bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Vitamin D Supplementation on Severe COVID-19 Outcomes in Patients With Vitamin D Insufficiency
Authors: Levitus Corinne , Chekuri Sweta , Assa Andrei , Mohrmann Laurel , Zindman Alexandra , Tabatabaie Vafa , Toscano Fabrizio , Ahmed Masud , Baron Sarah W 
Published: May 2021

Abstract
Introduction: Coronavirus Disease 2019 (COVID-19) deaths have surpassed one million worldwide with limited treatment modalities, and physicians are relying on alternative methods, such as Vitamin D supplementation, to prevent or halt disease progression without direct evidence. Research has proven that vitamin D supplementation can prevent inflammation based on its role in innate immune response; however, there have been limited studies regarding vitamin D supplementation in COVID-19. We aimed to determine whether vitamin D supplementation in vitamin D insufficient patients was associated with fewer severe COVID-19 outcomes, defined as mechanical ventilation or death. Methods: Retrospective study that analyzed data from all adult patients admitted to our tertiary care center between March 2020 and July 2020 with a positive RT-PCR for SARS CoV-2 and a serum 25-hydroxyvitamin D (25[OH]D) level measured within 90 days prior to the index admission. Patients with 25(OH)D &lt;30 ng/mL were considered vitamin D insufficient and patients ordered for least one weekly dose of ≥1,000 units of ergocalciferol or cholecalciferol were considered supplemented. Supplemented vitamin D insufficient patients were compared to non-supplemented vitamin D insufficient patients in terms of severe COVID-19 disease as defined by mechanical ventilation or death. Results: 129 COVID-19 patients with a vitamin D level &lt;30 ng/mL were identified, with a median vitamin D level of 21.4 ng/mL. A total of 43 patients (33.3%) had severe COVID-19 outcomes. 65 (50.4%) patients with vitamin D insufficiency were supplemented and 64 (49.6%) were not supplemented. Vitamin D supplementation with ≥1,000 units (OR 0.6, 95% CI 0.28 - 1.40; p=0.25), ≥5,000 units (OR 0.5, 95% CI 0.26 - 1.23; p=0.15), or ≥50,000 units (OR 1.0, 95% CI 0.42–2.20, p=0.92) weekly had no statistically significant effect on severe COVID-19 outcomes. The odds of severe COVID-19 outcomes in supplemented patients were non-significantly reduced at lower cutoff values for vitamin D insufficiency (&lt;20 ng/mL and &lt;12 ng/mL) for all supplementation amounts. Conclusion: Vitamin D supplementation in patients with vitamin D insufficiency did not significantly reduce severe COVID-19 outcomes; however, vitamin D supplementation was associated with non-statistically significant reduced odds of severe COVID-19 outcomes at lower cutoff values of vitamin D level. These results demonstrate that Vitamin D supplementation may have a protective effect against severe COVID-19 outcomes in patients with lower baseline levels of vitamin D.
CARF (CDKN2AIP) Regulates Hepatic Lipid Metabolism and Protects Against Development of Non-Alcoholic Fatty Liver Diseases
Authors: Hasan Kamrul M , Parveen Meher , Pena Alondra , Calles Erick Galdamez , Gergis Marvy , Espinoza-Derout Jorge , Sinha-Hikim Amiya , Friedman Theodore C 
Published: May 2021

Abstract
Non-alcoholic fatty liver diseases (NAFLD) is the most common form of liver diseases in the USA with 30–40% of American being affected and about 12% with nonalcoholic steatohepatitis (NASH), a leading cause of end-stage liver diseases. NAFLD has been linked with insulin resistance, type2 diabetes, obesity, and cardiovascular diseases but molecular mechanisms underlying the development of NAFLD and its association with metabolic syndromes are poorly understood. In this study, we explored the role of CARF (collaborator of ARF) also known as CDKN2AIP, a novel gene of ARF-MDM2-p53 pathway in the development of NAFLD. It has been shown that, p53, beyond its tumor suppressor functions, can regulate the cellular glucose and lipid metabolism and its activation has been reported to induce hepatic steatosis in mice. However, as a regulator of p53 pathway, the role of CARF in the lipid metabolism and associated metabolic diseases has not been studied yet. Using high-fat diet (HFD) fed obesity mouse model of NAFLD we found that the expression of CARF along with Sirt1, pAMPK, and pACC was significantly decreased in the HFD induced fatty livers compared to control. Similarly, CARF expression was also down-regulated in palmitate (PA)-treated HepG2 cells, an in vitro model of steatosis. We also observed that shRNA mediated knockdown or lentiviral vector mediated overexpression of CARF induced or reduced the endogenous fat accumulation, respectively, in HepG2 cells, suggesting that CARF expression is negatively regulated in NAFLD. Additionally, we performed RNA seq analysis after CARF silencing in HepG2 cells and demonstrated that silencing of CARF altered the expression of genes regulating hepatic de novo lipogenesis, beta-oxidation, and lipid secretion all of which favor the accumulation of fat in the hepatocytes. Furthermore, genes associated with mitochondrial functions such as the TCA cycle and oxidative phosphorylation were also altered which could play a role in the development of NAFLD. Finally, we demonstrated that AAV mediated hepatic overexpression of CARF in HFD fed mouse model significantly reduced the fat accumulation in the liver as evident by H&E staining of liver sections and intrahepatic triglyceride level. Altogether we conclude that CARF plays a vital role in hepatic lipid metabolism and its downregulation perturbs lipid homeostasis leading to hepatic steatosis and the development of NAFLD.
