Do we need another heart failure biomarker. focus on soluble suppression of tumorigenicity 2 (sST2)

If sST2 indeed turns into the HbA1c of heart failure, its value should increase exponentially in our management of patients with heart failure. Serial sST2 levels should allow us to titrate therapy and monitor the clinical state of the patient. In addition, since sST2 is such a strong marker of the risk of death, it would not be surprising to see a level be used to make decisions when patients are on the cusp of such therapies as ICD, CRT, CardioMems implantation and even left ventricular assist devices. A discussion about the use of biomarkers would not be complete without mentioning the issue of surrogates for determining the therapy effectiveness of some of the newer heart failure drugs. Novartis’s EntrestoVR , the brand name for its recently CE marked and FDA approved ARNI1 drug (previously known as LCZ696) and Servier’s ivabradine drug CorlanorVR (marketed by Amgen in the USA), also CE marked and FDA approved, while offering exciting potential benefits to heart failure patients—even being hailed ‘game-changer’ drugs by some—raises the thorny issue of cost vs. benefit. These new drugs are several times the cost of the generics that have become the mainstay of heart failure treatment, i.e. ACE inhibitors, angiotensin receptor blocker (ARBs), beta-blockers, etc. Pushback is therefore expected from payers. Because sST2 changes rapidly with the underlying condition of the patient, is not affected by normal confounding factors, and has a single cut point, it may be ideally suited to help clinicians determine if these newer mediations are effective for each patient, are improving quality of life, and whether dosing needs to be titrated or changed. The new reality of heart failure care is that while more treatment options have opened up, which can literally be a lifesaver for millions of patients, the burden on healthcare systems has skyrocketed. Biomarkers, and particularly sST2, could offer physicians and payers a way to bring treatment down to an individual patient level, providing

ST2 in Stable and Unstable Ischemic Heart Diseases

Circulating suppression of tumorigenicity 2 (ST2) predicts cardiovascular outcomes and mortality in ischemic heart disease (IHD). ST2 does not correlate with traditional risk indicators as closely as N-terminal pro–brain natriuretic peptide (NT-proBNP) and is only weakly correlated with other biomarkers, indicating distinct pathways for stimulus and release. Although of little diagnostic utility in IHD, ST2 does offer prognostic information. In ST elevation myocardial infarction, ST2 levels increase to peak above the normal reference range (within 6 to 18 hours of symptom onset) in about half of patients. Levels in the upper quartile observed in IHD independently predict cardiovascular death and heart failure with an approximate doubling of risk. Similar but weaker associations have been reported in non–ST elevation myocardial infarction, in which ST2 predicts short-term (30-day) and long-term (>1-year) death and heart failure independent of clinical indicators, but these relations are lost if Global Registry of Acute Coronary Events (GRACE) score and NT-proBNP are added to multivariate models. Early postinfarction levels of ST2 (i.e., <24 hours after admission) have the greatest prognostic utility. Early postinfarction ST2 levels and change over 24 weeks are related to infarct extent and remodeling to a similar extent as NT-proBNP and aldosterone, and ST2 may have a significant pathophysiological role in these postinfarction processes. In long-term follow-up of stable IHD, ST2 is predictive of all-cause and cardiovascular mortality independent of accepted clinical indicators and other biomarkers, including NT-proBNP, high-sensitivity C-reactive protein, interleukin-6, high-sensitivitiy cardiac troponin T, and galectin-3. In conclusion, ST2 in combination with NT-proBNP consistently improves risk stratification compared with either marker alone

GM-CSF and IL-3 Modulate Human Monocyte TNF-A Production and Renewal in In Vitro Models of Trained Immunity

