Circulating adipokine levels and COVID-19 severity in hospitalized patients.

BACKGROUND: Obesity is a risk factor for adverse outcomes in COVID-19, potentially driven by chronic inflammatory state due to dysregulated secretion of adipokines and cytokines. We investigated the association between plasma adipokines and COVID-19 severity, systemic inflammation, clinical parameters, and outcome of COVID-19 patients. METHODS: In this multi-centre prospective cross-sectional study, we collected blood samples and clinical data from COVID-19 patients. The severity of COVID-19 was classified as mild (no hospital admission), severe (ward admission), and critical (ICU admission). ICU non-COVID-19 patients were also included and plasma from healthy age, sex, and BMI-matched individuals obtained from Lifelines. Multi-analyte profiling of plasma adipokines (Leptin, Adiponectin, Resistin, Visfatin) and inflammatory markers (IL-6, TNFα, IL-10) were determined using Luminex multiplex assays. RESULTS: Between March and December 2020, 260 SARS-CoV-2 infected individuals (age: 65 [56-74] BMI 27.0 [24.4-30.6]) were included: 30 mild, 159 severe, and 71 critical patients. Circulating leptin levels were reduced in critically ill patients with a high BMI yet this decrease was absent in patients that were administered dexamethasone. Visfatin levels were higher in critical COVID-19 patients compared to non-COVID-ICU, mild and severe patients (4.7 vs 3.4, 3.0, and 3.72 ng/mL respectively, p < 0.05). Lower Adiponectin levels, but higher Resistin levels were found in severe and critical patients, compared to those that did not require hospitalization (3.65, 2.7 vs 7.9 µg/mL, p < 0.001, and 18.2, 22.0 vs 11.0 ng/mL p < 0.001). CONCLUSION: Circulating adipokine levels are associated with COVID-19 hospitalization, i.e., the need for oxygen support (general ward), or the need for mechanical ventilation and other organ support in the ICU, but not mortality.

Use of Salivary Iodine Concentrations to Estimate the Iodine Status of Adults in Clinical Practice.

BACKGROUND: Measurement of the 24-h urinary iodine concentration or urinary iodine excretion (UIE) is the gold standard to determine iodine status; however, this method is inconvenient. The use of salivary iodine could be a possible alternative since salivary glands express the sodium-iodine symporter. OBJECTIVES: We aimed to establish the correlation between the salivary iodine secretion and UIE, to evaluate the clinical applicability of the iodine saliva measurement. METHODS: We collected 24-h urine and saliva samples from 40 participants ≥18 y: 20 healthy volunteers with no specific diet (group 1), 10 patients with differentiated thyroid cancer with a low dietary intake (<50 µg/d, group 2), and 10 patients with a high iodine status as the result of the use of amiodarone (group 3). Urinary and salivary iodine were measured using a validated inductively coupled plasma MS method. To correct for differences in water content, the salivary iodine concentration (SIC) was corrected for salivary protein and urea concentrations (SI/SP and SI/SU, respectively). The intra- and inter-individual CVs were calculated, and the Kruskal-Wallis test and Spearman's correlation were used. RESULTS: The intra-individual CVs for SIC, SI/SP, and SI/SU were 63.8%, 37.7%, and 26.9%, respectively. The inter-individual CVs for SIC, SI/SP, and SI/SU were 77.5%, 41.6% and 47.0%, respectively. We found significant differences (P < 0.01) in urinary and salivary iodine concentrations between all groups [the 24-h UIE values were 176 µg/d (IQR, 96.1-213 µg/d), 26.0 µg/d (IQR, 22.0-37.0 µg/d), and 10.0*103 µg/d (IQR, 7.57*103-11.4*103 µg/d) in groups 1-3, respectively; the SIC values were 136 µg/L (IQR, 86.3-308 µg/L), 71.5 µg/L (IQR, 29.5-94.5 µg/L), and 14.3*103 µg/L (IQR, 10.6*103-25.6*103 µg/L) in groups 1-3, respectively]. Correlations between the 24-h UIE and SIC, SI/SP, and SI/SU values were strong (ρ = 0.80, ρ = 0.90, and ρ = 0.86, respectively; P < 0.01). CONCLUSIONS: Strong correlations were found between salivary and urinary iodine in adults with different daily iodine intakes. A salivary iodine measurement can be performed to assess the total iodine body pool, with the recommendation to correct for salivary protein or urea.

