Evaluation of SARS-CoV-2 interferon gamma release assay in BNT162b2 vaccinated healthcare workers.

To predict protective immunity to SARS-CoV-2, cellular immunity seems to be more sensitive than humoral immunity. Through an Interferon-Gamma (IFN-γ) Release Assay (IGRA), we show that, despite a marked decrease in total antibodies, 94.3% of 123 healthcare workers have a positive cellular response 6 months after inoculation with the 2nd dose of BNT162b2 vaccine. Despite the qualitative relationship found, we did not observe a quantitative correlation between IFN-γ and IgG levels against SARS-CoV-2. Using stimulated whole blood from a subset of participants, we confirmed the specific T-cell response to SARS-CoV-2 by dosing elevated levels of the IL-6, IL-10 and TNF-α. Through a 20-month follow-up, we found that none of the infected participants had severe COVID-19 and that the first positive cases were only 12 months after the 2nd dose inoculation. Future studies are needed to understand if IGRA-SARS-CoV-2 can be a powerful diagnostic tool to predict future COVID-19 severe disease, guiding vaccination policies.

Association of thyroid function, within the euthyroid range, with cardiovascular risk: The EPIPorto study.

Background: Thyroid hormones are important modulators of cardiovascular function. Both hypothyroidism and hyperthyroidism are known to contribute to an increased cardiovascular risk. It remains uncertain whether thyroid hormones level within the euthyroid range are associated with cardiometabolic risk. We aimed to evaluate the association between thyroid function levels within the euthyroid range and cardiovascular risk in a population-based cohort. Methods: Eight hundred thirty-five subjects aged ≥45 years from the EPIPorto population-based cohort were included. We excluded participants with TSH, free T4 (FT4), or free T3 (FT3) outside of the reference range, or with previous cardiovascular or thyroid disease. The associations between thyroid function, cardiovascular risk factors and the 10-year estimated risk of cardiovascular events (using SCORE2 and SCORE2-OP) were evaluated in linear and logistic regression models, crudely and adjusting for age, sex, BMI, diabetes, and smoking. Results: The mean age of the participants was 61.5 (SD 10.5) years and 38.9% were men. Eleven percent of the participants had diabetes, 47.8% had dyslipidemia, and 54.8% had hypertension. The mean body mass index (BMI) was 27.4 (SD 4.6) kg/m2, and the median (percentile25-75) 10-year risk of cardiovascular events was 5.46% (2.92, 10.11). Participants with higher BMI, larger waist circumference and higher hs-CRP had higher levels of FT3 and FT3/FT4 ratio. Lower FT3/FT4 ratio and higher FT4 levels were associated with higher prevalence of diabetes and more adverse lipid profile. Higher TSH, lower FT3 and lower FT3/FT4 ratio were associated with lower eGFR. Lower FT3, lower FT3/FT4 ratio and higher FT4 were associated with an increased 10-year risk of cardiovascular events. Conclusions: In a population-based study, variations of thyroid function within the euthyroid range were associated with cardiovascular risk factors. On one hand, individuals with higher BMI, larger waist circumference and higher hs-CRP had higher levels of FT3 and FT3/FT4 ratio. On the other hand, a decreased conversion of T4 to T3 (lower FT3, lower FT3/FT4 ratio and/or higher FT4) was associated with a higher prevalence of diabetes, a more adverse lipid profile, a lower eGFR and an increased 10-year risk of cardiovascular events.

The pro-proliferative effect of insulin in human breast epithelial DMBA-transformed and non-transformed cell lines is PI3K-, mTOR- and GLUT1-dependent.

Type 2 diabetes mellitus (T2DM) is linked to an increased risk of breast cancer. We aimed to investigate how T2DM-associated characteristics (high levels of glucose, insulin, leptin, inflammatory mediators and oxidative stress) influence breast cancer carcinogenesis, in DMBA-treated (MCF-12ADMBA ) and non-treated breast epithelial (MCF-12A) cell lines. Insulin (50 nM) promotes cell proliferation, 3 H-DG uptake and lactic acid production in both cell lines. The stimulatory effects of insulin upon cell proliferation and 3 H-DG uptake were hampered by rapamycin, LY294001 and BAY-876, in both cell lines. In conclusion, hyperinsulinemia, one important characteristic of T2DM, contributes to the initiation of breast cancer by a PI3K- and mTOR-dependent mechanism involving increased GLUT1-mediated glucose uptake. SIGNIFICANCE: The pro-proliferative effect of insulin in human breast epithelial DMBA-transformed and non-transformed cell lines is PI3K-, mTOR- and GLUT1-dependent.