Carotid Intima Media Thickness in Graves Disease: Comparing Overt Hyperthyroid and Remission State
Authors: Nurjannah Intan , Wisnu Wismandari , Tahapary Dicky L , Wijaya Ika Prasetya 
Published: May 2021

Abstract
Background/Objective: Hyperthyroid has been associated with increased cardiovascular event. Carotidintima media thickness (CIMT) is oftenly measured to evaluate the risk of cardiovascularevent. The aim of this study is to measure CIMT in Graves’ disease and to comparebetween subjects in overt hyperthyroidism and remission state. Methods: Our study was a cross-sectional study performed at the outpatient endocrinologyclinic of Dr. Cipto Mangunkusumo Hospital, a tertiary care hospital in Jakarta, Indonesia. Graves’ disease subjects were recruited, of whom then grouped into overthyperthyroidism (clinical signs and symptoms of hyperthyroidism, low THS, highthyroxine levels, treatment naïve of within 3 months of treatments) and remission state(no clinical signs and symptoms of hyperthyroidism, normal THs and thyroxine levels,without any anti thyroid drugs for at least 6 months). CIMT measurements wereperformed by trained physician on both right and left artery carotid arteries using anultrasound equipped with software that automatically measured the CIMT. We alsomeasured lipid profile, fasting blood glucose, and ECG. Results: We recruited 49 Graves’ disease subjects, of whom 32 and 17 subjects werein overt hyperthyroidism and remission state respectively. Median CIMT in overthyperthyroidism and remission state were 0,473 mm and 0,488 mm respectively, p:0,109. Among clinical and laboratory risk factors, only age which had an independentcorrelation with CIMT in Graves disease. (r: 0,371; p:&lt;0,0001). Discussion: Our is the first study that measured CIMT among subjects with Graves’disease in remission and overt hyperthyroidism state, of which we observed nodifferences. This might be due to the fact that the atherosclerosis risk factors were notdistributed evenly on both group, of which subjects were older in the remission group. Ithas been reported that there are increasing CIMT along with aging (0,003-0,010 mm peryear). Furthermore, in remission state we need to take metabolic and physical changesinto consideration, such as increasing weight as much as 2,5% from prior weight alongwith increasing total cholesterol and LDL-cholesterol which both can affect CIMT levels. Conclusions:
There are no significant differences in CIMT between overt hyperthyroid andremission state in Graves’ disease. Keywords: carotid intima media thickness, Graves’ disease, overt hyperthyroid, remission.