Prevalence and pathophysiology of early dumping in patients after primary Roux-en-Y gastric bypass during a mixed-meal tolerance test.

BACKGROUND: Early dumping is a poorly defined and incompletely understood complication after Roux-en-Y gastric (RYGB). OBJECTIVE: We performed a mixed-meal tolerance test in patients after RYGB to address the prevalence of early dumping and to gain further insight into its pathophysiology. SETTING: The study was conducted in a regional hospital in the northern part of the Netherlands. METHODS: From a random sample of patients who underwent primary RYGB between 2008 and 2011, 46 patients completed the mixed-meal tolerance test. The dumping severity score for early dumping was assessed every 30 minutes. A sum score at 30 or 60 minutes of ≥5 and an incremental score of ≥3 points were defined as indicating a high suspicion of early dumping. Blood samples were collected at baseline, every 10 minutes during the first half hour, and at 60 minutes after the start. RESULTS: The prevalence of a high suspicion of early dumping was 26%. No differences were seen for absolute hematocrit value, inactive glucagon-like peptide-1, and vasoactive intestinal peptide between patients with or without early dumping. Patients at high suspicion of early dumping had higher levels of active glucagon-like peptide-1 and peptide YY. CONCLUSION: The prevalence of complaints at high suspicion of early dumping in a random population of patients after RYGB is 26% in response to a mixed-meal tolerance test. Postprandial increases in both glucagon-like peptide-1 and peptide YY are associated with symptoms of early dumping, suggesting gut L-cell overactivity in this syndrome.

Reference values of fecal calgranulin C (S100A12) in school aged children and adolescents.

BACKGROUND: Calgranulin C (S100A12) is an emerging marker of inflammation. It is exclusively released by activated neutrophils which makes this marker potentially more specific for inflammatory bowel disease (IBD) compared to established stool markers including calprotectin and lactoferrin. We aimed to establish a reference value for S100A12 in healthy children and investigated whether S100A12 levels can discriminate children with IBD from healthy controls. METHODS: In a prospective community-based reference interval study we collected 122 stool samples from healthy children aged 5-19 years. Additionally, feces samples of 41 children with suspected IBD (who were later confirmed by endoscopy to have IBD) were collected. Levels of S100A12 were measured with a sandwich enzyme-linked immunosorbent assay (ELISA) (Inflamark®). The limit of detection was 0.22 µg/g. RESULTS: The upper reference limit in healthy children was 0.75 µg/g (90% confidence interval: 0.30-1.40). Median S100A12 levels were significantly higher in patients with IBD (8.00 µg/g [interquartile range (IQR) 2.5-11.6] compared to healthy controls [0.22 µg/g (IQR<0.22); p<0.001]). The best cutoff point based on receiver operating characteristic curve was 0.33 µg/g (sensitivity 93%; specificity 97%). CONCLUSIONS: Children and teenagers with newly diagnosed IBD have significantly higher S100A12 results compared to healthy individuals. We demonstrate that fecal S100A12 shows diagnostic promise under ideal testing conditions. Future studies need to address whether S100A12 can discriminate children with IBD from non-organic disease in a prospective cohort with chronic gastrointestinal complaints, and how S100A12 performs in comparison with established stool markers.

Combined effects of smoking and alcohol on metabolic syndrome: the LifeLines cohort study.

