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Autoantibodies to N-terminally Truncated GAD65(96-585): HLA Associations and Predictive Value for Type 1 Diabetes.
Pöllänen, PM, Härkönen, T, Ilonen, J, Toppari, J, Veijola, R, Siljander, H, Knip, M
The Journal of clinical endocrinology and metabolism. 2022;(3):e935-e946
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Abstract
OBJECTIVE To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD65(96-585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential human leukocyte antigen (HLA) associations with such autoantibodies. DESIGN In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention study, the DIABIMMUNE study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD65 (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants. RESULTS T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 (range 0.2-61.5) years. t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77% vs 53%; P < 0.001). CONCLUSIONS Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96-585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.
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Predictive value of cardiac markers in the prognosis of COVID-19 in children.
Güllü, UU, Güngör, Ş, İpek, S, Yurttutan, S, Dilber, C
The American journal of emergency medicine. 2021;:307-311
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Abstract
BACKGROUND AND AIM Occasionally, children with COVID-19 may develop arrhythmia, myocarditis, and cardiogenic shock involving multisystemic inflammatory syndrome in children (MIS-C). This study aimed to identify the laboratory parameters that may predict early cardiovascular involvement in these patients. MATERIALS AND METHODS Data of 320 pediatric patients, aged 0-18 years (average age, 10.46 ± 5.77 years; 156 female), with positive COVID-19 reverse transcription-polymerase chain reaction test and with cardiac biomarkers at the time of admission to the pediatric emergency department were retrospectively scanned. The age, sex, COVID-19-associated symptoms, pro-brain natriuretic peptide (proBNP), CK-MB, and troponin I levels of the patients were recorded. RESULTS Fever was noted in 58.1% of the patients, cough in 29.7%, diarrhea in 7.8%, headache in 14.7%, sore throat in 17.8%, weakness in 17.8%, abdominal pain in 5%, loss of taste in 4.1%, loss of smell in 5.3%, nausea in 3.4%, vomiting in 3.8%, nasal discharge in 4.4%, muscle pain in 5%, and loss of appetite in 3.1%. The proBNP value ≥282 ng/L predicted the development of MIS-C with 100% sensitivity and 93% specificity [AUC: 0.985 (0.959-1), P < 0.001]; CK-MB value ≥2.95 with 80% sensitivity and 77.6% specificity [AUC: 0.792 (0.581-1), P = 0.026]; and troponin I value ≥0.03 with 60% sensitivity and 99.2% specificity [AUC: 0.794 (0.524-1)]. CONCLUSIONS Cardiac markers (proBNP and troponin I), especially proBNP, could be used to detect early diagnosis of cardiac involvement and/or MIS-C in pediatric patients with COVID-19 and to predict related morbidity and mortality.
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Endotrophin is associated with chronic multimorbidity and all-cause mortality in a cohort of elderly women.
Staunstrup, LM, Bager, CL, Frederiksen, P, Helge, JW, Brunak, S, Christiansen, C, Karsdal, M
EBioMedicine. 2021;:103391
Abstract
BACKGROUND The signalling peptide endotrophin is derived through proteolytic cleavage of the carboxyl-terminal during formation of type VI collagen. It is expressed by most descendants of the mesenchymal stem cells lineage, including adipocytes and fibroblasts, and have been proposed to be a central extracellular matrix hormone associated with several age-related diseases. We aimed to assess the association of endotrophin with chronic disease incidence and death in older women. METHODS 5,602 elderly Danish women from the observational, prospective cohort: The Prospective Epidemiological Risk Factor (PERF) study were included in the analysis which covered baseline (BL) and follow-up (FU) 14 years later. An elastic net was used to investigate the relative importance of 58 variables to serum endotrophin-levels. 20 chronic diseases were defined on the basis of clinical variables available along with diagnoses extracted from both the National Patient Register, the National Diabetes Register and the Danish Cancer Registry. The cross-sectional associations between endotrophin-levels and these 17 chronic age-related diseases were investigated using logistic regression and a set-analysis explored disease-combinations within multimorbidity. The association of endotrophin with mortality was assessed by Cox proportional hazard models. FINDINGS Formation of type III collagen (PRO-C3), age and creatine-levels were the most influential variables of endotrophin-levels. Several chronic diseases were significantly associated with endotrophin-levels independent of age and BMI including chronic kidney disease (BL OR=3.7, p < 0.001; FU OR = 7.9 p < 0.001), diabetes (BL OR = 1.5, p = 0.0015, FU OR=1.6, p = 0.004) and peripheral arterial disease (BL OR = 1.3, p = 0.029; FU OR=2.4, p < 0.001). Lastly, endotrophin-levels were significantly rising with number of morbidities (p < 0.001) and a predictor of death after adjusting for age and BMI (BL HR=1.95; FU HR = 2.00). INTERPRETATION Endotrophin was associated with death and increased with number of morbidities. Endotrophin may be a central hormone of fibroblast that warrant investigation and possible targeted intervention in several chronic diseases. FUNDING The funder of the PERF study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Poor Masticatory Capacity and Blood Biomarkers of Elevated Cardiovascular Disease Risk in the Community: The Paris Prospective Study III.
