International variation in invasive care of the elderly with acute coronary syndromes

Aims To explore variations in invasive care of the elderly with acute coronary syndromes across international practice. Methods and results Using combined populations from the SYMPHONY and 2nd SYMPHONY trials, we describe 30-day cardiac catheterization in elderly (≥75 years; n=1794) vs. younger patients (<75 years; n=14 043) after multivariable adjustment and by region of enrolment. The use of cardiac catheterization and revascularization were not protocol-specified. Elderly patients (median age 78 years) were more often female and more frequently had hypertension, diabetes, prior myocardial infarction, and prior coronary bypass surgery. Overall, they underwent less cardiac catheterization than younger patients [53 vs. 63%; adjusted OR 0.53 (0.46, 0.60)]. The absolute rate of cardiac catheterization in the elderly varied from 77% (vs. 91% in younger patients) in the US cohort to 27% (vs. 41% in younger patients) in the non-US cohort. Revascularization of elderly who underwent cardiac catheterization was also higher in US than non-US cohorts (71.3 vs. 53.6%). There was a significant interaction between the patient age and the use of catheterization across US and non-US regions of enrolment, as well as differences in the predictors of catheterization in the elderly. Despite these findings, after adjustment, 90-day rates of death and death or myocardial infarction (MI) were not significantly different in elderly who underwent catheterization compared with those who did not. Conclusion Although older age is universally predictive of lower use of cardiac catheterization, marked variation in catheterization of the elderly exists across international practice. Demonstrated differences in patterns of use suggest a lack of consensus regarding optimal use of an invasive strategy in the elderl

Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial

AbstractObjectivesWe examined the clinical, angiographic, and procedural characteristics determining survival after percutaneous coronary intervention (PCI) for cardiogenic shock.BackgroundThe SHOCK (SHould we emergently revascularize Occluded coronaries for Cardiogenic shocK?) trial prospectively enrolled patients with shock complicating acute myocardial infarction (MI). Patients were randomized to a strategy of early revascularization or initial medical stabilization.MethodsPatients randomized to early revascularization underwent PCI or bypass surgery on the basis of predefined clinical criteria. Patients randomized to early revascularization who underwent PCI and had angiographic films available for analysis are the subject of this report (n = 82).ResultsThe median time from MI to PCI was 11 h. The majority of patients had occluded culprit arteries (Thrombolysis In Myocardial Infarction [TIMI] grade 0 or 1 flow in 62%) and multivessel disease (81%). One-year mortality in PCI patients was 50%. Mortality was 39% if PCI was successful but 85% if unsuccessful (p < 0.001). Mortality was 38% if TIMI flow grade 3 was achieved, 55% with TIMI grade 2 flow, and 100% with TIMI grade 0 or 1 flow (p < 0.001). Mortality was 67% if severe mitral regurgitation was documented. Independent correlates of mortality were as follows: increasing age (p < 0.001), lower systolic blood pressure (p = 0.009), increasing time from randomization to PCI (p = 0.019), lower post-PCI TIMI flow (0/1 vs. 2/3) (p < 0.001), and multivessel PCI (p = 0.040).ConclusionsRestoration of coronary blood flow is a major predictor of survival in cardiogenic shock. Benefit appears to extend beyond the generally accepted 12-h post-infarction window. Surgery should be considered in shock patients with severe mitral insufficiency or multivessel disease not amenable to relatively complete percutaneous revascularization

The global subject of precarity

Peer reviewedPostprin

Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization

peer reviewedBACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugre

The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System

INTRODUCTION Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1) antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction. METHODS The effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors. RESULTS AND CONCLUSIONS Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

Background: We evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Methods and Results: Plasma Lp‐PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA2 activity levels and outcomes. At baseline, the median Lp‐PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA2 activity. There were no associations between on‐treatment Lp‐PLA2 activity or changes of Lp‐PLA2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA2 activity or changes in Lp‐PLA2 activity levels and the effects of darapladib on outcomes. Conclusions: Although high Lp‐PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA2 activity

