bluuebunny/crossref_metadata_2025 huggingface dataset:
Community context modifies response of host-parasitoid interactions to phenological mismatch under warming
Authors: Pardikes Nicholas , Revilla Tomas , Lue Chia-Hua , Thierry Melanie , Souto-Villaros Daniel , Hrcek Jan
Published: June 2021

Climate change is altering the relative timing of species interactions
by shifting when species appear in a community and by accelerating
developmental rates. However, phenological shifts may be mediated
through community contexts, such as intraspecific competition and
alternative resource species, which can prolong the otherwise shortened
windows of availability. Using a combination of laboratory experiments
and dynamic simulations, we quantified how the effects of phenological
shifts in Drosophila-parasitoid interactions differed with concurrent
changes in temperature, intraspecific competition, and the presence of
alternative host species. We found that community context, particularly
the presence of alternative host species, supported interaction
persistence across a wider range of phenological shifts than pairwise
interactions. Parasitism rates declined under warming, which limited the
ability of community contexts to manage mismatched interactions. These
results demonstrate that ongoing declines in insect diversity may
exacerbate the effects of phenological shifts in ecological communities
under future global warming temperatures.
Severity of respiratory disease is correlated with time of first oral feeding and need for a gastrostomy tube at discharge in premature infants born at <30 weeks of gestation
Authors: Anderson Emily , Gregoski Matthew , Gehle Daniel , Head William , Hardy Thomas , Chapman Alison , Ryan Rita
Published: June 2021

Background: Premature infants who cannot achieve full oral feeds may
need a gastrostomy tube (GT) to be discharged from the neonatal
intensive care unit (NICU). We previously developed a model to predict
which infants born <30 weeks (w) gestational age (GA) will
require a GT before discharge. Here we report the detailed respiratory
variable data to describe the general respiratory course for infants in
the NICU <30w GA at birth and the association between
different levels of respiratory support with postmenstrual age (PMA) at
the time of first oral feeding attempt (PMAff), including later need for
GT for discharge. Methods: Retrospective chart review of 391 NICU
admissions comprising test (2015-2016) and validation (2017-2018)
cohorts. Data, including respiratory support, were collected on 204
infants, 41 GT and 163 non-GT, in the test cohort, and 187 infants, 37
GT and 150 non-GT, in the validation cohort. Results: Respiratory data
were significantly different between GT and non-GT infants. Infants who
required GT for discharge were on significantly higher respiratory
support at 30 days of age, 32w PMA, and 36w PMA. Respiratory parameters
were highly correlated with PMAff. Conclusion: Respiratory status
predicts PMAff, which was the variable in our previously described model
that was most predictive of failure to achieve full oral feeing. These
data provide a catalyst to develop strategies for improving oral feeding
outcome for infants requiring prolonged respiratory support in the NICU.
Effect of TiO2 on mullite formation in mixture of Nigeria sourced kaolinite and calcined alumina
Authors: Aladesuyi Olanrewaju , Das Swapan , Ajanaku Kolawole
Published: June 2021

In this study, the effect of TiO2 when added to a mixture of Nigerian sourced
of kaolin and calcined alumina powder (50:50) was investigated. The
influence of Ti4+ ion on the physico-mechanical property (apparent porosity,
bulk density and modulus of rupture), phase and microstructural evolution
was studied at sintering temperature of 1600?C when mullitisation has been
maximized based on previous reports. The sintered samples showed
considerably high porosity of about 16 %, a slight reduction of about 5 % in
porosity was observed on TiO2 addition. There was no appreciable change in
the bulk density due to TiO2 doping, but the modulus of rupture (MOR)
reduced appreciably from 43 MPa to 36 MPa on TiO2 doping. As shown by the
XRD, mullite was seen as the major phase with negligible cristobalite phase
for the undoped sample. The TiO2 doped sample displayed mullite as major and
corundum as minor phases. There appeared more mullite phases in the doped
sample than the undoped sample indicating a higher percentage of mullite
formation. The microstructural study shows the presence of acicular mullite
with round edges and good aspect ratio. The presence of inter-granular and
intra-granular pores in TiO2 doped samples might have contributed to the
reduction in strength observed at 1600?C.
Preparation, microstructure studies and mechanical properties of glazes ceramic sanitary ware based on kaolin
Authors: Benkacem Samra , Boudeghdegh Kamel , Zehani Fouzia , Hamidouche Mohamed , Belhocine Youghourta
Published: June 2021

In this paper, the use of local kaolin coming from Djebel Debbagh (denoted
DD1) in the composition of ceramic glazes for sanitary ware was examined.
Because of its natural abundance, low price and good characteristics, this
kaolin represents an interesting economic alternative to other mineral
clays. The chemical composition showed that this kaolin contains 38.49 wt.%
Al2O3 and 44.85 wt.% SiO2. Two glazes based on kaolin DD1 denoted as GaDD1
and GbDD1 were prepared with conventional ceramic processing techniques at
temperature 1250 oC. As a reference, another glaze (Gref) based on kaolin
Remblend was also prepared in the same conditions. The samples were
characterized with X-ray diffraction and Scanning Electron Microscope. The
results revealed that zircon and quartz are the crystalline phases present
in these glazes. In the sample GaDD1, it was found that the degree of
whiteness is very high and reaches 93.30 %. However, the water absorption
coefficient is low which is about 0.19 ? 0.04 %. In addition, the flexural
strength and the Vickers microhardness are respectively, about 56.07 ? 5.61
MPa and 7952.80 ? 101.76 MPa. These properties are compatible with those of
the glaze reference Gref and commercial sanitary ware glazes, indicating the
potential use of kaolin DD1 in the production of glazed ceramic for sanitary
ware applications.
Traditional folk economic buildings on the Tara mountain
Authors: Matic Milos
Published: June 2021