Iron Related Biomarkers Predict Disease Severity in a Cohort of Portuguese Adult Patients during COVID-19 Acute Infection.

Large variability in COVID-19 clinical progression urges the need to find the most relevant biomarkers to predict patients' outcomes. We evaluated iron metabolism and immune response in 303 patients admitted to the main hospital of the northern region of Portugal with variable clinical pictures, from September to November 2020. One hundred and twenty-seven tested positive for SARS-CoV-2 and 176 tested negative. Iron-related laboratory parameters and cytokines were determined in blood samples collected soon after admission. Demographic data, comorbidities and clinical outcomes were recorded. Patients were assigned into five groups according to severity. Serum iron and transferrin levels at admission were lower in COVID-19-positive than in COVID-19-negative patients. The levels of interleukin (IL)-6 and monocyte chemoattractant protein 1 (MCP-1) were increased in COVID-19-positive patients. The lowest serum iron and transferrin levels at diagnosis were associated with the worst outcomes. Iron levels negatively correlated with IL-6 and higher levels of this cytokine were associated with a worse prognosis. Serum ferritin levels at diagnosis were higher in COVID-19-positive than in COVID-19-negative patients. Serum iron is the simplest laboratory test to be implemented as a predictor of disease progression in COVID-19-positive patients.

Thyroid Hormones within the Normal Range and Cardiac Function in the General Population: The EPIPorto Study.

BACKGROUND: Hypothyroidism and hyperthyroidism are associated with marked changes in cardiac structure and function. However, the association of thyroid function within the normal range with cardiac structure and function in the general population remains uncertain. METHODS: Eight hundred thirty-five subjects aged ≥45 years from the EPIPorto cohort (evaluation between 2006 and 2008) were cross-sectionally analyzed. We excluded participants with TSH, free T4 (FT4), or free T3 (FT3) outside of the reference range or with self-reported cardiovascular or thyroid disease. Cardiac structure and function were evaluated by echocardiography. We used linear regression models unadjusted and adjusted for sex and age (model 1), and sex, age, BMI, diabetes, hypertension, and smoking (model 2). Nonlinear associations were assessed using restricted cubic splines. RESULTS: The mean age was 61.5 years (SD 10.5); 61.1% of the patients were women. In the adjusted model 2, heart rate was positively associated with FT3; diastolic blood pressure was positively associated with TSH; LV end-diastolic and end-systolic volumes were inversely associated with TSH, and ejection fraction was nonlinearly associated with FT3, with higher ejection fractions near the limits of the reference range. Left ventricle (LV) posterior wall thickness was nonlinearly associated with FT4 in the adjusted model 1, with a greater thickness near the limits of the reference range. Regarding diastolic function, no significant associations were observed in adjusted models. CONCLUSIONS: Thyroid function within the reference range was associated with heart rate, blood pressure, cardiac structure, and function. Increasing thyroid function (lower TSH, higher FT4, or higher FT3) was associated with a higher heart rate, a lower diastolic blood pressure, and larger LV volumes. LV wall thickness and ejection fraction had a U-shaped association with thyroid hormones.

The in vitro effect of the diabetes-associated markers insulin, leptin and oxidative stress on cellular characteristics promoting breast cancer progression is GLUT1-dependent.

Obesity and type 2 diabetes mellitus (T2DM) associate with increased incidence and mortality from many cancers, including breast cancer. The mechanisms involved in this relation remain poorly understood. Our study aimed to investigate the in vitro effect of high levels of glucose, insulin, leptin, TNF-α, INF-γ and oxidative stress (induced with tert-butylhydroperoxide (TBH)), which are associated with T2DM, upon glucose uptake by breast cancer (MCF-7 and MDA-MB-231) and non-cancer (MCF-12A) cells and to correlate this effect with their effects upon cellular characteristics associated with cancer progression (cell proliferation, viability, migration, angiogenesis and apoptosis). 3H-DG uptake was markedly inhibited by a selective GLUT1 inhibitor (BAY-876) in all cell lines, proving that 3H-DG uptake is mainly GLUT1-mediated. TBH (2.5 µM), insulin (50 nM), leptin (500 ng/ml) and INF-y (100 ng/ml) stimulate GLUT1-mediated 3H-DG (1 mM) uptake by both ER-positive and triple-negative breast cancer cell lines. TBH and leptin, but not insulin and INF-γ, increase GLUT1 mRNA levels. Insulin and leptin (in both ER-positive and triple-negative breast cancer cell lines) and TBH (in the triple-negative cell line) have a proproliferative effect and leptin possesses a cytoprotective effect in both breast cancer cell lines that can contribute to cancer progression. The effects of TBH, insulin, leptin and INF-γ upon breast cancer cell proliferation and viability are GLUT1-dependent. In conclusion, T2DM-associated characteristics induce changes in GLUT1-mediated glucose uptake that can contribute to cancer progression. Moreover, we conclude that BAY-876 can be a strong candidate for development of a new effective anticancer agent against breast cancer.

Effects of a 16-week recreational team handball intervention on aerobic performance and cardiometabolic fitness markers in postmenopausal women: A randomized controlled trial.

BACKGROUND: Postmenopausal women have an elevated risk of developing cardiovascular diseases, which can be counteracted by conventional exercise regimes or recreational football. Less is known about the impact of exercise programmes based on other team sports. Thus, we examined the effects of recreational team handball on aerobic performance, cardiorespiratory fitness and cardiometabolic health in untrained postmenopausal women. METHODS: Sixty-seven participants (age 68 ± 6 years, stature 157 ± 6 cm, body mass 67 ± 10 kg, fat mass 37 ± 7%, VO2peak 25.2 ± 3.6 mL/min/kg, Yo-Yo intermittent endurance level 1 test performance (YYIE1) 230 ± 103 m) with no previous experience of team handball were randomly allocated to either a team handball (THG, n = 41) or a control (CG, n = 26) group. THG performed 2-3 60-min training sessions per week for 16 weeks. YYIE1 performance and cardiometabolic markers were evaluated at baseline and post-intervention. RESULTS: Average attendance during recreational team handball training was 1.9 ± 0.4 sessions per week, with mean heart rates of 76 ± 6%HRmax and 18 ± 9 min (44 ± 20% of total time) played at HR > 80%HRmax. A between-group effect was observed for YYIE1 performance, with a more pronounced improvement in aerobic exercise performance in THG compared to CG (70 ± 62 vs 15 ± 44%; p < 0.001). Within-group improvements (p < 0.05) were observed for THG with regard to VO2peak (7 ± 10%), incremental treadmill test time to exhaustion (TTE) (11 ± 14%), total cholesterol (-3 ± 9%) and low-density lipoprotein cholesterol (-2 ± 14%), with no significant changes in CG except an increase (p < 0.05) in TTE. Post-intervention values were higher for THG vs CG for YYIE1 performance (88%; 406 ± 216 vs 216 ± 75 m) and VO2peak (10%; 27.5 ± 3.8 vs 24.9 ± 3.6 mL/min/kg). CONCLUSIONS: Recreational team handball can be used to obtain moderate-to-vigorous aerobic intensities, and just 2 weekly 60-min team handball training sessions for 16 weeks can result in improvements in aerobic performance and in markers of cardiorespiratory fitness in postmenopausal women with no previous experience of the sport.

Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1ß production.

Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1ß is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1ß production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.

Prenatal alcohol exposure affects renal function in overweight schoolchildren: birth cohort analysis.