Carotid Intima Media Thickness in Young Peruvians With Onset of Type 2 Diabetes Mellitus, an Early Marker of Vascular Compromise
Authors: Manrique Helard Andres , Nuñez Pedro 
Published: May 2021

Abstract
Objective: To evaluate the relationship between the thickness of the carotid intima media (GIMT) with clinical and laboratory parameters in young people to identify asymptomatic endothelial dysfunction and prevent future vascular complications. Methods: This is a cross-sectional study of 81 adolescents from 10 to 18 years of age distributed in three groups: (i) 27 with onset of type 2 diabetes (DM2), (ii) 22 were non-diabetic obese; and (iii) 32 with normal weight, non-diabetic BMI from a National Reference Hospital in Lima, Peru. Laboratory evaluation consisted of fasting glucose levels, HbA1C, lipid profile, us-CRP, and Doppler ultrasound for measurement of the common carotid artery (right and left, both?). Results: In total 81 participants, 27 of them with a previous diagnosis of type 2 diabetes mellitus, of which 22 obese patients without the onset of type 2 diabetes mellitus and 32 normal weight without onset of type 2 diabetes mellitus, the median for age was 20, 19.5 and 20 years respectively, with a predominance of the female sex in the three groups; the median time of illness in years for the study group was 6 years (IQR 3–8) with DM2; Regarding treatment, metformin was the main drug used (20 patients) followed by sulfonylureas (glimepiride and glyburide, 9 patients), insulin (7 patients) and DPP4 inhibitors (vildagliptin and sitagliptin, 06 patients); Differences were found between the groups of patients with DM2, obese patients without DM2, and normal weight subjects without DM2, this difference being stronger in terms of body mass index (26.29, 31.35, 23.73 kg / m2, respectively); abdominal girth (91, 97.25, 78 cm, respectively); fasting blood glucose (126, 87.5, 94 mg / dl, respectively); glycosylated hemoglobin (7.77, 4.85, 4.97%, respectively), all of these with a p: 0.001; diastolic blood pressure (74, 68, 64 mmHg, respectively); and triglycerides (112, 112.5 and 65.5 mg / dl, respectively); The median IMT ± iqr was 0.430 ± 0.08 mm in adolescents with DM2; 0.420 ± 0.03 mm, in non-diabetic obese adolescents; and 0.405 mm ± 0.02 mm, in non-diabetic adolescents with normal weight. In general, lean, non-diabetic adolescents had a lower IMT than adolescents with DM2 (p = 0.003) and obese adolescents (p = 0.006). Conclusions: Adolescents with DM2 had a higher median IMT compared to lean, non-diabetic adolescents that reflect the onset of early vascular damage due to DM 2.
Epigenetic Programming Reverses Cardiometabolic Dysfunctions and Modulates Hypothalamic Genes Involved in Oxidative Stress and Inflammation in Angiotensin II-Treated Male Mice
Authors: Elgazzaz Mona , Mauvais-Jarvis Franck , Lazartigues Eric 
Published: May 2021

Abstract
Cardiometabolic disease is a global health issue that affects millions of people worldwide. Environmental perinatal exposure affects the health outcomes of the offspring and determines their disease susceptibility later in life. Angiotensin-II (Ang-II) is a peptide known to cause vasoconstriction, elevated blood glucose levels and inflammation. Previously, we reported that perinatal exposure to a hypercaloric diet (HD) results in elevated blood pressure (BP), weight gain, fasting hyperglycemia and glucose intolerance only in male mice. In addition, subcutaneous infusion of a sub-pressor dose of Ang-II was associated with a normalization in fasting blood glucose levels and a reversal of glucose intolerance only in programmed male mice. We hypothesize that epigenetic programming blocks the deleterious effects of Ang-II by altering its inflammatory signaling pathway. C57BL6/J dams were fed HD or regular diet (RD) for 1 month before mating with RD-fed males. After weaning, offspring of HD dams (programmed) and of RD dams (controls) were maintained on RD until 3 months of age. Mice then underwent 24 h BP recording (telemetry) and were implanted with Ang-II osmotic pumps (200 ng/kg/min/2 weeks). BP (24 h) was recorded weekly for 2 weeks. Mice were then sacrificed and hypothalami were harvested for mRNA sequencing (Illumina NextSeq). Programmed mice had lower 24 h systolic BP levels compared to control males (area under the curve: 41844 ±263.2 vs. 44522 ±275.6; p&lt;0.0001). For RNAseq analysis, data showed 62 differentially expressed genes (DEG) in programmed males compared to controls. Using iPathway analysis, we found that some of the DEG are correlated to cholinergic synapse pathway (p=0.005) and neuroactive ligand-receptor interaction pathway (p=0.003). Nicotinic acetylcholine alpha-7 receptor (Chrna7) gene, known for its anti-inflammatory and hypoglycemic effects was upregulated in programmed males (p=0.024). On the other hand, genes involved in metabolic pathways and oxidative stress were differentially expressed as well. Phospholipase A2 group 3 (Pla2g3) gene, known to be overexpressed in oxidative stress was downregulated in programmed males (p=0.04). Moreover, Thiosulfate sulfurtransferase (Tst) gene, an antioxidant enzyme and used as a marker for enhanced insulin sensitivity was upregulated (p=0.023) in programmed males. Interestingly, female mice did not show any changes in BP or gene expression between the two groups. In conclusion, perinatal exposure to HD alters the cardiovascular response to Ang-II possibly through the modulation of gene expression of Chrna7 gene and genes involved in oxidative stress. Future experiments will be investigating the signaling pathways used in epigenetic programming to affect inflammation and oxidative stress in male mice.