Traditional folk architecture on Tara mountain, generally speaking, belongs
to cultural areal of traditional building of dinarska brvnara type, i.e.
building made of wood. In direct connection with Zlatibor mountain, where we
can find some of the best examples of vernacular architecture, traditional
building on Tara mountain does not show any specificity but at the same time
does not lag behind comparison with other regions with the same type of
building. In this paper we are presenting results of ethnographic field
research in traditional folk construction of economic buildings. The field
research was accomplished during years 2015 and 2016 in villages on Tara.
The emphasis is on the economic buildings which are directly derived from
structure of economic activities of rural population and we are taking into
account both traditional and contemporary economic buildings. In this paper
basic forms of organisation of space in households are presented as well.
Preliminary analysis of the economic buildings on Tara shows that they
clearly follow needs of traditional economy, needs which are determined with
the culture of social organization as well as with the structure of economic
organization. Construction and architecture of economic buildings also
points out that they are on high utilitarian level and that they can
represent relations between some economic activities.
1015-P: Cost of Diabetes Complications in U.S. Adults Aged 65 Years or Older
Authors: WANG YU , ZHANG PING , SHAO HUI , ANDES LINDA J. , IMPERATORE GIUSEPPINA
Published: June 2021

This study estimated the cost associated with 17 diabetes complications and treatment procedures (hypoglycemia, ketoacidosis, photocoagulation, retinopathy intravitreal injections, nephropathy, dialysis, kidney transplantation, neuropathy, foot ulcer, lower-extremity amputation, retinopathy, blindness, congestive heart failure, myocardial infarction, stroke, angina, revascularization) among US Medicare beneficiaries. Data were from 100% Medicare fee-for-service claims from 2006 to 2017. ICD 9, ICD 10, and diagnosis-related group codes were used to identify persons ≥65 years old with diabetes by type and diabetes complications. We used a longitudinal cohort design in which persons with diabetes were followed from the index year until death, exiting the health plan, or December 31, 2017, whichever came first. The index year was the year when diabetes code first appeared in inpatient claims, or in outpatient claims combined with another diabetes claim in the following 2 years. We used person-level fix-effect regression models to estimate the cost of each complication in the year when the event occurred and the follow-up years for non-acute complications. All costs were standardized to 2017 dollars. Our study included 11,028,910 patients with type 2 diabetes (T2D) and 195,546 with type 1 diabetes (T1D) in 10 cohorts. The follow-up times of the 10 cohorts ranged from 3 to 10 years. Costs of the diabetes complications varied from $375 to $ 86,639. The top three costliest complications were kidney transplantation (T2D: year of occurrence $86,639 vs. following years $15,898, T1D: $78,684 vs. $8,545), dialysis (T2D: $63,079 vs. $42,751, T1D: $60,772 vs. $43,214), and lower-extremity amputation (T2D: $45,142 vs. $8,079, T1D: $44,813 vs. $8,025). Our cost estimates provide the cost parameter needed by type 1 and type 2 diabetes simulation models and by economic evaluation of efforts to prevent/delay diabetes complications.

Disclosure

Y. Wang: None. P. Zhang: None. H. Shao: Research Support; Self; Sanofi. L. J. Andes: None. G. Imperatore: None.
1019-P: Outcomes of Hospitalized DKA Patients with Hypocalcemia: An Analysis of National Inpatient Sample
Authors: MURTHI MUKUNTHAN , CORPUZ CARLOS GABRIEL D. , VELAGAPUDI SUJITHA , RAMIREZ MARCELO , ATLURI RAMTEJ , SHAKA HAFEEZ
Published: June 2021

Background: Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus (DM), associated with significant mortality. Patients frequently develop a constellation of electrolyte disturbances, including hypocalcemia. We wanted to analyze the in-hospital outcomes of DKA patients with hypocalcemia.

Methods: We conducted a retrospective observational study using the National Inpatient Sample (NIS) from 2017 and 2018. Patients with type 1 and 2 DM with a principal diagnosis of DKA were selected and stratified based on the presence of hypocalcemia. The primary outcome was in-hospital mortality. The secondary outcomes included the development of sepsis, acute kidney injury (AKI), Acute respiratory failure(ARF), cerebral edema (CE), length of stay (LOS), and total charges. Confounders were adjusted for using multivariate regression analysis. We included AKI and Sepsis in the multivariate analysis for mortality since hypocalcemia can be seen in both conditions.

Results: Out of 379,614 DKA admissions during the study period, 6894(1.8%) had hypocalcemia. When adjusted to patient characteristics, co-morbidities and hospital characteristics, those with hypocalcemia had higher odds of AKI (aOR=1.28, CI=1.13-1.45, p=<0.001), sepsis (aOR=2.88, CI=2.07-4.01, p=<0.001), ARF (aOR=3.23, CI=2.59-4.03, p=<0.001) and CE (aOR=2.51, CI=1.24-5.12, p=0.011) compared to those with only DKA. When adjusted to the occurrence of AKI and sepsis, patients with hypocalcemia and DKA had higher odds of in-hospital mortality (aOR= 2.61, CI=1.47-4.64, p=0.001), longer LOS (+1.01 day, CI 0.79-1.24, p<0.001) and higher total hospital charges (+$14,649, CI $11,442-17,855, p<0.001).

Conclusion: Hypocalcemia is associated with increased odds of mortality in patients admitted with DKA and it could be used as a disease severity marker. Further studies need to be done to determine if hypocalcemia in DKA is merely a predictive factor or a direct contributor to increased mortality.

