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This work reports the first solvent-free catalytic approach for the cleavage of the fluorenylmethoxycarbonyl (Fmoc) protecting group from amine and alcohol functionalities. Various saccharide, peptide, and glyco-amino acid substrates were efficiently deprotected by simple treatment with 20 mol % neat 4-dimethylaminopyridine (DMAP) (one of the effective base catalysts found), without any solvent or stoichiometric additives. Small model structures were finally assembled through one-pot, base-catalyzed, solvent-free multistep sequences combining the Fmoc cleavage with esterification, amidation, and/or glycosylation steps.

Aims: The role of coronary calcification on clinical outcomes among different revascularization strategies in patients presenting with acute coronary syndromes (ACSs) has been rarely investigated. The aim of this investigation is to evaluate the role of coronary calcification, detected by coronary angiography, in the whole spectrum of patients presenting with acute ACS., Methods and Results: The present study was a post hoc analysis of the MATRIX programme. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction (MI), or stroke up to 365 days. Among the 8404 patients randomized in the MATRIX trial, data about coronary calcification were available in 7446 (88.6%) and therefore were included in this post hoc analysis. Overall, 875 patients (11.7%) presented with severe coronary calcification, while 6571 patients (88.3%) did not present severe coronary calcification on coronary angiography. Fewer patients with severe coronary calcification underwent percutaneous coronary intervention whereas coronary artery bypass grafting or medical therapy-only was more frequent compared with patients without severe calcification. At 1-year follow-up, MACE occurred in 237 (27.1%) patients with severe calcified coronary lesions and 985 (15%) patients without severe coronary calcified lesions [hazard ratio (HR) 1.91; 95% confidence interval (CI) 1.66-2.20, P < 0.001]. All-cause mortality was 8.6% in patients presenting with and 3.7% in those without severe coronary calcification (HR 2.38, 1.84-3.09, P < 0.001). Patients with severe coronary calcification incurred higher rate of MI (20.1% vs. 11.5%, HR 1.81; 95% CI 1.53-2.1, P < 0.001) and similar rate of stroke (0.8% vs. 0.6%, HR 1.35; 95% CI 0.61-3.02, P = 0.46)., Conclusion: Patients with ACS and severe coronary calcification, as compared to those without, are associated with worse clinical outcomes irrespective of the management strategy., Competing Interests: Conflict of interest: J.S.S. has received minor speaking honoraria from Terumo, Cordis, Biotronik, and Medtronic. H.M.G.-G. reports the following institutional grant support: Biotronik, Boston Scientific, Medtronic, Abbott, Neovasc, Shockwave, Phillips, and Corflow. G.A. reports minor speaking honoraria from Chiesi, Daiichi Sankyo, Boeringer Ingelheim, Bayer, Pfizer, and Biosensors. D.H. has participated on data safety monitoring board or advisory board of switch. S.L. has received consulting fees from AstraZeneca, Bayer, BMS/Pfizer, Chiesi, Daiichi-Sankyo, Icon, and Novonordisk. M.S. has received consulting fees from Abbott Vascular and iVascular. A.v.H. reports unrestricted grants from Medtronic, Abbott Vascular, and Boehringer Ingelheim and consulting fees from Celecor Therapeutics. P.V. reports consulting fees from Daiichi Sankyo, CSL Behring, Pfizer/Bristol Meyers Squibb alliance, Bayer AG, and Novartis; minor speaking honoraria from Daicchi Sankyo and Pfizer/Bristol Meyers Squibb alliance. M.V. reports consulting fees from Abbott, Alvimedica, Bayer Healthcare, Biotronik, Boston Scientific Corporation, Chiesi Farmaceutici, CoreFlow, Daiichi Sankyo, Idorsia, Medtronic, Novartis Pharma, PHASEBIO, Terumo, University of Basel, Vesalio, and Vifor Pharma. The rest of authors have no disclosures to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Data on left main (LM) percutaneous coronary interventions (PCI) have mostly been obtained in studies using drug-eluting stent (DES) platforms without dedicated large-vessel devices and with limited expansion capability., Aims: Our study aimed to investigate the safety and efficacy of LM PCI with the latest-generation Resolute Onyx DES., Methods: ROLEX (Revascularization Of LEft main with resolute onyX) is a prospective, multicentre study (ClinicalTrials.gov: NCT03316833) enrolling patients with unprotected LM coronary artery disease and a SYNTAX score <33 undergoing PCI with the Resolute Onyx zotarolimus-eluting coronary stent, that includes dedicated extra-large vessel platforms. The primary endpoint (EP) was target lesion failure (TLF): a composite of cardiac death, target vessel myocardial infarction (TVMI) and ischaemia-driven target lesion revascularisation (ID-TLR), at 1 year. All events were adjudicated by an independent clinical event committee. An independent core lab analysed all procedural angiograms., Results: A total of 450 patients (mean age 71.8 years, SYNTAX score 24.5±7.2, acute coronary syndrome in 53%) were enrolled in 26 centres. Of these, 77% of subjects underwent PCI with a single-stent and 23% with a 2-stent technique (8% double kissing [DK] crush, 6% culotte, 9% T/T and small protrusion [TAP] stenting). Intravascular imaging guidance was used in 45% (42% intravascular ultrasound [IVUS], 3% optical coherence tomography [OCT]). At 1 year, the primary EP incidence was 5.1% (cardiac death 2.7%, TVMI 2.7%, ID-TLR 2.0%). The definite/probable stent thrombosis rate was 1.1%. In a prespecified adjusted subanalysis, the primary EP incidence was significantly lower in patients undergoing IVUS/OCT-guided versus angio-guided PCI (2.0 vs 7.6%; hazard ratio [HR] 0.28, 95% confidence interval [CI]: 0.13-0.58; p<0.001)., Conclusions: In this large, multicentre, prospective registry, LM PCI with the Resolute Onyx DES showed good safety and efficacy at 1 year, particularly when guided by intracoronary imaging.

