bluuebunny/crossref_metadata_2025_split huggingface dataset:
171-OR: Effect of Interventions on Blood Pressure for Black Persons with Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Controlled Trials
Authors: JIANG CHERRY , OSMAN FAWSIA , DECKARD AMBER , WAN WEN , ALEXANDER JASON , SHETTY RAJ , STAAB ERIN M. , LAITEERAPONG NEDA 
Published: May 2022

Background: Uncontrolled blood pressure (BP) is a major cardiovascular disease (CVD) risk factor, and CVD is the leading cause of death among non-Hispanic Black persons with type 2 diabetes (T2D) . While many interventions have been designed to improve BP control in this population, disparities persist. A meta-analysis of randomized controlled trials was conducted to evaluate the effectiveness of T2D interventions at improving BP.
Methods: An electronic search of Medline, PubMed, Scopus, CINAHL, and PsychINFO was conducted from 1985 to 2019. Keywords included those related to diabetes, study design and race/ethnicity. We included non-pharmacologic trials with ≥12.5% Black persons (using the 2020 US Census as a standard) . Interventions were aimed at improving outcomes including HbA1c, BP, weight and lipids. For this analysis, we focused on the outcomes mean systolic (SBP) and diastolic blood pressure (DBP) differences between control and experimental groups. A random effects meta-analysis was performed to calculate the pooled effect size to provide summary estimates.
Results: Sixteen trials (n=2314) reported SBP and DBP outcomes; two additional trials (total n=2919) reported only SBP outcomes. The participants were 59% Black and 71% female with a mean age of 55.9 years. Average baseline BP was similar for the control and intervention groups (134/78 and 134/77, respectively) . Interventions included self-management education, telehealth support, lifestyle programs, and pharmacist-led support. Compared to control, these interventions demonstrated no difference in SBP (0.01, 95% CI -0.to 0.mmHg, p=0.55, I2=0%) or DBP (-0.05, 95% CI -0.15 to 0.mmHg, p=0.20, I2=22%) .
Conclusion: In this meta-analysis of trials aimed to improve outcomes in Black patients with T2D, there was no improvement in BP control. Given the high risk of CVD in this population, more effective interventions are needed to improve BP control in Black persons with T2D.

Disclosure
C.Jiang: None. F.Osman: None. A.Deckard: None. W.Wan: n/a. J.Alexander: None. R.Shetty: None. E.M.Staab: None. N.Laiteerapong: None.
176-OR: The Effect of Low-Dose Empagliflozin on Glucose Control in Suboptimally Controlled Adults with Type 1 Diabetes on a Closed-Loop Insulin Delivery System
Authors: PASQUA MELISSA-ROSINA , JAFAR ADNAN , KOBAYATI ALESSANDRA , TSOUKAS MICHAEL , HAIDAR AHMAD 
Published: May 2022

Background: For some with type 1 diabetes (T1D) , hybrid closed-loop insulin therapy is insufficient to achieve glycemic targets. Low doses of SGLT2i may improve glycemia in those not able to achieve their targets.
Methods: A double-blinded, cross-over, randomized controlled trial was performed in sub-optimally controlled (HbA1c 7.0-10.5%) adults with T1D who were not able to achieve a time-in-range (3.9-10.0 mmol/L) of &gt; 70% after 14 days on closed-loop therapy. Three 14-day interventions were performed with placebo, empagliflozin 2.5 mg, or empagliflozin 5 mg, as adjunct to closed-loop therapy, with daily ketone testing.
Results: 24 participants completed the study (50% male, age 33 ± 14 yrs, HbA1c 8.1 ± 0.5%) . The time in range was 59 ± 9% for placebo, 72 ± 10% for empagliflozin 2.5 mg, and 70 ± 8 for empagliflozin 5 mg (p &lt; 0.between placebo and empagliflozin 2.5 mg, and placebo and empagliflozin 5 mg) . Empagliflozin 2.5 mg did not increase time spent below 3.9 mmol/L though empagliflozin 5 mg did (p = 0.01) . Average ketone levels were not different between arms (p=ns) . There were no serious adverse events in any intervention.
Conclusion: Both empagliflozin 2.5 mg and 5 mg increased the time spent in target on hybrid closed-loop therapy by 11-13 % compared to placebo, in those who otherwise were unable to attain glycemic targets.