Chatzopoulou, E, Rangé, H, Deraz, O, Boutouyrie, P, Perier, MC, Guibout, C, Thomas, F, Andrieu, M, Bailly, K, Vedie, B, et al
Arteriosclerosis, thrombosis, and vascular biology. 2021;(7):2225-2232
Abstract
[Figure: see text].
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MR-proADM as marker of endotheliitis predicts COVID-19 severity.
García de Guadiana-Romualdo, L, Calvo Nieves, MD, Rodríguez Mulero, MD, Calcerrada Alises, I, Hernández Olivo, M, Trapiello Fernández, W, González Morales, M, Bolado Jiménez, C, Albaladejo-Otón, MD, Fernández Ovalle, H, et al
European journal of clinical investigation. 2021;(5):e13511
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BACKGROUND Early identification of patients at high risk of progression to severe COVID-19 constituted an unsolved challenge. Although growing evidence demonstrates a direct association between endotheliitis and severe COVID-19, the role of endothelial damage biomarkers has been scarcely studied. We investigated the relationship between circulating mid-regional proadrenomedullin (MR-proADM) levels, a biomarker of endothelial dysfunction, and prognosis of SARS-CoV-2-infected patients. METHODS Prospective observational study enrolling adult patients with confirmed COVID-19. On admission to emergency department, a blood sample was drawn for laboratory test analysis. Primary and secondary endpoints were 28-day all-cause mortality and severe COVID-19 progression. Area under the curve (AUC) and multivariate regression analysis were employed to assess the association of the biomarker with the established endpoints. RESULTS A total of 99 patients were enrolled. During hospitalization, 25 (25.3%) cases progressed to severe disease and the 28-day mortality rate was of 14.1%. MR-proADM showed the highest AUC to predict 28-day mortality (0.905; [CI] 95%: 0.829-0.955; P < .001) and progression to severe disease (0.829; [CI] 95%: 0.740-0.897; P < .001), respectively. MR-proADM plasma levels above optimal cut-off (1.01 nmol/L) showed the strongest independent association with 28-day mortality risk (hazard ratio [HR]: 10.470, 95% CI: 2.066-53.049; P < .005) and with progression to severe disease (HR: 6.803, 95% CI: 1.458-31.750; P = .015). CONCLUSION Mid-regional proadrenomedullin was the biomarker with highest performance for prognosis of death and progression to severe disease in COVID-19 patients and represents a promising predictor for both outcomes, which might constitute a potential tool in the assessment of prognosis in early stages of this disease.
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Associations Between Dietary Patterns and Subclinical Cardiac Injury: An Observational Analysis From the DASH Trial.
