Diuqin lechiguanae gen. et sp. nov., a new unenlagiine (Theropoda: Paraves) from the Bajo de la Carpa Formation (Neuquén Group, Upper Cretaceous) of Neuquén Province, Patagonia, Argentina.

BACKGROUND: Unenlagiine paravians are among the most relevant Gondwanan theropod dinosaur clades for understanding the origin of birds, yet their fossil record remains incomplete, with most taxa being represented by fragmentary material and/or separated by lengthy temporal gaps, frustrating attempts to characterize unenlagiine evolution. RESULTS AND CONCLUSIONS: Here we describe Diuqin lechiguanae gen. et sp. nov., a new unenlagiine taxon from the Upper Cretaceous (Santonian) Bajo de la Carpa Formation of the Neuquén Basin of Neuquén Province in northern Patagonia, Argentina that fills a substantial stratigraphic gap in the fossil record of these theropods. Although known only from a very incomplete postcranial skeleton, the preserved bones of Diuqin differ from corresponding elements in other unenlagiines, justifying the erection of the new taxon. Moreover, in several morphological aspects, the humerus of Diuqin appears intermediate between those of geologically older unenlagiines from the Neuquén Basin (e.g., Unenlagia spp. from the Turonian-Coniacian Portezuelo Formation) and that of the stratigraphically younger, larger-bodied Austroraptor cabazai from the Campanian-Maastrichtian Allen Formation. Consequently, the morphology of the new taxon appears to indicate a transitional stage in unenlagiine evolution. Phylogenetic analysis recovers Diuqin as a paravian with multiple plausible systematic positions, but the strongest affinity is with Unenlagiinae. The humerus of the new form exhibits subcircular punctures near its distal end that are interpreted as feeding traces most likely left by a conical-toothed crocodyliform, mammal, or theropod, the latter potentially corresponding to a megaraptorid or another unenlagiine individual. Thus, in addition to filling important morphological and temporal gaps in unenlagiine evolutionary history, the new taxon also offers information relating to the paleoecology of these theropods.

New information on paleopathologies in non-avian theropod dinosaurs: a case study on South American abelisaurids.

Studies on pathological fossil bones have allowed improving the knowledge of physiology and ecology, and consequently the life history of extinct organisms. Among extinct vertebrates, non-avian dinosaurs have drawn attention in terms of pathological evidence, since a wide array of fossilized lesions and diseases were noticed in these ancient organisms. Here, we evaluate the pathological conditions observed in individuals of different brachyrostran (Theropoda, Abelisauridae) taxa, including Aucasaurus garridoi, Elemgasem nubilus, and Quilmesaurus curriei. For this, we use multiple methodological approaches such as histology and computed tomography, in addition to the macroscopic evaluation. The holotype of Aucasaurus shows several pathognomonic traits of a failure of the vertebral segmentation during development, causing the presence of two fused caudal vertebrae. The occurrence of this condition in Aucasaurus is the first case to be documented so far in non-tetanuran theropods. Regarding the holotype of Elemgasem, the histology of two fused vertebrae shows an intervertebral space between the centra, thus the fusion is limited to the distal rim of the articular surfaces. This pathology is here considered as spondyloarthropathy, the first evidence for a non-tetanuran theropod. The microstructural arrangement of the right tibia of Quilmesaurus shows a marked variation in a portion of the outer cortex, probably due to the presence of the radial fibrolamellar bone tissue. Although similar bone tissue is present in other extinct vertebrates and the cause of its formation is still debated, it could be a response to some kind of pathology. Among non-avian theropods, traumatic injuries are better represented than other maladies (e.g., infection, congenital or metabolic diseases, etc.). These pathologies are recovered mainly among large-sized theropods such as Abelisauridae, Allosauridae, Carcharodontosauridae, and Tyrannosauridae, and distributed principally among axial elements. Statistical tests on the distribution of injuries in these theropod clades show a strong association between taxa-pathologies, body regions-pathologies, and taxa-body regions, suggesting different life styles and behaviours may underlie the frequency of different injuries among theropod taxa.

Breast density quantitative measures and breast cancer risk among screened Black women.

Mammographic density is a strong predictor of breast cancer but only slightly increased the discriminatory ability of existing risk prediction models in previous studies with limited racial diversity. We assessed discrimination and calibration of models consisting of the Breast Cancer Risk Assessment Tool (BCRAT), Breast Imaging-Reporting and Data System density and quantitative density measures. Patients were followed up from the date of first screening mammogram until invasive breast cancer diagnosis or 5-year follow-up. Areas under the curve for White women stayed consistently around 0.59 for all models, whereas the area under the curve increased slightly from 0.60 to 0.62 when adding dense area and area percent density to the BCRAT model for Black women. All women saw underprediction in all models, with Black women having less underprediction. Adding quantitative density to the BCRAT did not statistically significantly improve prediction for White or Black women. Future studies should evaluate whether volumetric breast density improves risk prediction.

Galectin-3 is Associated with Heart Failure Incidence: A Meta-Analysis.

INTRODUCTION: Heart failure (HF) is a leading cause of death worldwide. The global prevalence of heart failure is projected to increase rapidly in the coming decades, and significant attention has turned to improving biomarker-based risk prediction of incident HF. This paper aimed to qualitatively and quantitatively evaluate the evidence associating levels of galectin-3 with the risk of incident HF. METHODS: A review of PUBMED-indexed peer-reviewed literature was performed. Nine studies met the inclusion criteria, and all nine had data eligible for conversion and pooling. A randomeffects meta-analysis was performed using hazard ratios and 95% confidence intervals from a minimally adjusted model, a further adjusted model, and from subgroups within the further-adjusted model. RESULTS: The minimally-adjusted model provided an HR of 1.97 (95% CI 1.74-2.23) when comparing the top quartile of log-gal-3 to the bottom quartile. The further-adjusted model provided an HR of 1.32 (95% CI 1.21-1.44) for the same comparison. The positive, significant association was conserved during sensitivity analysis. CONCLUSION: There is a significant positive association between circulating galectin-3 and the risk of incident heart failure. Given the complex mechanistic relationship between galectin-3 and cardiovascular pathophysiology, further investigation is recommended for the possible implementation of galectin-3 into clinical risk prediction models.

The Role of Zn Ions in the Structural, Surface, and Gas-Sensing Properties of SnO2:Zn Nanocrystals Synthesized via a Microwave-Assisted Route.

Although semiconducting metal oxide (SMOx) nanoparticles (NPs) have attracted attention as sensing materials, the methodologies available to synthesize them with desirable properties are quite limited and/or often require relatively high energy consumption. Thus, we report herein the processing of Zn-doped SnO2 NPs via a microwave-assisted nonaqueous route at a relatively low temperature (160 °C) and with a short treatment time (20 min). In addition, the effects of adding Zn in the structural, electronic, and gas-sensing properties of SnO2 NPs were investigated. X-ray diffraction and high-resolution transmission electron microscopy analyses revealed the single-phase of rutile SnO2, with an average crystal size of 7 nm. X-ray absorption near edge spectroscopy measurements revealed the homogenous incorporation of Zn ions into the SnO2 network. Gas sensing tests showed that Zn-doped SnO2 NPs were highly sensitive to sub-ppm levels of NO2 gas at 150 °C, with good recovery and stability even under ambient moisture. We observed an increase in the response of the Zn-doped sample of up to 100 times compared to the pristine one. This enhancement in the gas-sensing performance was linked to the Zn ions that provided more surface oxygen defects acting as active sites for the NO2 adsorption on the sensing material.

Comparing Musculoskeletal Injuries across Dance and Gymnastics in Adolescent Females Presenting to Emergency Departments.

(1) Background: Studies have yet to identify if there are any differences in musculoskeletal injury patterns between dance and gymnastics. This study aimed to determine if different injury patterns exist in adolescent females participating in those two popular sports. (2) Methods: A cross-sectional study was conducted using data collected from patients presenting to U.S. emergency departments participating in the publicly available, de-identified U.S. Consumer Product Safety Commission's National Electronic Injury Surveillance System (NEISS) throughout the year 2020. Regression analyses were performed to explore if injury patterns were predictive of gymnastics or dancing participation. (3) Results: 518 adolescent females with dance-related injuries and 597 adolescent females with gymnastics-related injuries in 2020 were examined. Strain/sprains (33.3%) and fractures (37.3%) were the most reported dance- and gymnastics-related diagnoses, respectively. Participants were 74% less likely to have a strain/sprain diagnosis in gymnastics compared to dance (OR = 0.26, 95% CI [0.18, 0.38]) and were 3.84 times more likely to have a fracture diagnosis from gymnastics compared to dance (OR = 3.84, 95% CI [2.67, 5.57]), even after adjusting for body party injured. (4) Conclusions: Dance is associated with more sprains while gymnastics typically resulted in a greater likelihood for fractures.

Surgical clip closure of the left atrial appendage.

Atrial fibrillation (AF) is the most common atrial arrhythmia, but it is not a benign disease. AF is an important risk factor for thromboembolic events, causing significant morbidity and mortality. The left atrial appendage (LAA) plays an important role in thrombus formation, but the ideal management of the LAA remains a topic of debate. The increasing popularity of surgical epicardial ablation and hybrid endoepicardial ablation approaches, especially in patients with a more advanced diseased substrate, has increased interest in epicardial LAA management. Minimally invasive treatment options for the LAA offer a unique opportunity to close the LAA with a clip device. This review highlights morphologic, electrophysiologic, and surgical aspects of the LAA with regard to AF surgery, and aims to illustrate the importance of surgical clip closure of the LAA.

The Emotional Bank Account and the Four Horsemen of the Apocalypse in Romantic Relationships of People with Borderline Personality Disorder: A Dyadic Observational Study.

Few studies have examined behaviors in romantic relationships associated with borderline personality disorder (BPD). We assessed critical variables from marital research: the "emotional bank account" (positive-to-negative behaviors; Gottman, 1993) and the "four horsemen of the apocalypse" (criticism, defensiveness, contempt, and stonewalling; Gottman & Silver, 1999; Gottman & Krokoff, 1989). Couples (N = 130, or 260 participants) engaged in a conflict task and reported relationship satisfaction at intake and 12-months. Clinician-rated BPD and avoidant PD (APD) criteria were examined. People with more BPD symptoms and their partners were less satisfied, which worsened by follow-up. Conflict behaviors partially explained these associations. Partners of people with more BPD symptoms had a worse emotional bank account, which then predicted (a) poorer satisfaction for both members and (b) worsening partner satisfaction. People with more BPD symptoms criticized more; their partners defended and stonewalled more. APD predicted worsening satisfaction. BPD appears to link specifically with relationship dysfunction, partly through associations with partner behavior.

The role of benzathine penicillin G in predicting and preventing all-cause acute respiratory disease in military recruits: 1991-2017.

The adenovirus vaccine and benzathine penicillin G (BPG) have been used by the US military to prevent acute respiratory diseases (ARD) in trainees, though these interventions have had documented manufacturing problems. We fit Poisson regression and random forest models (RF) to 26 years of weekly ARD incidence data to explore the impact of the adenovirus vaccine and BPG prophylaxis on respiratory disease burden. Adenovirus vaccine availability was among the most important predictors of ARD in the RF, while BPG was the ninth most important. BPG was a significant protective factor against ARD (incidence rate ratio (IRR) = 0.68; 95% confidence interval (CI) 0.67-0.70), but less so than either the old or new adenovirus vaccine (IRR = 0.39, 95% CI 0.38-0.39 and IRR = 0.11, 95% CI 0.11-0.11), respectively. These results suggest that BPG is moderately predictive of, and significantly protective against ARD, though to a lesser extent than either the old or new adenovirus vaccine.

Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure.

The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A1Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization (p = n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF (p = 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF.

Identifying Subpopulations with Distinct Response to Treatment Using Plasma Biomarkers in Acute Heart Failure: Results from the PROTECT Trial : Differential Response in Acute Heart Failure.

BACKGROUND: Over the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. We hypothesize that this might be related to a differential response to pharmacological therapy. METHODS: We studied the magnitude of treatment effect of rolofylline across clinical characteristics and plasma biomarkers in 2033 AHF patients and derived a biomarker-based responder sum score model. Treatment response was survival from all-cause mortality through day 180. RESULTS: In the overall study population, rolofylline had no effect on mortality (HR 1.03, 95% CI 0.82-1.28, p = 0.808). We found no treatment interaction across clinical characteristics, but we found interactions between several biomarkers and rolofylline. The biomarker-based sum score model included TNF-R1α, ST2, WAP four-disulfide core domain protein HE4 (WAP-4C), and total cholesterol, and the score ranged between 0 and 4. In patients with score 4 (those with increased TNF-R1α, ST2, WAP-4C, and low total cholesterol), treatment with rolofylline was beneficial (HR 0.61, 95% CI 0.40-0.92, p = 0.019). In patients with score 0, treatment with rolofylline was harmful (HR 5.52, 95% CI 1.68-18.13, p = 0.005; treatment by score interaction p < 0.001). Internal validation estimated similar hazard ratio estimates (0 points: HR 5.56, 95% CI 5.27-7-5.87; 1 point: HR 1.31, 95% CI 1.25-1.33; 2 points: HR 0.75, 95% CI 0.74-0.76; 3 points: HR 1.13, 95% CI 1.11-1.15; 4 points, HR 0.61, 95% CI 0.61-0.62) compared to the original data. CONCLUSION: Biomarkers are superior to clinical characteristics to study treatment heterogeneity in acute heart failure.