External Validation of Prediction Models for Unilateral Primary Aldosteronism
Authors: Sam Davis , Kline Gregory A , So Benny , Pasieka Janice L , Harvey Adrian , Hundemer Gregory L , Chin Alex , Przybojewski Stefan J , Leung Alexander A 
Published: May 2021

Abstract
Primary aldosteronism (PA) is the most common cause of remediable hypertension. Treatment is informed by establishing whether disease is unilateral (localized to one adrenal gland) or bilateral. Adrenalectomy is the guideline-recommended treatment of choice for unilateral PA. However, the currently recommended subtyping test, adrenal vein sampling (AVS), is often limited in accessibility. Thus, prediction models have been developed to diagnose unilateral PA and therefore bypass AVS. However, their generalizability remains unknown. In this retrospective study, we aimed to externally validate the performance of prediction models for unilateral PA in a large population of PA patients at a Canadian referral center who underwent AVS during 2006–2018. The presence of unilateral disease was indicated by a lateralization index of &gt;3 on AVS. We identified 6 clinical prediction models from the literature. The discrimination and calibration of each model were systematically evaluated. For the original models, the derivation cohorts were based out of Japan, France, Italy, and England, with mean age between 46–54 years and 43–56% being male. The derivation cohorts were generally small, with 4 of the 6 studies reporting less than 50 people with unilateral PA. Common variables reported to be predictive of unilateral PA included male sex, hypokalemia, elevated aldosterone-renin ratio, and the presence of a unilateral adrenal nodule on imaging. The validation cohort included 342 PA patients who underwent successful AVS (average age, 52.1 years; 58.8% male). Among them, 186 (54.4%) demonstrated unilateral disease, and the remaining 156 (45.6%) were considered to have bilateral disease. The baseline characteristics of the validation cohort were broadly similar to those of the derivation cohorts, except for potential differences in ethnicity. When applying the models to the validation cohort, subjects were excluded if any candidate variables were missing. All 6 models demonstrated poor discrimination in the validation set (C-statistics; range, 0.59–0.72), representing a marked decrease compared to the derivation sets where they were reported (range, 0.80–0.87). Assessment of calibration by comparing observed and predicted probabilities of the unilateral subtype revealed significant miscalibration. Calibration-in-the-large for every model was &gt;0 (range, 0.36–2.23), signifying systematic underprediction of unilateral PA. Calibration slopes were all &lt;1 (range, 0.35–0.85), indicating poor performance at the extremes of risk. These results suggest that the original models were optimistic due to overfitting in the derivation cohorts and therefore lack generalizability. This is primarily because these models were developed in small data sets. In conclusion, clinical assessment with prediction models for unilateral PA cannot be readily used to bypass AVS in the general PA population.
Insulin Resistance Is Associated With Impaired HDL Function and Atherogenic Modification of LDL in Polycystic Ovarian Syndrome
Authors: Ho Jan Hoong , Adam Safwaan , Liu Yifen , Dhage Shaishav , Tsimikas Sotirios , Soran Handrean , Gibney James 
Published: May 2021

Abstract
Background and Aims: Polycystic ovarian syndrome (PCOS) is associated with increased risk of cardiovascular disease (CVD). The aim of this study was to assess the association between PCOS and markers of HDL functionality and atherogenic LDL modification. Methods: This is a cross-sectional study of 104 women with PCOS [median (IQR); age 29 (24–36) years, and BMI 32.9 (25.7–38.5) kg/m2] and 103 BMI-matched healthy participants (age 34 (27–37) years, and BMI 31.1 (27.6–35.5) kg/m2). PCOS was defined using the NIH criteria. Measurement of lipid profile and glycaemic blood parameters were undertaken. Patients with PCOS were divided into tertiles of insulin resistance assessed using the homeostatic model assessment (HOMA-IR). Cholesterol efflux capacity (CEC), and paraoxonase-1 (PON1) activity were measured as markers of HDL functionality. Oxidized LDL (OxLDL), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized phoshopholipids on apolipoprotein B-100 (OxPL-apoB) and apolipoprotein(a) (OxPL-apo(a)), and glycated