Juraschek, SP, Kovell, LC, Appel, LJ, Miller, ER, Sacks, FM, Christenson, RH, Rebuck, H, Chang, AR, Mukamal, KJ
Annals of internal medicine. 2020;(12):786-794
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BACKGROUND The DASH diet has been found to lower blood pressure (BP) and low-density lipoprotein cholesterol levels. OBJECTIVE To compare diets rich in fruits and vegetables with a typical American diet in their effects on cardiovascular injury in middle-aged adults without known preexisting cardiovascular disease (CVD). DESIGN Observational study based on a 3-group, parallel-design, randomized trial conducted in the United States from 1994 to 1996. (ClinicalTrials.gov: NCT00000544). SETTING 3 of the 4 original clinical trial centers. PARTICIPANTS 326 of the original 459 trial participants with available stored specimens. INTERVENTION Participants were randomly assigned to 8 weeks of monitored feeding with a control diet typical of what many Americans eat; a diet rich in fruits and vegetables but otherwise similar to the control diet; or the DASH diet, which is rich in fruits, vegetables, low-fat dairy, and fiber and has low levels of saturated fat and cholesterol. Weight was kept constant throughout feeding. MEASUREMENTS Biomarkers collected at baseline and 8 weeks: high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). RESULTS The mean age of participants was 45.2 years, 48% were women, 49% were black, and mean baseline BP was 131/85 mm Hg. Compared with the control diet, the fruit-and-vegetable diet reduced hs-cTnI levels by 0.5 ng/L (95% CI, -0.9 to -0.2 ng/L) and NT-proBNP levels by 0.3 pg/mL (CI, -0.5 to -0.1 pg/mL). Compared with the control diet, the DASH diet reduced hs-cTnI levels by 0.5 ng/L (CI, -0.9 to -0.1 ng/L) and NT-proBNP levels by 0.3 pg/mL (CI, -0.5 to -0.04 pg/mL). Levels of hs-CRP did not differ among diets. None of the markers differed between the fruit-and-vegetable and DASH diets. LIMITATION Short duration, missing specimens, and an inability to isolate the effects of specific foods or micronutrients. CONCLUSION Diets rich in fruits and vegetables given over 8 weeks were associated with lower levels of markers for subclinical cardiac damage and strain in adults without preexisting CVD. PRIMARY FUNDING SOURCE National Institutes of Health, National Heart, Lung, and Blood Institute.
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Associations of Green Tea Consumption and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.
Ma, YH, Wu, JH, Xu, W, Shen, XN, Wang, HF, Hou, XH, Cao, XP, Bi, YL, Dong, Q, Feng, L, et al
Journal of Alzheimer's disease : JAD. 2020;(1):411-421
Abstract
BACKGROUND Green tea has been widely recognized in ameliorating cognitive impairment and Alzheimer's disease (AD), especially the progression of cognitive dysfunction. But the underlying mechanism is still unclear. OBJECTIVE This study was designed to determine the role of green tea consumption in the association with cerebrospinal fluid (CSF) biomarkers of AD pathology and to ascertain whether specific population backgrounds showed the differences toward these relationships. METHODS Multivariate linear models analyzed the available data on CSF biomarkers and frequency of green tea consumption of 722 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, and we additionally detected the interaction effects of tea consumption with APOEɛ4 status and gender using a two-way analysis of covariance. RESULTS Frequent green tea consumption was associated with a decreased level of CSF total-tau protein (t-tau) (p = 0.041) but not with the levels of CSF amyloid-β 42 (Aβ42) and CSF phosphorylated tau. The more pronounced associations of green tea consumption with CSF t-tau (p = 0.007) and CSF t-tau/Aβ42 (p = 0.039) were observed in individuals aged 65 years or younger. Additionally, males with frequent green tea consumption had a significantly low level of CSF t-tau/Aβ42 and a modest trend toward decreased CSF t-tau. There were no interaction effects of green tea consumption with APOEɛ4 and gender. CONCLUSION Collectively, our findings consolidated the favorable effects of green tea on the mitigation of AD risk. The constituents of green tea may improve abnormal tau metabolism and are promising targets in interventions and drug therapies.
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Red blood cell distribution width in addition to N-terminal prohormone of B-type natriuretic peptide concentration improves assessment of risk of cardiovascular events in adult patients with congenital heart disease.
Martínez-Quintana, E, Estupiñán-León, H, Riaño-Ruiz, M, Rodríguez-González, F, Tugores, A
Archives of cardiovascular diseases. 2020;(10):607-616
Abstract
BACKGROUND Red blood cell distribution width (RDW) is a predictor of adverse outcomes in patients with heart disease. AIM: To establish predictors of high RDW values in patients with congenital heart disease (CHD), and their relationship with cardiovascular events. METHODS Overall, 561 patients with stable CHD who attended a single outpatient clinic and a matched control population of 2128 patients were studied. Exclusion criteria were renal failure, anaemia, receiving iron therapy and cyanosis. Blood tests included glucose, creatinine, iron, apoferritin, liver enzymes and a complete blood count. C-reactive protein and N-terminal prohormone of B-type natriuretic peptide (NT-pro-BNP) concentrations were also measured in patients with CHD. Major adverse cardiac events (MACE) were defined as cardiovascular/total mortality, arterial thrombotic events, arrhythmias, major bleedings, pulmonary embolism or heart failure needing hospital admission. RESULTS The median age in patients with CHD was 23 (17-36) years and the median follow-up time was 5.8 (3.2-8.7) years; 103 (4.8%) controls and 40 (7.1%) patients with CHD had an RDW>15% (P=0.032). During follow-up, MACE were reported in 48 patients. CHD of great complexity, cardiovascular risk factors, low haemoglobin concentration and high NT-pro-BNP concentration were risk factors for an RDW>15%. Kaplan-Meier analysis showed a significantly worse cardiovascular outcome in patients with CHD with an RDW>15% (P<0.001). The multivariable survival analysis determined that age, CHD of great complexity, high NT-pro-BNP concentration and an RDW>15% were independent predictive factors for MACE. CONCLUSION RDW and NT-pro-BNP concentration are independent analytical predictors of MACE in patients with CHD.