GM-CSF and IL-3 are hematopoietic cytokines that modulate the effector functions of several immune cell subsets. In particular, GM-CSF and IL-3 exert a significant control on monocyte and macrophage effector functions, as assessed in experimental models of inflammatory and autoimmune diseases and in human studies. Here we sought to investigate the mechanisms and the extent to which GM-CSF and IL-3 modulate the pro-inflammatory, LPS-mediated, activation of human CD14+ monocytes taking into account the new concept of trained immunity (i.e. the priming stimulus modulates the response to subsequent stimuli mainly by enhancing immune activation status). We demonstrate that GM-CSF and IL-3 priming enhances TNF-α production upon subsequent LPS stimulation (short-term model of trained immunity) in a p38- and SIRT2-dependent manner without increasing TNF mRNA or primary transcript levels (a more direct measure of transcription), thus supporting a post-transcriptional regulation of TNF- α in primed monocytes. GM-CSF and IL-3 priming followed by 6 days of resting also results in increased TNF-α production upon LPS stimulation (long-term model of trained immunity). In this case, however, GM-CSF and IL-3 priming induces a c-Myc-dependent monocyte renewal and increase in cell number that is in turn responsible for heightened TNF-α production. Overall, our results provide insights to understand the biology of monocytes in health and disease conditions in which the hematopoietic cytokines GM-CSF and IL-3 play a role and also extend our knowledge of the cellular and molecular mechanisms of trained immunity

La carta naturale e culturale del Parco Nazionale del Gran Sasso e Monti della Laga

Lo scopo del seguente lavoro è la costruzione di un GeoDataBase relativo ai beni culturali ed ambientali del Parco Nazionale del Gran Sasso e Monti della Laga attraverso un approccio neogeografico. Il lavoro è organizzato in tre fasi: nella prima fase è stato necessario eseguire un’analisi bibliografica ed inventariale per identificare le evidenze culturali ed ambientali del Parco. È stata poi determinata una tassonomia, articolata in sette categorie e ventitré sotto categorie, sulla base delle direttive dei vari consigli d’Europa riguardanti il patrimonio culturale che si sono susseguiti dagli anni Sessanta ad oggi e sulle raccomandazioni internazionali dell’UNESCO. Infine sono stati rilevati sul campo i beni inizialmente inventariati e, una volta riconosciuti, è avvenuta la creazione del GeoDataBase (GDB), l’assegnazione della categoria tassonomica di appartenenza ad ogni singolo elemento e la rappresentazione cartografica.The aim of this study is to create a natural and cultural map related to the environmental and historical heritage of Gran Sasso and Monti della Laga National Park through a neogeographical approach. The study has been divided into three phases: for the first phase, in order to spot the Park’s peculiarities, it was necessary to make a bibliographic and stock-list analysis of the Park which lead to classification of seven categories and twenty-three under-categories taxonomy, based on data Unesco international advises as well as from the EU’s guidelines over Europe’s cultural heritage from the 60’s to these days. Finally stock-listed materials have been detected and it was possible to build a GDB and to allocate the correct taxonomy to each element which have been then represented on cartographic graph

An Update of Armamentarium for Non Invasive Cardiac Haemodynamics and Congestion Evaluation for Acute Heart Failure Patients

In the management of Acute Heart Failure(AHF) patients ,current guidelines  suggest  to make a prompt  clinical assessments that include  patient’s congestion and perfusion status evaluation, in order to  start appropriate treatments. Unfortunately ,so far, an accurate evaluation of haemodynamic and fluid status of AHF patients is only possible using invasive methods ;conseguently there is an unmeet need for noninvasive technologies to easly detect  different phenotypes of AHF subjects based on different cardiac haemodynamic profiles . Technological advances such as: Biva,Nexfin or NICas   could  allow for routine noninvasive continuous monitoring of Cardiac Hemodymanics and Fluid content in Acute Heart Failure patients. These  non invasive measurements may provide important information  for improving diagnosis, developing individualized therapeutic management plans/disposition decisions and predicting short term mortalit

The impact of impaired self-awareness on the assessment of fatigue and rehabilitation in brain injury

