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Background— In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations. Methods and Results— The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality ( P P r =0.047). Conclusions— This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00537628.

Few tools exist that provide objective accurate prediction of short-term mortality risk in patients presenting with acute heart failure (AHF). The purpose was to describe the accuracy of several biomarkers for predicting short-term death rates in patients diagnosed with AHF in the emergency department (ED).

ACADEMIC EMERGENCY MEDICINE 2011; 18:851–859 © 2011 by the Society for Academic Emergency Medicine Abstract Objectives: Patients presenting to emergency departments (ED) with nonspecific complaints (NSCs) such as “not feeling well,”“feeling weak,”“being tired,”“general deterioration,” or other similar chief complaints that do not have a readily identifiable probable etiology are a common patient group at risk for adverse outcomes. Certain biomarkers, which have not yet been tested for prognostic value when applied to ED patients with NSCs, have emerged as useful tools for predicting prognosis in patients with a variety of diseases. This study tested the hypothesis that two of these novel markers, copeptin (a C-terminal portion of provasopressin) and/or peroxiredoxin-4 (Prx4), an enzyme that degrades hydrogen peroxide, singly or together are helpful in predicting death in the near term among patients presenting to the ED with NSCs. Methods: The Basel Non-specific Complaints (BANC) study is a delayed type cross-sectional diagnostic study with a prospective 30-day follow-up. ED patients with NSCs were consecutively enrolled. Patients with vital parameters out of the normal range were excluded. The primary endpoint of this study was the predictive value of copeptin and Prx4 for 30-day mortality in patients with NSCs. Measurement of both copeptin and Prx4 was performed in serum samples with sandwich immunoluminometric assays. Results: On follow-up at 30 days after ED presentation, 28 of 438 patients with NSC had died. Copeptin and Prx4 concentrations were significantly higher in nonsurvivors than in survivors (Kruskal-Wallis test, p = 0.0001 and p

Objectives The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath. Background The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p Methods The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission. Results Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 90-day all-cause mortality in patients presenting with acute dyspnea (c index = 0.755, p 3.28), and it was also superior to all other biomarkers. MR-proADM added significantly to the best clinical model (bootstrap-corrected c index increase: 0.775 to 0.807; adjusted standardized hazard ratio: 2.59; 95% confidence interval: 1.91 to 3.50; p Conclusions MR-proADM identifies patients with high 90-day mortality and adds prognostic value to natriuretic peptides in patients presenting with acute shortness of breath. Serial measurement of this biomarker may also prove useful for monitoring, although further studies will be required. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628 )

Background There is almost no data about the influence of antimicrobial pre-treatment (APT) on levels of inflammatory markers in community acquired pneumonia (CAP). The aim of this study was to investigate the influence of APT on inflammatory markers in CAP. Methods 991 hospitalized patients (64.3 ± 17.6 years, 61% male) with CAP were enrolled. In all patients procalcitonin (PCT), C-reactive protein (CRP), and leukocyte count (WBC) were determined. Patients were followed-up for 28 days for survival. Results 232 patients (23.4%) had APT, 759 had no APT. Patients without APT had significantly higher levels of PCT and WBC but not of CRP compared to those with APT. In patients without APT, survivors compared to non-survivors had lower values of PCT (0.20 ng/mL; 0.02–169.10 vs. 0.83 ng/mL; 0.04–516.30, p 9 /L; 1.3–49.9 vs. 14.9 × 10 9 /L; 3.7–34.5, p = 0.047) and CRP (107.0 mg/mL; 0.3–567.0 vs. 143.5 mg/mL; 5.0–589.0, p = 0.006). However, in patients with APT, the values of PCT, WBC and CRP were not significantly different in survivors and non-survivors. Cox regression analysis confirmed that PCT, CRP and WBC were predictive for 28 day mortality in patients without APT but not in those with APT. Conclusions PCT and WBC but not CRP levels are higher in patients without APT compared to those with APT. PCT, CRP and WBC are predictive for 28 days mortality exclusively in patients without APT. Interpretation of inflammatory parameters has to take into account possible APT.

BACKGROUND The early detection of acute kidney injury (AKI) in patients with chronic kidney disease (CKD) is an unmet clinical need. Proenkephalin (PENK) might improve the early detection of AKI. METHODS One hundred and eleven hospitalized CKD patients undergoing radiographic contrast procedures were enrolled. PENK was measured in a blinded fashion at baseline (before contrast media administration) and on day 1 (after contrast media administration). The potential of PENK levels to predict contrast-induced AKI was the primary endpoint. RESULTS Baseline creatinine and baseline PENK were similar in AKI and no-AKI patients. In AKI patients, day 1 PENK (198 pmol/L vs 121 pmol/L, P

Aims Beyond erythropoiesis, iron is involved in numerous biological processes crucial for maintenance of homeostasis. Patients with chronic heart failure (CHF) are prone to develop iron deficiency (ID), and iron supplementation improves their functional status and quality of life. We sought to examine the relationship between ID and survival in patients with systolic CHF. Methods and results In a prospective observational study, we evaluated 546 patients with stable systolic CHF [age: 55 ± 11 (mean ± standard deviation) years, males: 88%, left ventricular ejection fraction: 26 ± 7%, New York Heart Association (NYHA) class (I/II/III/IV): 57/221/226/42]. Iron deficiency was defined as: ferritin

ObjectivesEarly identification of myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation.BackgroundThe aim of the current investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to cardiac troponin in early evaluation of patients with suspected myocardial infarction.MethodsBetween January 2007 and July 2008, patients with suspected acute coronary syndrome were consecutively enrolled in this multicenter study. Copeptin, troponin T (TnT), myoglobin, and creatine kinase-myocardial band were determined at admission and after 3 and 6 h.ResultsOf 1,386 (66.4% male) enrolled patients, 299 (21.6%) had the discharge diagnosis of acute myocardial infarction, 184 (13.3%) presented with unstable angina, and in 903 (65.2%) an acute coronary syndrome could be excluded. Combined measurement of copeptin and TnT on admission improved the c-statistic from 0.84 for TnT alone to 0.93 in the overall population and from 0.77 to 0.9 in patients presenting within 3 h after chest pain onset (CPO) (p < 0.001). In this group the combination of copeptin with a conventional TnT provided a negative predictive value of 92.4%.ConclusionsIn triage of chest pain patients, determination of copeptin in addition to troponin improves diagnostic performance, especially early after CPO. Combined determination of troponin and copeptin provides a remarkable negative predictive value virtually independent of CPO time and therefore aids in early and safe rule-out of myocardial infarction.