Disclosure
M.Pasqua: None. A.Jafar: None. A.Kobayati: None. M.Tsoukas: Speaker's Bureau; AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk Canada Inc. A.Haidar: Consultant; Eli Lilly and Company, Research Support; ADOCIA, Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc.

Funding
National Institutes of Health (1DP3DK106930)
179-LB: Characteristic Cluster of Metabolic Disorders in Relation to Risk of Cancer in Chinese Patients with Type 2 Diabetes
Authors: ZHANG LEI , WANG JUN , YANG YUXIU , DONG YANHU 
Published: May 2022

Aims: The study aimed to investigate the relationship between components of metabolic syndrome (MS) and risk of cancer in patients with type 2 diabetes (T2DM) .
Methods: We enrolled 6587 patients with T2DM who were hospitalized in Qingdao Endocrine and Diabetes Hospital from Feb 2005 to Jan 2016. According to the number of MS component each patient had, they were divided into isolated T2DM, T2DM plus 1 component,2 components, 3 components and 4 components, respectively. The IDF Worldwide Definition of the Metabolic Syndrome was applied. Information on the diagnosis of cancer was obtained by matching ICD-10 codes recorded in local Healthcare medical records database. Prevalence of cancer was compared using Chi-square test. Logistic regression model was used to evaluate risk of cancer associated with MS.
Results: The prevalence of cancer was 4.2% among 6587 patients with T2DM. Female patients had higher prevalence than did male in total or in the MS subgroup. The prevalence of cancer were 3.8%, 3.9%, 3.8%, 5.1% and 5.0% in isolated DM, T2DM plus 1 component of MS, T2DM plus 2, T2DM plus 3 and T2DM plus 4 components, respectively (P for trend &lt;0.05) . Compared with those with less than 3 components, T2DM plus 3 or 4 components had increased risk of having cancer (OR=1.32, 95% CI: 1.04-1.69) . Among T2DM patients who had more than 3 components of MS, a specific cluster of increased waist, elevated triglycerides (TG) and decreased High-Density Lipoprotein Cholesterol (HDL-C) was associated with the highest prevalence of cancer (10.7%) , followed by 8.3% in T2DM patients plus hypertension, elevated TG and decreased HDL-C and 3.2% in T2DM patients plus hypertension, increased waist and elevated TG (χ2=26.6, P&lt;0.05) .
Conclusions: A cluster of metabolic disorders consisting of increased waist, elevated TG and decreased HDL-C seems to be oncogenic among Chinese patients with T2DM. For patients in combination with 3 or 4 MS components, it is important to conduct early cancer screening and prevention.

Disclosure
L. Zhang: n/a. J. Wang: None. Y. Yang: None. Y. Dong: None.
179-OR: Cardiovascular Effectiveness of Empagliflozin vs. Glucagon-Like Peptide-1 Receptor Agonists or Liraglutide in the EMPRISE Study
Authors: HTOO PHYO T. , TESFAYE HELEN , PAIK JULIE M. , WEXLER DEBORAH J. , NAJAFZADEH MEHDI , GLYNN ROBERT , DERUAZ-LUYET ANOUK , FARSANI SOULMAZ F. FAZELI , KOENEMAN LISETTE , SCHNEEWEISS SEBASTIAN , PATORNO ELISABETTA 
Published: May 2022