Disclosure

M. Murthi: None. C. D. Corpuz: None. S. Velagapudi: None. M. Ramirez: None. R. Atluri: None. H. Shaka: None.
1024-P: Association, Prevalence, and Occurrence of Depression and Anxiety in Indian T2DM Patients
Authors: KUMAR NAWEEN , CHANDRA ABHISHEK K. , AHSAN SAJJAD , KUMAR ABHISHEK
Published: June 2021

Background: Depression is found to be common among patients with diabetes and it is associated with poor outcomes in disease control. Mani objective of the study was to study the prevalence and occurrence of depression and anxiety in patients of type 2 diabetes mellitus (T2DM).

Materials:115 adults with T2DM without prior diagnosis of depression and 115 matched controls were evaluated. Sociodemographic and relevant clinical variables were collected. They were evaluated for depression and anxiety using Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale respectively.

Results: Significantly larger proportion of diabetic patients had depression [32 (27.8%) vs. 11 (9.57%), P = 0.005), anxiety (38 (33%) vs. 16 (13.9%, P = 0.005) and comorbid depression and anxiety (28 (24.3%) vs. 10 (8.7%), P = 0.005) as compared to healthy controls. The prevalence rate of depression was higher in age between 41 and 60 years (18.8% vs. 7.6%, respectively) in diabetic and healthy control group. Diabetic women had higher depression (21.2% vs. 8.7%) and anxiety (18.8% vs. 9.7%) than men. Depression was found significantly associated with retinopathy 28.6% (p=0.005), nephropathy 16.3% (p=0.005) and ischemic heart disease (IHD) 17.2% (p=0.005) in the present study. Comorbid depression and anxiety was significantly associated with age (40-60 years), obesity (BMI ≥ 25 kg/m2), poor glycemic control (≥7.5%), insulin therapy, nephropathy, neuropathy, and IHD but no significant association was found with education level.

Conclusion: This study found a high proportion of depression and anxiety among patients with T2DM. Public health measures are required to create more awareness for managing depression in diabetes.

Disclosure

N. Kumar: None. A. K. Chandra: None. S. Ahsan: None. A. Kumar: None.
1045-P: Impact of Type 2 Diabetes Mellitus with Hyperosmolar Hyperglycemic State on Patients Admitted for Heart Failure: Insights from the National Inpatient Sample
Authors: ASEMOTA IRIAGBONSE R. , SHAKA HAFEEZ , EDIGIN EHIZOGIE , ALMANI MUHAMMAD USMAN , AKUNA EMMANUEL
Published: June 2021

Background: Diabetes and Congestive Heart Failure frequently coexist in the same patients. This aim of the study was to compare the adverse outcome rates of diabetic patient admitted for hyperosmolar hyperglycemic state with concomitant heart failure compared to those without heart failure.

Method: Data were obtained from The National Inpatient Sample (NIS) 2016 and 2017 Database. The NIS was searched for hospitalization for HF as principal diagnosis with and without a secondary diagnosis of diabetes mellitus type 2 with hyperglycemic hyperosmolar state (DM2 with HHS) using International Classification of Diseases, Tenth Revision (ICD-10) codes. Multivariate logistic and linear regression analysis was used accordingly to adjust for possible confounders.

Results: The combined 2016 and 2017 NIS database contained 2,586,684 hospitalizations for adult patients (aged ≥ 18 years) with a principal ICD-10 diagnosis for DM2 with HHS. Among this group, 500 (1.1%) had co-existing HF. Of note, patient admitted for HHS with secondary diagnosis of HF had increased inpatient mortality but did not reach statistical significance (2.0% vs. 0.7%, AOR:1.66, 95% CI 0.41-6.67, p<0.474) compared to those without HF. The adjusted mean LOS in patients with HHS and coexisting HF increased by 2.7 days (7.4 days vs. 3.7 days, 95% CI 1.15-4.24, p=0.001) longer than those without HF. Patient hospitalized with HHS with coexisting HF had higher adjusted mean total hospital charge of $31,287 ($71,589 vs. $32,082, CI 9,677-52,897, p=0.005) compared to those without HF.

Conclusion: Patients admitted for HHS with co-existing heart failure have similar inpatient mortality, however Total hospital charges and LOS were increased in those with HF compared to the patients without HF. Patients with concomitant heart failure and diabetes have diverse pathophysiological mechanism that may contribute to worse outcomes that need to be explored further.

Disclosure

I. R. Asemota: None. H. Shaka: None. E. Edigin: None. M. Almani: None. E. Akuna: None.
1048-P: Factors Contributing to Early Mortality in Persons with Type 2 Diabetes with Lower Extremity Amputation
Authors: CHAN JEFFREY , YAN KUN
Published: June 2021

Introduction: Type 2 diabetes continues to be one of the most common and costly conditions in the United States. Complications and co-morbidities that develop, such as amputations, add to the financial toll and can reduce the life expectancy of these individuals. The aim of this study was to identify risk factors that lead to early mortality (12 months or less) following subacute inpatient, interdisciplinary rehabilitation at a VA Community Living Center (CLC).

Methods: A retrospective medical chart review was conducted on forty-seven Veterans who had a lower extremity amputation and died between 2015-2018. Demographic variables collected included age, months between discharge and death, and social support at home. Conditions on status of hypertension, type 2 diabetes, coronary artery disease, congestive heart failure, smoking status, end-stage renal disease and chronic renal disease were gathered at date of death.