BACKGROUND: Prenatal ethanol exposure has been shown to reduce nephron endowment in animal models, but the effect of alcohol during human pregnancy on postnatal kidney function has not been explored. We aim to investigate the potential association of maternal alcohol consumption during pregnancy with the offspring renal function, considering potential confounding by intrauterine growth and children's current nutritional status. METHODS: Prospective longitudinal study in a random sample of 1093 children from a population-based birth cohort. Anthropometrics and estimated glomerular filtration rate (eGFR) were assessed at 7 years of age. Multiple linear regression models were fitted, adjusting for child's gender, age, birthweight, and maternal age, education, prepregnancy nutritional status, and smoking. RESULTS: Thirteen percent of mothers consumed alcohol during pregnancy. At 7 years of age, eGFR was significantly lower in children with prenatal alcohol exposure (134 ± 17 vs.138 ± 16 mL/min/1.73m2, p = 0.014). The effect was dose dependent and only present in overweight and obese children, among whom adjusted eGFR was -6.6(-12.0 to -1.1)mL/min/1.73m2 and -11.1(-21.3 to -1.2)mL/min/1.73m2 in those exposed to ≤ 40 g and to > 40 g of alcohol per week, respectively, compared to no consumption (ptrend = 0.002). CONCLUSIONS: Prenatal alcohol exposure has a dose-dependent adverse effect on renal function at school age in overweight and obese children.

Bone formation and resorption markers at 7 years of age: Relations with growth and bone mineralization.

PURPOSE: We aimed to describe bone formation and resorption markers in generally healthy prepubertal children using total alkaline phosphatase (tALP), osteocalcin (OC) and ß-isomerized C-terminal telopeptides of type I collagen (ß-CTx) serum concentrations and to estimate markers' correlations with anthropometric growth (height, weight, body mass index and trajectories of weight gain) as well as bone mineral content (BMC) and areal density (aBMD). METHODS: We assessed 395 7-year-old children from the Generation XXI cohort with tALP, OC and ß-CTx concentrations determined from a fasting venous blood sample and BMC/aBMD measured by dual-energy X-ray absorptiometry. Gender-specific reference intervals for tALP, OC and ß-CTx in 7-year-old children were established by calculating the 2.5th and 97.5th percentiles. Pearson and partial correlation coefficients (controlling for sex, age, body size and season) between bone markers and growth measures were computed. RESULTS: tALP increased with height (rpartial controlled for sex = 0.26, 95%CI: 0.17, 0.35), was higher in overweight than in healthy weight children, and in children who gained weight above average during infancy. No correlations were found between OC or ß-CTx and growth. In girls, OC was slightly correlated with subtotal BMC (rpartial = 0.22, 95%CI: 0.08, 0.35), subtotal aBMD (rpartial = 0.20, 95%CI: 0.06, 0.33) and lumbar spine aBMD (rpartial = 0.23, 95%CI: 0.09, 0.36). tALP and ß-CTx were not correlated with any of the DXA-derived bone measures. CONCLUSION: This study contributed to the description of bone turnover at 7 years of age and suggested that bone metabolism markers measured in a single point in time have limited ability to describe anthropometric growth and overall bone status in generally healthy prepubertal children.

Association of Serum 25-Hydroxyvitamin D Concentration with Pulmonary Function in Young Adults.

The role of vitamin D on pulmonary function is unclear and is mostly studied in patients, smokers and elderly people. The aim of this paper was to evaluate the association between serum 25-hydroxyvitamin D [25(OH)D] concentration and pulmonary function in young adults. Cross-sectional analysis of 499 individuals that were evaluated at 21 years of age as part of the population-based cohort Epidemiological Health Investigation of Teenagers in Porto (EPITeen). Serum 25(OH)D was categorized according to the Institute of Medicine. Pulmonary function was evaluated using spirometry. Linear regression models were used to estimate the regression coefficients (ß) and its 95% confidence intervals (95% CI), and were adjusted for confounders. Education, smoking, body mass index, and season of evaluation were determinants of serum 25(OH)D concentration. Prevalence of serum 25(OH)D concentration <50 nmol/L was 48.9%. A decrease in all pulmonary function parameters, with the decrease of serum 25(OH)D, was observed. The higher effect was found for peak expiratory flow (PEF). Having as reference participants with serum 25(OH)D concentration ≥50 nmol/L, PEF was significantly lower for those with a concentration of 30 to <50 nmol/L (ß= -0.576; 95% CI: -0.943, -0.210), and for those with a concentration of <30 nmol/L (ß= -0.650; 95% CI: -1.155, -0.146). Although only PEF attained statistical significance, the consistent results with the other parameters support the role of serum 25(OH)D to promote better pulmonary function in young adults.

Is Low-Dose Radiation Exposure a Risk Factor for Atherosclerotic Disease?

Nontargeted late effects of radiation include an increased risk of cardiovascular disease, although this is still debatable in the context of low-dose radiation. Tinea capitis patients treated in childhood with X rays to induce scalp epilation received a low dose of radiation to their carotids. To better clarify this issue, we evaluated carotid atherosclerosis in a cohort of such patients treated in 1950-1963 in Portugal. A group of 454 individuals randomly chosen from previously observed Portuguese tinea capitis patients and a control group mainly composed of their spouses (n = 280) were enrolled. Cardiovascular risk factors such as waist circumference, body mass index, blood pressure and tobacco consumption, as well as biochemical measurements were obtained. Ultrasound imaging of carotid arteries for intima media thickness and stenosis evaluation were performed according to a standardized protocol. In comparison to the control group, the irradiated cohort members were significantly older, more frequently never smokers, hypertensive, and presented higher glycated hemoglobin and alkaline phosphatase levels. In addition, the irradiated cohort showed a higher frequency of carotid stenosis ≥30% than the nonirradiated group (13.9% vs. 10.7%), although this was not significant ( P = 0.20). Stenosis was ≥50% in 2.9% of the irradiated group and 0.4% of the nonirradiated group ( P = 0.02). Likewise, the frequency of intima media thickness ≥1 mm was significantly higher in the irradiated group (16.8% vs. 10.7%; P = 0.02). Multivariate analysis, including other cardiovascular risk factors, showed that exposure to low-dose radiation increased the risk of carotid stenosis by ≥50% [odds ratio (OR) = 8.85; P = 0.04] and intima media thickness by ≥1 mm (OR = 1.82; P = 0.02). These findings confirm that low-dose exposure is a risk factor of carotid atherosclerotic disease.

Nontuberculous mycobacteria in a tertiary Hospital in Portugal: A clinical review.

BACKGROUND: Nontuberculous mycobacteria (NTM) form a heterogeneous group regarding their ability to cause disease. To further understand their clinical relevance, the characteristics of patients who had positive cultures for NTM at a tertiary hospital in Portugal were reviewed. METHODS: Retrospective analysis of patients assessed at the Infectious Diseases (ID) Department of the São João Hospital Center, from January 2007 to December 2014, from whom at least one biological sample was tested culture positive for NTM. RESULTS: A total of 74 patients with at least one positive culture for NTM were identified. Forty-nine (66.2%) were infected by the human immunodeficiency virus, 4 (5.4%) had cancer, and 7 (9.5%) were under immunosuppressive medication. A total of 13 patients (17.6%) fulfilled the American Thoracic Society/ID Society of America criteria for pulmonary NTM disease and treatment was initiated in 12 other patients (16.2%), all of which were immunocompromised. Mycobacterium avium complex was more frequently associated with disease, responsible for 56% of the patients treated. Patients were treated with antituberculosis drugs adjusted for the species isolated, and cure was achieved in 13 patients (52%). CONCLUSION: The present study highlights the importance of understanding the epidemiology of NTM to better comprehend their clinical impact.

Dipeptidyl peptidase-IV in chronic heart failure with reduced ejection fraction.

BACKGROUND: An association between dipeptidyl peptidase-IV (DPP-IV) inhibitors with worse prognosis in HF has been suggested. We aimed to assess the serum DPP-IV levels in chronic stable HF patients and determine their association with prognosis. METHODS AND RESULTS: Chronic stable HF patients with optimized prognostic-modifying therapy were prospectively recruited. EXCLUSION CRITERIA: 1) ejection fraction>50%, 2) hospitalizations or therapeutic adjustments in the previous 2months; 3) patients on renal replacement therapy, and 4) use of DPP-IV inhibitors. A fasting venous blood sample was collected and DPP-IV was measured. Patients were followed-up for 3years and the endpoint studied was all-cause death. Patients' characteristics were compared according to DPP-IV quartiles. A Cox regression analysis was performed and multivariate models were built. The 3rd DPP-IV quartile was the reference category. We studied 264 patients. Mean age: 69 (±13)years, 70.5% were male and 33.7% diabetic. Median (IQR) serum DPP-IV levels were 455.6 (350.0-625.5)ng/mL. DPP-IV had an inverse relationship with age. Patients in 3rd DPP-IV quartile were in lower NYHA classes and had the lowest 3years all-cause mortality. Patients in the 1st DPP-IV quartile had a multivariate adjusted HR of 3-year mortality of 2.62 (95%CI: 1.15-5.95) when compared with reference category and the HR for the 4th quartile was of 3.79 (95%CI: 1.68-8.54). CONCLUSIONS: There is a U-shaped association of serum DPP-IV with mortality in chronic systolic HF patients. Patients in the 3rd DPP-IV quartile have the best multivariate adjusted 3-year survival. DPP-IV inhibition might be harmful in patients with low DPP-IV.