Within the EMPRISE® monitoring program, we evaluated the cardiovascular effectiveness of empagliflozin (EMPA) vs. glucagon-like peptide-1 receptor agonists (GLP1RA) or liraglutide using data from Medicare and 2 U.S. commercial claims databases [2014- (2018 for Medicare) ]. We identified patients ≥18 years with type 2 diabetes initiating (i) EMPA vs. GLP1-RA or (ii) EMPA vs. liraglutide. Primary outcomes were hospitalization for heart failure (HHF) , myocardial infarction (MI) , stroke, and all-cause mortality (Medicare only) . After 1:1 propensity score matching, we estimated pooled HR (95% CI) overall and in subgroups of patients with and without baseline cardiovascular disease (CVD) . We identified 105,955 pairs of EMPA vs. GLP1RA initiators and 72,498 pairs of EMPA vs. liraglutide initiators (Table) . Relative to GLP1RA, EMPA had a lower risk of HHF [HR:0.62 (95% CI, 0.53, 0.71) ] and a similar risk of MI [0.95 (0.85, 1.07) ], stroke [1. (0.94, 1.27) ], and mortality [0.91 (0.77, 1.08) ]. Results were consistent for patients with and without CVD. When we compared EMPA vs. liraglutide, estimates were similar to those from GLP1 RA, both overall and across subgroups. Among real-world patients, EMPA was associated with a reduced risk of HHF, but with similar risk of MI, stroke, and mortality, across the broad spectrum of CVD, compared with GLP-1RA overall or liraglutide.

Disclosure
P.T.Htoo: Employee; Johnson & Johnson. S.Schneeweiss: None. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. H.Tesfaye: None. J.M.Paik: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. M.Najafzadeh: None. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis AG, Pfizer Inc. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH, Other Relationship; IQVIA Inc., Sanofi. S.F.Fazeli farsani: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.
180-LB: Plasma miRNAs May Be Associated with Waist Circumference and Insulin Resistance among Women with Polycystic Ovary Syndrome—Pilot Study
Authors: WANDER PANDORA , ENQUOBAHRIE DANIEL , BAMMLER THEO , MACDONALD JAMES , SRINOUANPRACHANH SENGKEO , KALERU THANMAI , KHAKPOUR DORI , TRIKUDANATHAN SUBBULAXMI 
Published: May 2022

Background: Insulin resistance (IR) and central obesity are common in PCOS, but pathomechanisms for IR in PCOS are not established. Circulating microRNAs (miRNAs) are non-invasive biomarkers of tissue gene expression that may contribute to the pathogenesis of IR and central adiposity in PCOS.
Methods: We conducted a pilot study to examine associations of circulating miRNAs with IR and central adiposity among women with PCOS (n=11) using high-throughput miRNA sequencing. We fit generalized linear models examining associations of waist circumference and HOMA-IR with plasma miRNAs. We used false discovery rate (FDR) -adjusted cutoff p&lt;0.1 to adjust for multiple testing. We used the miRDB’s Gene Ontology (GO) tool to identify predicted pathways for top hits.
Results: Participants were 27.9 years old on average with mean BMI 32.5 kg/m2. At an FDR&lt;0.1, lower levels of miR-1294 were associated with higher waist circumference (β = -0.10, FDR=0.095) . While no miRNAs were associated with HOMA-IR at our predetermined cut off, 11 miRNAs were associated with waist circumference and 14 miRNAs with HOMA-IR at p&lt;0.01 (Table 1) . Pathways identified in the GO analysis of miR-1294 include “negative regulation of insulin receptor signaling” (p=0.019) .
Conclusions: Plasma miRNAs may be associated with IR and central obesity among PCOS patients.

Disclosure
P. Wander: None. D. Enquobahrie: None. T. Bammler: None. J. Macdonald: None. S. Srinouanprachanh: None. T. Kaleru: None. D. Khakpour: None. S. Trikudanathan: Research Support; Bionic pancreas, Bionic pancreas, Insulet Corporation, Insulet Corporation.