Dalla progettazione all’utilizzo di un sistema informativo geologico al servizio del rilevamento geologico: la banca dati della Regione Lombardia e la cartografia geologica derivata

In questa Tesi è descritto il processo di creazione di un Sistema Informativo Geologico e degli strumenti informatici per la gestione dell’informazione su base geografica, o più semplicemente GIS (Geographic Information System), al servizio delle attività di rilevamento geologico, finalizzato alla raccolta dei dati ed alla loro rappresentazione cartografica nell'ambito di un Sistema Informativo Territoriale (SIT). Un SIT è definibile come l'insieme di uomini, strumenti e procedure che, nell’ambito di una organizzazione, permettono l’acquisizione e la distribuzione dei dati relativi alla conoscenza dei fenomeni e degli attori presenti su territorio; tutto questo è facilitato in gran parte dalle capacità e funzionalità dei GIS. Il Sistema Informativo Territoriale orientato alla Geologia (SIG – Sistema Informativo Geologico) della Regione Lombardia è costituito da un gruppo di lavoro composto da geologi, informatici e geologi-informatici dell’Ente regionale e della società Lombardia Servizi (Gruppo Lombardia Informatica). Ho fatto parte del team di consulenza tecnico-scientifica incaricato da Lombardia Servizi per la realizzazione del SIG regionale. I compiti del gruppo di lavoro sono: - definizione di ruoli e metodi per la costituzione del SIG; - definizione delle logiche per la creazione di strumenti finalizzati all’archiviazione del dato geologico in una banca dati geologica e loro manutenzione; Il progetto è inserito nel più ampio processo di aggiornamento della Cartografia Geologica nazionale (progetto CARG). Il SIG ha come principali obiettivi: - la pianificazione ed esecuzione del rilevamento geologico di dettaglio (scala 1:10.000) del territorio lombardo; - la costruzione di un database della geologia di superficie (ma anche del sottosuolo per le aree di pianura) interrogabile e aggiornabile ; - il supporto ai processi di analisi finalizzati alla descrizione della geologia superficiale e ricostruzione degli eventi che hanno creato il paesaggio attuale; - la rappresentazione cartografica dell’ambiente geologico a partire dal database creato. - la distribuzione dell’informazione geologica archiviata in vari formati (cartaceo e digitale); Sono qui descritte ed analizzate criticamente la filosofia di costruzione delle procedure e le soluzioni tecniche e metodologiche adottate per realizzare gli obiettivi prefissi. L’APAT (Agenzia per la Protezione dell'Ambiente e per i servizi Tecnici nazionali) ha ereditato dal Servizio Geologico il compito di rilevare, aggiornare e pubblicare la Carta Geologica d'Italia (progetto nazionale CARG) quale organo cartografico dello Stato in base alla legge 68/60. Nel 1976 era stato completato il rilevamento della Carta geologica d'Italia alla scala 1:100.000 costituita da 278 fogli a copertura del territorio nazionale; per il suo aggiornamento sono stati definiti strumenti normativi idonei a garantire l'omogeneità dei contenuti e della rappresentazione cartografica; la definizione delle norme discende dall'applicazione di linee guida, frutto dell'attività di Commissioni e Gruppi di lavoro, pubblicate nei Quaderni della serie III (ed. APAT). L’Ente Regione Lombardia, per rispondere all’impegno istituzionale di aggiornamento della Carta Geologica, all’interno del più ampio e strutturato Sistema Informativo Territoriale regionale, ha dunque creato il Sistema Informativo Geologico (SIG) regionale. Il rapido evolversi delle ricerche nel campo delle Scienze della Terra e l'importanza che riveste la cartografia geologica nella gestione del territorio, hanno spinto la Regione Lombardia a progettare un rilevamento geologico di dettaglio per dotarsi di una banca dati geologica dalla quale derivare la propria cartografia geologica (alla scala 1:10.000). Sono stati quindi definiti standard specifici rispondenti a questa esigenza di maggior dettaglio (rispetto a quanto indicato dal progetto nazionale CARG) ed è stato pianificato