This portfolio thesis involves three parts. Part one includes a systematic literature review, part two includes an empirical paper and part three includes the appendices. Part one- Systematic Literature Review The Systematic Literature Review explored the impact of impaired self-awareness (ISA) on the process of rehabilitation in acquired brain injury populations. This review identified 16 studies which were analysed using Narrative Synthesis. Four key themes arose from the analysis, including goal setting, treatment adherence, engagement and willingness to change and time spent in hospital. The findings explored the impact that ISA can have on different areas of the rehabilitation process and how this can impact on recovery. The clinical implications and areas for further research are described. Part two- Empirical Paper The empirical paper is part of a larger project to validate and explore the Brain Injury Fatigue Scale (BIFS). The BIFS is an unpublished measure of fatigue that is widely used in clinical practice. This study investigated the degree of agreement between the self and proxy (i.e., carer/relative/friend) ratings of the BIFS and explored what variables best predict any differences in scores, including level of awareness and patients’ mood. Eleven individuals with acquired brain injuries (ABI) or neurological conditions and their proxies completed the BIFS and Patient Competency Rating Scale (PCRS). Patients also completed the Hospital Anxiety and Depression Scale (HADS) and their demographic data was collected. This study found that that 63.64% of patients rated their fatigue within the same clinical cut off category as their proxies’ ratings. It was also found that ISA and mood did not predict BIFS-Discrepancy scores. This study therefore found a moderate level of agreement between patient and proxy BIF ratings; however, it also emphasises the importance of using proxy ratings scales within this area, which has not previously been explored. Further self and proxy ratings of fatigue is required. Part three- Part three includes the appendices relating to the systematic literature review and the empirical paper, as well as the epistemological and reflective statements

Circulating Biologically Active Adrenomedullin Predicts Organ Failure and Mortality in Sepsis

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Biologically active adrenomedullin (bio-ADM) is an emerging biomarker for sepsis. We explored whether bio-ADM concentration could predict severity, organ failure, and 30-day mortality in septic patients. METHODS: In 215 septic patients (109 patients with sepsis; 106 patients with septic shock), bio-ADM concentration was measured at diagnosis of sepsis, using sphingotest bio-ADM (Sphingotec GmbH, Hennigsdorf, Germany) and analyzed in terms of sepsis severity, vasopressor use, and 30-day mortality. The number of organ failures, sequential (sepsis-related) organ failure assessment (SOFA) score, and 30-day mortality were compared according to bio-ADM quartiles. RESULTS: Bio-ADM concentration was significantly higher in patients with septic shock, vasopressor use, and non-survivors than in patients with solitary sepsis, no vasopressor use, and survivors, respectively (all P&lt;0.0001). Bio-ADM quartiles were associated with the number of organ failures (P&lt;0.0001), as well as SOFA cardiovascular, renal, coagulation, and liver subscores (all P&lt;0.05). The 30-day mortality rate showed a stepwise increase in each bio-ADM quartile (all P&lt;0.0001). Bio-ADM concentration and SOFA score equally predicted the 30-day mortality (area under the curve: 0.827 vs 0.830). CONCLUSIONS: Bio-ADM could serve as a useful and objective biomarker to predict severity, organ failure, and 30-day mortality in septic patients

Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis

Introduction: The incidence of death among patients admitted for severe sepsis or septic shock is high. Adrenomedullin (ADM) plays a central role in initiating the hyperdynamic response during the early stages of sepsis. Pilot studies indicate an association of plasma ADM with the severity of the disease. In the present study we utilized a novel sandwich immunoassay of bioactive plasma ADM in patients hospitalized with sepsis in order to assess the clinical utility.Methods: We enrolled 101 consecutive patients admitted to the emergency department with suspected sepsis in this study. Sepsis was defined by fulfillment of at least two systemic inflammatory response syndrome (SIRS) criteria plus clinical suspicion of infection. Plasma samples for ADM measurement were obtained on admission and for the next four days. The 28-day mortality rate was recorded.Results: ADM at admission was associated with severity of disease (correlation with Acute Physiology and Chronic Health Evaluation II (APACHE II) score: r = 0.46; P &lt;0.0001). ADM was also associated with 28-day mortality (ADM median (IQR): survivors: 50 (31 to 77) pg/mL; non-survivors: 84 (48 to 232) pg/mL; P &lt;0.001) and was independent from and additive to APACHE II (P = 0.02). Cox regression analysis revealed an additive value of serial measurement of ADM over baseline assessment for prediction of 28-day mortality (P &lt; 0.01). ADM was negatively correlated with mean arterial pressure (r = -0.39; P &lt;0.0001), and it strongly discriminated those patients requiring vasopressor therapy from the others (ADM median (IQR): no vasopressors 48 (32 to 75) pg/mL; with vasopressors 129 (83 to 264) pg/mL, P &lt;0.0001).Conclusions: In patients admitted with sepsis, severe sepsis or septic shock plasma ADM is strongly associated with severity of disease, vasopressor requirement and 28-day mortality

Rationale and study design of intravenous loop diuretic administration in acute heart failure. DIUR-AHF

Aims: Although loop diuretics are the most commonly used drugs in acute heart failure (AHF) treatment, their short-term and long-term effects are relatively unknown. The significance of worsening renal function occurrence during intravenous treatment is not clear enough. This trial aims to clarify all these features and contemplate whether continuous infusion is better than an intermittent strategy in terms of decongestion efficacy, diuretic efficiency, renal function, and long-term prognosis. Methods and results: This is a prospective, multicentre, randomized study that compares continuous infusion to intermittent infusion and a low vs. high diuretic dose of furosemide in patients with a diagnosis of acute heart failure, BNP ≥ 100 pg/mL, and specific chest X-ray signs. Randomization criteria have been established at a 1:1 ratio using a computer-generated scheme of either twice-daily bolus injection or continuous infusion for a time period ranging from 72 to 120 h. The initial dose will be 80 mg/day of intravenous furosemide and, in the case of poor response, will be doubled using an escalation algorithm. A high diuretic dose is defined as a furosemide daily amount >120 mg/day respectively. Conclusions: Continuous and high dose groups could reveal a more intensive diuresis and a greater decongestion with respect to intermittent and low dose groups; high dose and poor loop diuretic efficiency should be related to increased diuretic resistance, renal dysfunction occurrence, and greater congestion status. Poor diuretic response will be associated with less decongestion and an adverse prognosis

Soluble suppression of tumorigenicity 2 and echocardiography in sepsis

Soluble suppression of tumorigenicity 2 (sST2) has emerged as a biomarker of cardiac stretch or remodeling, and has demonstrated a role in acutely decompensated heart failure. However, its role in sepsis-induced cardiac dysfunction is still unknown. We explored whether sST2 serum concentration reflects either systolic or diastolic dysfunction as measured by Doppler echocardiography. In a total of 127 patients with sepsis, correlations between sST2 and blood pressure, left ventricular (LV) ejection fraction, LV diastolic filling (ratio of early transmitral flow velocity to early diastolic mitral annulus velocity), and resting pulmonary arterial pressure were evaluated. Correlations between sST2 and other sepsis biomarkers (high-sensitivity C-reactive protein [hs-CRP] and procalcitonin) were also examined. sST2 showed a moderate correlation with mean arterial pressure (r=-0.3499) but no correlation with LV ejection fraction, diastolic filling, or resting pulmonary hypertension. It showed moderate correlations with hs-CRP and procalcitonin (r=0.2608 and r=0.3829, respectively). sST2 might have a role as a biomarker of shock or inflammation, but it cannot reflect echocardiographic findings of LV ejection fraction or diastolic filling in sepsis