Funding
NIDDK (K08103945)
181-OR: Sympathetic Activity in Patients with Type 2 Diabetes Mellitus Treated with Empagliflozin or Hydrochlorothiazide
Authors: HEUSSER KARSTEN , TANK JENS , FISCHER ANNELIE , HEISE TIM , JORDAN JENS 
Published: May 2022

Changes in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose transporter (SGLT2) inhibition on cardiovascular outcomes. We hypothesized that SGLT inhibition with empagliflozin lowers sympathetic activity compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from non-specific responses to increased natriuresis. In this double-blind, randomized study patients with type 2 diabetes mellitus on metformin monotherapy received either 25 mg/day empagliflozin (n=20) or 25 mg/day HCT (n=21) for 6 weeks. Muscle sympathetic nerve activity (MSNA) , blood pressure, cardiovascular, and metabolic biomarkers were assessed at baseline and end of treatment. Empagliflozin significantly increased urinary glucose excretion (difference in change from baseline 47.4 mmol/l vs. HCT) , reduced fasting plasma glucose (-1.91 mmol/l) , HbA1c (-0.58%) , and body weight (-1.23 kg, all p&lt;0.05) . Office systolic blood pressure decreased with both treatments. MSNA (burst frequency -1.95 [95% confidence interval -8.67; 4.78] bursts/min) , baroreflex heart rate control (0.84 [-1.18; 2.87] ms/mmHg) and plasma catecholamines did not change significantly with either treatment. MSNA increased with higher body weight loss with both treatments, but more pronounced and significant only with HCT (p=0.0015) .
In conclusion, neither empagliflozin nor HCT treatment led to clinically relevant changes in sympathetic activity. Given the important role of the sympathetic nervous system in the progression of cardiovascular disease, mechanisms attenuating sympathetic activity in the face of increased sodium excretion deserve further attention.

Disclosure
K.Heusser: None. J.Tank: None. A.Fischer: None. T.Heise: Advisory Panel; Novo Nordisk A/S, Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. J.Jordan: Consultant; Novo Nordisk, Other Relationship; Eternygen, Research Support; Boehringer Ingelheim International GmbH.
182-LB: Delayed Onset of Parkinson’s Disease among Type 2 Diabetes Subjects—Data from an Observational Study
Authors: COLOSIMO SANTO , CEREDA EMANUELE , DEL SORBO FRANCESCA , CALANDRELLA DANIELA , BARICHELLA MICHELA , PEZZOLI GIANNI 
Published: May 2022

Background and aim: Parkinson's disease (PD) is a common neurodegenerative movement disorder. Treatment aims at symptoms control and prevention of complications. Although type 2 diabetes (T2D) is a well-established risk factor for cerebrovascular diseases, evidence is lacking with regards to the possible association between T2D and PD. With the present study we aimed at investigating the prevalence and relative time of occurrence of T2D in a cohort of PD patients from an Italian tertiary level center and compare it with the Italian general population.
Methods: For this retrospective observational study, the database of the Parkinson Institute ASST Pini-CTO in Milan was queried. We have selected from the database to include and analyze in the study the records of consecutive patients with an established diagnosis of PD based on the UK Parkinson disease Brain Bank criteria followed at our Institute over a 10-year period, from January 2010 to December 2019.
Results: A total of 8380 patients were included in the study. At the last follow-up visit, 673 (8.4%) PD patients had T2D. Standardized prevalence of T2D was lower among PD patients compared to the Italian general population (3.8 % vs. 5.3%, p&lt;.05) . Age at PD onset was approximately 67 years in those who had already diagnosed with T2D, a higher mean onset age of 7 years compared with both PD patients with later occurrence of T2D and PD patients without T2D (p&lt;.001) . A multivariate regression analysis showed that PD onset in patients who had T2D for seven years or less was delayed by an average of 2.7 years, while patients with a T2D duration for over seven years displayed a mean delay of 5.7 years compared with patients without T2D before PD onset (p&lt;.001) .
Discussion: As per our knowledge so far no other conditions or agents are associated with a delay in the onset of PD. Data from this study show that patients with T2D have a significant delay in PD onset. Causes may be further investigated looking at treatments, hormones, metabolic changes and dietary regimen of T2D. Whether this delay has an impact on the prevalence of PD in the T2D population, remains unclear and need to be studied.