Results: The mean age at CLC admission was 68 years and the average time of death was 14.2 months after discharge. It was shown that 50.5% of the patients returned home to social support. Mean HbA1c was 7.1% prior to amputation. A multiple logistic regression was performed associating status of persons with type 2 diabetes (P=.043, 95% CI = .09 - 5.25) and concurrent chronic renal disease (P=.02, 95% CI = .33 - 4.79) leading to death at less than 12 months. There was no significant relationship between hypertension, smoking, age, end-stage renal disease, congestive heart failure with mortality after discharge from the CLC. No association was found between pre-operative HbA1c status and survivorship.

Conclusion: There was a relationship between those who died within 12 months and diagnosis with both type 2 diabetes and chronic renal disease after an inpatient stay at a VA Community Living Center. These results suggest diabetes along with concurrent chronic renal disease management needs to be maintained after an inpatient stay to prevent premature death.

Disclosure

J. Chan: None. K. Yan: None.
1057-P: Predictors of Food Insecurity among Ambulatory Patients with Diabetes
Authors: ALVER AMALIE , BASU ARPITA , CAPURRO ANTONINA , GEWELBER CIVON L. , BACA KRISTIN , WILLIAMS SHELLEY J. , EBERSOLE JEFFREY L. , BATRA KAVITA , PATEL AMRITA M. , IZUORA KENNETH
Published: June 2021

Background: Limited access to adequate, affordable, and nutritious foods can drive adverse outcomes in patients with diabetes mellitus (DM). Understanding factors that impact food insecurity is vital in developing strategies to improve holistic health outcomes among patients with DM.

Method: Seventy-one ambulatory patients with type 2 DM were recruited using an investigator-administered questionnaire and chart review. Variables on demographics, oral health, DM outcomes, and accessibility to healthy food were collected. Their oral health was inspected. Data were analyzed using multiple logistic regression.

Results: Among study participants, 60.6% were female, 63.4% were non-white, mean age: 64.10±10.3 years, mean duration of diabetes: 15.80 ±9.1 years, and mean HbA1c: 7.80 ±1.5%. Vascular complications were present among 66.2% of participants. The logistic regression model was statistically significant (p < 0.0001) and explained 44.5% of food insecurity variance. Significant predictors of food insecurity include having less than high school education (OR 12.6, p = 0.04), living below the federal poverty threshold (OR 4.3, p = 0.04), and younger age (OR 0.91, p = 0.01). Race/ethnicity, gender, oral health indicators, and DM complications did not significantly predict food insecurity.

Conclusions: In our study sample, younger patients with less than high school education and living below the federal poverty threshold were at higher risk of food insecurity. These findings underscore the need for targeted interventions among this high-risk group to reduce food insecurity and improve DM outcomes.

Disclosure

A. Alver: None. K. Izuora: None. A. Basu: None. A. Capurro: None. C. L. Gewelber: None. K. Baca: None. S. J. Williams: None. J. L. Ebersole: None. K. Batra: None. A. M. Patel: None.
1064-P: Trends in Heavy Metal Mixtures among U.S. Adults by Diabetes and Cardiovascular-Renal Diseases in NHANES, 1999-2016
Authors: YANG JINGLI , LO KENNETH , YANG AIMIN
Published: June 2021

Background: Growing evidences have linked the exposure to heavy metals to the risk of type 2 diabetes (T2D), cardiovascular diseases (CVD), and chronic kidney disease (CKD). In the present analysis, we examined secular trends in levels of four toxic metals (arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg)) in urine among adults aged 20 years or above from nine cycles of National Health and Nutrition Examination Survey (NHANES 1999-2016).

Methods: We calculated the age- and sex-standardized geometric means of urinary metal levels, and further stratified them by comorbidities including T2D, CVD and CKD. Joint-point regression model was used to estimate trends over time.

Results: A total of 17,083 participants were included. Urinary Cd (4.35*10-2-3.70*10-2 μg/g creatinine; AAPC=-1.1, 95% CI= -1.5, -0.7), Pb (6.53-4.62 μg/g creatinine; AAPC=-2.2, 95% CI= -2.6, -1.9), Hg (6.58-3.80 μg/g creatinine; AAPC=-2.7, 95% CI= -3.6, -1.8) declined during 1999 and 2016, and urinary As (2.58-2.34 μg/g creatinine; AAPC=-0.9, 95% CI= -2.1, 0.2) declined during 2003 and 2016. When stratified by comorbidities, in 2009-2010, urinary As was higher among participants with T2D, CVD or CKD. Urinary Cd was higher among participants with T2D in the 2003-2004 survey, among participants with CVD in the 1999-2000 survey, and among participants with CKD in the 2007-2008 survey. In the 1999-2000 survey, urinary Pb was higher among participants with T2D, CVD or CKD. Urinary Hg was higher among participants with T2D in the 2005-2006 survey, among participants with CVD in the 2001-2002 survey, and among participants with CKD in the 1999-2000 survey.

Conclusion: The levels of toxic heavy metal in urine have inclined among U.S. adults in the past 18 year but the extent varied by comorbidities.