e in gran parte realizzato un rilevamento ex-novo finalizzato alla pubblicazione del dato alla scala del rilevamento e per la sua generalizzazione alle scale 1:25.000 e 50.000. Alla fine del processo saranno stati realizzati 14 fogli del territorio lombardo relativamente alle aree alpine e di passaggio alla pianura (Bergamo, Bormio, Breno, Clusone, Lecco, Iseo, Malonno, Ponte di Legno, Sondrio, Vimercate, Milano, Bagolino, Seregno, Voghera). In tale progetto sono anche coinvolti le Università di Milano, di Pavia e di Bolona, il Politecnico di Milano e il CNR - Centro di Studio per la Geodinamica Alpina e Quaternaria di Milano. L’attività di rilevamento geologico è di competenza dei funzionari regionali della Struttura Sistema Informativo Territoriale della Direzione Generale Territorio e Urbanistica che, coadiuvati da geologi rilevatori, realizzano tutte le fasi del lavoro, dalla raccolta del dato fino alla sua pubblicazione. L’ambiente informatico GIS sviluppato, denominato CARGeo (Cartografia Geologica), permette di inserire i dati raccolti da geologi rilevatori in un database appositamente predisposto, mediante interfacce grafiche semplificate e procedure standard di archiviazione e controllo di correttezza formale. La banca dati è costruita in modo da facilitare l’archiviazione della maggior parte dei dati che normalmente il geologo registra nella carta e nei taccuini di terreno e, allo stesso tempo, guidarlo nella raccolta organica dell’informazione geologica. Nella strutturazione del database è stata privilegiata la possibilità di inserire attributi direttamente associabili agli elementi geometrici anziché attraverso schede associate a punti di osservazione. Il geologo rilevatore interviene per correggere errori di digitalizzazione o di attribuzione con un processo ciclico, fino ad ottenere una banca dati corretta secondo gli standard predefiniti. Gli strumenti di creazione della banca dati permettono anche di: - disegnare gli schemi accessori (sezioni geologiche, schemi stratigrafici e strutturali etc.); - eseguire lo “sfoltimento” e posizionamento delle annotazioni sulla mappa (sigle di unità litologiche e parametri di inclinazione delle giaciture) secondo criteri di leggibilità della carta - creare le legende; - creare banche dati a scala inferiore (1:25.000 e 50.000); - stampare e pubblicare carte geologiche complete di schemi e legende. Il sistema contiene gli strumenti necessari alla migrazione della banca dati dalla struttura proprietaria CARG-Regione Lombardia a quella CARG-APAT secondo la struttura definita nei Quaderni della serie III Il Sistema nel corso del biennio 2006-2007 ha raggiunto la fase di consegna dei dati (derivazione e generalizzazione della banca dati CARG-APAT 1.50.000 da quella 1:10.000 CARG-Regione Lombardia) dei primi fogli completati (ISEO, MALONNO, LECCO e SONDRIO) con ritardo rispetto alla programmazione. Sono state analizzate le cause che hanno portato a questo rallentamento del flusso di lavoro, quindi apportate le necessarie modifiche al Sistema. Sono qui descritti i problemi e le soluzioni trovate per migliorare l'efficienza del sistema. Attualmente il Sistema Informativo Geologico è in una fase di ristrutturazione, che vede la migrazione verso un’architettura informatica basata sulla piattaforma ARCGis® 9.x. Attraverso il Sistema Informativo Geologico viene tentata una sintesi fra le logiche metodologiche dei due ambiti tecnico-scientifici coinvolti (Geologia e Informatica), in un ambiente dove ricercatori e tecnici lavorano sperimentando l’interazione tra le conoscenze e le metodologie conoscitive tipiche delle Scienze Geologiche e le tecnologie e processi logici delle Scienze Informatiche. Con questa Tesi è documentato tutto il percorso di costruzione della banca dati geologica attraverso e all’interno del sistema realizzato assieme gruppo di lavoro composto da geologi e tecnici informatici, cui ho partecipato, riassumendo gli oltre 9 anni di lavoro dall’ideazione del progetto CARGeo, anche in funzione del suo miglioramento

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention