump use, or baseline A1c between youth from high vs. low vaccine counties. Overall there was increased visit frequency in the pandemic (5.1±3.0) vs. pre-pandemic (4.7±2.6) (p=0.03) . The mode of visits shifted from in person to virtual during the pandemic (p&lt;0.001) . In adjusted models, there was no association between county-level COVID vaccination coverage and visit frequency (OR 1.03, 95% CI 0.99-1.07) .
Conclusion: The COVID 19 pandemic resulted in a shift in care delivery to telehealth. Telehealth allowed for increased visit frequency. Patients coming from low COVID 19 vaccination counties attended diabetes visits as frequently as those coming from high COVID vaccination counties. County COVID vaccine status did not impact visit frequency of a chronic condition.

Disclosure
S. Ojukwu: None. A. Adam: None. T. Kaushal: None. C. Chen: None. L. J. Tinsley: None. L. K. Volkening: None. L. M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc.

Funding
National Institutes of Health (K12DK094721, P30DK036836)
156-LB: New Gestational Diabetes Mellitus Risk Algorithm
Authors: MENDIZABAL LEIRE , ARREGI MADDI , DEOGRACIA JOHANNA VALERIO , RAMOS LEVI ANA M. , BARABASH ANA , DE LA TORRE NURIA GARCÍA , ARANA EUNATE , URRUTIA INES , GAZTAMBIDE SONIA , CASTANO LUIS , MARTÍNEZ MARÍA DE LOS ANGELES M. , CAMARILLO-ROMERO ENEIDA , ZERÓN HUGO MENDIETA , GARDUNO-GARCIA JESUS , CORCOY ROSA , SIMON LAUREANO , ZULUETA MIRELLA , CALLE ALFONSO L. 
Published: May 2022

Background and Objective: GDM is associated with life-long adverse outcomes for mother and baby, and its incidence is increasing. Markers beyond clinical factors are needed to identify women at high risk and catalyze early preventive interventions. Our aim was to develop a risk assessment algorithm that integrates genetic and clinical variables.
Methods: We analyzed a retrospective cohort of 711 women from Hospital Clínico San Carlos (HCSC, Madrid, Spain) , with 425 control pregnancies and 286 GDM cases diagnosed per IADPSG criteria. The HCSC cohort was randomly divided into a training/development dataset (70% of cohort) for algorithm development and a test dataset (30% of cohort) for validation. In addition, we tested the model in a cohort of 157 women (89 controls, 68 cases diagnosed per NDDG criteria from Hospital Cruces (Bilbao, Spain) and in a cohort of 416 women (346 controls, 70 cases per IADPSG criteria from HMPMPS, México) . A total of 114 SNPs were selected for this analysis after exhaustive exploration of the databases published to date of SNPs associated with GDM. The SNPs were selected based on their predictive power and population frequency, with the following criteria: OR&gt;1.2, RAF&gt;0.20, p&lt;1×10-5. Discrimination and calibration of risk scores were assessed using the receiver operating characteristic (ROC) curve in the internal and the external validation groups.
Results: The algorithm provided a risk score for GDM, integrating 10 SNPs, maternal age, and pregestational BMI. In the training dataset the AUC was 0.74, sensitivity of 77% and specificity of 64%. AUCs in the HCSC, UAEM and Cruces validation sets were 0.71, 0.70 and 0.62 respectively.
Conclusions: This new tool for GDM risk assessment suggests that the utilization of genetic markers in combination with clinical characteristics may improve GDM risk evaluation and accelerate adoption of prevention interventions. Our study also highlights the importance of applying consensus criteria for the diagnosis of GDM.

Disclosure
L. Mendizabal: Employee; Patia Biopharma S. A. L. Castano: None. M. M. Martínez: None. E. Camarillo-romero: None. H. Mendieta zerón: None. J. Garduno-garcia: Speaker's Bureau; Boehringer Ingelheim International GmbH. R. Corcoy: None. L. Simon: Board Member; Nelum Corp., Oncomatryx Biopharma SL, Patia Biopharma S. A., Quimatryx, SunRock Biopharma S. L., Other Relationship; Precsion Diabetes, Inc. M. Zulueta: None. A. L. Calle: None. M. Arregi: Employee; Patia Biopharma S. A. J. Valerio deogracia: None. A. M. Ramos levi: None. A. Barabash: None. N. García de la torre: Other Relationship; Ferrer. E. Arana: None. I. Urrutia: None. S. Gaztambide: None.
16-OR: Protein Kinase C d Mediates Cytokine-Induced ß-Cell Death via Upregulation of Pro-apoptotic Signaling
Authors: COLLINS JILLIAN , FARNSWORTH NIKKI L. , BENNINGER RICHARD K. 
Published: May 2022