Background and Objective: In the last few decades, several studies have been performed to investigate traumatic brain injuries (TBIs) and to understand the biomechanical response of brain tissues, by using experimental and computational approaches. As part of computational approaches, human head finite element (FE) models show to be important tools in the analysis of TBIs, making it possible to estimate local mechanical effects on brain tissue for different accident scenarios. The present study aims to contribute to the computational approach by means of the development of three advanced FE head models for accurately describing the head tissue dynamics, the first step to predict TBIs., Methods: We have developed three detailed FE models of human heads from magnetic resonance images of three volunteers: an adult female (32 yrs), an adult male (35 yrs), and a young male (16 yrs). These models have been validated against experimental data of post mortem human subjects (PMHS) tests available in the literature. Brain tissue displacements relative to the skull, hydrostatic intracranial pressure, and head acceleration have been used as the parameters to compare the model response with the experimental response for validation. The software CORAplus (CORrelation and Analysis) has been adopted to evaluate the bio-fidelity level of FE models., Results: Numerical results from the three models agree with experimental data. FE models presented in this study show a good bio-fidelity for hydrostatic pressure (CORA score of 0.776) and a fair bio-fidelity brain tissue displacements relative to the skull (CORA score of 0.443 and 0.535). The comparison among numerical simulations carried out with the three models shows negligible differences in the mechanical state of brain tissue due to the different morphometry of the heads, when the same acceleration history is considered., Conclusions: The three FE models, thanks to their accurate description of anatomical morphology and to their bio-fidelity, can be useful tools to investigate brain mechanics due to different impact scenarios. Therefore, they can be used for different purposes, such as the investigation of the correlation between head acceleration and tissue damage, or the effectiveness of helmet designs. This work does not address the issue to define injury thresholds for the proposed models., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: Fascicle and sarcomere lengths are important predictors of muscle mechanical performance. However, their regulation during stretch-shortening cycle (SSC) activities in usual and challenging conditions is poorly understood. In this study, we aimed to investigate muscle fascicle and sarcomere behavior during drop jumps (a common SSC activity) in conditions of variable gravity. Methods: Fifteen volunteers performed repeated drop jumps in 1 g, hypo-gravity (0 to 1 g), and hyper-gravity (1 to 2 g) during a parabolic flight. Gastrocnemius medialis (GM) electromyographic activity and fascicle length (Lf) were measured at drop-off, ground contact (GC), minimum ankle joint angle (MAJ), and push-off. GM sarcomere number was estimated by dividing Lf, measured by ultrasound at rest, by published data on GM sarcomere length, and measured in vivo at the same joint angle. Changes in sarcomere length were estimated by dividing GM Lf in each jump phase by sarcomere number calculated individually. The sarcomere force-generating capacity in each jump phase was estimated from the sarcomere length-tension relationship previously reported in the literature. Results: The results showed that, regardless of the gravity level, GM sarcomeres operated in the ascending portion of their length-tension relationship in all the jump phases. Interestingly, although in hypo-gravity and hyper-gravity during the braking phase (GC-MAJ) GM fascicles and sarcomeres experienced a stretch (as opposed to the quasi-isometric behavior in 1 g), at MAJ they reached similar lengths as in 1 g, allowing sarcomeres to develop about the 70% of their maximum force. Conclusion: The observed fascicle behavior during drop jumping seems useful for anchoring the tendon, enabling storage of elastic energy and its release in the subsequent push-off phase for effectively re-bouncing in all gravity levels, suggesting that an innate neuromuscular wisdom enables to perform SSC movements also in challenging conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Monti, Waldvogel, Ritzmann, Freyler, Albracht, Helm, De Cesare, Pavan, Reggiani, Gollhofer and Narici.)