Objectives Our purpose was to assess the diagnostic utility of mid-regional pro–atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with AHF. Background There are some caveats and limitations to natriuretic peptide testing in the acute dyspneic patient. Methods The BACH (Biomarkers in Acute Heart Failure) trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. A noninferiority test of MR-proANP versus B-type natriuretic peptide (BNP) for diagnosis of AHF and a superiority test of MR-proADM versus BNP for 90-day survival were conducted. Other end points were exploratory. Results MR-proANP (≥120 pmol/l) proved noninferior to BNP (≥100 pg/ml) for the diagnosis of AHF (accuracy difference 0.9%). In tests of secondary diagnostic objectives, MR-proANP levels added to the utility of BNP levels in patients with intermediate BNP values and with obesity but not in renal insufficiency, the elderly, or patients with edema. Using cut-off values from receiver-operating characteristic analysis, the accuracy to predict 90-day survival of heart failure patients was 73% (95% confidence interval: 70% to 77%) for MR-proADM and 62% (95% confidence interval: 58% to 66%) for BNP (difference p Conclusions MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret. MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628)

Midregional Proenkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) are stable fragments of the precursor peptides for enkephalins and substance P, respectively. We measured MR-PENK A and NT-PTA concentrations by sensitive chemiluminescence immunoassays in cerebrospinal fluid (CSF) of 19 neurologically healthy controls (NHC), 28 patients with other neurologic disorders (OND), 70 patients with dementia disorders (38 Alzheimer's disease [AD], 8 dementia with Lewy bodies [DLB], 12 frontotemporal dementia [FTD], and 12 patients with vascular dementia [VD]), and 16 patients with acute neuroinflammation (AN). Median concentrations of NT-PTA were decreased in all patient groups compared to NHC showing significant differences between patients with NHC and AN (p0.001), OND and AN (p0.001), FTD and AN (p0.01) and pAD and AN (p0.05). Median MR-PENK A levels were lower in patients with OND, dementia disorders (including AD, FTD, DLB and VD) and AN compared to NHC subjects, although this differences did not reach statistical significance (p0.05). A maximum difference of both proneuropeptide fragments was found between NHC subjects and patients with AN, with a more than 2fold decrease in median NT-PTA and a 1.5fold decrease in median MR-PENK A levels. Concentrations of both proneuropeptide fragments were positively correlated in all patients (r=0.77, p0.001). Our results indicate alterations of the cerebral PENK A- and PTA-system in both, dementia and acute neuroinflammatory disorders. These neuropeptide systems seem to be highly correlated in healthy and pathological status.

Background Community-acquired pneumonia (CAP) is the most important clinical infection with a high longterm mortality rate. The aim of this study was to evaluate the value of biomarkers for the prediction of short-term and long-term mortality in CAP. Methods A total of 1740 patients of mean6SD age 60618 years (45% female) with proven CAP were enrolled in the study. Mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-atrial vasopressin (CT-proAVP), procalcitonin , C-reactive protein, leucocyte count (WBC) and CRB-65 score were determined on admission. Patients were followed up for 180 days. Results MR-proANP and CT-proAVP levels increased with increasing severity of CAP, classified according to CRB-65 score. In patients who died within 28 and 180 days, median MR-proANP (313.9 vs 80.0 and 277.8 vs 76.0 pmol/l, each p

Enkephalins are opioid peptides and enkephalin and its precursor pro-enkephalin (pro-ENK) are found to be widely distributed in organ tissues including the kidney [1]. Pro-ENK is a predictor for acute kidney injury (AKI) in patients after cardiac surgery and can detect severity of AKI in patients admitted to the emergency department with sepsis [2, 3]. In surgical ICU-patients with sepsis, information on the suitability of pro-ENK to determine kidney function is lacking.

Synthesis and liberation of adrenomedullin (ADM) are found in different tissues and endothelial cells and ADM is induced by hypoxia, oxidative stress, and pro-inflammatory cytokines [1]. The prognostic value of ADM is described in general patient populations, in medical patients and in particular recently in patients with suspected sepsis in the emergency department [2, 3]. In surgical patients, the obstacle is to differentiate between postoperative inflammation and sepsis and to assess the patients' prognosis.

Background Point of care testing (POCT) assays for cardiac troponin (cTn) are hampered by lower analytical sensitivity and thus suboptimal rule-out of myocardial infarction (MI). We investigated, whether additional measurement of copeptin using an ultrasensitive assay improves diagnostic performance of POCT for cTn T compared to a high sensitivity troponin T (hsTnT) assay. Methods 131 patients with suspected acute coronary syndrome were prospectively enrolled in our center 08/2010 to 11/2011. In blood samples obtained at presentation, ultrasensitive copeptin (Kryptor, BRAHMS) and two commercially available POCT assays, AQT90 Flex Radiometer (Radiometer) and Cobas h232 POC-System (Cobas), were tested. HsTnT (Cobas E411, Roche) at baseline and after 3 and 6h in the central laboratory served as reference. Results Copeptin improved rule-out of non-STEMI combined with all tested troponin assays. Addition of copeptin increased sensitivity of Cobas from 67.9% (95% CI: 0.506; 0.852) to 89.3% (95% CI: 0.778; 1.007) and Radiometer from 71.4% (95% CI: 0.547; 0.882) to 85.7% (95% CI: 0.728; 0.987), achieving the sensitivity of hsTnT alone at admission of 85.7% (95% CI: 0.728; 0.987). The area under the curve (AUC) of Radiometer (0.822) was numerically but insignificantly (p=0.17) higher than AUC of Cobas (0.725). Addition of copeptin increased AUC of Radiometer to 0.826 (p=0.96) and AUC of Cobas to 0.814 (p=0.20). Conclusions Additional use of ultrasensitive copeptin improves diagnostic performance of conventional sensitive POCT assays overcoming lower sensitivities at the cost of a drop of clinical specificity. When hsTn is temporarily unavailable, copeptin and POCT for cTn may allow initial evaluation at a comparable performance as hsTnT at admission.

The chromosomal translocation t(8;21) is associated with 10-15% of all cases of acute myeloid leukaemia (AML). The resultant fusion protein AML1/MTG8 interferes with haematopoietic gene expression and is an important regulator of leukaemogenesis. We studied the effects of small interfering RNA (siRNA)-mediated AML1/MTG8 depletion on global gene expression in t(8;21)-positive leukaemic cell lines and in primary AML blasts using cDNA arrays, oligonucleotide arrays and real-time reverse transcription-polymerase chain reaction (RT-PCR). Suppression of AML1/MTG8 results in the increased expression of genes associated with myeloid differentiation, such as AZU1, BPI, CTSG, LYZ and RNASE2 as well as of antiproliferative genes such as IGFBP7, MS4A3 and SLA both in blasts and in cell lines. Furthermore, expression levels of several genes affiliated with drug resistance or indicative of poor prognosis AML (BAALC, CD34, PRG2, TSPAN7) are affected by AML1/MTG8 depletion. In conclusion, siRNA-mediated suppression of AML1/MTG8 cause very similar changes in gene expression pattern in t(8;21)-positive cell lines and in primary AML blasts. Furthermore, the results suggest that the specific targeting of AML1/MTG8 function may be a promising approach for complementing existing treatment strategies.

