bluuebunny/crossref_metadata_2025_split huggingface dataset:
1660-P: Rhinosinusitis, Diabetes Mellitus, and Risk of Atrial Fibrillation: A Nationwide Population-Based Cohort Study
Authors: LIU HAN-WEN , FANG YU-ANN , LEE TING-I , LIU JU-CHI 
Published: June 2019

Background: The association between atrial fibrillation (AF) and inflammation has been established. Diabetes mellitus (DM) is associated with increase inflammation and is an independent important risk factor of AF. Moreover, rhinosinusitis is an inflammation of the paranasal sinuses and nasal cavity. However, the association of rhinosinusitis as a risk factor of AF is unknown. The present study aimed to examine the association between rhinosinusitis, DM and AF.
Methods: A total of 229,100 patients with the diagnosis of rhinosinusitis were identified as the study cohort from the Taiwan National Health Insurance Research Database from January 1, 2001, through December 31, 2012. The comparison cohort consisted of patients without rhinosinusitis and were match for age and sex with the study cohort at a ratio of 1:1. Incidence and hazard ratio (HR) of AF were calculated by Multivariable Cox regression models.
Results: The incidence rate of AF was 142.4 per 10,000 person-years (95% CI 136.8-148.0) for the study cohort and 116.5 (95% CI 111.4-121.6) for the comparison cohort. Adjusted HR was 1.17 (95% CI 1.11-1.25) for the total study cohort, 1.18 (95% CI 1.11-1.25) for patients with acute sinusitis and 1.14 (95% CI 1.00-1.31) for chronic sinusitis. In subgroup analysis, HR for patients with DM was 1.23 (95% CI 1.09-1.39) for total study cohort, 1.20 (95% CI 1.06-1.37) for acute sinusitis and 1.44 (95% CI 1.13-1.84) for chronic sinusitis. The risk was less significant for patients with metformin use more than 28 days. HR 1.09 (95% CI 0.94-1.26) for total study cohort, 1.08 (95% CI 0.93-1.26) for acute sinusitis and 1.18 (95% CI 0.85-1.63) for chronic sinusitis.
Conclusion: Rhinosinusitis was associated with the risk of AF. Sinusitis patients with DM had a higher risk than patients without DM. The use of metformin might reduce the risk of AF in DM patients. Further clinical investigation is warranted.

Disclosure
H. Liu: None. Y. Fang: None. T. Lee: None. J. Liu: None.
1663-P: Monophasic Glucose Response Curve Reflective of Glucose Intolerance in Young Mexican Americans
Authors: JENKINS JASMIN , MEZA CESAR , AMADOR MANUEL , MCAINCH ANDREW J. , BAJPEYI SUDIP 
Published: June 2019

The glucose response curve of an oral glucose tolerance test (OGTT) has been associated with insulin sensitivity. A monophasic curve has been shown to be more prevalent in hyperglycemic and T2D population. However, it is unknown whether shape of curve in a healthy normoglycemic population can be indicative of risk for developing T2D.
Purpose: We aimed to determine if glucose response morphology, monophasic (M) versus biphasic (B), may be indicative of glucose tolerance and a family history of T2D (FH).
Methods: Normoglycemic Mexican American Males (mean ± SEM; age 23.26 ± 0.66 years, BMI 25.69 ± 0.97 kg/m2) with (n=7) or without (n=7) a FH participated in this study. Body composition was measured by DXA, substrate utilization was measured by indirect calorimetry, maximal aerobic capacity (VO2max) was measured by a standardized graded exercise test. Participants consumed 75 g of glucose while fasting and blood glucose were assessed at 0, 30, 60, 90, and 120 min. Based on Tschritter et al. (2003) classification, glucose response curves were separated into M (n=10) and B (n=4) groups.
Results: There were no significant differences in body weight, BMI, fat mass, fat free mass, resting substrate utilization, VO2max and fasting blood glucose (BG) between groups (all P &gt; 0.05). However, M were significantly glucose intolerant compared to B evident by a greater glucose area under the curve (M: 263.63 ± 11.34 AU; B: 209.20 ± 4.46 AU; p=0.01) and a significantly greater BG levels during OGTT at minute 30 (149.97 ± 8.53 vs. 110.53 ± 12.60 mg/dl; p=0.02), 60 (149.80 ± 9.33 vs. 104.99 ± 17.21 mg/dl; p=0.03) and 90 (116.48 ± 6.62 vs. 71.71 ± 10.11 mg/dl; p&lt; 0.01) compared to B. All individuals with a monophasic OGTT response had a FH whereas most individuals with biphasic OGTT response (7/10) did not.
Conclusion: Although having similar fasting BG, body composition, substrate utilization, and aerobic fitness, a monophasic compared to biphasic, OGTT reflects glucose intolerance and risk for developing T2D.

Disclosure
J. Jenkins: None. C. Meza: None. M. Amador: None. A.J. McAinch: None. S. Bajpeyi: None.
1665-P: Fracture Risk in Patients Using Sodium-Glucose Cotransporter 2 Inhibitors: A Real-World Study
Authors: ABRAHAMI DEVIN , DOUROS ANTONIOS , YIN HUI , YUN YU ORIANA HOI , AZOULAY LAURENT 
Published: June 2019

There are concerns that sodium-glucose co-transporter 2 inhibitors (SGLT2Is) may increase the risk of fractures in patients with type 2 diabetes. To date, large cardiovascular outcome trials have generated conflicting findings, and few real-world studies have been conducted to assess this association. As fracture risk in this vulnerable population is associated with increased mortality, there is an urgent need to address this safety issue using real-world data. Thus, the objective of this population-based cohort study is to determine if use of SGLT2Is is associated with an increased fracture risk in patients with type 2 diabetes. Using the UK Clinical Practice Research Datalink, a large primary care database, we identified a cohort of patients newly treated with antihyperglycemic drugs between January 2013 and December 2017. Use of SGLT2Is was modeled as a time-varying exposure and compared with use of dipeptidyl peptidase-4 inhibitors (DPP-4Is). Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs of incident fractures associated with use of SGLT2Is overall and according to specific SGLT2Is (dapagliflozin, empagliflozin, canagliflozin). We conducted several sensitivity analyses to address potential sources of bias. The cohort included 73,178 patients, which generated 153,179 person-years of observation. During follow-up, 1,973 patients were newly diagnosed with fractures (incidence rate: 12.9/1000 per year). Compared with DPP-4Is, SGLT2Is were not associated with an increased risk of fracture (HR: 0.97, 95% CI: 0.79-1.19). Similar findings were observed when stratifying on specific SGLT2Is, with HRs ranging between 0.67 and 1.42, with all CIs including the null value. The sensitivity analyses yielded highly consistent findings. The results of this large population-based study suggest that use of SGLT2Is is not associated with fracture incidence. This finding should provide reassurance on the safety of this class of drugs.

Disclosure
D. Abrahami: None. A. Douros: None. H. Yin: None. O. Yu: None. L. Azoulay: None.

Funding
Canadian Institutes of Health Research
167-LB: Cost Optimization of Dorzagliatin Using Artificial Intelligence-Powered Population Modeling
Authors: BENNETT BRITTANY , ALLEN SYDNEY , EILERMAN BRADLEY , TESTA LEONARD J. 
Published: June 2019

Introduction: Consideration of the role of new therapeutic agents has taken new dimensions in light of emerging cardiovascular and renal data in addition to consideration of total cost of care. Simulated decision made through Artificial Intelligence systems such as GlucosePATH can be used to determine the fit of new compounds to treating type 2 diabetes. Glucokinase activators are not available as therapeutic agents in the U.S.A. Phase 3 data of dorzagliatin was used to model projected retail cost in the current environment.
Methods: A data set of 366 patients with HbA1c &gt; 7 was drawn from a distribution of patients from the GlucosePATH database. Total monthly cost of care was computed based on the mean retail cost drawn from the GoodRX API. Using scores drawn from GlucosePATH, drugs were redistributed to find the lowest total cost at which the population's score was &gt; 70 out of 100. Total retail cost of care averaged $371.39 per month per patient for the 366 patients. Redistributed medication at this price generated a mean composite score of 80.36 at a projected mean HbA1c of 7.5.
Two price points were established for dorzagliatin. The "maximal price" (MP) is the highest price at which use of the agent in the population does not exceed the control group’s retail cost of care and the composite score threshold is met. (That is, introducing the new agent does not increase cost or worsen results for the population.) The "maximal revenue" (MR) is the price at which the agent’s manufacturer maximizes their gross revenue for the agent in the population.
Results: Price optimization for dorzagliatin showed a MP of approximately $145. At its MP, dorzagliatin would be prescribed to approximately 5% of the population with mean composite score of 80.17 and mean HbA1c 7.5. At dorzagliatin’s MR of approximately $75 per month, it would be prescribed to approximately 23% of the population and generate a mean composite score of 80.54 with a mean HbA1c of 7.5.

Disclosure
B. Bennett: None. S. Allen: None. B. Eilerman: Advisory Panel; Self; Dexcom, Inc., Medtronic. Speaker’s Bureau; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Corcept Therapeutics, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Stock/Shareholder; Self; PATH Decision Support Software LLC. L.J. Testa: Stock/Shareholder; Self; PATH Decision Support Software LLC.
1677-P: Ethnic Differences in the Peri-diagnostic Period of Type 1 Diabetes (T1D)
Authors: TOSUR MUSTAFA , CLEVES MARIO A. , SOSENKO JAY , LIBMAN INGRID , BAIDAL DAVID , REDONDO MARIA JOSE 
Published: June 2019

We have previously shown that Hispanic ethnicity influences progression to T1D with interaction by obesity in children &lt; 12 years of age. In this study, we aimed to compare ethnicities for characteristics in the peri-diagnostic period of T1D. We studied participants in TrialNet New Onset Intervention Trials (n=501, 9.4% Hispanics, 86.4% non-Hispanic whites [NHW], 4.2% non-Hispanic other) followed prospectively. We analyzed clinical, immunological and metabolic characteristics in the peri-diagnostic period of T1D. Mixed meal tolerance tests (MMTT) were performed within 6 months (median: 2 months, range: 4 days - 6 months) following diagnosis and then every 5-6 months in the first 3 years after diagnosis. Race and ethnicity categories were based on self-report and on standard NIH classifications. Unless otherwise indicated, all analyses were adjusted for age, age and sex-adjusted BMI Z-score, sex, as well as days from diagnosis to MMTT. Median ages (IQR) at enrollment were 14.1(6) years in Hispanics and 14.3(7.5) years in NHW. 44.7% of Hispanics and 41.8% of NHW were female. At T1D clinical diagnosis, Hispanics, compared with NHW, had a higher frequency of diabetic ketoacidosis [DKA] (42.9% vs. 22.8%, OR=2.45, p=0.008), lower fasting glucose (97.5 vs. 108.5 mg/dL, p=0.011), higher frequency of ZnT8 autoantibody positivity (n=201, 94.1% vs. 63.5%, p=0.039), and a trend for higher fasting C-peptide (0.39 vs. 0.32 ng/mL, p=0.093). When analyzing C-peptide trajectories by ethnicity in eligible participants (n=310), there were no significant differences during 3-year follow-up after adjusting for BMI-Z score and age (mean C-peptide AUC, p=0.74).
In conclusion, despite ethnic differences in the frequency of DKA, and metabolic and immunological characteristics at clinical diagnosis of T1D, C-peptide trajectories did not differ in the first 3 years following diagnosis between Hispanics and NHW. These findings may inform the design of observational studies and intervention trials in the peri-diagnostic period of T1D.

Disclosure
M. Tosur: None. M.A. Cleves: None. J. Sosenko: None. I. Libman: Consultant; Self; Novo Nordisk Inc. D. Baidal: None. M.J. Redondo: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
1684-P: Using Index60 to Detect Heterogeneity and Identify Subpopulations with Characteristic Type 1 Diabetes (T1D) Profiles among Individuals with Normal Two-Hour Glucose Levels
Authors: NATHAN BRANDON M. , GEYER SUSAN , BOCCHINO LAURA E. , PALMER JERRY P. , JACOBSEN LAURA M. , REDONDO MARIA JOSE , SIMS EMILY K. , SKYLER JAY S. , SOSENKO JAY M. 
Published: June 2019

We assessed whether Index60 could identify subpopulations with heterogeneous T1D features among autoantibody positive (Ab+) individuals with a normal 2-hour glucose. Index60 is a composite measure of fasting C-peptide, 60-minute C-peptide, and 60-minute glucose that has potential utility as a prediabetes endpoint when values are ≥1.00. Baseline 2-hour OGTTs of Ab+ TrialNet Pathway to Prevention participants in the normal 2-hour glucose (&lt;140 mg/dl) range and low Index60 range (&lt;1.00) were studied. The top 2-hour glucose &lt;140 mg/dl quartile was compared with the top Index60 &lt;1.00 quartile for characteristic T1D features (groups mutually exclusive).
Those in the top Index60 quartile (Group B) or in both top quartiles (Group C) had profiles more typical of T1D than those in the top 2-hour glucose quartile (Group A), who had higher C-peptide levels, lower Ab+ frequencies, and were older (Table).
Also, as indicated by within group odds ratios, Group A had less association of DR3-DQ2/DR4-DQ8 with the top quartile (Group A: 1.19, ns; Group B: 1.49, p&lt;0.01; Group C: 1.63, p&lt;0.01).
In summary, Index60 can detect heterogeneity among those with normal 2-hour glucose levels, and identify subpopulations with appreciably more characteristic T1D features. The atypia of Group A demonstrates the importance of this Index60 utility.