Combining Diuretic Response and Hemoconcentration to Predict Rehospitalization After Admission for Acute Heart Failure.

BACKGROUND: Both diuretic response and hemoconcentration are indicators of decongestion and have individually been found to predict rehospitalization after admission for acute heart failure (HF). This study examines the value of combining diuretic response and hemoconcentration to better predict patients at low risk for rehospitalization after admission for acute HF. METHODS AND RESULTS: Diuretic response (defined as weight change per 40 mg of furosemide on day 4 after admission) and hemoconcentration (change in hemoglobin at discharge or day 7) were tested both individually and combined to predict the risk of HF and cardiovascular rehospitalization 60 days after hospitalization for acute HF. Analyses were performed in 1180 patients enrolled in the Placebo-Controlled Randomized Study of the Selective Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial and validated in 1776 patients enrolled in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Poor diuretic response was associated with low systolic blood pressure, high blood urea nitrogen, and history of coronary revascularization in both data sets (all P<0.05). Hemoconcentration was mainly associated with better renal function (P<0.05). Patients who displayed both favorable diuretic response and hemoconcentration had a markedly lower risk of rehospitalization for HF in PROTECT (multivariable HR, 0.41; 95% CI, 0.24 to 0.70; P<0.001) compared with all other patients. This finding was confirmed in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82; P=0.004) for patients with favorable diuretic response and hemoconcentration compared with all other patients. CONCLUSIONS: Combining 2 indicators of decongestion, hemoconcentration and diuretic response improves risk prediction for early rehospitalization after an admission for acute HF and may provide clinicians with an easily accessible tool to identify low-risk patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00354458 and NCT00071331.

Abnormal liver function tests in acute heart failure: relationship with clinical characteristics and outcome in the PROTECT study.

AIMS: Episodes of acute heart failure (AHF) unfavourably affect multiple organs, which may have an adverse impact on the outcomes. We investigated the prevalence and clinical consequences of abnormal liver function tests (LFTs) in AHF patients enrolled in the PROTECT study. METHODS AND RESULTS: The LFTs comprised serial assessment of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin at baseline and during follow-up (daily until discharge, on days 7 and 14). The prevalence of abnormal LFTs (above upper limit of normal for AST and ALT or below lower limit of normal for albumin) was: at baseline AST 20%, ALT 12%, albumin 40%; and at day 14: AST 15%, ALT 9%, albumin 26%. Abnormal LFTs at baseline were associated with a higher risk of in-hospital death with odds ratios [95% confidence interval (CI)] of 3.5 (1.7-7.3) for AST, 3.9 (1.8-8.4) for ALT, and 2.8 (1.3-5.9) for albumin (all P < 0.01). Abnormal baseline and discharge LFTs had an unfavourable impact on 180-day mortality with hazard ratios (95% CI) for baseline AST, ALT, and albumin of 1.3 (1.0-1.7), 1.1 (1.0-1.2), 1.4 (1.1-1.8), respectively, and 1.5 (1.1-2.0), 1.5 (1.0-2.2), and 1.6 (1.2-2.1), for discharge AST, ALT, albumin, respectively (all P < 0.05). Analysis of LFTs trajectories (calculated as changes in LFTs over time) revealed that increasing AST and ALT on day 3 as well as decreasing albumin on day 4 were independent prognosticators of 180-day outcome (all P < 0.05). CONCLUSIONS: Abnormal LFTs are frequent in AHF at baseline and during hospital stay and predict worse outcomes. Whether this association is causal and what are the underlying mechanisms involved require further study.

Cardiac adaption during pregnancy in women with congenital heart disease and healthy women.