Wilms tumor is the most frequent renal neoplasm in children, but our understanding of its genetic basis is still limited. We performed cDNA microarray experiments using 63 primary Wilms tumors with the aim of detecting new candidate genes associated with malignancy grade and tumor progression. All tumors had received preoperative chemotherapy as mandated by the SIOP protocol, which sets this study apart from related approaches in the Unites States that are based on untreated samples. The stratification of expression data according to clinical criteria allowed a rather clear distinction between different subsets of Wilms tumors. Clear-cut differences in expression patterns were discovered between relapse-free as opposed to relapsed tumors and tumors with intermediate risk as opposed to high risk histology. Several differentially expressed genes, e.g. TRIM22, CENPF, MYCN, CTGF, RARRES3 and EZH2, were associated with Wilms tumor progression. For a subset of differentially expressed genes, microarray data were confirmed by real-time RT-PCR on the original set of tumors. Interestingly, we found the retinoic acid pathway to be deregulated at different levels in advanced tumors suggesting that treatment of these tumors with retinoic acid may represent a promising novel therapeutic approach. (c) 2005 Wiley-Liss, Inc. (Less)

We have previously demonstrated that c-Myc impairs p53-mediated apoptosis in K562 human leukemia cells, which lack ARF. To investigate the mechanisms by which c-Myc protects from p53-mediated apoptosis, we used K562 cells that conditionally express c-Myc and harbor a temperature-sensitive allele of p53. Gene expression profiles of cells expressing wild-type conformation p53 in the presence of either uninduced or induced c-Myc were analysed by cDNA microarrays. The results show that multiple p53 target genes are downregulated when c-Myc is present, including p21WAF1, MDM2, PERP, NOXA, GADD45, DDB2, PIR121 and p53R2. Also, a number of genes that are upregulated by c-Myc in cells expressing wild-type conformation p53 encode chaperones related to cell death protection as HSP105, HSP90 and HSP27. Both downregulation of p53 target genes and upregulation of chaperones could explain the inhibition of apoptosis observed in K562 cells with ectopic c-Myc. Myc-mediated impairment of p53 transactivation was not restricted to K562 cells, but it was reproduced in a panel of human cancer cell lines derived from different tissues. Our data suggest that elevated levels of Myc counteract p53 activity in human tumor cells that lack ARF. This mechanism could contribute to explain the c-Myc deregulation frequently found in cancer.

Broad differentiation capacity has been described for mesenchymal stem cells (MSC) from human bone marrow. We sought to identify genes associated with the immature state and pluripotency of this cell type. To prove the pluripotent state of the MSC, differentiation into osteocytes, adipocytes, and chondrocytes was performed in vitro. In contrast, normal skin cells did not harbor these differentiation abilities. We compared the expression profile of human bone marrow MSC with cDNA from one primary human skin cell line as control, using a cDNA chip providing 9600 genes. The identity of all relevant genes was confirmed by direct sequencing. Data of gene array expression were corroborated employing quantitative PCR analysis. About 80 genes were differently expressed more than threefold in MSC compared to mature skin fibroblasts. Interestingly, primary human MSC were found to upregulate a number of genes important for embryogenesis such as distal-less homeo box 5, Eyes absent homolog 2, inhibitor of DNA binding 3, and LIM protein. In contrast, mesenchymal lineage genes were downregulated in MSC in comparison to skin cells. We also detected expression of some genes involved in neural development, indicating the broad differentiation capabilities of MSC. We conclude that human mesenchymal stem cells harbor an expression profile distinct from mature skin fibroblast, and genes associated with developmental processes and stem cell function are highly expressed in adult mesenchymal stem cells.

DeltaNp73alpha is an isoform of the p53 homologue p73 that lacks an amino-terminal transactivation domain and antagonizes the induction of gene expression by p53. Here, we examined whether DeltaNp73alpha might also modulate cellular transcription in the absence of p53. The expression of DeltaNp73alpha in the p53-/- cell line H1299 reduced the mRNA levels of p21/CDKN1A, but did not affect other p53-responsive genes. Correspondingly, the p21/CDKN1A promoter was downregulated by DeltaNp73alpha in reporter assays, whereas other p53-responsive promoters were not inhibited. To identify additional genes that respond to DeltaNp73alpha in the absence of p53, microarrays carrying 4600 cDNA clones were hybridized. The expression of 30 genes was found to be altered more than threefold by overexpressed DeltaNp73alpha. For instance, DeltaNp73alpha increased the expression of EGR1 and CDC6, whereas it decreased the mRNA levels of c-MYC, cyclin A2/CCNA2, NF-kappaB1, ODC1, and RET finger protein/RFP. Semiquantitative reverse transcription-PCR confirmed these results and further revealed that the influence of DeltaNp73alpha on the regulation of these genes differs from other p73 isoforms and p53. We conclude that the impact of DeltaNp73alpha on gene expression is not limited to p53-responsive genes. Rather, DeltaNp73alpha can regulate the expression of a variety of genes independently of p53.

Rats treated with monocrotaline (MCT) develop pulmonary hypertension. Their right ventricles (RVs) exhibit severe pressure overload-induced hypertrophy, whereas the left ventricles (LVs) are normally loaded. In contrast, enhanced neuroendocrine stimulation during the transition to heart failure affects both ventricles. We assessed gene expression levels of Ca 2+ -regulating proteins in RVs and LVs of control and MCT rats in transition to heart failure to identify biomechanical load-regulated genes. In MCT RVs, both mRNA and protein levels of the Ca 2+ -ATPase of the sarcoplasmic/endoplasmic reticulum (SERCA2a) were reduced by 36% ( P =0.001) and 17% ( P =0.016), respectively, compared with control RVs. Phospholamban and ryanodine receptor mRNA levels likewise were reduced (by 27% [ P =0.05] and 21% [ P =0.011], respectively) in MCT RVs, whereas sarcolemmal Na + -Ca 2+ exchanger expression was not altered. MCT LVs exhibited no significant expression changes compared with control LVs. Isometrically contracting MCT intact RV trabeculae showed enhanced baseline force development. Although control RV preparations exhibited a positive force-frequency relationship, MCT RVs showed a negative force-frequency relationship and blunted postrest potentiation. Contractile function of MCT LV trabeculae was normal. Maximum Ca 2+ -activated tension was enhanced by 64% in permeabilized RV MCT preparations ( P =0.013). β-Myosin heavy chain protein was upregulated in MCT RVs ( P 2+ -cycling proteins.