INTRODUCTION: The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. METHODS: 64,046 participants aged 18-80 years from the LifeLines Cohort study were categorized into three body mass index (BMI) classes (BMI<25, normal weight; BMI 25-30, overweight; BMI≥30 kg/m2, obese). MetS was defined according to the revised criteria of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III). Within each BMI class and smoking subgroup (non-smoker, former smoker, <20 and ≥20 g tobacco/day), the cross-sectional association between alcohol and individual MetS components was tested using regression analysis. RESULTS: Prevalence of MetS varied greatly between the different smoking-alcohol subgroups (1.7-71.1%). HDL cholesterol levels in all alcohol drinkers were higher than in non-drinkers (0.02 to 0.29 mmol/L, P values<0.001). HDL cholesterol levels were lower when they were also a former or current smoker (<20 and ≥20 g tobacco/day). Consumption of ≤1 drink/day indicated a trend towards lower triglyceride levels (non-significant). Concurrent use alcohol (>1 drink/day) and tobacco showed higher triglycerides levels. Up to 2 drinks/day was associated with a smaller waist circumference in overweight and obese individuals. Consumption of >2 drinks/day increased blood pressure, with the strongest associations found for heavy smokers. The overall metabolic profile of wine drinkers was better than that of non-drinkers or drinkers of beer or spirits/mixed drinks. CONCLUSION: Light alcohol consumption may moderate the negative associations of smoking with MetS. Our results suggest that the lifestyle advice that emphasizes smoking cessation and the restriction of alcohol consumption to a maximum of 1 drink/day, is a good approach to reduce the prevalence of MetS.

Associations between smoking, components of metabolic syndrome and lipoprotein particle size.

BACKGROUND: The clustering of metabolic and cardiovascular risk factors is known as metabolic syndrome (MetS). The risk of having MetS is strongly associated with increased adiposity and can be further modified by smoking behavior. Apolipoproteins (apo) associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) may be altered in MetS. This study aimed to examine the association between smoking and the following parameters: MetS and its components, levels of apolipoproteins and estimated lipoprotein particle size, separately for men and women, and in different body mass index (BMI) classes. METHODS: We included 24,389 men and 35,078 women aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012; 5,685 men and 6,989 women were current smokers. Participants were categorized into three different body mass index (BMI) classes (BMI <25; BMI 25 to 30; BMI ≥30 kg/m²). MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP:ATPIII) criteria. Blood pressure, anthropometric and lipid measurements were rigorously standardized, and the large sample size enabled a powerful estimate of quantitative changes. The association between smoking and the individual MetS components, and apoA1 and apoB, was tested with linear regression. Logistic regression was used to examine the effect of smoking and daily tobacco smoked on risk of having MetS. All models were age adjusted and stratified by sex and BMI class. RESULTS: Prevalence of MetS increased with higher BMI levels. A total of 64% of obese men and 42% of obese women had MetS. Current smoking was associated with a higher risk of MetS in both sexes and all BMI classes (odds ratio 1.7 to 2.4 for men, 1.8 to 2.3 for women, all P values <0.001). Current smokers had lower levels of HDL cholesterol and apoA1, higher levels of triglycerides and apoB, and higher waist circumference than non-smokers (all P <0.001). Smoking had no consistent association with blood pressure or fasting blood glucose. In all BMI classes, we found a dose-dependent association of daily tobacco consumption with MetS prevalence as well as with lower levels of HDL cholesterol, higher triglyceride levels and lower ratios of HDL cholesterol/apoA1 and, only in those with BMI <30, LDL cholesterol/apoB (all P <0.001). CONCLUSIONS: Smoking is associated with an increased prevalence of MetS, independent of sex and BMI class. This increased risk is mainly related to lower HDL cholesterol, and higher triglycerides and waist circumference. In addition, smoking was associated with unfavorable changes in apoA1 and apoB, and in lipoprotein particle size. Please see related commentary: http://www.biomedcentral.com/1741-7015/11/196.

Thyroid hormone status and health-related quality of life in the LifeLines Cohort Study.