Disclosure

J. Yang: None. K. Lo: None. A. Yang: None.
108-OR: Islet-Derived Preproinsulin T Cell Receptor Sequences Are Present throughout the Stages of Type 1 Diabetes Development
Authors: BASCHAL ERIN E. , MITCHELL ANGELA M. , MCDANIEL KRISTEN , ALKANANI AIMON , ARMSTRONG TAYLOR , LANDRY LAURIE , WAUGH KATHLEEN , REWERS MARIAN , NAKAYAMA MAKI , MICHELS AARON W.
Published: June 2021

Type 1 diabetes (T1D) results from the T cell-mediated destruction of insulin-producing pancreatic β-cells as evidenced by CD8 and CD4 T cells being present within the inflamed islets of recent-onset T1D organ donors. We isolated, sequenced the T cell receptor (TCR) from ∼3,500 T cells in the residual islets of T1D organ donors (n=9), and determined antigen specificity to 41 preproinsulin-reactive T cells from these islet sequences. Among the T1D organ donor islet sequences, 32% are shared (identical Vβ, Jβ, CDR3β) within the peripheral blood of new-onset T1D patients that had sequencing done from whole blood DNA (n=162, 34x106 TCR sequences, Adaptive Biotechnologies). Similar numbers of sequences are shared between both CD4 and CD8 T cells. Furthermore, 53 unique sequences were disease-specific, as they were identified in <1% of TCR sequences from controls (n=786, 275x106 sequences), whereas they were detected in 54% of new-onset T1D patients (p<0.001). These disease-specific and preproinsulin-reactive TCR sequences are good candidates for biomarkers in T1D. Therefore, we next sequenced the TCR beta chains throughout the disease course of five participants in the Diabetes AutoImmunity Study in the Young (DAISY) at 4 time points (early in life, prior to islet autoantibody seroconversion, post-autoantibody seroconversion, and at T1D onset). 10% of these insulin-reactive TCR sequences, including those to hybrid insulin peptides, are present throughout the disease course. Interestingly, insulin-reactive CD4 TCRs were predominant early in life, while higher frequencies of both insulin-reactive CD8 and CD4 were present at clinical T1D diagnosis. With continued TCR sequencing from longitudinal patient samples across the stages of T1D and identifying antigen specificity to more islet-derived T cells outside of preproinsulin, TCR sequences from genomic DNA have the potential to be a powerful disease biomarker during the progression to clinical type 1 diabetes.

Disclosure

E. E. Baschal: None. A. W. Michels: Stock/Shareholder; Self; IM Therapeutics. A. M. Mitchell: None. K. Mcdaniel: None. A. Alkanani: None. T. Armstrong: None. L. Landry: None. K. Waugh: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research & Development, LLC, JDRF. M. Nakayama: None.

Funding

National Institutes of Health (DK108868, DK110845, DK032083, DK099317, DK032493)
1106-P: Glycemic Burden and Obesity Independently Increased Risk of Liver Cancer in Type 2 Diabetes: Hong Kong Diabetes Register (1995-2019)
Authors: MAO DANDAN , LAU ERIC S.H. , YANG AIMIN , WU HONGJIANG , SHI MAI , KONG ALICE P. , MA RONALD C. , CHOW ELAINE , LUK ANDREA , CHAN JULIANA C.
Published: June 2021

The incidence of liver cancer and related mortality is increasing globally. Liver is a major site for glucose metabolism. People with type 2 diabetes (T2D) had increased risk of liver cancer. However, the association of glycemic burden (GB) with liver cancer in T2D remains unclear. We calculated GB using area under the curve above 5.7% of HbA1c (AUC_A1c) in patients with T2D enrolled in the prospective Hong Kong Diabetes Register established since 1995. Structured baseline data were linked to laboratory and hospitalization records in a territory-wide electronic medical record system with data censored in 2019. We performed Cox regression analysis to investigate the association of GB with incident liver cancer defined as first hospitalization with ICD9 code (155). We included 18,173 patients (50.93% male, age: 58.43±12.48 years, HbA1c: 7.58±1.66%, BMI: 25.51±4.06 kg/m2, disease duration: 20.68 ±7.63 years), who had ≥ 10 years of disease duration, > 3 years of observation, and ≥ 5 HbA1c measurements (21.98±12.33). During a median (IQR) follow up period of 10.62 (8.09, 15.88) years (218,381patient-years), 160 patients developed liver cancer with an incidence of 7.33 per 10,000 patient-years. We excluded 3 years of HbA1c values prior to incident liver cancer to avoid reverse causality. After adjusting for confounders, every 1 unit increase in AUC_A1c increased the hazard ratio (HR) of liver cancer by 1.22 (95% CI: 1.01-1.47), while AUC_A1c top quantile group had a HR of 1.78 (1.01-3.13) versus the lowest quantile group. In subgroup analysis, obese patients (BMI>25 kg/m2) had a HR of 1.34 (1.05-1.70) for liver cancer versus non-obese subjects. Amongst patients who developed liver cancer (n=1420) within 3 years of enrolment, one unit increase of AUC_A1c was associated with a HR of 1.49 (1.07-2.07) for liver cancer. GB and obesity independently increased the risk of liver cancer in T2D, emphasizing the importance of metabolic control for cancer risk reduction.

Disclosure

D. Mao: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. S. H. Lau: None. A. Yang: None. H. Wu: None. M. Shi: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. Luk: None.
111-OR: Macrophage IPLA2ß-Derived Lipid (iDL) Signaling Promote Type 1 Diabetes Development
Authors: ALMUTAIRI ABDULAZIZ , GAI YING , LEI XIAOYONG Y. , STEPHENSON DANIEL , CHALFANT CHARLES , RAMANADHAM SASANKA
Published: June 2021

Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells, and the leading causes for this process are incompletely understood. Our previous work revealed that Ca2+-independent phospholipase A2β (iPLA2β), which hydrolyzes membrane phospholipids at the sn-2 position and releases bioactive lipids, modulates polarization of macrophages (MΦ). Several of the iPLA2β derived lipid signals (iDLs) are proinflammatory, which can initiate immune cell infiltration and β-cell damage. Our recent work suggests that MΦ-derived from spontaneous-T1D prone nonobese diabetic mice (NOD) produce a proinflammatory lipids including (PGE2, 5-HETEs, 20-HETEs, DHETs, LTB4) at the early stage of the disease (4 weeks), interestingly, the proinflammatory lipid signature is similar to a high-risk T1D individuals. Here, we examined the effects of MΦ-iPLA2β iDLs by generating a select conditional decrease in iPLA2β in NOD MΦ (NOD.cMiPLA2𝛽;;;;+/-). We found that (1) that the selective decrease of iPLA2β in MΦ significantly reduces T1D incidence and immune cell infiltration to the islets in the NOD mice. (2) NOD.cMiPLA2𝛽;;;;+/- bone marrow-derived (BMD) MΦ are skewed towards an anti-inflammatory phenotype in comparison to NOD BMD MΦ, favoring an anti-inflammatory phenotype. (4) Selective inhibition of (PGE2 and DHETs) shifted NOD MΦ towards an anti-inflammatory phenotype. These findings suggest that MΦ-iDLs contribute to T1D development, and inhibition of select iDLs production can be targeted to counter T1D development.

Disclosure

A. Almutairi: None. Y. Gai: None. X. Y. Lei: None. D. Stephenson: None. C. Chalfant: None. S. Ramanadham: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743)
112-OR: Adoptive Transfer of CD4+ T Cells with Reduced iPLA2b Expression Mitigates T1D Development
Authors: WHITE TAYLEUR , RAMANADHAM SASANKA , CHALFANT CHARLES , DILORENZO TERESA
Published: June 2021

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic islet β-cells. An understudied area is the role lipid signaling plays in this process. We find that the Ca2+-independent phospholipase A2β (iPLA2β) is induced under a diabetic milieu and mitigation of iPLA2β activity attenuates β-cell death. iPLA2β, a member of the PLA2 family, hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid. When the fatty acid is arachidonic acid, it can be metabolized to eicosanoids, many of which are pro-inflammatory. To address our overarching hypothesis that iPLA2β-derived lipids (iDLs) contribute to T1D development, we investigated the role of immune cell-iDLs by utilizing a splenocyte adoptive transfer protocol. Our findings suggested that reduced iPLA2β expression in splenocytes: (1) delayed T1D incidence, (2) improved glucose homeostasis and (3) reduced the production of iDLs. To further elucidate the link between iPLA2 expression and T lymphocytes in T1D progression, we investigated the role of T-cell derived iDLs by utilizing combinations of T-cell transfers. We isolated CD4+/8+ T-cells from splenocytes prepared from 6-week-old donor NOD and NOD iPLA2β+/- (NOD.HET). These were transferred to 4-week-old immunodeficient NOD.scid recipient mice. We find that: (1) WT4/8 recipient mice develop T1D between 14-16 weeks of age. In contrast, T1D onset in HET4/8 recipient mice is delayed by 16 weeks, (2) temporal IPGTTs reveal that recipient mice of HET4/8 T-cells were more glucose tolerant, compared to recipients of the WT4/8 T-cells, (3) reduced iPLA2β expression in CD4 T cells proved to be effective in delaying T1D progression, and (4) HET donor T-cell production of select pro-inflammatory iDLs is decreased. These findings suggest that iPLA2β in CD4 T-cells is a critical contributor to the production of pro-inflammatory iDLs and could be a potential target in reducing T1D development.

Disclosure

T. White: None. S. Ramanadham: None. C. Chalfant: None. T. Dilorenzo: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743)
1126-P: Activating SKAP2 Mutation Linked to Diabetes with Multiple Autoimmune and Inflammatory Conditions
Authors: CHAMBERLAIN CHESTER , RUTSCH NIKLAS , DIXON WESLEY , LETOURNEAU-FREIBERG LISA R. , PHILIPSON LOUIS H. , GERMAN MICHAEL , ANDERSON MARK S. , LOWELL CLIFFORD A.
Published: June 2021

Recent insights into human autoimmunity and immune tolerance have come from studies of rare monogenic disorders. For example, type 1 diabetes (T1D) and thyroid autoimmunity are frequent features in patients with mutations in AIRE and FOXP3. Dissecting the consequences of these mutations has improved our understanding of the role of central T cell tolerance and T regulatory cells in controlling these organ-specific autoimmune diseases. Over the last decade, rapid advances in genetic sequencing have now allowed for a deeper exploration and discovery of rare variants that are linked to disease with techniques like whole exome sequencing. Using this approach in both kindreds and outlier patients with de novo germline mutations, there has been expanding discovery of mutations in other pathways with a link to organ-specific autoimmunity that include STAT3, STAT1, CTLA4, and LRBA. Here, we utilized a similar approach on a single patient with T1D and other autoimmune and inflammatory conditions. We identified a de novo heterozygous c.457G>A/p.Gly153Arg mutation in the SKAP2 gene. SKAP2 encodes a critical mediator of integrin signaling pathways that regulate myeloid immune cell function. Monocyte-derived macrophages from the individual displayed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. We propose that SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, resulting in a break in immune tolerance and T1D. This particular mutation in a patient with T1D and multiple autoimmunity implicates a role for activating SKAP2 variants in autoimmune T1D.  