OBJECTIVE: Pregnancy in women with congenital heart disease (CHD) is associated with deterioration in cardiac function. However, longitudinal data are scarce. This study describes serial changes in cardiac dimensions and function during pregnancy in women with CHD and compares these with healthy pregnant women (controls). METHODS: Eight tertiary centres prospectively enrolled 125 pregnant women with CHD (pregnancy duration <20 weeks). Controls (N=49) were recruited from low-risk midwife practices. Standardised echocardiography at 20 and 32 weeks gestation and 1 year postpartum was performed. RESULTS: Age and parity were comparable between both groups (p>0.1). Left ventricular ejection fraction (LVEF) <45% was present in 3.2% of women with CHD and 14.4% had tricuspid annular plane systolic excursion (TAPSE) <16 mm. Absolute values of ventricular function parameters and diameters were less favourable in women with CHD. No permanent changes occurred in right and left ventricular function parameters and dimensions in women with CHD. The patterns of change in cardiac function and dimensions were comparable between women with CHD and controls, except for LVEF (p=0.026). In women with right-sided CHD the pattern of TAPSE over time differed from controls (p=0.043) (no decrease in TAPSE postpregnancy in CHD). In women with left-sided CHD left ventricular end-diastolic diameter (LVEDD) tended to increase compared with controls (p=0.045). CONCLUSIONS: Absolute levels of ventricular function parameters and diameters differ between CHD and controls, but changes during and after pregnancy are generally comparable. However, different patterns over time seen for TAPSE and LVEDD in women with right-sided and left-sided CHD, respectively, compared with controls indicate the importance of echocardiographic follow-up during pregnancy in women with CHD.

MicroRNAs relate to early worsening of renal function in patients with acute heart failure.

BACKGROUND: Deregulation of microRNAs (miRNAs) may be involved in the pathogenesis of heart failure (HF) and renal disease. Our aim is to describe miRNA levels related to early worsening renal function in acute HF patients. METHOD AND RESULTS: We studied the association between 12 circulating miRNAs and Worsening Renal Function (WRF; defined as an increase in the serum creatinine level of 0.3mg per deciliter or more from admission to day 3), absolute change in creatinine and Neutrophil Gelatinase Associated Lipocalin (NGAL) from admission to day 3 in 98 patients hospitalized for acute HF. At baseline, circulating levels of all miRNAs were lower in patients with WRF, with statistically significant decreased levels of miR-199a-3p, miR-423-3p, and miR-let-7i-5p (p-value<0.05). The increase in creatinine during the first 3 days of hospitalization was significantly associated with lower levels of miR-199a-3p, miR-27a-3p, miR-652-3p, miR-423-5p, and miR-let-7i-5p, while the increase in NGAL was significantly associated with lower levels of miR-18a-5p, miR-106a-5p, miR-223-3p, miR-199a-3p and miR-423-3p. MiR-199a-3p was the strongest predictor of WRF, with an Odds Ratio of 1.48 (1.061-2.065; p-value=0.021) and a C-index of 0.701. CONCLUSIONS: Our results show that the levels of circulating miRNAs at hospital admission for acute HF were consistently lower in patients who developed worsening of renal function. MiR-199a-3p was the best predictor of WRF in these patients.

Optimizing clinical use of biomarkers in high-risk acute heart failure patients.

AIM: The clinical value of single biomarkers at single time-points to predict outcomes in patients with acute heart failure (AHF) is limited. We performed a multimarker, multi-time-point analysis of biomarkers for the prediction of post-discharge clinical outcomes in high-risk AHF patients. METHODS AND RESULTS: A set of 48 circulating biomarkers were measured in the PROTECT trial which enrolled 2033 patients with AHF. Associations between baseline levels of biomarkers and outcomes (30-day all-cause mortality, 30-day death or rehospitalization for renal/cardiovascular causes and 180-day all-cause mortality) were evaluated. Prognostic accuracies of baseline, days 2 or 3, 7, and 14 biomarker measurements were estimated and compared utilizing a time-dependent area under the curve (AUC) analysis. Forty-four biomarkers were significantly associated with outcomes, but 42 had limited prognostic value (C-index < 0.70). However, multimarker models combining best-performing biomarkers from different clusters had a much stronger prognostic value. Combining blood urea nitrogen (BUN), chloride, interleukin (IL)-6, cTnI, sST-2 and VEGFR-1 into a clinical model yielded a 11% increase in C-index to 0.84 and 0.78 for 30-day and 180-day all-cause mortality, respectively, and cNRI of 0.86 95% CI [0.55-1.11] and 0.76 95% CI [0.57-0.87]. Prognostic gain was modest for the 30-day death/rehospitalization for cardiovascular or renal causes endpoint. Comparative time-dependent AUC analysis indicated that late measurements provided superior accuracy for the prediction of all-cause mortality over 180 days, with few exceptions including BUN and galectin-3. However, the predictive value of most biomarkers showed a diminishing pattern over time irrespective of moment of measurement. CONCLUSIONS: Multimarker models significantly improve risk prediction. Subsequent measurements, beyond admission, are needed for majority of biomarkers to maximize prognostic value over time, particularly in the long term.

A combined clinical and biomarker approach to predict diuretic response in acute heart failure.

BACKGROUND: Poor diuretic response in acute heart failure is related to poor clinical outcome. The underlying mechanisms and pathophysiology behind diuretic resistance are incompletely understood. We evaluated a combined approach using clinical characteristics and biomarkers to predict diuretic response in acute heart failure (AHF). METHODS AND RESULTS: We investigated explanatory and predictive models for diuretic response--weight loss at day 4 per 40 mg of furosemide--in 974 patients with AHF included in the PROTECT trial. Biomarkers, addressing multiple pathophysiological pathways, were determined at baseline and after 24 h. An explanatory baseline biomarker model of a poor diuretic response included low potassium, chloride, hemoglobin, myeloperoxidase, and high blood urea nitrogen, albumin, triglycerides, ST2 and neutrophil gelatinase-associated lipocalin (r(2) = 0.086). Diuretic response after 24 h (early diuretic response) was a strong predictor of diuretic response (ß = 0.467, P < 0.001; r(2) = 0.523). Addition of diuretic response after 24 h to biomarkers and clinical characteristics significantly improved the predictive model (r(2) = 0.586, P < 0.001). CONCLUSIONS: Biomarkers indicate that diuretic unresponsiveness is associated with an atherosclerotic profile with abnormal renal function and electrolytes. However, predicting diuretic response is difficult and biomarkers have limited additive value. Patients at risk of poor diuretic response can be identified by measuring early diuretic response after 24 h.

Signature of circulating microRNAs in patients with acute heart failure.

AIMS: Our aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF). METHODS AND RESULTS: Plasma miRNA profiling included 137 patients with AHF from 3 different cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR-18a-5p, miR-26b-5p, miR-27a-3p, miR-30e-5p, miR-106a-5p, miR-199a-3p, and miR-652-3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180-day mortality in a subset of the identified miRNAs. CONCLUSIONS: Declining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in-hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch-pad for molecular pathway studies to identify new pharmacological targets and miRNA-based therapies.

Long-term changes in renal function and perfusion in heart failure patients with reduced ejection fraction.

INTRODUCTION: Little is known about the natural course of renal function and renal hemodynamics in heart failure patients with reduced ejection fraction (HFREF). METHODS AND RESULTS: We prospectively studied effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in 73 HFREF patients with (125)I-iothalamate/(131)I-hippuran clearances with a mean follow-up of 34.6 ± 4.4 months. Fifteen percent were female, with age 58 ± 12 years and left ventricular ejection fraction (LVEF) 29 ± 10%. Baseline GFR was 81 ± 23 mL/min/1.73 m(2) and declined 0.6 ± 4.7 mL/min/1.73 m(2) per year. Baseline ERPF was 292 ± 83 mL/min/1.73 m(2) and declined 4.3 ± 19 mL/min/1.73 m(2) per year. Of the baseline variables, older age and high urinary kidney injury molecule-1 were the only variables associated with GFR decline (p < 0.05). Following stepwise backward analysis, only age (p < 0.001) remained significant. In addition, we found an association between change in GFR and changes in ERPF, N-terminal pro-brain natriuretic peptide and renovascular resistance. In the multivariable analysis, only the change in ERPF remained significantly associated with a change in GFR (p < 0.001). CONCLUSION: In this cohort of stable chronic HFREF patients, the average decline in GFR over time was small. The decline of GFR was associated with a higher age and a lower baseline GFR, and was strongly related to changes in renal perfusion.