apoB were used as markers of atherogenic modification of LDL. Results: Patients with PCOS in the upper tertile of insulin resistance had impaired HDL functionality compared to the lower tertile and controls, with lower CEC [13.7 (12.4–14.6) vs 14.9 (13.6–17.0), P=0.003; and 14.5 (13.0–16.0) %, P=0.063 respectively] and PON1 activity [77.2 (48.2–129.2) vs 112.9 (54.0–175.4), P=0.043; and 131.6 (89.5–195.1) nmol/ml/min, P&lt;0.001 respectively]. Markers of atherogenic modification of LDL were also increased in the upper tertile compared to the lower tertile and controls, with higher levels of OxLDL [91.6 (58.8–120.9) vs 67.2 (20.1–86.3), P=0.016; and 74.8 (47.6–89.5) ng/ml, P=0.013 respectively], LpPLA2 [1.66 (1.48–1.84) vs 1.48 (1.39–1.60), P=0.004; and 1.53 (1.37–1.70) µg/ml, P=0.015 respectively], small-dense LDL cholesterol (sdLDL) [24.8 (16.8–35.0) vs 15.3 (11.3–20.1), P&lt;0.001; and 20.9 (14.6–29.0) mg/dl, P&lt;0.001 respectively], and glycated apoB [4.02 (3.63–4.33) vs 3.51 (3.27–3.70), P&lt;0.001; and 3.48 (3.20–3.96), P&lt;0.001 respectively]. Both BMI and insulin resistance were associated with adverse lipoprotein modification, correlating positively with OxLDL, LpPLA2, sdLDL, and glycated apoB (Spearman’s ρ=0.244–0.325 and Spearman’s ρ=0.254–0.377 respectively, all P&lt;0.050); and negatively with CEC (Spearman’s ρ=-0.244 and
Spearman’s ρ=0.254 respectively, both P&lt;0.050). OxPL-apoB, OxPL-apo(a), and lipoprotein(a) did not differ between PCOS and controls. Conclusions: Insulin resistance is a key determinant of decreased HDL functionality and increased oxidative modification and glycation of LDL in PCOS, which is likely to contribute to the increased CVD risk.
Laterality Diagnosis of Adrenal Vein Sampling for Primary Aldosteronism Using Aldosterone Alone
Authors: Wada Norio , Baba Shuhei , Sugawara Hajime , Miyoshi Arina , Obara Shinji , Usubuchi Hiroaki , Terae Satoshi 
Published: May 2021

Abstract
Background: In adrenal vein sampling (AVS) for primary aldosteronism (PA), cortisol concentration is used to determine successful AVS, and laterality diagnosis is performed using a combination of aldosterone and cortisol concentrations. In this study, we examined the comparison with the conventional method when AVS was determined by aldosterone alone. Subjects and methods: We studied the data from 277 patients with PA who underwent AVS in Sapporo City General Hospital from July 2007 to April 2020. The patients with autonomous cortisol production were excluded. Using the blood samples from adrenal veins and inferior vena cava (IVC) after ACTH stimulation, the predicting ability of the left and right ratio of aldosterone concentration (aldosterone ratio, AR) for lateralization Index (LI) was examined by Receiver operating characteristic (ROC) analysis. The predicting abilities of the ratio of aldosterone concentration between adrenal vein and IVC (aldosterone index, AI) and aldosterone concentration for selectivity index (SI) and contralateral ratio (CR) were also examined by ROC analysis. Results: Six samples (0.01%) with SI &lt;5 after ACTH stimulation those were determined unsuccessful AVS. The results of the area under the curve (AUC) in ROC analysis of aldosterone concentration and AI for prediction of SI&gt;5 was 0.998, 0.990, respectively, p=0.39. The optimal cut-off values of aldosterone concentration and AI for prediction successful AVS were 1700 pg/ml (sensitivity 99.5%, specificity 100%), 7.44 (sensitivity 94.0%, specificity 100%), respectively. Seventy-two patients (27.3%) had LI &gt;4 who were diagnosed as unilateral aldosterone excess. AR had 0.94 of AUC for prediction of LR &gt;4. The optimal cut-off value of AR was 3.53 (sensitivity 86.1%, specificity 94.8%). Eighty-two patients (31.1%) had unilateral CR&lt;1. The AUC of aldosterone concentration and AI for prediction of CR&lt;1 was 0.96, 0.98, respectively, p=0.07. The optimal cut-off values of aldosterone concentration and AI were 13600 pg/ml, 42, respectively. The sensitivity and the specificity at the optimal cut-off points of aldosterone concentration and AI were 91.5%, 91.5% and 91.5%, 94.8%, respectively. Conclusions: The determination of successful AVS and unilateral result in AVS can be predicted using aldosterone alone. It was suggested that AR is useful for tentative interpretation in the cases where the results of aldosterone were previously reported and lateralizing diagnosis of the cases with autonomous cortisol production.