BACKGROUND: Thyroid disorders are prevalent in Western society, yet many subjects experience limited symptoms at diagnosis, especially in hypothyroidism. We hypothesize that health-related quality of life (HR-QOL) is more severely impaired in subjects with more abnormal thyroid hormone function tests. METHODS: This is a cross-sectional study of Dutch adults participating in the LifeLines Cohort Study between December 2009 and August 2010. In 9491 Western European participants (median age 45 years; 3993 men and 5498 women), without current or former use of thyroid medication, we compared HR-QOL using the RAND 36-Item Health Survey between subjects with normal thyrotropin (TSH) values and subjects with disturbed thyroid hormone status (serum TSH, free thyroxine, and free triiodothyronine). The influence of possible confounders (age, smoking, co-morbidity) on HR-QOL was evaluated as well. RESULTS: Suppressed TSH values (TSH < 0.5 mU/L) were found in 114 (1.2%), while 8334 (88.8%) had TSH within the normal range, 973 participants (10.3%) had TSH between 4 and 10 mU/L, and 70 (0.7%) had TSH > 10 mU/L. Men had a higher HR-QOL than women (70-92 vs. 65-89; p < 0.001), except for the domain "general health" (72 vs. 72; p = 0.692). Men with suppressed or elevated TSH values did not score significantly lower than euthyroid men for any of nine domains of the RAND 36-Item Health Survey. Compared with euthyroid women, women with suppressed TSH scored significantly lower in the domains "physical functioning" (84 vs. 89, p = 0.013) and "general health" (67 vs. 72, p = 0.036). Women with markedly elevated TSH (> 10 mU/L) had a score in all HR-QOL domains that was similar to that of women with normal TSH values. There were no differences in the physical component score and the mental component score between any of the TSH groups. Physical component score and mental component score were mainly determined by smoking status, co-morbidity, and body mass index or waist circumference. CONCLUSIONS: In this population-based study, HR-QOL scores of subjects with suppressed TSH values or markedly elevated TSH values were generally not significantly lower than those of subjects with normal or mildly elevated TSH values.

Determinants and prognostic significance of an intra-dialysis rise of cardiac troponin I measured by sensitive assay in hemodialysis patients.

BACKGROUND: Previous studies using conventional cTnI assays reported conflicting results on the evolution of cTnI levels during hemodialysis. The determinants and prognostic significance of changes in cTnI during hemodialysis are presently unknown. The aim of this prospective study was to characterize the determinants and prognostic significance of intra-dialysis changes in cTnI using a sensitive assay. METHODS: cTnI was measured before and after hemodialysis with a sensitive assay in 90 chronic patients without acute cardiac symptoms. Multivariable regression analyses were used to identify factors that were associated with intra-dialysis rise in cTnI. The prognostic effect of an intra-dialysis rise in cTnI during a 52-month follow-up was evaluated using Cox regression models. The primary and secondary endpoint was the incidence of major adverse cardiovascular events and all-cause mortality, respectively. RESULTS: Pre-dialysis cTnI was elevated in 31 patients (34 %). cTnI increased significantly during dialysis and this had a trend to be associated with longer dialysis vintage. A greater intra-dialysis rise in cTnI was associated with a significantly higher incidence of cardiovascular events, also after correction for age, gender, dialysis vintage, residual diuresis, previous cardiovascular events, and pre-dialysis cTnI levels (HR per 10 ng/L rise in cTnI: 1.21; CI 1.06-1.38; p 0.005). CONCLUSION: TnI levels rise significantly during hemodialysis and a greater intra-dialysis rise in cTnI is associated with an increased incidence of cardiovascular events. These findings suggest that hemodialysis has an acute deleterious effect on the heart. An intra-dialysis rise in cTnI may help identify patients who are susceptible to the hemodynamic stress of hemodialysis.

Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study.

BACKGROUND: Vitamin B(12) deficiency occurs frequently, especially among the elderly. However, screening for vitamin B(12) deficiency is hampered by poor sensitivity of the existing total vitamin B(12) assay. Methylmalonic acid (MMA) is considered as the most representative indicator of metabolic vitamin B(12) deficiency and is used as such in this study. The aim of this study was to validate the clinical usefulness of holotranscobalamin (holoTC) as an initial screening assay for metabolic vitamin B(12) deficiency in a mixed patient population. METHODS: Three hundred and sixty blood samples were collected by five Dutch hospitals. Vitamin B(12) and holoTC in serum were measured (AxSYM; Abbott). MMA in serum was measured by tandem mass spectrometry (LC-MS/MS). RESULTS: Receiver operating curve (ROC) analysis demonstrated a greater area under the curve (AUC) for holoTC than for vitamin B(12) in detecting vitamin B(12) deficiency characterized by three predefined cut-off levels of MMA. A cut-off value of 32 pmol/L of holoTC resulted in the highest sensitivity (83%) with acceptable specificity (60%) in detecting MMA concentrations above 0.45 µmol/L. The combination of vitamin B(12) and holoTC did not improve diagnostic accuracy at this cut-off level. CONCLUSIONS: HoloTC has a better diagnostic accuracy than vitamin B(12) and can replace the existing vitamin B(12) assay as a primary screening test in patients suspected of vitamin B(12) deficiency. Critical evaluation of cut-off values of holoTC indicated that a cut-off value of 32 pmol/L can be considered in screening for metabolic vitamin B(12) deficiency (defined by MMA > 0.45µmol/L) in a mixed patient population.