During infection with adenovirus, massive changes in the transcription of virus genes are observed, suggesting that the expression of cellular genes may also be modulated. To characterize the levels of cellular RNA species in infected cells, cDNA arrays were screened 24 h after infection of HeLa cells with wild-type adenovirus type 5, strain dl309. Despite complete transduction of the cells, fewer than 20 cellular genes (out of 4,600 analyzed and 1,200 found detectable and expressed above background) were altered more than threefold in their corresponding RNA levels compared to mock-infected cells. In particular, the expression of the myc oncogene was reduced at the mRNA level. This reduction was dependent on the replication of virus DNA and partially dependent on the presence of the adenovirus gene products E1B-55 kDa and E4orf6, but not E4orf3. On the other hand, MYC protein had an increased half-life in infected cells, resulting in roughly constant steady-state protein levels. The adenovirus E1A gene product is necessary and sufficient to stabilize MYC. Overexpressed MYC inhibited adenovirus replication and the proper formation of the virus replication centers. We conclude that adenovirus infection leads to the stabilization of MYC, perhaps as a side effect of E1A activities. On the other hand, myc mRNA levels are negatively regulated during adenovirus infection, and this may avoid the detrimental effect of excessive MYC on adenovirus replication.

Backgound : The exact pathomechanism of inflammation progress and fibrosis in chronic obstructive sialadenitis is unknown. The aim of the present study was to assess whether there is an association between transforming growth factor beta (TGF-β) and fibrogenic process of chronic sialadenitis. Methods : Tissue samples of 12 patients with chronic sialadenitis and 4 normal tissue samples of the submandibular gland were examined immunohistochemically for identification of TGF-β. TGF-β1 messenger RNA (mRNA) expression was analysed semiquantitatively using reverse transcription polymerase chain reaction and gel electrophoresis to correlate its expression levels with stages of the disease. Results : TGF-β positive cells could be found in the secretory duct system of all examined samples. However, an intense TGF-β immunoreactivity was observed in inflamed salivary glands. With progress of disease TGF-β1 mRNA expression increases significantly. Conclusion : Expression of TGF-β in chronic sialadenitis and its apparent increase in advanced stages of the disease, suggests that this growth factor may play a role in glandular fibrosis.

This editorial refers to ‘Evidence for obesity paradox in patients with acute coronary syndromes. A report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR)’, by O. Angeras et al. , doi:10.1093/eurheartj/ehs217 and ‘The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness’, by F.B. Ortega et al. , doi:10.1093/eurheartj/ehs174 Oodles of studies have been published with regards to the obesity paradox in chronic disease. Still, researchers remain confused, clinicians unconvinced, and Joe Bloggs does not want to be overweight anyway—mostly because over the last three decades he has been exposed to diverse forms of education saying that ‘obesity makes you ill and kills you’. In the words of the Roman philosopher Seneca (4 BC–65 AD): ‘Every man prefers belief to the exercise of judgement’.1 Since public belief prefers being slim to being overweight or obese, the prevailing wisdom holds that being slim must be generally good for you. In addition, numerous studies have shown that overweight and obesity confer disadvantages, as their presence is associated with the development of cardiovascular disease, diabetes mellitus, and several other metabolic perturbations. Thus, obesity must be bad. The question that has arisen over the last 13 years is whether this concept is true, irrespective of a given individual's circumstances. The original description of the obesity paradox was published in 1999 using data from >1300 patients with chronic kidney disease undergoing haemodialysis.2 The authors of that study concluded that ‘nutrition aimed to achieve the high end of normal body mass index (BMI) may help to reduce the high mortality and morbidity in hemodialysis patients’. This conclusion extrapolated far beyond the data obtained in the study, because nutritional intake was not even analysed; however, it paved the way for a vast array of similar studies in patients with chronic obstructive pulmonary disease, …

Digital maps are a key information for road course estimation in large distances, especially for automated driving with higher speeds or during nighttime. However, digital maps may contain errors caused by road changes or inaccurate recordings. As these errors may lead to severe application level failures, early and reliable detection of these errors, generally termed map verification, is a must. This work presents an online approach to verification of digital maps for automotive use based on neural multi-sensor fusion. Unlike previous works, the system is able to verify the digital map integrity ahead of the vehicle, before the error position is reached. Thus, appropriate countermeasures to mitigate possible effects can be initiated upfront. On the basis of a large database of map geometry and sensor information, a neural network is trained to classify the digital map integrity by optimally fusing sensor information at different abstraction levels. Using this technique, the authors system is able to verify the map integrity 100 meters ahead of the vehicle with an error rate of less than 3.4%, while being real-time capable at the same time. Experiments validate the performance and robustness of this approach.

Digital maps are becoming increasingly important for driver assistance systems: providing optimal lighting conditions in night scenarios, presenting the road geometry to the driver, or for usage in autonomous driving tasks. However, recorded digital maps own one drawback: due to road changes and inaccurate recordings, discrepancies between the map and the real world exist. Because these discrepancies can lead to severe application level failures, detection of map errors is essential to ensure overall system integrity. This work proposes a new approach to online verification of digital maps for automotive usage. In contrast to previous work, the described system is able to detect errors in front of the vehicle. On the basis of a large database of map geometry and sensor information, a neural network is trained to classify the digital map integrity by optimally fusing different information sources depending on their strength and reliability. Although generally applicable, it is shown that a combination of orthogonal measurement principles is greatly beneficial for this decision task. A radar sensor, infra-red imagery and road geometry information estimated from visible light images are employed as input for the neural fusion. Experiments on real-world data verify the proposed concepts.

Dysnatremia is a frequent finding in patients with community acquired pneumonia (CAP) and a predictor of mortality. We studied the relation between dysnatremia, comorbidities and CT-pro-AVP and MR-proANP.We enrolled 2138 patients (60 ± 18 years, 55% male) with CAP from the CAPNETZ database. Pro-atrial natriuretic peptide (proANP), pro-vasopressin (proAVP), serum sodium and CRB-65 score were determined on admission. Patients were followed up for 28 days. Sodium concentration on admission was examined as a function of mortality at 28 days. Hyponatremia (HypoN) was defined as admission serum sodium136 mmol/L, hypernatremia (HyperN) as admission serum sodium145 mmol/L.HypoN was diagnosed in 680 (31.8%) patients, HyperN in 29 (1.4%) patients. Comorbidities were associated with sodium levels, and CT-pro-AVP and MR-proANP were inversely related to sodium levels. Patients with HypoN were older, had a higher CRB-65 score and higher values of CT-proAVP and MR-proANP (all p0.05). When examined as a function of sodium values, a U-shaped association was found between sodium levels and 28 day mortality. In multivariate Cox proportional hazards analysis, HypoN and HyperN were independent predictors of 28 day mortality. Sodium levels added to the predictive potential of proAVP and proANP.HypoN is common at admission among CAP patients and is independently associated with mortality. HyperN is rare at admission among CAP patients but is also independently associated with mortality. The combination of sodium and CT-pro-AVP and MR-proANP levels achieved the highest prediction of mortality.