IL6-174 G>C Polymorphism (rs1800795) Association with Late Effects of Low Dose Radiation Exposure in the Portuguese Tinea Capitis Cohort.

Head and neck cancers, and cardiovascular disease have been described as late effects of low dose radiation (LDR) exposure, namely in tinea capitis cohorts. In addition to radiation dose, gender and younger age at exposure, the genetic background might be involved in the susceptibility to LDR late effects. The -174 G>C (rs1800795) SNP in IL6 has been associated with cancer and cardiovascular disease, nevertheless this association is still controversial. We assessed the association of the IL6-174 G>C SNP with LDR effects such as thyroid carcinoma, basal cell carcinoma and carotid atherosclerosis in the Portuguese tinea capitis cohort. The IL6-174 G>C SNP was genotyped in 1269 individuals formerly irradiated for tinea capitis. This sampling group included thyroid cancer (n = 36), basal cell carcinoma (n = 113) and cases without thyroid or basal cell carcinoma (1120). A subgroup was assessed for atherosclerosis by ultrasonography (n = 379) and included matched controls (n = 222). Genotypes were discriminated by real-time PCR using a TaqMan SNP genotyping assay. In the irradiated group, we observed that the CC genotype was significantly associated with carotid plaque risk, both in the genotypic (OR = 3.57, CI = 1.60-7.95, p-value = 0.002) and in the recessive (OR = 3.02, CI = 1.42-6.42, p-value = 0.004) models. Irradiation alone was not a risk factor for carotid atherosclerosis. We did not find a significant association of the IL6-174 C allele with thyroid carcinoma or basal cell carcinoma risk. The IL6-174 CC genotype confers a three-fold risk for carotid atherosclerotic disease suggesting it may represent a genetic susceptibility factor in the LDR context.

Normalization of glomerular filtration rate in obese children.

BACKGROUND: Glomerular filtration rate (GFR) is conventionally indexed to body surface area (BSA), but this may lead to biased results when applied to subjects of abnormal body size. The aim of our study was to examine the impact of normalization to the BSA and alternative body size descriptors on measured and estimated GFR in overweight and obese children. METHODS: This was a cross-sectional study of 313 children aged 8-9 years old. GFR was measured by 24-h creatinine clearance (CrCl) and additionally estimated from serum creatinine and cystatin C (CysC) using the combined Zappitelli formula, both as absolute values and adjusted to various body size descriptors. The results were compared between 163 normal-weight, 89 overweight and 61 obese children. RESULTS: Compared to the normal-weight children, mean absolute GFR (both measured and estimated) was higher in the overweight and obese children, whereas BSA-adjusted GFR was lower. Linear regression models fitted in normal-weight children revealed equally close associations between absolute GFR and squared height, ideal body weight (IBW) and BSA derived from IBW. Normalization of GFR to the IBW-derived BSA completely eliminated the discrepancy between absolute and BSA-indexed GFR in overweight and obese children. CONCLUSIONS: Indexing of GFR to BSA calculated from the ideal-rather than actual-body weight is a promising approach to avoid overcorrection when studying obese children. Further studies should assess the accuracy of this approach across the full range of age and BMI distribution.

Prognostic Value of Osteoprotegerin in Acute Heart Failure.

