Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy.

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1-3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver-a frequent site of metastasis4 that is often associated with a poor prognosis5. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth.

Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells.

Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17∼92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.

Infection-elicited microbiota promotes host adaptation to nutrient restriction.

The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent.

Prevention of dsRNA-induced interferon signaling by AGO1x is linked to breast cancer cell proliferation.

Translational readthrough, i.e., elongation of polypeptide chains beyond the stop codon, was initially reported for viral RNA, but later found also on eukaryotic transcripts, resulting in proteome diversification and protein-level modulation. Here, we report that AGO1x, an evolutionarily conserved translational readthrough isoform of Argonaute 1, is generated in highly proliferative breast cancer cells, where it curbs accumulation of double-stranded RNAs (dsRNAs) and consequent induction of interferon responses and apoptosis. In contrast to other mammalian Argonaute protein family members with primarily cytoplasmic functions, AGO1x exhibits nuclear localization in the vicinity of nucleoli. We identify AGO1x interaction with the polyribonucleotide nucleotidyltransferase 1 (PNPT1) and show that the depletion of this protein further augments dsRNA accumulation. Our study thus uncovers a novel function of an Argonaute protein in buffering the endogenous dsRNA-induced interferon responses, different than the canonical function of AGO proteins in the miRNA effector pathway. As AGO1x expression is tightly linked to breast cancer cell proliferation, our study thus suggests a new direction for limiting tumor growth.

Electrochemical Diselenation of BODIPY Fluorophores for Bioimaging Applications and Sensitization of 1 O2.

We report a rapid, efficient, and scope-extensive approach for the late-stage electrochemical diselenation of BODIPYs. Photophysical analyses reveal red-shifted absorption - corroborated by TD-DFT and DLPNO-STEOM-CCSD computations - and color-tunable emission with large Stokes shifts in the selenium-containing derivatives compared to their precursors. In addition, due to the presence of the heavy Se atoms, competitive ISC generates triplet states which sensitize 1 O2 and display phosphorescence in PMMA films at RT and in a frozen glass matrix at 77 K. Importantly, the selenium-containing BODIPYs demonstrate the ability to selectively stain lipid droplets, exhibiting distinct fluorescence in both green and red channels. This work highlights the potential of electrochemistry as an efficient method for synthesizing unique emission-tunable fluorophores with broad-ranging applications in bioimaging and related fields.

Electrochemical Diselenation of BODIPY Fluorophores for Bioimaging Applications and Sensitization of 1 O2.

Invited for the cover of this issue are the groups of Holger Braunschweig at the Julius-Maximilians-Universität Würzburg, Germany and Eufrânio N. da Silva Júnior at the Universidade Federal de Minas Gerais, UFMG, Brazil. The image depicts the electrochemical synthesis of selenium-containing BODIPY molecules with lightning symbolizing the electrifying synthetic process, while the surrounding elemental chaos hints at the red-shifted absorption and emission and the transformative photophysical properties of these new compounds. Read the full text of the article at 10.1002/chem.202303883.

Association of polymorphism in leptin receptor gene with susceptibility of adolescent idiopathic scoliosis.

PURPOSE: Abnormal leptin bioavailability has play key roles in the etiology of adolescent idiopathic scoliosis (AIS). Both leptin and its receptor levels may be modulated by the presence of genetic polymorphisms. This study aimed to evaluate the role of polymorphisms in the leptin (LEP) and its main receptor (LEPR) genes in the AIS susceptibility in girls. METHODS: A retrospective case-control study was conducted with 189 AIS and 240 controls. LEP rs2167270 and LEPR rs2767485 polymorphisms were genotyped using a TaqMan validated assay. Associations were evaluated by odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The AIS group showed a predominance of girls under 18 years old (n = 140, 74.1%), 148 (78.3%) had low or normal BMI, 111 (58.7%) had Cobb ≥ 45º and 130 (68.7%) were skeletally mature. Minor allele frequencies of rs2167270 and rs2767485 were 35.7% and 18.3%, for AIS and 35.6% and 25.4% for controls, respectively. LEPR rs2767485 T and TC + TT were associated with higher risk of AIS (OR = 1.53; 95% CI = 1.09-2.13 and OR = 1.84; 95% CI = 1.69-2.01, respectively), since CC genotype was only present in the control group. In addition, the LEP rs2167270 GA + AA was more frequent in low weight group (BMI ≤ 24.9) of girls with AIS. There was no significant association between LEP rs2167270 and AIS susceptibility, and LEPR rs2767485 and BMI. CONCLUSION: The LEPR rs2767485 was associated with the genetic susceptibility of AIS and LEP rs2167270 with low BMI. These data can contribute to the identification of genetic biomarkers to improve the diagnosis and treatment.