Disclosure
B.M. Nathan: None. S. Geyer: None. L.E. Bocchino: None. J.P. Palmer: None. L.M. Jacobsen: None. M.J. Redondo: None. E.K. Sims: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Applied Therapeutics, Dance Biopharm Holdings Inc., Orgenesis Ltd., Tolerion, Inc., Viacyte, Inc. Board Member; Self; Dexcom, Inc., Intarcia Therapeutics, Inc., Moerae Matrix, Inc. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dalcor, Dialogics, Elcelyx Therapeutics, Inc., Esperion, GeNeuro Innovation, Ideal Life, Immunomolecular Therapeutics, Intrexon, Kamada, Nestlé, Sanofi, Valeritas, Inc., Zafgen, Inc. Stock/Shareholder; Self; Dexcom, Inc., Ideal Life, Intarcia Therapeutics, Inc., Intrexon, Moerae Matrix, Inc. J.M. Sosenko: None.

Funding
National Institutes of Health; JDRF
1685-P: Type 1 Diabetes Mellitus and Incident Bladder Cancer: A Systematic Review and Meta-analysis
Authors: OSKOUI HELENA B. , BOGUMIL DAVID D. , KYSH LYNN , BARRETT MALCOLM , SIEGMUND KIMBERLY , CORTESSIS VICTORIA K. 
Published: June 2019

Background: A credible body of epidemiologic evidence documents elevated bladder cancer risk among patients with type 2 diabetes, but risk among those with type 1 diabetes (T1DM) has received less attention. We sought to identify and quantitatively synthesize epidemiologic data on the association between T1DM and incident bladder cancer.
Methods: We searched Medline, Embase, Cochrane, and Web of Science through June 5, 2018, to identify non-redundant English language reports of original human data estimating the association between T1DM and incident bladder cancer addressing age as potential confounder. Additional citations were identified through hand searching efforts including a Google Scholar search, contacting authors, and retrieving citations in selected studies. Candidate reports were critically appraised by two independent reviewers, with conflicts resolved by consensus. Harmonized estimates of the T1DM-bladder cancer association were extracted from qualifying reports and synthesized by random effects meta-analysis.
Findings: Among 7,673 reports identified in the search, 59 warranted critical full text review, and 4 described 7 non-redundant studies satisfying inclusion criteria (N=362 T1DM patients). Estimate of the overall summary odds ratio association was 1.07 (95% CI: 0.87-1.32; I2: 69.1%, p heterogeneity= 0.001; 7 studies). Gender-specific summary estimates were 1.40 (95% CI: 0.95-2.05; I2: 73.9%, p heterogeneity= 0.002; 6 studies) for females, and 0.95 (95% CI: 0.71-1.26; I2: 61.4%, p heterogeneity= 0.024; 6 studies) for males.
Interpretation: Available data reveal a modest positive association between incident bladder cancer and T1DM that does not achieve statistical significance. Etiologic interpretation is precluded by indicators of heterogeneity and design limitations of contributing studies, primarily confounding by smoking and error in measurement of diabetes in referent groups.

Disclosure
H.B. Oskoui: None. D.D. Bogumil: None. L. Kysh: None. M. Barrett: None. K. Siegmund: None. V.K. Cortessis: None.
1686-P: Lifetime Exposure to Diabetic Ketoacidosis Is Associated with Impaired Executive Function among Older Adults with Type 1 Diabetes: The Study of Longevity in Diabetes
Authors: LEIGH MARY E.LACY. , GILSANZ PAOLA , BEERI MICHAL S. , KARTER ANDREW J. , QUESENBERRY CHARLES , WHITMER RACHEL A. 
Published: June 2019

Background: Diabetic ketoacidosis (DKA) is a life-threatening complication common in type 1 diabetes (T1D). DKA is associated with short-term cognitive impairment in children and adolescents with T1D, but it is unknown if a lifetime history of DKA is associated with poorer cognition in older adults.
Methods: We examined the association between self-reported frequency of lifetime DKA hospitalizations and cognition in 720 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Cognitive tests assessed 4 cognitive domains identified via factor analysis (language, executive function, episodic memory, attention). We examined: 1) the association between DKA and cognitive domains using adjusted linear regression; and 2) frequency of cognitive impairment (1.5 SD below mean) by DKA exposure.
Results: Overall, 28% of participants reported DKA resulting in hospitalization in their lifetime (18% had 1 hospitalization; 10% had 2+ hospitalizations). Compared to those with no DKA hospitalizations, those with 2+ had lower executive function scores and were more likely to have impaired executive function. Language, episodic memory and simple attention did not differ by DKA.
Conclusions: In older adults with T1D, lifetime exposure to DKA is associated with long-term impairment in cognition, specifically through executive function.

Disclosure
M.E.L. Leigh: None. P. Gilsanz: None. M.S. Beeri: None. A.J. Karter: None. C. Quesenberry: None. R.A. Whitmer: None.

Funding
National Institutes of Health (R01AG047500, T32AG049663, R01DK103721, R01DK081796, P30DK092924); Patient-Centered Outcomes Research Institute (PPRN-1306-04709)
1691-P: A Variant in the Melanocortin-4 Receptor (MC4R) Locus Is Associated with Glycemic Control and Insulin Resistance (IR) in Type 1 Diabetes (T1D)
Authors: MILLER RACHEL G. , COSTACOU TINA , ONENGUT-GUMUSCU SUNA , CHEN WEI-MIN , RICH STEPHEN S. , ORCHARD TREVOR J. 
Published: June 2019

The MC4R gene (18q21.32) plays a role in regulating appetite and energy homeostasis and is consistently linked with obesity. A variant near MC4R (rs12970134) has also been associated with IR and type 2 diabetes, independent of BMI. We examined the association of rs12970134 with HbA1c, IR, and BMI in the Pittsburgh Epidemiology of Diabetes Complications study, a prospective T1D cohort (mean age 27, T1D duration 18 years at baseline, 1986-88). In 422 EDC participants of European ancestry with available DNA, we assessed associations between 16 published IR SNPs, including rs12970134, and longitudinal measures of HbA1c, estimated glucose disposal rate (eGDR, an inverse measure of IR), and BMI over 18 years of follow-up (1986-88 to 2004-06). General additive mixed models were adjusted for sex, T1D duration, and principal components of ancestry. The rs12970134 SNP was associated with longitudinal HbA1c (β=0.33, p=5x10-5, see Figure) and eGDR (β=-0.31, p=0.008) trajectories, but not BMI (β=0.21, p=0.38). The associations remained significant after adjusting for BMI and insulin dose. There was no evidence for a SNP x time interaction (p&gt;0.25 for both); all groups showed a similar fall in HbA1c after publication of the DCCT results. Thus, the rs12970134 SNP near MC4R is associated with glycemic control and insulin resistance, despite no association with BMI, in this T1D cohort.

Disclosure
R.G. Miller: None. T. Costacou: None. S. Onengut-Gumuscu: None. W. Chen: None. S.S. Rich: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH.

Funding
National Institutes of Health; Rossi Memorial Fund; JDRF
1694-P: A New Developmental Model of Type 1 Diabetes—An Association between Autoimmunity, the Dynamics of Gut Amyloid-Producing E. Coli, and Their Phages
Authors: TETZ GEORGE 
Published: June 2019

Background: The increase in incidence of type 1 diabetes (T1D) is not solely a result of genetics and environmental factors, but also that of gut microbiota, which play a crucial role in disease onset.
Methods: We performed a longitudinal microbiome analysis (Illumina Hiseq2500) in children (0-3 years) with HLA-susceptibility to T1D, using an algorithm focusing on amyloid producing bacteria. This analysis revealed an overlooked association between autoimmunity and the dynamics of gut amyloid-producing E. coli.
Results: Our analysis revealed a statistically significant association between the development of autoantibodies in T1D HLA-susceptible children and (i) significantly (p&lt;0.05) high initial (0-12 months of age) abundance of gut amyloid-producing E. coli, (ii) depletion of E. coli prior to seroconversion due to prophage induction, and (iii) triggering of islet autoimmunity and T1D development. Notably, alterations in E. coli abundance were identified only in children who further developed seroconversion and T1D. E. coli depletion was found before the appearance of antibodies, suggesting a role of E. coli in disease onset. Further, our in vitro study revealed a highly immunogenic complex (amyloid curli-DNA composites) released from E. coli biofilms upon prophage induction, which triggered the production of type I IFN through the TLR2/9 stimulation of β-cells and DCs, and autoimmune cascade through the TLR-2-MyD88-NF-kB pathway.
Conclusions: Our study suggests that E. coli biofilm-derived highly immunogenic amyloid curly-DNA complexes might be involved in the activation of a pro-diabetic pathway in children who are at a risk of T1D. Besides, amyloid protein producing E. coli and their phages are the factors associated with T1D development that were previously overlooked.

Disclosure
G. Tetz: None.