In type 1 diabetes (T1D) , autoreactive immune cells secrete cytokines, such as tumor necrosis factor-α (TNF-α) , interleukin-1β (IL-1β) , and interferon-γ (IFN-γ) that can initiate β-cell apoptosis. Protein kinase C delta (PKCδ) plays a role in mediating cytokine-induced β-cell apoptosis; however, the exact mechanisms and role in T1D are unknown. We hypothesize that PKCδ mediates cytokine-induced β-cell apoptosis via nuclear translocation and activation of pro-apoptotic signaling. Islets from WT or mice with a β-cell specific knockout of PKCδ (PKCδβ-KO) were cultured for 24hr with cytokines (10ng/ml TNFα, 5ng/ml IL-1β, 100ng/ml IFN-γ) , a caspase-3 inhibitor (Z-DEVD-FMK, 10µg/ml) , or an adenoviral vector for GFP-tagged PKCδ, GFP only, and a PKCδ mutant that cannot be cleaved by caspase-3 (CM-GFP-PKCδ) . Human islets were treated with 10μM PKCδ inhibitor (δV1-1) for 24hr with or without cytokines. Translocation was determined by GFP colocalization with a nuclear stain. Apoptosis was determined by fluorescent microscopy. PKCδ activity was determined with a FRET-based sensor in MIN6 cells. PKCδ’s role in activating pro-apoptotic signaling was determined via western blot. Decreasing PKCδ activity protected against cytokine-induced apoptosis in mouse (p=0.003) and human (p=0.020) islets. PKCδ translocation and activity increased in nuclei of cytokine treated islets (p&lt;0.001, p=0.039) compared to untreated controls. Islets treated with caspase inhibitor (p&lt;0.001) and CM-GFP-PKCδ islets were protected from cytokine-induced death. Western blot analysis demonstrates that PKCδ regulates pro-apoptotic signaling. Inhibiting PKCδ protected islets from cytokine-induced death. The role we identified for PKCδ in mediating pro-apoptotic proteins will provide novel insight to protect against cytokine-induced β-cell death. Our data suggests targeted inhibition of PKCδ has the potential to prevent cytokine-mediated β-cell death in T1D.

Disclosure
J.Collins: None. N.L.Farnsworth: None. R.K.Benninger: n/a.

Funding
American Diabetes Association (7-21-JDF-020) ; Juvenile Diabetes Research Foundation (1-FAC-2020-891-A-N)
161-OR: Cognitive Impairment in Individuals with Post-Bariatric Hypoglycemia
Authors: SHAMLOO TERMEH , CRAIG COLLEEN M. , SNYDER MICHAEL , MCLAUGHLIN TRACEY 
Published: May 2022

Background: Post-bariatric hypoglycemia (PBH) is characterized by repeated episodes of severe hypoglycemia accompanied by neuroglycopenic signs and/or symptoms. Many individuals with PBH report chronic symptoms of cognitive impairment even when blood glucose values are not acutely low. In this study, cognitive function in individuals with PBH compared to age- and BMI-matched healthy controls (HC) was assessed using a quantitative visual paired comparison (VPC) task; a measurement validated to predict cognitive decline and Alzheimer’s disease.
Methods: 20 patients with confirmed PBH (plasma glucose &lt;50 mg/dL with concomitant insulin ≥3 uU/mL, other causes having been ruled out) following Roux-en-Y gastric bypass surgery were compared to 54 age- (46±vs. 50±9 yrs, p=0.05) and BMI- (31±vs. 28±4 kg/m2, p=0.07) matched HCs. Patient-reported frequency of clinically-important hypoglycemic events, defined as fingerstick or plasma glucose &lt;60 mg/dL, was collected by standardized questionnaire. The VPC task, which measures cognitive function by utilizing infrared eye tracking to assess the participant’s novelty preference when presented with a series of novel and familiar images, was conducted under standardized conditions when blood glucose was in the normal range in the clinical research unit.
Results: Compared to HCs, PBH patients scored 12% lower on the VPC task (0.65± 0.vs. 0.57 ±0.15, P= 0.005) . The mean VPC score in PBH patients was in the range that predicts a 22% risk of cognitive decline or Alzheimer’s disease over a 3-year period. Among PBH patients, patient-reported frequency of clinically important hypoglycemic events correlated significantly with VPC score (r=0.44, p=0.047) .
Conclusions: Patients with PBH exhibit cognitive impairment when compared to age- and BMI-matched HCs and the degree of impairment correlates with the frequency of clinically important hypoglycemic events.

Disclosure
T.Shamloo: None. C.M.Craig: Employee; Eiger BioPharmaceuticals, Stock/Shareholder; Eiger BioPharmaceuticals. M.Snyder: Stock/Shareholder; January, Inc. T.Mclaughlin: Board Member; January, Inc., Research Support; Merck & Co., Inc., Novo Nordisk, Stock/Shareholder; Eiger BioPharmaceuticals.

Funding
American Diabetes Association (1-19-ICTS-073) ; NIH 1U54DE02378901
162-OR: Effect of Automated Insulin Delivery on Glucose Counterregulation in Long-Standing Type 1 Diabetes
Authors: FLATT ANNELIESE , PELECKIS AMY J. , DALTON-BAKES CORNELIA V. , NGUYEN HUONG-LAN T. , ILANY SARAH , MATUS AUSTIN M. , MALONE SUSAN K. , JANG SOOYONG , WEIMER JAMES , LEE INSUP , RICKELS MICHAEL R. 
Published: May 2022

Automated insulin delivery (AID) systems are likely of value in individuals with long-standing T1D where recurrent hypoglycemia reduces counterregulatory response. This study assessed the impact of 18M AID on counterregulatory response to insulin-induced hypoglycemia in individuals with long-standing T1D and impaired awareness of hypoglycemia.
participants mean±SD age 49±16 years and diabetes duration 34±16 years were initiated on AID systems. CGM outcomes were paired with actigraphy data to assess daytime and sleep hypoglycemia exposure every 3 months. Hyperinsulinemic stepped-hypoglycemic clamp experiments were performed at baseline, 6 and 18 months. Ten and nine participants have been followed-up to 6M and 18M respectively.
Severe hypoglycemia events were reduced from median (IQR) 3 (3-10) to 0 (0-1) events/person·year over 18M (p=0.005) with improved hypoglycemia severity (HYPO, Pre:1134 (808-1686) to 18M:26 (0-128) , p&lt;0.01) and awareness scores (Clarke, Pre:5 (5-6) to 18M:4 (1-5) , p&lt;0.01) . Hypoglycemia exposure was rapidly reduced with effects sustained (%Time&lt;54 mg/dl, Pre:4 (3-7) , 3M:1 (0-1) , 18M:0 (0-1) , p&lt;0.01) and most marked over periods of sleep (%Time&lt;70mg/dl, Pre:11 (4-17) , 3M:1 (0-3) , 18M:0 (0-1) , p&lt;0.001) . Glucose variability was reduced (p&lt;0.01) with more time in range and less in marked hyperglycemia (p=0.02) . HbA1c and insulin dose were not different.
The autonomic symptom response to hypoglycemia improved (Pre:6±2, 6M:6±2, 18M:10±2, p&lt;0.05) with an increase in pancreatic polypeptide (Pre:62±29, 6M:127±44, 18M:187±64 pmol/l, p&lt;0.01) and epinephrine response (Pre:199±53, 6M:332±91, 18M:386±95 pg/ml, p&lt;0.01) . Glucagon and endogenous glucose production response were unchanged.
AID systems lead to a sustained reduction of hypoglycemia exposure and improvement in symptom and epinephrine response however with persistent impairment in glucose counterregulation and so ongoing compromised physiologic defense against hypoglycemia.

Disclosure
A.Flatt: None. I.Lee: Other Relationship; VitalCore Software. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. A.J.Peleckis: None. C.V.Dalton-bakes: None. H.T.Nguyen: None. S.Ilany: None. A.M.Matus: None. S.K.Malone: None. S.Jang: None. J.Weimer: Other Relationship; Neuralert Technologies, Vasowatch.