Neutrophil Extracellular Trap-related Biomarkers Are Increased in the Synovial Fluid of Patients With Periprosthetic Joint Infections.

BACKGROUND: The diagnosis of periprosthetic joint infection (PJI) is a major challenge in clinical practice. The role of neutrophils in fighting infection has been increasingly understood, and one mechanism of action of these cells is neutrophil extracellular traps. However, little is known about this process in PJI. QUESTIONS/PURPOSES: (1) Are the biomarkers of neutrophil extracellular trap formation (citrullinated histone H3 [H3Cit], cell-free DNA [cf-DNA], and myeloperoxidase [MPO]) increased in the synovial fluid of patients with PJI? (2) What is the diagnostic accuracy of biomarkers of neutrophil extracellular trap formation for PJI? METHODS: Between May 2020 and March 2021, 43 patients who underwent revision THA or TKA were enrolled in this study. Eleven patients were excluded and 32 patients were categorized into the PJI group (n = 16) or non-PJI group (n = 16) according to the 2018 Second International Consensus Meeting on Musculoskeletal Infection criteria. There were 15 men and 17 women in this study, with a median (range) age of 70 years (60 to 80 years). Twenty-seven patients had TKA and five had THA. We measured cf-DNA, MPO, and H3Cit in synovial fluid. The sensitivity, specificity, and receiver operating characteristic curve were calculated for each biomarker using the Musculoskeletal Infection Society criteria as the gold standard for diagnosis and considering a clinical surveillance of 2 years for patients in the non-PJI group. RESULTS: Patients with PJI had higher levels of synovial fluid cf-DNA (median [range] 130 ng/µL [18 to 179] versus 2 ng/µL [0 to 6]; p < 0.001), MPO (1436 ng/µL [55 to 3996] versus 0 ng/µL [0 to 393]; p < 0.001), and H3Cit (2115 ng/µL [5 to 2885] versus 3 ng/µL [0 to 87]; p < 0.001) than those in the non-PJI group. In receiver operating characteristic curve analyses, we observed near-perfect performance for all biomarkers evaluated, with an area under the curve of 1 (95% CI 0.9 to 1), 0.98 (95% CI 0.9 to 1), and 0.94 (95% CI 0.8 to 0.99) for cf-DNA, MPO, and H3Cit, respectively. The sensitivity for detecting PJI using synovial fluid was 100% for cf-DNA, 94% for MPO, and 88% for H3Cit. The specificity was 100% for cf-DNA and MPO, and 88% for H3Cit. CONCLUSION: Our results show that neutrophils in the periprosthetic microenvironment release neutrophil extracellular traps as part of the bactericidal arsenal to fight infection. These results allow a better understanding of the cellular and molecular processes that occur in this microenvironment, enabling the design of more assertive strategies for identifying new biomarkers and improving the available ones. Novel studies are needed to define whether and how neutrophil extracellular trap-related biomarkers can be useful for diagnosing PJI. LEVEL OF EVIDENCE: Level II, diagnostic study.

Biological parameters for quality evaluation of allografts from the Brazilian National Institute of Traumatology and Orthopedics tissue bank.

Bone allografts are clinically used in a variety of surgical procedures, and tissue banks are responsible for harvesting, processing, quality testing, storing, and delivering these materials for transplantation. In tissue banks, the bone is processed for the removal of all organic content, remaining only the tissue structure (scaffold). However, several studies have shown that even after using different processing methods, viable cells, functional proteins, and DNA may still persist in the tissue, which constitute the main causes of graft rejection. Therefore, the objective of this study was to establish techniques and biological parameters for quality validation of allografts. To this end, we propose the use of 3 combined methods such as microscopy, histology, and molecular biology techniques to evaluate the quality of allografts harvested and processed by the Brazilian National Institute of Traumatology and Orthopedics (INTO) tissue bank according to the donation criteria of the Brazilian National Health Surveillance Agency and the Brazilian National Transplant System. Bone fragments from different processing stages showed no viable cells on histology, an intact extracellular matrix on scanning electron microscopy, and gradual reduction in DNA amount. Different techniques were used to demonstrate the quality of allografts produced by the INTO tissue bank and to establish biological parameters for ensuring the safety and quality of these products. Future studies need to be undertaken to assess and validate the efficacy of the decellularization process in larger bone grafts with diverse architectural configurations.

Genetic Variations in Susceptibility to Traumatic Muscle Injuries and Muscle Pain among Brazilian High-Performance Athletes.

Traumatic muscle injuries (TMIs) and muscle pain (MP) negatively impact athletes' performance and quality of life. Both conditions have a complex pathophysiology involving the interplay between genetic and environmental factors. Yet, the existing data are scarce and controversial. To provide more insights, this study aimed to investigate the association of single-nucleotide polymorphisms (SNPs) previously linked to athletic status with TMI and MP after exercise among Brazilian high-performance athletes from different sports modalities (N = 345). The impact of important environmental determinants was also assessed. From the six evaluated SNPs (ACTN3 rs1815739, FAAH rs324420, PPARGC1A rs8192678, ADRB2 rs1042713, NOS3 rs1799983, and VDR rs731236), none was significantly associated with TMI. Regarding MP after exercise, ACTN3 rs1815739 (CC/CT vs. TT; adjusted odds ratio (aOR) = 1.90; 95% confidence interval (95%Cl), 1.01-3.57) and FAAH rs324420 (AA vs. AC/CC; aOR = 2.30; 95%Cl, 1.08-4.91) were independent predictors according to multivariate binomial analyses adjusted for age (≥23 vs. <23 years), sex (male vs. female), and tobacco consumption (yes vs. no). External validation is warranted to assess the predictive value of ACTN3 rs1815739 and FAAH rs324420. This could have implications for prophylactic interventions to improve athletes' quality of life.

Mechanisms linking endoplasmic reticulum (ER) stress and microRNAs to adipose tissue dysfunction in obesity.

Over accumulation of lipids in adipose tissue disrupts metabolic homeostasis by affecting cellular processes. Endoplasmic reticulum (ER) stress is one such process affected by obesity. Biochemical and physiological alterations in adipose tissue due to obesity interfere with adipose ER functions causing ER stress. This is in line with increased irregularities in other cellular processes such as inflammation and autophagy, affecting overall metabolic integrity within adipocytes. Additionally, microRNAs (miRNAs), which can post-transcriptionally regulate genes, are differentially modulated in obesity. A better understanding and identification of such miRNAs could be used as novel therapeutic targets to fight against diseases. In this review, we discuss ways in which ER stress participates as a common molecular process in the pathogenesis of obesity-associated metabolic disorders. Moreover, our review discusses detailed underlying mechanisms through which ER stress and miRNAs contribute to metabolic alteration in adipose tissue in obesity. Hence, identifying mechanistic involvement of miRNAs-ER stress cross-talk in regulating adipose function during obesity could be used as a potential therapeutic approach to combat chronic diseases, including obesity.

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients.

BACKGROUND: Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. METHODS: Blood and spot urine were collected in "severe" (n = 26), "critically ill" (n = 17) and "critically ill on VV-ECMO" (n = 17) patients with COVID-19 at days 1-2 (admission), 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. RESULTS: U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. CONCLUSIONS: U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

Recreational futsal provides broad-spectrum fitness and health benefits but no blood pressure effects in men with treated hypertension - a randomised controlled trial.

We determined the coadjuvant effect of a recreational futsal (RF) programme versus standard care alone (CON) in men with treated arterial hypertension (TAHT). Thirty-nine men with TAHT were randomised to RF (N = 20; 48 ± 8 years; systolic blood pressure [SBP]: 122 ± 14 mmHg) with 2-3 one-hour sessions/week for 3 months, or to CON (N = 19; 51 ± 6 years; SBP: 126 ± 13 mmHg). Participants were assessed at baseline, at 3 months, and after 1 month of training cessation (4 months). Mean training attendance was 60 ± 23%. At 3-months, there were no between-group differences in BP parameters (SBP: 0.44 mmHg; 95% CI: -5.79, 6.67). However, compared to CON, RF was effective for peak oxygen uptake (2.76 mL.min-1.kg-1; 95% CI: 0.26, 5.26), time to exhaustion (1.15 min; 95% CI: 0.59, 1.69), Yo-Yo IE1 performance (365 m; 95% CI: 175, 556), resting heart rate (RHR; -5 b.min-1; 95% CI: -10, -1), glycated haemoglobin (-0.52 mmol/L; 95% CI: -0.84, -0.19), blood glucose (-0.25 mmol/L; 95% CI: -0.44, -0.06), left femur bone mineral content (1.96 g; 95% CI: 0.29, 3.65), and postural balance (-2.3 falls; 95% CI: -3.9, -0.6). Similar findings were observed after 1-month of training cessation, except for RHR and blood glucose that returned to baseline levels in the RF group. In conclusion, RF provides broad-spectrum fitness and health benefits but no BP effects in men with TAHT.

Conventional versus locked plates for hip dislocation in cerebral palsy: a matched cohort analysis.

PURPOSE: Bone quality of non-ambulatory patients with cerebral palsy (CP) is a matter of concern for proximal femoral varus derotational osteotomies (VDRO). Locking plates (LCP) have been designed to compensate this biological downfall. Little data exist comparing the LCP with the conventional femoral blade plate. METHODS: We retrospectively studied 32 patients submitted to VDRO (40 hips), operated with blade plates or LCP. Groups were matched, and the minimal follow-up was 36 months. Clinical (age at surgery, sex, GMFCS class, CP patterns) and radiological characteristics (neck shaft angle [NSA], acetabular index [AI], Reimers migration index [MP] and time until bone healing), as well as postoperative complications and the cost of treatment, were evaluated. RESULTS: Preoperative clinical characteristics and radiographic measurements were comparable, except for a higher AI in the BP group (p < 0.01). Mean follow-up was longer in the LCP group (57.35 vs 34.6 months). Mean NSA, AI and MP had comparable correction with surgery (p < 0.01). At final follow-up, dislocation recurrence speed was higher in BP group although not statistically significant (0.56% vs 0.35%/month; p = 0.29). The complication rate was similar in both groups (p > 0.05). Finally, the cost of the treatment was 62% higher in the LCP group (p = 0.01). CONCLUSION: Our cohorts showed LCP or BP equivalence clinically and radiographically in mid-term follow-up, with the former increasing the cost of treatment by a mean of 62%. This may raise a question on the real necessity of locked implants for these operations. LEVEL OF EVIDENCE: Level III-Retrospective comparative study.

Diabetic ketoacidosis and COVID-19: what have we learned so far?

In December 2019, a pandemic emerged due to a new coronavirus that imposed various uncertainties and discoveries. It has been reported that diabetes is a risk factor for worst outcomes of COVID-19 and also that SARS-CoV-2 infection was correlated with the occurrence of diabetic ketoacidosis (DKA) in patients. The aim of this work is to discuss this correlation emphasizing the main case reports from 2020 while exploring the management of DKA during the course of COVID-19. Web of Science, PubMed, and Scopus databases were searched using two sets of Medical Subject Heading (MeSH) search terms or Title/Abstract words: Coronavirus Infections (Coronavirus Infections, Middle East Respiratory Syndrome, COVID-19) and Diabetic Ketoacidosis (Diabetic Ketoacidosis, Diabetic Acidosis, Diabetic Ketosis). There is a clear correlation between COVID-19 and DKA. The SARS-Cov-2 infection may precipitate both a hyperglycemic state and ketoacidosis occurrence in patients with diabetes and nondiabetic patients, which may lead to fatal outcomes. DKA in patients with COVID-19 may increase risk and worse outcomes. Hence, the SARS-Cov-2 infection presents a new perspective toward the management of glycemia and acidosis in patients with diabetes and nondiabetic patients, highlighting the need for rapid interventions to minimize the complications from COVID-19 while reducing its spreading.

Shared genetic influences on resting-state functional networks of the brain.

The amplitude of activation in brain resting state networks (RSNs), measured with resting-state functional magnetic resonance imaging, is heritable and genetically correlated across RSNs, indicating pleiotropy. Recent univariate genome-wide association studies (GWASs) explored the genetic underpinnings of individual variation in RSN activity. Yet univariate genomic analyses do not describe the pleiotropic nature of RSNs. In this study, we used a novel multivariate method called genomic structural equation modeling to model latent factors that capture the shared genomic influence on RSNs and to identify single nucleotide polymorphisms (SNPs) and genes driving this pleiotropy. Using summary statistics from GWAS of 21 RSNs reported in UK Biobank (N = 31,688), the genomic latent factor analysis was first conducted in a discovery sample (N = 21,081), and then tested in an independent sample from the same cohort (N = 10,607). In the discovery sample, we show that the genetic organization of RSNs can be best explained by two distinct but correlated genetic factors that divide multimodal association networks and sensory networks. Eleven of the 17 factor loadings were replicated in the independent sample. With the multivariate GWAS, we found and replicated nine independent SNPs associated with the joint architecture of RSNs. Further, by combining the discovery and replication samples, we discovered additional SNP and gene associations with the two factors of RSN amplitude. We conclude that modeling the genetic effects on brain function in a multivariate way is a powerful approach to learn more about the biological mechanisms involved in brain function.

Persistent weight gain between 0 and 4 years of age is associated with higher dehydroepiandrosterone sulphate levels at 7 years old: Data from the Generation XXI birth cohort.

OBJECTIVE: To assess the influence of longitudinal weight gain from 0 to 4 years old on dehydroepiandrosterone sulphate (DHEAS) levels at 7 years old. DESIGN: DHEAS levels were measured at 7 years old in a subsample of 587 children from the Generation XXI birth cohort. Weight trajectories (0-4 years of age) were identified using model-based clustering and categorized as "normal weight gain," "weight gain during infancy," "weight gain during childhood" and "persistent weight gain." MEASUREMENTS: Differences in DHEAS levels at age 7 between the four weight trajectories were analysed through analysis of covariance (ANCOVA), adjusted for birth weight (BW) and body mass index (BMI). RESULTS: In the crude analysis, compared with the "normal weight gain" trajectory (5.53 (95% CI: 5.10-5.98] µmol/L), DHEAS levels were significantly higher in children in the "persistent weight gain" (8.75 [95% CI: 7.23-10.49] µmol/L, p < .001] and in children in the "weight gain during infancy" trajectories (7.68 [95% CI: 6.22-9.49] µmol/L, p = .021] and marginally significantly higher in children in the "weight gain during childhood" trajectory (6.89 (95% CI: 5.98-8.00) µmol/L; p = .052). In BW- and BMI-adjusted model, a statistically significant difference in DHEAS levels was found between the "persistent weight gain" (7.93 [95% CI: 6.43-9.86] µmol/L) and the "normal weight gain" trajectories ([5.75 [95% CI: 5.32-6.23] µmol/L; p = .039). CONCLUSION: Higher DHEAS levels are found in 7-year-old children following a trajectory of persistent weight gain from 0 to 4 years, independently of their BW or current BMI, highlighting the impact of exposure to overweight in the first years of life on prepubertal adrenal androgen production.

Interleukin-6, infection and cardiovascular outcomes in acute heart failure: Findings from the EDIFICA registry.

AIMS: Interleukin-6 (IL-6) is upregulated in response to infectious and inflammatory triggers and independently predicts all-cause mortality in acute heart failure (AHF). However, the association of IL-6 with cardiovascular outcomes and its interplay with C-reactive protein and infection, a major precipitating factor in AHF, remains poorly understood. METHODS AND RESULTS: The association between IL-6 and clinical outcomes (180 days) in AHF was evaluated using a cohort of 164 patients from the EDIFICA registry. Median IL-6 levels at admission were 17.4 pg/mL. Patients in the higher admission IL-6 tertile presented with lower blood pressure and more congestion, were diagnosed more frequently with infection, and had a longer hospital stay. Higher IL-6 levels were associated with increased risk of HF rehospitalization (hazard ratio per log2 3.69, 95% confidence interval (CI) 1.26-10.8, p =.017) and the composite of HF rehospitalization or cardiovascular death (hazard ratio per log2 3.50; 95% CI 1.28-9.57; p =.014), independently of major AHF prognosticators, including B-type natriuretic peptide and renal function. However, no independent associations were found for all-cause rehospitalization or mortality. Despite a moderate correlation of IL-6 with C-reactive protein (CRP) levels (R = .51), the latter were not associated with clinical outcomes in this population. CONCLUSIONS: IL-6 levels associate with higher rate of cardiovascular events in AHF, independently of classical prognosticators and evidence of infection, outperforming CRP as an inflammatory outcome biomarker.

Association of dehydroepiandrosterone sulfate, birth size, adiposity and cardiometabolic risk factors in 7-year-old children.

BACKGROUND: Low birth size (BS) and obesity have been associated with higher dehydroepiandrosterone sulfate (DHEAS) levels in childhood, insulin acting as a mediator, despite contradictory findings. To further explore these issues, we studied the associations between DHEAS, BS, adiposity, maternal characteristics, and cardiometabolic risk indicators, in participants of Generation XXI, a population-based birth cohort. METHODS: A sample of 700 children (mean age 7.1 yr) was randomly selected. Data on maternal characteristics, BS, body mass index (BMI), waist-to-height ratio, body fat (dual-energy X-ray absorptiometry), insulin, lipid profile, and high-sensitivity C-reactive protein were analyzed in relation to DHEAS. RESULTS: DHEAS was negatively associated with BS and positively associated with all adiposity indicators, with no sex differences. DHEAS was positively associated with insulinemia independently of the child's BS or BMI. No significant association was found between DHEAS, maternal characteristics, lipid profile, or high-sensitivity C-reactive protein. Including insulin in the model did not affect the association between BS and DHEAS but reduced the magnitude of the BMI effect by 24% for boys and 30% for girls. CONCLUSION: Higher DHEAS levels at 7 years old were associated with lower BS and higher adiposity. DHEAS levels were positively associated with insulinemia independently of BS or BMI. IMPACT: Low birth weight and obesity have been associated with higher dehydroepiandrosterone sulfate (DHEAS) levels in prepuberty. Insulin has been suggested as a mediator, despite previous studies failing to show an association between DHEAS and insulin levels. In a randomly selected population of 700 7-year-old children from the Generation XXI birth cohort, higher DHEAS levels were associated with a lower birth size and higher adiposity, with no sex differences. DHEAS was positively related to insulinemia independently of the child's birth size or body mass index. No association was found between DHEAS and other cardiometabolic risk factors.