Disclosure

C. Chamberlain: None. N. Rutsch: None. W. Dixon: None. L. R. Letourneau-freiberg: None. L. H. Philipson: Advisory Panel; Self; Nevro Corp., Research Support; Self; Provention Bio, Inc. M. German: Stock/Shareholder; Self; Viacyte, Inc. M. S. Anderson: Consultant; Self; Provention Bio, Inc., VielaBio, Stock/Shareholder; Self; Medtronic, Merck & Co., Inc. C. A. Lowell: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (G-2018PG-T1D018); Larry L. Hillblom Foundation (2014-D-004-NET); University of California San Francisco Parnassus Flow Core (RRID:SCR_018206); National Institutes of Health (P30 DK063720, S101S10OD021822-01); German Research Foundation (ZA428/11-1, ZA428/18-1, INST211/604-1)
113-OR: Identification of Sorafenib for the Treatment of Type 1 Diabetes
Authors: ZENG QIN , SONG JIANFENG , SUN XIAOXIAO , WANG DANDAN , XIAO YANG , ZHOU ZHIGUANG , DENG TUO
Published: June 2021

Type 1 diabetes (T1D) is an immune-mediated disease characterized by impairment of pancreatic beta cells. To date, a comprehensive cure is not available. Th1 cell activation is considered a key mediator of the pathogenesis of T1D. IL-12-induced STAT4 activation is a paramount signaling pathway to instigate Th1 cell differentiation. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of T1D. However, given the critical function of Th1 in the immune system, the potential side effects hinder the application of anti-Th1 therapy in the treatment of T1D. To identify safe anti-Th1 treatment(s), we screened the FDA-approved tyrosine kinase inhibitor (TKI) drug library using an IL-12-induced Th1 differentiation cell model. We found that sorafenib, an oral anti-cancer drug, is a top contender for inhibition of Th1 differentiation relative to induced toxicity. Sorafenib inhibited IL-12-induced Th1 cell differentiation in a dose-dependent manner without any change of CD4+ T-cell viability. Treatment of NOD mice with sorafenib significantly impeded the development of T1D and ameliorated insulitis, which coincided with a specifically decreased aggregate of Th1 cell population in pancreas but not in peripheral immune organs. Inflammatory cytokines and Th1 signature transcription factor Tbet mRNA expression in pancreas were decreased in sorafenib-treated NOD mice compared to vehicle-treated NOD mice. Mechanistically, sorafenib directly inhibited JAK2 activity and blocked IL-12-induced phosphorylations of JAK2 and STAT4.

In conclusion, sorafenib administration inhibits the development of T1D by suppressing IL-12b/JAK2/STAT4 signaling-mediated Th1 cell differentiation specifically in pancreas in NOD mice. Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapeutic for T1D in humans.

Disclosure

Q. Zeng: None. J. Song: None. X. Sun: None. D. Wang: None. Y. Xiao: None. Z. Zhou: None. T. Deng: None.
1130-P: A GWAS of Gene by Smoking Interaction on Type 2 Diabetes
Authors: FERDOS SEPIDEH N. , SALEM RANY
Published: June 2021

Genome wide association studies (GWAS) of type 2 diabetes (T2D) have identified hundreds of genetic variants. However, the majority of these studies fail to consider the multifactorial nature and the interplay of genetic and environmental factors on disease risk, e.g., gene x environment interaction analyses. The role of smoking as a modulator in the association between genetic variants and T2D is of particular importance, since it is a modifiable risk factor for T2D. We performed a large-scale gene x smoking analysis on 345,955 individuals from 14 studies retrieved from dbGaP and UK Biobank. Phenotypic data was reviewed and harmonized prior to performing a gene by smoking GWAS for each study. A joint (main and interaction effect) framework was performed for each study. Individual study GWAS statistics were combined through meta-analysis, stratified by racial/ethnic group. The study sample includes 40,994 diabetics and 34,764 current smokers, and 324,834 of European-, 9,040 of African-, 6,125 of Hispanic-, and 5,956 of Asian-ancestry subjects. Results from the meta-analysis in the European ancestry group revealed a genome wide significant signal (p<5x10-8) in the TCF7L2 gene (main effect, p-value 9.59x10-33) and several genome-suggestive (p<1x10-5) loci. We are currently expanding the analyses to include data from a total of 20 studies and 700,000 subjects. Gene by smoking interaction analysis on T2D underscores the importance of both genetic and environmental risk factors and has the potential to unveil novel variants, genes, and biological pathways that influence disease vulnerability typically missed by traditional analytic approaches.

Disclosure

S. N. Ferdos: None. R. Salem: None.

Funding

Tobacco Related Disease Research Program (T29IR0770)
1135-P: Type 2 Diabetes Modulates DNA Methylation in Human Sperm
Authors: SU LEI , WOLFS DANIELLE , HIVERT MARIE-FRANCE , PATEL JAY , RICHARDSON LAUREN , CHARMANT CHARNICE O. , ISGANAITIS ELVIRA M. , PATTI MARY-ELIZABETH
Published: June 2021

Paternal obesity and diabetes are associated with cardiometabolic risk in offspring. To test the hypothesis that paternal metabolism could exert these effects via modulation of the sperm epigenome, we collected motile sperm at two study visits 3 months apart in men with and without T2D (NCT03860558). Sperm DNA methylation was quantified in 32 samples using the Infinium MethylationEPIC array. HbA1c was higher in men with T2D vs. controls (7.6±1.1% vs. 5.2±0.2%, n=9 vs. 7, p<0.0001). Age (49.6±7.5 vs. 40.9±12.3 years, p=0.1), BMI (34.4±6.7 vs. 30.3±4.0 kg/m2, p=0.17), waist circumference and fat % were similar. There were no differences in sperm concentration or motility, testosterone, LH, estradiol, or prolactin levels. Methylation data were pre-processed using Partek Genomics Suite 7.19. After filtering cross-reactive probes and probes overlapping with SNP, 790508 probes were analyzed. Two-way ANOVA (disease group/time as factors) revealed 7 CpG sites differentially methylated between control and T2D (FDR q<0.05, differences in beta>0.2), including sites annotated to SLFN5, MMAA, and LOC101927829. All 7 sites were hypermethylated in T2D, with mean difference in beta of 26.4%. Paired analysis between study visits for individual participants revealed no significant CpG, indicating stability of sperm methylation over time. Genes annotated to differentially methylated CpG at both study visits (n=89, nominal p<0.01) were enriched for genes involved in morphogenesis and neuron development; the majority of these CpG also had higher methylation in T2D. In a linear regression model, 10 CpG sites showed positive and 2 sites showed negative association with HbA1c (FDR q<0.05).