Acute kidney injury (AKI) aggravates the prognosis of patients with sepsis. Reliable biomarkers for early detection of AKI in this setting are lacking. Enkephalins influence kidney function, and may have a role in AKI from sepsis. We utilized a novel immunoassay for plasma proenkephalin (pro-ENK), a stable surrogate marker for endogenous enkephalins, in patients hospitalized with sepsis, in order to assess its clinical utility.In an observational retrospective study we enrolled 101 consecutive patients admitted to the emergency department (ED) with suspected sepsis. Plasma levels of pro-ENK and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated at ED arrival for their association with presence and severity of AKI and 7-day mortality.pro-ENK was inversely correlated to creatinine clearance (r = -0.72) and increased with severity of AKI as determined by RIFLE (risk, injury, failure, loss of function, end-stage renal disease) stages (p 0.0001; pro-ENK median [interquartile range, IQR]) pmol/l: no AKI: 71 [41-97]; risk: 72 [51-120]; injury: 200 [104-259]; failure: 230 [104-670]; loss of function: 947 [273-811]. The majority of septic patients without AKI or at risk had pro-ENK concentrations within the normal range. While NGAL was similarly associated with AKI severity, it was strongly elevated already in septic patients without AKI. pro-ENK added predictive information to NGAL for detecting kidney dysfunction (added χ (2) 10.0, p = 0.0016). Admission pro-ENK outperformed creatinine clearance in predicting 7-day mortality (pro-ENK: χ (2) 13.4, p 0.001, area under curve, AUC 0.69; creatinine clearance: χ (2) 4, p = 0.045, AUC: 0.61), and serial measurement improved prediction.Use of pro-ENK in septic patients can detect the presence and severity of AKI. Moreover, pro-ENK is highly predictive of short-term mortality and could enable early identification of patients at risk of death.

This paper presents an advanced road course prediction algorithm focusing on longer distances. It shows how to simply combine the different sensors available in modern cars for a road course estimation task. Concretely, a digital-map-based estimation is fused with an optical lane recognition system. Both sensors are evaluated on a representative subset of test sequences to characterize their measurement uncertainties. Then a Bayesian fusion system combines the advantages of the single sensors. Extensive evaluations with high precision ground truth data demonstrate the feasibility of this approach.

Detecting the road geometry at night time is an essential precondition to provide optimal illumination for the driver and the other traffic participants. In this paper we propose a novel approach to estimate the current road curvature based on three sensors: A far infrared camera, a near infrared camera and an imaging radar sensor. Various Convolutional Neural Networks with different configuration are trained for each input. By fusing the classifier responses of all three sensors, a further performance gain is achieved. To annotate the training and evaluation dataset without costly human interaction a fully automatic curvature annotation algorithm based on inertial navigation system is presented as well.

The purpose of this study was to assess the impact of atrial fibrillation (AF) on the performance of mid-region amino terminal pro-atrial natriuretic peptide (MR-proANP) in comparison with the B-type peptides (BNP and NT-proBNP) for diagnosis of acute heart failure (HF) in dyspneic patients.The effects of AF on the diagnostic and prognostic performance of MR-proANP in comparison with the B type natriuretic peptides have not been previously reported.A total of 1,445 patients attending the emergency department with acute dyspnea had measurements taken of MR-proANP, BNP, and NT-proBNP values on enrollment to the BACH trial and were grouped according to presence or absence of AF and HF.AF was present in 242 patients. Plasma concentrations of all three peptides were lowest in those with neither AF nor HF and AF without HF was associated with markedly increased levels (p0.00001). HF with or without AF was associated with a significant further increment (p0.00001 for all three markers). Areas under receiver operator characteristic curves (AUCs) for discrimination of acute HF were similar and powerful for all peptides without AF (0.893 to 0.912; all p0.001) with substantial and similar reductions (0.701 to 0.757) in the presence of AF. All 3 peptides were independently prognostic but there was no interaction between any peptide and AF for prediction of all-cause mortality.AF is associated with increased plasma natriuretic peptide (MR-proANP, BNP and NT-proBNP) levels in the absence of HF. The diagnostic performance of all three peptides is impaired by AF. This warrants consideration of adjusted peptide thresholds for diagnostic use in AF and mandates the continued search for markers free of confounding by AF.

For object detection in monocular images, the Boosted Cascade [1] has become the standard approach for driver assistance systems. This paper studies the discriminative power of different features for common automotive object detection tasks: pedestrian and vehicle detection using infrared cameras at night, as well as pedestrian and vehicle detection in daylight conditions. It is shown that the use of intra-stage information propagation with Activation History Features (AHFs) [2] significantly speeds up the detection at the same detection rate. Thus, AHFs offer a speedup at no cost.

Rationale Stroke-associated pneumonia is one of the most common causes of poor outcome in stroke patients. Clinical signs and laboratory parameters of stroke-associated infections are often inconclusive. Biomarkers may help to identify stroke patients at high risk for pneumonia and to guide physicians in an early antibiotic treatment, thereby improving stroke outcome. Aim The aim of the present study is to investigate whether procalcitonin ultrasensitive-guided antibiotic treatment improves functional outcome after severe ischaemic stroke by early treatment of pneumonia. Design STRAWINSKI is an investigator-initiated, multicentre, randomized, controlled trial with blinded assessment of outcome comparing procalcitonin ultrasensitive-guided antibiotic treatment with standard care. Study 200 patients with ischaemic stroke in the middle cerebral artery territory and a score >9 on the National Institutes of Health Stroke Scale will be included and randomly assigned to two groups. One group will receive procalcitonin-based antibiotic therapy guidance; the other group will receive standard stroke unit care. Outcomes The primary endpoint is functional outcome at day 90 after stroke on the modified Rankin Scale, dichotomized as favourable (0–4) or unfavourable outcome ( 5 ,– 6 ). Secondary endpoints are time to first event of death, rehospitalization, or recurrent stroke; death rate, infection rate, and days with fever up to day 7; length of hospital stay and hospital discharge disposition; shift analysis of the modified Rankin Scale; Barthel Index and days alive and out of hospital at day 90; use of antibiotics until day 90; and modified Rankin Scale, Barthel Index, and infarct volume at day 180.