Reference values for aldosterone-renin ratios in normotensive individuals and effect of changes in dietary sodium consumption.

BACKGROUND: Determination of the aldosterone-to-renin ratio (ARR) in blood is the preferred screening test for primary aldosteronism. Renin can be measured as the plasma renin activity (PRA) or the plasma renin concentration (PRC). Consequently, the ARR can be measured either based on the PRA (ARR(pra)) or based on the PRC (ARR(prc)). In contrast with the ARR(pra), the data on reference values for the ARR(prc) are limited. Moreover, whether the ARR(pra) or ARR(prc) is affected by variations in salt intake is unknown. METHODS: We measured the PRA, the PRC, and serum aldosterone in 100 normotensive individuals between 20 and 70 years of age before and after a 3-day oral sodium-loading test (SLT). Participants were stratified according to age and sex. Data are presented as the median and interquartile range (IQR). RESULTS: Urinary sodium excretion after the SLT was ≥200 mmol/24 h in all participants. Serum aldosterone, PRA, and PRC values were significantly reduced after the SLT. PRC and PRA results were highly correlated [Spearman rank correlation r(s) = 0.80 and 0.74 before and after SLT, respectively; P < 0.001 for both]. The central 95% reference intervals for ARR(pra) before and after SLT were 0.07-1.45 h(-1) and 0.06-1.84 h(-1), respectively. The corresponding reference intervals for ARR(prc) were 4.1-81.3 pmol/ng and 3.9-74.8 pmol/ng. The median ARR(prc) decreased after the SLT from 19.5 pmol/ng (IQR, 13.0-29.4 pmol/ng) to 18.6 pmol/ng (IQR, 9.4-27.1 pmol/ng) (P = 0.005), whereas the median ARR(pra) did not change (P = 0.12). Both the ARR(prc) and ARR(pra) at baseline were higher in women than in men, whereas no sex difference was observed after sodium loading. CONCLUSIONS: We present reference values for the ARR(prc) for healthy individuals. The ARR is affected to a variable degree by sex and sodium intake.

The subcutaneous abdominal fat and not the intraabdominal fat compartment is associated with anovulation in women with obesity and infertility.

CONTEXT: Abdominal fat contributes to anovulation. OBJECTIVE: We compared body fat distribution measurements and their contribution to anovulation in obese ovulatory and anovulatory infertile women. DESIGN: Seventeen ovulatory and 40 anovulatory women (age, 30 +/- 4 yr; body mass index, 37.7 +/- 6.1 kg/m(2)) participated. Body fat distribution was measured by anthropometrics, dual-energy x-ray absorptiometry, and single-sliced abdominal computed tomography scan. Multiple logistic regression analysis was applied to determine which fat compartments significantly contributed to anovulation. RESULTS: Anovulatory women had a higher waist circumference (113 +/- 11 vs. 104 +/- 9 cm; P < 0.01) and significantly more trunk fat (23.0 +/- 5.3 vs. 19.1 +/- 4.2 kg; P < 0.01) and abdominal fat (4.4 +/- 1.3 kg vs. 3.5 +/- 0.9 kg; P < 0.05) on dual-energy x-ray absorptiometry scan than ovulatory women despite similar body mass index. The volume of intraabdominal fat on single-sliced abdominal computed tomography scan was not significantly different between the two groups (203 +/- 56 vs. 195 +/- 71 cm(3); P = 0.65), but anovulatory women had significantly more sc abdominal fat (SAF) (992 +/- 198 vs. 864 +/- 146 cm(3); P < 0.05). After multiple logistic regression analysis, only trunk fat, abdominal fat, and SAF were associated with anovulation. CONCLUSIONS: Abdominal fat is increased in anovulatory women due to a significant increase in SAF and not in intraabdominal fat. SAF and especially abdominal and trunk fat accumulation are associated with anovulation.