In summary, DNA methylation is altered in motile sperm from men with T2D, with hypermethylation at significant CpG sites. These alterations may reflect differential transcriptional regulation at developmentally important loci, and should be investigated as potential contributors to the impact of paternal metabolism on offspring.

Disclosure

L. Su: None. D. Wolfs: None. M. Hivert: None. J. Patel: None. L. Richardson: None. C. O. Charmant: None. E. M. Isganaitis: None. M. Patti: Consultant; Self; Cello Health, Fractyl Laboratories, Inc., MBX, Poxel SA, WGBH, Other Relationship; Self; Xeris Pharmaceuticals, Inc., Research Support; Self; Dexcom, Inc.

Funding

National Institutes of Health (R21HD091974)
1137-P: Liver Regulatory Variants and Genes at Metabolic Trait Loci
Authors: PANDEY GAUTAM , CURRIN KEVIN , VADLAMUDI SWAROOPARANI , BROADAWAY K. ALAINE , MOHLKE KAREN L.
Published: June 2021

Genome-wide association studies (GWAS) have identified many loci that affect liver- and lipid-related metabolic traits, but the causal variants, target genes and mechanisms for most loci have not been characterized. GWAS loci are often enriched in tissue-specific transcriptional regulatory elements that drive physiological changes, and loci can be annotated with colocalized molecular quantitative traits for gene expression (eQTL) and accessible chromatin (caQTL) to identify candidate variants and genes. We previously profiled chromatin accessibility in 20 human liver samples, identified caQTL variants that colocalized with GWAS loci for metabolic traits, and predicted target genes based on promoter proximity, Hi-C chromatin contact with a promoter, and co-localization with liver eQTL. Here, we examined selected GWAS loci and tested variants for effects on gene regulation. We prioritized loci based on trait, gene function, and QTL characteristics and selected four variant-gene pairs to study. To evaluate effects of specific variants on gene expression, we performed transcriptional reporter assays in HepG2 cells. Three caQTL variants exhibited significant (P<0.05) allelic differences in transcriptional activity. rs13395911, near EFHD1 and associated with liver enzyme gamma glutamyl transferase, showed allelic differences in enhancer activity (P=0.008). In addition, rs9556404, near GPR180 and associated with triglycerides, and rs34003091, near ZNF329 and associated with LDL-cholesterol, also showed significant allelic effects on transcriptional activity (P<0.05). To study EFHD1 function in liver metabolism, we used gene-specific shRNA constructs in HepG2 cells and observed up to 90% reduction of EFHD1 mRNA expression compared to scramble shRNA. Subsequent metabolic assays will test role of EFHD1 on hepatic lipid and glucose metabolism. These data identified candidate regulatory variants that may be responsible for nearby GWAS loci and suggest genes as therapeutic targets for fatty liver disease.

Disclosure

G. Pandey: None. K. Currin: None. S. Vadlamudi: None. K. Broadaway: None. K. L. Mohlke: None.
1142-P: Update on BCG Clinical Trial Programs in Patients with Advanced Type 1 Diabetes
Authors: KUHTREIBER WILLEM , TAKAHASHI HIROYUKI , KEEFE RYAN , NELSON KACIE , NG NATHAN , BRALEY JOAN , ZHENG HUI , FAUSTMAN DENISE L.
Published: June 2021

The bacillus Calmette-Guerin (BCG) vaccine was first introduced a century ago for tuberculosis prevention and is today being tested in clinical trials for treatment of diverse forms of autoimmunity, including type 1 diabetes (T1D). Long-term follow up of a Phase I study of the BCG vaccine in longstanding T1D revealed potential disease-modulating effects after repeated BCG vaccination, including long-term reductions of HbA1c, death of autoreactive cells, modest restoration of insulin secretion and induction of beneficial regulatory T cells (Tregs). Here we provide an update on the BCG clinical trial program current underway at Massachusetts General Hospital (MGH): enrollment numbers, study timelines and interim outcomes for key T1D biomarkers. To date, 236 patients have been enrolled in the randomized and open-label MGH trials and 143 patients have received at least two doses of BCG, 34 of whom are being followed in open-label, unblinded trials. Enrollment of 150 participants in a pediatric study is planned for 2021. Data from ongoing analysis of the open-label BCG trials shows lowered insulin needs and decreases in HbA1c as compared to reference populations. Patients are also being monitored by RNAseq, epigenetics, Treg cell numbers and Treg signature gene expression to better define the mechanism of beneficial effects. We show a gradual and stable 3-year time course of demethylation of signature Treg genes known to be associated with Treg potency, including Foxp3, which was observed to be over-methylated at baseline in T1D and, over 3 years after BCG vaccination, demethylated to a level close to controls without T1D. The clinical time course of BCG-related improvements (i.e., improvement in HbA1C) appears to correlate with the time course of Treg induction through epigenetic modifications.

Disclosure

W. Kuhtreiber: None. H. Takahashi: None. R. Keefe: None. K. Nelson: None. N. Ng: None. J. Braley: None. H. Zheng: None. D. L. Faustman: None.