Funding
Public Health Services research grants: RDK091331, UDK070430, UL1 TR001878, and P30 DK19525
165-OR: Norepinephrine Acts on Glutamatergic Neurons in the Ventromedial Hypothalamus to Stimulate the Release of Counterregulatory Hormones
Authors: APPADURAI DANIEL A. , CHAN OWEN 
Published: May 2022

Release of glutamate in the ventromedial hypothalamus (VMH) is important for stimulating the counterregulatory hormone responses to hypoglycemia. It is currently not known whether VMH glutamatergic neurotransmission is influenced by adrenergic inputs. To address this question, we examined whether ß2-adrenergic receptors are expressed on VMH glutamatergic neurons using immunohistochemistry. Coronal brain sections collected from Sprague Dawley (SD) rats showed fairly extensive co-localization of Vglut2 (a marker of glutamatergic neurons) and ß2-adrenergic receptors. We then used local microinjection in combination with microdialysis to examine whether norepinephrine administration into the VMH stimulated the release of neurotransmitter glutamate and the counterregulatory hormones in the absence of hypoglycemia. About 7-8 rats were randomly allocated to one of two treatment groups: Controls, which received an infusion of artificial extracellular fluid, or the NE group, which received an infusion of 400 nM of norepinephrine. Our results indicate that NE administration into the VMH caused a marked increase in glutamate that was accompanied by an ∼3-fold increase in both plasma glucagon and epinephrine release (P&lt;0.vs. Control) . Our data suggests that NE enhances the release of neurotransmitter glutamate in the VMH that in turn, may stimulate the release of counterregulatory hormones.

Disclosure
D.A.Appadurai: None. O.Chan: None.

Funding
NIH (DK099315)
166-OR: Brain Responses to Hypoglycemia following Contrasting Hypoglycemia Awareness Restoration Strategies: A Comparison of the HARPdoc and HypoAware Studies
Authors: JACOB PETER , AMIEL STEPHANIE A. , NWOKOLO MUNACHISO , CHOUDHARY PRATIK 
Published: May 2022

Background: Restoration of symptoms in response to hypogycemia has been seen in people with type 1 diabetes (T1D) and impaired awareness of hypoglycaemia (IAH) using an education and diabetes technology approach (HypoAware Study) and a psycho-educational approach addressing cognitions (HARPdoc Trial) . We investigated regional brain responses to hypoglycemia following restoration of IAH between the interventions.
Methods: Twelve people with T1D and IAH from HypoAware and from HARPdoc underwent two-step hyperinsulinemic hypoglycemic clamps before and after their intervention. pCASL fMRI brain blood flow images were acquired. A 2x2 study by timepoint ANOVA interaction design was conducted to compare the effect of each intervention on hypoglycemia-euglycemia difference brain blood flow maps. Within group analysis of the difference maps was conducted using paired t-tests.
Results: HARPdoc participants were older, mean±SD age 54.1±12.3 vs. 34.7±9.0 yrs (p&lt;0.001) with similar HbA1c, 7.8±0.9 vs. 7.8±0.7%, Gold score, 6.0±1.0 vs. 6.0±1.0, BMI 24.6±4.6 vs. 24.4±3.6 and diabetes duration 22.2±7.2 vs. 23.6±7.7 yrs (all p&gt;0.05) . Each intervention was associated with enhanced activation in the anterior cingulate cortex (ACC) in within group studies (HARPdoc FWEp=0.048, HypoAware FWEp=0.011) . In the between group analysis, a superior frontal gyrus (SFG) region was more activated at hypoglycemia following HARPdoc than HypoAware (FWEp=0.044) .
Conclusion: We have shown different brain responses to hypoglycemia in treated IAH depending on the therapeutic approach. Enhanced ACC responses were expected following recovery of symptoms. However, the cognitive approach of HARPdoc enhances the hypoglycemia response in the SFG, known to be involved in self-awareness and appreciation of symptoms, is unique to HARPdoc and is consistent with its psychological and cognitive nature. This may increase the potential for lasting effect.

Disclosure
P.Jacob: None. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. M.Nwokolo: None. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker's Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi.

Funding
Juvenile Diabetes Research Foundation (3-SRA-2017-484-S-B)