To assess the value of mid-regional pro-adrenomedullin (MR-proADM) in guiding patient disposition from the emergency department (ED), as one of the key factors of hospital resource utilisation, in undifferentiated patients with acute dyspnoea.We used clinical and outcome data from a large international biomarker study (BACH trial) and analysed data of all 1557 patients of the European and US sites presenting with acute dyspnoea. Patients were discharged or transferred from the ED to different levels of care (general ward, monitoring unit, intensive care unit). This original patient disposition was compared with the hypothetical disposition based on an adapted method of net reclassification improvement (NRI), which upgraded or downgraded patients from one level of care to the other based on the MR-proADM test result.MR-pro-ADM was significantly higher in patients who died during the follow-up than in survivors (p0.0001). When applying the adapted NRI model, 30 additional patients from the European Union (EU) and 55 additional patients from USA were theoretically discharged (increase of 16.5%) if MR-proADM had been used for patient management. The overall NRI, adding up the rates of upgrades and downgrades, in the EU was 16.0% (95% CI 8.2% to 23.9%). A total of n=72 (9.9%) patients changed disposition when adding MR-pro ADM. In the USA, the overall NRI was 12.0% (5.7%-18.4%) and a total of n=81 (11.2%) patients changed disposition.MR-proADM has the potential to guide initial disposition of undifferentiated ED patients with acute dyspnoea and might therefore be helpful to improve resource utilisation and patient care.

Rapid and reliable exclusion of acute myocardial infarction during emergency department triage is an important clinical need. The purpose of this study was to evaluate the potential role of copeptin, a marker of acute endogenous stress, together with high sensitive troponin-I for a rapid and early rule-out of acute myocardial infarction.Copeptin and myoglobin were measured in 80 subjects presenting to the emergency department with chest pain and symptoms suggestive of acute myocardial infarction, 46 patients had a negative high sensitive troponin-I concentration at presentation, 3, 6 and 12 hours; whereas 34 patients had negative or very low high sensitive troponin-I at presentation, but rising troponin values at 3, 6 and 12 hours.Copeptin was significantly higher in patients with evidence of myocardial damage (median 92.2 pmol/L vs 8.5 pmol/L, p0.0001). The area under the receiver-operating characteristic curve (AUC) for copeptin at initial presentation was 0.86 (95 % confidence interval, CI: 0.76 to 0.93), which was significantly higher than 0.68 (95% CI: 0.57 to 0.78, p0.05) for myoglobin but not significantly different from 0.88 (95% CI: 0.79 to 0.93) for high sensitive troponin-I. The combination of high sensitive troponin-I and copeptin resulted in an AUC of 0.94 (95% CI: 0.86 to 0.98), while the combination of high sensitive troponin-I and myoglobin results in an AUC of 0.89 (95% CI: 0.81 to 0.95).Copeptin concentrations are more sensitive than myoglobin as an early marker of myocardial damage. Although copeptin provides significant incremental value on top of high sensitivity troponin-I, myoglobin does not.

Background C-terminal portion of provasopressin (copeptin) has recently been discussed as a novel biomarker for the early rule-out of acute myocardial infarction (AMI). The aim is to investigate the prognostic value of copeptin with regard to mortality and morbidity in patients with symptomatic coronary artery disease (CAD). Methods We consecutively recruited a cath lab cohort of 2,700 patients (74.1% male; AMI, n=1316; stable angina pectoris, n=1384) presenting to the emergency department of a large primary care hospital. All patients received coronary angiography. Copeptin and other laboratory markers were sampled at the time of presentation or in the cath lab. Clinical outcomes were assessed by hospital chart analysis and telephone interviews. 2621 patients (97.1%) have been successfully followed-up at three months. The primary endpoint was a combined endpoint of rehospitalization for cardiovascular events, stroke, and all-cause death. Results Using receiver operating characteristic curves, we calculated areas under the curve of 0.703 (95%confidence interval(CI):0.681–0.725) for the composite endpoint after three months (myocardial reinfarction, stroke, all-cause death;n=183), and 0.770 (95%CI:0.736–0.803) for all-cause death (n=76) for copeptin. A cutoff value of 21.6pmol/L for the composite endpoint yielded a sensitivity of 56.3% and a specificity of 78.6%. The predictive performance of copeptin was independent of other clinical variables or cardiovascular risk factors, and superior to that of troponin I or other cardiac biomarkers (all:P Conclusions Copeptin may help in the prediction of major adverse cardiovascular events in patients with symptomatic CAD. Further studies should substantiate the findings and support the suggested cutoff value of the present study.

Patients presenting to emergency departments (ED) with nonspecific complaints (NSCs) such as "not feeling well,""feeling weak,""being tired,""general deterioration," or other similar chief complaints that do not have a readily identifiable probable etiology are a common patient group at risk for adverse outcomes. Certain biomarkers, which have not yet been tested for prognostic value when applied to ED patients with NSCs, have emerged as useful tools for predicting prognosis in patients with a variety of diseases. This study tested the hypothesis that two of these novel markers, copeptin (a C-terminal portion of provasopressin) and/or peroxiredoxin-4 (Prx4), an enzyme that degrades hydrogen peroxide, singly or together are helpful in predicting death in the near term among patients presenting to the ED with NSCs.The Basel Non-specific Complaints (BANC) study is a delayed type cross-sectional diagnostic study with a prospective 30-day follow-up. ED patients with NSCs were consecutively enrolled. Patients with vital parameters out of the normal range were excluded. The primary endpoint of this study was the predictive value of copeptin and Prx4 for 30-day mortality in patients with NSCs. Measurement of both copeptin and Prx4 was performed in serum samples with sandwich immunoluminometric assays.On follow-up at 30 days after ED presentation, 28 of 438 patients with NSC had died. Copeptin and Prx4 concentrations were significantly higher in nonsurvivors than in survivors (Kruskal-Wallis test, p = 0.0001 and p0.0001, respectively). In univariate models, Prx4 (likelihood ratio [LR] χ(2) = 22.24, p0.00001, concordance index [C-index] = 0.749) and copeptin (LR χ(2) = 16.98, p = 0.00004, C-index = 0.724) were both predictive of 30-day mortality, and elevated levels were associated with an increased mortality. The bivariable model, which included both Prx4 and copeptin (LR χ(2) = 28.22, p0.00001, C-index = 0.783), allows a significantly better prediction than the univariate Prx4 (p = 0.00025) and copeptin models (p = 0.00099), respectively. Both biomarkers provided independent and additional information to clinical risk scores (Katz Activities of Daily Living [ADL] and Charlson Comorbidity Index [CCI], all p0.0005).Copeptin and Prx4 are new prognostic markers in patients presenting to the ED with NSCs. Copeptin and Prx4 might be valuable tools for risk stratification and decision-making in this patient group.