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Impact of ultra-marathon and marathon on biomarkers of myocyte necrosis and cardiac congestion: a prospective observational study.
Wegberger, C, Tscharre, M, Haller, PM, Piackova, E, Vujasin, I, Gomiscek, A, Tentzeris, I, Freynhofer, MK, Jäger, B, Wojta, J, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2020;(11):1366-1373
Abstract
BACKGROUND An elevation of cardiac biomarkers is observed after intense or long-lasting physical activity. However, a recent meta-analysis has suggested that there might be an inverse relationship between duration of exercise and degree of biomarker elevation. The objective of this observational study was to investigate the impact of ultra-marathon (UM) vs. marathon (M) on biomarkers of myocyte necrosis and hemodynamic stress/congestion. METHODS Well-trained endurance athletes were recruited to participate in a 130-km UM and a M run. Troponin I (TnI), creatine kinase (CK), N-terminal pro-brain natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), and copeptin were measured after both events, respectively. RESULTS Fifteen athletes (14 males, one female) were included. There was no difference in exercise intensity according to the Borg scale (UM 16 [IQR 15-17], M 16 [IQR 14-17]; p = 0.424). Biomarkers of myocyte necrosis both differed significantly with higher levels of TnI (UM 0.056 ng/L [IQR 0.022-0.104), M 0.028 ng/L [IQR 0.022-0.049]; p = 0.016) and CK (UM 6992 U/l [IQR 2886-23038], M 425 U/l [IQR 327-681]; p = 0.001) after UM compared to M. Also, NT-proBNP (UM 723 ng/L [IQR 378-1152], M 132 ng/L [IQR 64-198]; p = 0.001) and MR-proADM (UM 1.012 nmol/L [IQR 0.753-0.975], M 0.877 nmol/L [IQR 0.550-0.985]; p = 0.023) as markers of myocardial congestion were significantly higher after UM. There was a tendency for elevated copeptin levels after M, but did not reach statistical significance (p = 0.078). CONCLUSION Ultra-marathon is associated with higher levels of biomarkers of myocyte necrosis and cardiac congestion compared to marathon, highlighting the impact of exercise duration on the cardiovascular system.
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Sustained heavy drinking over 25 years is associated with increased N-terminal-pro-B-type natriuretic peptides in early old age: Population-based cohort study.
Britton, A, O'Neill, D, Kuh, D, Bell, S
Drug and alcohol dependence. 2020;:108048
Abstract
UNLABELLED Heavy alcohol consumption is associated with an increased risk of heart failure. We sought to investigate whether levels of NT-proBNP differ by alcohol consumption profiles, both current drinking as well as cumulative exposure to drinking over several decades in a general population sample. METHODS Data on 2054 participants (49% male) were taken from the UK Medical Research Council National Survey for Health and Development, a longitudinal cohort study based on a nationally representative sample of births in 1946. Categories of long-term alcohol consumption were created based on consumption over 25 years of observations and compared with levels of NT-proBNP measured at mean age 63. RESULTS We found that those who drank heavily (both currently and long-term) had higher levels of NT-proBNP than moderate drinkers, after adjusting for major confounders (age, sex, socio-economic position and smoking). As NT-proBNP has attracted attention as a biomarker for heart failure, this suggests a critical pathway through which heavy drinking may increase risk of this cardiovascular disease. When we looked at heavy drinkers who varied their intake over the decades, it was only the recently heavy group that had higher levels of NT-proBNP. Further work is needed to demonstrate whether effects are reversible upon cessation of heavy drinking, but this finding highlights the need to have repeated data to unpack dynamics over time. CONCLUSION Our findings suggest heavy drinkers could be screened for NT-proBNP levels in order to identify those at high risk earlier in the clinical stages of heart failure and targeted for risk reduction strategies.