Disclosure
S. Colosimo: None. E. Cereda: None. F. Del Sorbo: None. D. Calandrella: None. M. Barichella: None. G. Pezzoli: None.

Funding
Fondazione Grigioni per il Parkinson, Brain and Malnutrition in Chronic Diseases Association
183-LB: High Daily Doses of Insulin in Type 2 Diabetes—Predictors beyond Weight
Authors: DURON TABORA JAVIER , AMBLEE AMBIKA , TAHSIN BETTINA , FOGELFELD LEON 
Published: May 2022

In clinical practice, needing ≥ 200 units insulin/day is defined as severe insulin resistance. This study seeks to identify predictive characteristics of those with type 2 diabetes and severe insulin resistance (≥ 200 units insulin/day) vs. those using &lt;100 units insulin/day.
This retrospective cross-sectional study analyzed data for a six-month period gathered from a diabetes clinic electronic database. Compared were 59 patients using &gt;200 units daily (high insulin users - HIU) vs. 59 patients using &lt;100 units (low insulin users - LIU) .
For the entire study group (n=118) , mean age was 57.7 ± 9.5 years, 66% were female and 52% Hispanic. Comparing groups, no differences seen in age, race, ethnicity, and A1c. Compared to LIU, HIU had more men (26 vs. 14, P=0.032) , higher BMI (41.8 ± 9.5 vs. 35.1 ± 6.6 kg/m2, p&lt;0.001) , less physically active (42.5 (0.0, 120.0) vs. 140.0 (80.0, 180.0) min/week, p&lt;0.001) , lower HDL (37.5 (32.0, 46.0) vs. 43.0 (37.0, 52.0) mg/dL, p=0.005) , higher insulin units/kg/day (2.3 ± 0.7 vs. 0.9 ± 0.3, p&lt;0.001) , higher use of GLP1-RA medication (16 vs. 6, p=0.018) , higher incidence diabetic neuropathy (36 vs. 18, P&lt;0.001) and co-morbid metabolic conditions like hypertension (58 vs. 50, p=0.024) , congestive heart failure (13 vs. 4, p=0.018) , metabolic liver disease (12 vs. 4, p=0.031) , and obstructive sleep apnea (18 v 7, p=0.013) . Per stepwise multivariate analysis, significant predictors of needing more insulin were being less active, lower HDL, co-morbid conditions like hypertension, neuropathy, obstructive sleep apnea, use of GLP1-RA and higher insulin/kg/day.
Factors responsible for high insulin requirements go beyond weight alone as evidenced by higher insulin/kg/day in HIU. Insulin resistance may be exaggerated in the HIU by physical inactivity. Beta cell secretory dysfunction in HIU may also play a role as implied by their longer diabetes duration and higher rate of metabolic comorbid conditions.

Disclosure
J. Duron tabora: None. A. Amblee: n/a. B. Tahsin: n/a. L. Fogelfeld: Research Support; Lilly, Sanofi.
184-LB: Patient-Reported Outcomes (PROs) to Treatment in Type 1 Diabetes (T1D) from the International Diabetes Management Practices Study (IDMPS)
Authors: GAGLIARDINO JUAN J. , ASCHNER PABLO , ILKOVA HASAN M. , RAMACHANDRAN AMBADY , CLAUDE MBANYA JEAN , SHESTAKOVA MARINA V. , PILORGET VALERIE , MELAS-MELT LYDIE , CHANTELOT JEAN-MARC , CHAN JULIANA C. 
Published: May 2022