Social search platforms like Aardvark or Yahoo Answers have attracted a lot of attention lately. In principle, participants have two strategic dimensions in social search systems: (1) Interaction selection, i.e., forwarding/processing incoming requests (or not), and (2) contact selection, i.e., adding or dropping contacts. In systems with these strategic dimensions, it is unclear whether nodes cooperate, and if they form efficient network structures. To shed light on this fundamental question, we have conducted a study to investigate human behavior in interaction selection and to investigate the ability of humans to form efficient networks. In order to limit the degree of problem understanding necessary by the study participants, we have introduced the problem as an online game. 193 subjects joined the study that was online for 67 days. One result is that subjects choose contacts strategically and that they use strategies that lead to cooperative and almost efficient systems. Surprisingly, subjects tend to overestimate the value of cooperative contacts and keep cooperative but costly contacts. This observation is important: Assisting agents that help subjects to avoid this behavior might yield more efficiency.

Objective: Development of biomarkers for early detection of Alzheimer's disease (AD) is a major clinical research goal. On the basis of the hypothesis that cardiovascular risk factors contribute to the pathogenesis of AD, we investigated whether the cardiovascular risk markers midregional proadrenomedullin (MR-proADM) and midregional proatrial natriuretic peptide (MR-proANP) predict a major clinical milestone, ie, conversion from predementia mild cognitive impairment (MCI) to manifest AD. Method: A group of 134 MCI patients, among 137 originally prospectively recruited at the memory disorder clinic at Malmo University Hospital, Malmo, Sweden, between July 1998 and June 2001, was clinically followed for 4-6 years. We determined whether plasma concentrations of MR-proADM and MR-proANP at baseline predicted time to conversion from MCI to clinically diagnosed AD (DSM-III-R). MCI was diagnosed according to Petersen criteria. Results: During follow-up, 41.8% of MCI patients remained cognitively stable, 42.5% converted to possible and probable AD, and 15.7% converted to other forms of dementia (MCI-other). MCI converters and MCI-other patients showed increased concentrations of MR-proANP and MR-proADM compared to the stable MCI patients (P=.0001). At a cutoff of 87 pmol/L, MR-proANP yielded a sensitivity of 73.7% and a specificity of 64.3% for predicting conversion to All. The survival analysis showed that higher values of MR-proANP and MR-proADM were associated with progression to AD. In a multivariate Cox regression model including known risk factors, MR-proANP and MR-proADM remained independent risk factors for conversion to AD for patients below the age of 72 years. Conclusions: Our study shows that plasma concentrations of MR-proANP and MR-proADM have predictive value in the progression from predementia MCI to clinical AD. Sensitivity was particularly high, which may recommend this test for first-stage screening in patients at risk for AD. J Clin Psychiatry 2011;72(4): 556-563 (C) Copyright 2010 Physicians Postgraduate Press, Inc. (Less)

Few tools exist that provide objective accurate prediction of short-term mortality risk in patients presenting with acute heart failure (AHF). The purpose was to describe the accuracy of several biomarkers for predicting short-term death rates in patients diagnosed with AHF in the emergency department (ED).The Biomarkers in ACute Heart failure (BACH) trial was a prospective, 15-center, international study of patients presenting to the ED with nontraumatic dyspnea. Clinicians were blinded to all investigational markers, except troponin and natriuretic peptides, which used the local hospital reference range. For this secondary analysis, a core lab was used for all markers except troponin. This study evaluated patients diagnosed with AHF by the on-site emergency physician (EP).In the 1,641 BACH patients, 466 (28.4%) had an ED diagnosis of AHF, of whom 411 (88.2%) had a final diagnosis of AHF. In the ED-diagnosed HF patients, 59% were male, 69% had a HF history, and 19 (4.1%) died within 14 days of their ED visit. The area under the curve (AUC) for the 14-day mortality receiver operating characteristic (ROC) curve was 0.484 for brain natriuretic peptide (BNP), 0.586 for N-terminal pro-B-type natriuretic peptide (NT-proBNP), 0.755 for troponin (I or T), 0.742 for adrenomedullin (MR-proADM), and 0.803 for copeptin. In combination, MR-proADM and copeptin had the best 14-day mortality prediction (AUC = 0.818), versus all other markers.MR-proADM and copeptin, alone or in combination, may provide superior short-term mortality prediction compared to natriuretic peptides and troponin. Presented results are explorative due to the limited number of events, but validation in larger trials seems promising.

Hypertension is a major risk factor of Alzheimer's disease (AD); however, controlled studies on the effect of antihypertensive treatment on the risk of dementia are inconclusive. Therefore, a biological marker that predicts individual response to antihypertensive treatment would be of high clinical relevance. Midregional proatrial natriuretic peptide (MR-proANP), an inactive surrogate molecule of the mature atrial natriuretic peptide, is related to circulatory function and hypertension.A sample population of 134 subjects with mild cognitive impairment (MCI) was followed for up to 6 years. Multivariable Cox regression analysis was conducted to predict conversion to AD based on all relevant variables.Baseline MR-proANP was significantly increased in the AD converter group (p.0001). The conversion rate of patients treated with antihypertensive drugs was significantly reduced only in patients with elevated MR-proANP at baseline (p = .046). Using an optimized MR-proANP cutoff of 74 pmol/L, representing a value in the upper normal range, treatment with antihypertensive drugs reduced the conversion rate to AD by 36% (p = .035) for patients with levels74 pmol/L. Further subgrouping by age (/≤ 72 years at baseline) increased the positive correlation of antihypertensive treatment and MCI outcome for patients below the age of 72 years (conversion rate reduced by 74%, p = .016).These data seem to support the notion of a potential impact of circulatory function for the prognosis of AD at a prodromal stage. The MR-proANP levels may be useful to predict the effect of antihypertensive treatment on conversion rates to AD in subjects with MCI.

Social network analysis (SNA) has attracted a lot of attention over the past years. Existing tools for SNA do not allow a user-centric analysis of the social neighborhood, i.e., the subgraph of the user's friends and friends of a friend. In this paper, we introduce SONAR, an open source Web application for user-centric SNA. Its extensible architecture and flexible data model allows developers to embed SONAR directly into social networking websites. A performance evaluation shows that our application scales well with the number of users and adds only minimal overhead to the SNA algorithms.