BACKGROUND: Osteoprotegerin (OPG) is promising as a predictor of adverse prognosis in patients with acute coronary syndromes and chronic heart failure. Its prognostic value in acute heart failure (AHF) is unknown. The aim of this study was to assess the prognostic value provided by serum OPG levels at discharge after an admission for AHF. METHODS: In a prospective study, we enrolled 338 patients consecutively admitted with AHF to the internal medicine department of a tertiary care university hospital in Porto, Portugal between March 2009 and December 2010. OPG was measured using a commercial enzyme-linked immunosorbent assay and was both analyzed as a continuous variable and categorized by quartiles. Patients were followed for up to 6 months after discharge to ascertain the occurrence of all-cause death or hospital readmission resulting from AHF. RESULTS: During follow-up, 119 patients died or were readmitted for AHF. A graded increase in the risk of the combined end point was observed across quartiles of OPG. At 6 months, the cumulative risk of the end point was 25% for the first quartile and 50% for the fourth quartile. The multivariable adjusted risk of death or hospitalization for AHF increased progressively across categories of OPG up to a statistically significant 2.44-fold increase in risk in the highest category (P for linear trend = 0.002, ie, by 5% per 10 pg/mL increase in OPG). CONCLUSIONS: Serum OPG was directly associated with a higher probability of death or readmission for AHF within 6 months, irrespective of other known prognostic markers. This was true both when the ejection fraction was preserved and when it was reduced.

Decreased renal function in overweight and obese prepubertal children.

BACKGROUND: Obesity is a potentially modifiable risk factor for the development and progression of kidney disease, both in adults and children. We aim to study the association of obesity and renal function in children, by comparing estimated glomerular filtration rate (eGFR) in nonoverweight and overweight/obese children. Secondarily, we aim to evaluate the accuracy of equations on eGFR estimation when compared to 24-h urinary creatinine clearance (CrCl). METHODS: Cross-sectional study of 313 children aged 8-9 y, followed in the birth cohort Generation XXI (Portugal). Creatinine and cystatin C, GFR estimated by several formulas and CrCl were compared in 163 nonoverweight and 150 overweight/obese, according to World Health Organization growth reference. RESULTS: Overweight/obese children had significantly lower eGFR, estimated by all methods, except for CrCl and revised Schwartz formula. Despite all children having renal function in the normal range, eGFR decreased significantly with BMI z-score (differences ranging from -4.3 to -1.1 ml/min/1.73 m(2) per standard deviation of BMI). The Zappitelli combined formula presented the closest performance to CrCl, with higher correlation coefficients and higher accuracy values. CONCLUSION: Young prepubertal children with overweight/obesity already present significantly lower GFR estimations that likely represent some degree of renal impairment associated with the complex deleterious effects of adiposity.

Prognostic value of sST2 added to BNP in acute heart failure with preserved or reduced ejection fraction.

BACKGROUND: Natriuretic peptides and suppression of tumorigenicity 2 (ST2) represent two different physiopathological pathways. We evaluated the prognostic accuracy and complementarity of B-type natriuretic peptide (BNP) and soluble ST2 (sST2) plasma levels at discharge from a hospital admission for acute heart failure, both in patients with preserved (HFpEF) and depressed (HFrEF) systolic function. METHODS AND RESULTS: We enrolled 195 consecutive patients discharged alive and followed them prospectively for 6 months. The endpoint was all-cause death or hospital readmission for heart failure. Seventy-six patients had HFpEF and 119 had HFrEF, of whom 23 (30.3%) and 43 (36.1%) reached the combined endpoint, respectively. In both HFpEF and HFrEF, having the two biomarkers into account added prognostic information, with the highest risk in patients with both biomarkers above the median in their group (approximately 40% hospitalization-free survival in both groups at 6 months). These associations translated into a significant fourfold increase in risk of the endpoint for one elevated biomarker and sevenfold for both biomarkers elevated in HFrEF, and no association for one elevated biomarker and fivefold increase in risk for both biomarkers elevated in HFpEF. Considering the reclassification of risk added to BNP by measurement of sST2, net reclassification index was 0.31 (p = 0.21) among patients with HFpEF and 0.70 (p < 0.001) among patients with HFrEF. CONCLUSIONS: sST2 provides robust prognostic information in acute heart failure with HFrEF, while this pattern was less clear in HFpEF. When sST2 was measured together with BNP, it improved prognostic accuracy in both groups, more clearly in HFrEF.