Carotid artery intima media thickness is inversely related to serum free thyroxine in euthyroid subjects.

OBJECTIVE: The effect of thyroid function on cardiovascular risk may extend to the euthyroid range. In euthyroid subjects, we determined whether carotid artery intima media thickness (IMT), a measure of subclinical atherosclerosis, is related to thyroid function. DESIGN AND SUBJECTS: Cross-sectional study in a cohort of 78 nonsmoking, predominantly middle-aged, euthyroid subjects (44 men and 34 women, mean age 56 years, TSH between 0.5 mU/l and 4.0 mU/l and FT4 between 11.0 pmol/l and 19.5 pmol/l). MEASUREMENTS: IMT (mean of three segments in both carotid arteries by ultrasonography), clinical factors, insulin resistance (HOMA(ir)), plasma lipids, C-reactive protein (CRP), serum FT4, TSH and thyroid autoantibodies. RESULTS: In several multiple linear regression models, age- and sex-adjusted IMT was found to be independently related to either pulse pressure and body mass index (BMI), to high density lipoprotein (HDL) cholesterol or to FT4, but not to TSH, thyroid autoantibodies, HOMA(ir), CRP, non-HDL cholesterol and triglycerides. In a subsequent model which included age, sex, pulse pressure, body mass index (BMI), HDL cholesterol and FT4, IMT was independently and positively related to age (beta = 0.43, P < 0.001), male sex (beta = 0.34, P = 0.014), pulse pressure (beta = 0.29, P = 0.002), BMI (beta = 0.24, P = 0.007) and inversely related to FT4 (beta = -0.19, P = 0.046). IMT was also inversely related to FT4 in a model which included HDL cholesterol, non-HDL cholesterol and triglycerides. CONCLUSIONS: In euthyroid subjects, IMT is associated with FT(4), after controlling for clinical factors, lipid levels and thyroid autoantibodies. These findings raise the possibility that, even within the euthyroid range, low normal thyroid function may adversely affect cardiovascular risk.

Inhibition of p38 mitogen-activated protein kinase: dose-dependent suppression of leukocyte and endothelial response after endotoxin challenge in humans.

OBJECTIVE: We studied the activity of a single oral dose of RWJ-67657, a synthetic p38 mitogen-activated protein kinase inhibitor, in preventing dual leukocyte/endothelial activation after endotoxin infusion in healthy volunteers. DESIGN: Prospective placebo-controlled study. SETTING: Intensive care unit at a university medical center. SUBJECTS: Twenty-one healthy male volunteers. INTERVENTIONS: Endotoxin (4 ng/kg) as a 1-min infusion. According to randomization, the volunteers received placebo (n = 6) or 1400 mg (n = 4), 700 mg (n = 6), or 350 mg (n = 5) of RWJ-67657. MEASUREMENTS AND MAIN RESULTS: Neutrophil activation was investigated by analyzing the extent of membrane expression of adhesion markers by calibrated flow cytometry. Circulating intercellular adhesion molecule-1 and E-selectin were measured by enzyme-linked immunosorbent assays. The endotoxin-induced shedding of L-selectin was diminished in a dose-dependent manner (p <.0001). High-dose RWJ-67657 prevented up-regulation of the integrins CD11b (p <.01) and CD 66b (p <.01) on neutrophils. The endotoxin-induced increase in circulating intercellular adhesion molecule-1 and circulation E-selectin was almost completely prevented by high-dose RWJ-67657. CONCLUSION: A single oral dose of RWJ-67657 prevented neutrophil and endothelial activation after endotoxin infusion.