Iron is an indispensable element of hemoglobin, myoglobin, and cytochromes, and, beyond erythropoiesis, is involved in oxidative metabolism and cellular energetics. Hence, iron deficiency (ID) is anticipated to limit exercise capacity. We investigated whether ID predicted exercise intolerance in patients with systolic chronic heart failure (CHF).We prospectively studied 443 patients with stable systolic CHF (age 54 ± 10 years, males 90%, ejection fraction 26 ± 7%, New York Heart Association Class I/II/III/IV 49/188/180/26). ID was defined as: serum ferritin100 μg/L or serum ferritin 100-300 μg/L with serum transferrin saturation20%. Exercise capacity was expressed as peak oxygen consumption (VO(2)) and ventilatory response to exercise (VE-VCO(2) slope). ID was present in 35 ± 4% (±95% confidence interval) of patients with systolic CHF. Those with ID had reduced peak VO(2) and increased VE-VCO(2) slope as compared to subjects without ID (peak VO(2): 13.3 ± 4.0 versus 15.3 ± 4.5 mL•min•kg, VE-VCO(2) slope: 50.9 ± 15.8 versus 43.1 ± 11.1, respectively, both P.001, P.05). In multivariable models, the presence of ID was associated with reduced peak VO(2) (β = -0.14, P.01 P.05) and higher VE-VCO(2) slope (β = 0.14, P.01 P .05), adjusted for demographics and clinical variables. Analogous associations were found between serum ferritin, and both peak VO(2) and VE-VCO(2) slope (P.05).ID independently predicts exercise intolerance in patients with systolic CHF, but the strength of these associations is relatively weak. Whether iron supplementation would improve exercise capacity in iron-deficient subjects requires further studies.

Several new biomarkers are related to mortality in community-acquired pneumonia (CAP).Aim of this study was to compare new biomarkers for the prediction of short- and long-term all-cause mortality in CAP.We enrolled 728 patients (59.0 ± 18.2 yr) with CAP. Midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), proarginin-vasopressin (copeptin), proendothelin-1 (CT-proET-1), procalcitonin (PCT), C-reactive protein, white blood cell (WBC) count, and clinical confusion, respiratory rate, blood pressure, and age over 65 years (CRB-65) score were determined on admission. Patients were followed up for 180 days.In patients who died of any cause within 28 and 180 days (2.5 and 5.1%, respectively), MR-proADM, MR-proANP, copeptin, CT-proET-1 and PCT as well as CRB-65 were significantly higher compared with survivors. MR-proADM had the best performance for 28 days (HR 3.67) and 180 days (HR 2.84) survival. The C index of MR-proADM for 28-day survival (0.85) was superior to MR-proANP (0.81), copeptin (0.78), CT-proET-1 (0.79), and CRB-65 (0.72) for the prediction of mortality. For prediction of mortality at 180 days, the C index of MR-proADM (0.78) was higher than that for MR-proANP (0.74), copeptin (0.73), CT-proET-1 (0.76), PCT, C-reactive protein, and white blood cells. MR-proADM was independent of CRB-65, and added prognostic information for short- and long-term mortality. MR-proADM was an independent and strong predictor of short- and long-term mortality.All new biomarkers were good predictors of short- and long-term all-cause mortality, superior to inflammatory markers, and at least comparable to CRB-65 score. MR-proADM showed the best performance. A combination of CRB-65 with MR-proADM might be the best predictor for mortality.

ObjectivesWe hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP).MethodsWe examined 491 patients with systolic CHF (age: 63±11 years, 91% men, New York Heart Association [NYHA] class [I/II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology). Plasma CT-proET-1 was detected using a chemiluminescence immunoassay.ResultsIncreasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04-1.95, p = 0.03) after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF), age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40). Both NT-proBNP and CT-proET-1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (pConclusionsPlasma CT-proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes.

Increasing worldwide development of antimicrobial resistance and the association of resistance development and antibiotic overuse make it necessary to seek strategies for safely reducing antibiotic use and selection pressure. In a first step, in a non-interventional study, the antibiotic prescription rates, initial procalcitonin (PCT) levels and outcome of 702 patients presenting with acute respiratory infection at 45 primary care physicians were observed. The second part was a randomised controlled non-inferiority trial comparing standard care with PCT-guided antimicrobial treatment in 550 patients in the same setting. Antibiotics were recommended at a PCT threshold of 0.25 ng·mL −1 . Clinical overruling was permitted. The primary end-point for non-inferiority was number of days with significant health impairment after 14 days. Antibiotics were prescribed in 30.3% of enrolled patients in the non-interventional study. In the interventional study, 36.7% of patients in the control group received antibiotics as compared to 21.5% in the PCT-guided group (41.6% reduction). In the modified intention-to-treat analysis, the numbers of days with significant health impairment were similar (mean 9.04 versus 9.00 for PCT-guided and control group, respectively; difference 0.04; 95% confidence interval -0.73–0.81). This was also true after adjusting for the most important confounders. In the PCT group, advice was overruled in 36 cases. There was no significant difference in primary end-point when comparing the PCT group treated as advised, the overruled PCT group and the control group (9.008 versus 9.250 versus 9.000 days; p = 0.9605). A simple one-point PCT measurement for guiding decisions on antibiotic treatment is non-inferior to standard treatment in terms of safety, and effectively reduced the antibiotic treatment rate by 41.6%.

Aims The aim of the present study was to compare the prognostic value of a novel and promising marker, copeptin, with B-type natriuretic peptide (BNP), and N-terminal pro-BNP (NT-proBNP), on death or a composite cardiovascular endpoint in patients who developed heart failure after an acute myocardial infarction (AMI). Methods and results From a subset of 224 patients of the OPTIMAAL study, blood samples were drawn at a mean of 3 days after AMI when all patients had signs and/or symptoms of heart failure or a left ventricular ejection fraction

Purpose: We have shown that DNA methylation of the PITX2 gene predicts risk of distant recurrence in steroid hormone receptor-positive, node-negative breast cancer. Here, we present results from a multicenter study investigating whether PITX2 and other candidate DNA methylation markers predict outcome in node-positive, estrogen receptor-positive, HER-2-negative breast cancer patients who received adjuvant anthracycline-based chemotherapy. Experimental Design: Using a microarray platform, we analyzed DNA methylation in regulatory regions of PITX2 and 60 additional candidate genes in 241 breast cancer specimens. Using Cox regression analysis, we assessed the predictive power of the individual marker/marker panel candidates. Clinical endpoints were time to distant metastasis, disease-free survival, and overall survival. A nested bootstrap/cross-validation strategy was applied to identify and validate marker panels. Results: DNA methylation of PITX2 and 14 other genes was correlated with clinical outcome. In multivariate models, each methylation marker added significant information to established clinical factors. A four-marker panel including PITX2, BMP4, FGF4, and C20orf55 was identified that resulted in improvement of outcome prediction compared with PITX2 alone. Conclusions: This study provides further evidence for the PITX2 biomarker, which has now been successfully confirmed to predict outcome among different breast cancer patient populations. We further identify new DNA methylation biomarkers, three of which can be combined into a panel with PITX2 to increase the outcome prediction performance in our anthracycline-treated primary breast cancer population. Our results show that a well-defined panel of DNA methylation markers enables outcome prediction in lymph node-positive, HER-2-negative breast cancer patients treated with anthracycline-based chemotherapy.