Introduction: Achieving optimal HbA1c in people with T1D requires good treatment acceptance and self-management.
Methods: IDMPS is an international, observational study investigating care practices and clinical profiles of people with diabetes in developing countries. The present analysis of Wave 8 evaluated PROs in people with T1D and their associations with glycemic control using 1) the chronic treatment acceptance questionnaire (ACCEPT) to assess acceptance of long-term medication advantages/disadvantages, and 2) the diabetes self-management questionnaire (DSMQ) to assess health-related behaviors.
Results: Of 1103 people with T1D (mean ± SD age 34 ± 12 years, diabetes duration 14 ± 10 years, HbA1c 8.6 ± 2.0 %, 52% were women and 19% had HbA1c &lt;7 %) from 13 countries, 69% reported 0-2 hours of diabetes-related education in total, and 52% had experienced hypoglycemia symptoms within the previous 3 months. Most patients completed ACCEPT (99%) and DSMQ (99%) . Acceptance was high for medication effectiveness and side effects, but low for length of treatment, regimen constraints, and medication inconvenience (Figure A) . Self-management scores were low, particularly for physical activity and health care use (Figure B) .
Conclusions: Further education for people with T1D could improve self-management and consequently could benefit medication effectiveness.

Disclosure
J. J. Gagliardino: None. J. C. Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. P. Aschner: Advisory Panel; Merck & Co., Inc., Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. H. M. Ilkova: Advisory Panel; Novo Nordisk. A. Ramachandran: None. J. Mbanya: Advisory Panel; Novo Nordisk, Sanofi, Servier Laboratories. M. V. Shestakova: None. V. Pilorget: None. L. Melas-melt: None. J. Chantelot: Employee; Sanofi, Stock/Shareholder; Sanofi.

Funding
Sanofi
185-LB: Pulmonary Function and Diabetes Risk in a Cohort of Black and White Current and Former Smokers
Authors: CONWAY REBECCA B. , YOUNG KENDRA , LI YISHA , AUSTIN ERIN , KINNEY GREGORY L. 
Published: May 2022

The recent COVID-19 pandemic, which saw an increased risk of subsequent diabetes among persons with COVID-19 as well as greater casualties among persons with diabetes, has brought renewed attention to the role of lung function in diabetes. We tested the relationship of lung function and chronic obstructive pulmonary disease (COPD) with diabetes in a population of current and former smokers.
Using data from the COPD Genetic Epidemiology (COPDGene) cohort, we conducted a diabetes follow-up (2012-2018) of a cohort of Black and White current and former smokers with (n=2442) and w/out (n=2214) COPD, aged 39-85 years and w/out diabetes at cohort entry. Lung function was modeled using Forced Expiratory Volume at 1 second % predicted (FEV1%P) . COPD was defined as the ratio of FEV1% to FVC% &lt;0.7. Logistic regression was used to compute ORs (95% CIs) for risk of incident diabetes.
The incidence of diabetes was 8% over the five years of follow-up, representing a 43% increase in prevalence. After controlling for age, sex, and race, COPD at baseline was a significant risk factor for diabetes (OR=1.51, 1.21-1.88) . Significant interaction existed between baseline COPD and baseline Fev1%p (p-interaction=0.01) , such that Fev1%p only predicted diabetes among those w/out (OR=0.98, 0.96-0.99) but not among those with COPD at baseline (OR=0.99, 0.99-1.00) . Upon stratification by race, Fev1%p was a significant predictor among Blacks but not Whites, but effect modification by race was not observed. Blacks were at twice the risk of diabetes overall (OR=2.04, 1.59-2.60) and were at 3 times the risk among those w/out COPD (OR=2.91, 1.98-4.27) . BMI increased risk in both races regardless of COPD status; however, a higher BMI was a stronger risk factor for diabetes among Whites than Blacks, particularly for those with baseline COPD (race*BMI interaction p=0.06) .
In this large population of current and former smokers, our data suggest that lower lung function prior to the development of COPD is a risk factor for diabetes, particularly among Blacks. BMI is an important risk factor in both races, but appears to play a stronger role among Whites.

Disclosure
R. B. Conway: None. K. Young: None. Y. Li: Employee; Vertex Pharmaceuticals Incorporated. E. Austin: None. G. L. Kinney: None.

Funding
National Institutes of Health (U01HL089897)