Objective  The aim of the study is to describe the real-world use of the P2Y 12 inhibitor cangrelor as a bridging strategy in patients at high thrombotic risk after percutaneous coronary intervention (PCI) and referred to surgery requiring perioperative withdrawal of dual antiplatelet therapy (DAPT). Materials and Methods  We collected data from nine Italian centers on patients with previous PCI who were still on DAPT and undergoing nondeferrable surgery requiring DAPT discontinuation. A perioperative standardized bridging protocol with cangrelor was used. Results  Between December 2017 and April 2019, 24 patients (mean age 72 years; male 79%) were enrolled. All patients were at high thrombotic risk after PCI and required nondeferrable intermediate to high bleeding risk surgery requiring DAPT discontinuation (4.6 ± 1.7 days). Cangrelor infusion was started at a bridging dose (0.75 µg/kg/min) 3 days before planned surgery and was discontinued 6.6 ± 1.5 hours prior to surgical incision. In 55% of patients, cangrelor was resumed at 9 ± 6 hours following surgery for a mean of 39 ± 38 hours. One cardiac death was reported after 3 hours of cangrelor discontinuation prior to surgery. No ischemic outcomes occurred after surgery and up to 30-days follow-up. The mean hemoglobin drop was <2 g/dL; nine patients received blood transfusions consistent with the type of surgery, but no life-threatening or fatal bleeding occurred. Conclusion  Perioperative bridging therapy with cangrelor is a feasible approach for stented patients at high thrombotic risk and referred to surgery requiring DAPT discontinuation. Larger studies are warranted to support the safety of this strategy., Competing Interests: Conflict of Interest R.R. reports payment as an individual for consulting fee or honorarium from Eli Lilly and Co., and Daiichi Sankyo, Inc, Astra Zeneca, Bayer, and Pfizer. G.M. reports honoraria for lectures from Eli Lilly and Co., and Daiichi Sankyo, Inc, Astra Zeneca, St. Jude Medical, and Abbott Vascular. D.J.A. declares that he has received consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and the Medicines Company and has received payments for participation in review activities from CeloNova and St. Jude Medical. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions. The other authors report no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: The optimal timing to administer a P2Y12 inhibitor in patients presenting with a non-ST elevation acute coronary syndrome remains a topic of debate. Pretreatment with ticagrelor before coronary anatomy is known as a widely adopted strategy. However, there is poor evidence on how this compares with administration of a P2Y12 inhibitor after defining coronary anatomy (i.e., downstream administration). Moreover, there are limited head-to-head comparisons of the two P2Y12 inhibitors-ticagrelor and prasugrel-currently recommended by the guidelines., Study Design: DUBIUS is a phase 4, multicenter, parallel-group, double randomized study conducted in NSTE-ACS patients designed to compare a pretreatment strategy (including only ticagrelor) versus a downstream strategy (including prasugrel or ticagrelor) and to compare downstream prasugrel with downstream ticagrelor. A total of 2520 patients will be randomly assigned to pretreatment with ticagrelor or to no pretreatment. The PCI group of the downstream arm will be further randomized to receive prasugrel or ticagrelor. The two primary hypotheses are that the downstream strategy is superior to the upstream strategy and that downstream ticagrelor is non-inferior to downstream prasugrel, both measured by the incidence of a composite efficacy and safety endpoint of death from vascular causes, non-fatal MI, or non-fatal stroke, and Bleeding Academic Research Consortium (BARC) type 3, 4, and 5 bleedings., Conclusions: The DUBIUS study will provide important evidence related to the benefits and risks of pretreatment with ticagrelor compared with a strategy of no pretreatment. Moreover, the clinical impact of using downstream ticagrelor compared with downstream prasugrel will be assessed., Trial Registration: ClinicalTrials.gov NCT02618837 . Registered on 1 December 2015.

Background: Although oral P2Y 12 inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined., Objectives: The purpose of this study was to compare downstream and upstream oral P2Y 12 inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment., Methods: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit)., Results: We randomized 1,449 patients to downstream or upstream oral P2Y 12 inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment)., Conclusions: Downstream and upstream oral P2Y 12 inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y 12 Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837)., Competing Interests: Author Relationship With Industry This work was funded by the Italian Society of Interventional Cardiology (SICI-GISE). Dr. Tarantini has received Speakers Bureau fees from AstraZeneca, Daiichi-Sankyo, and Eli Lilly. Dr. Mojoli has received individual payments for participating on the Advisory Boards of The Medicines Company and Abbott Vascular; and has been a speaker at scientific congresses from AstraZeneca, Daiichi-Sankyo, Chiesi Farmaceutici, and Servier; and his institution has received an unconditioned research grant from Chiesi Farmaceutici. Dr. Varbella has received consulting fees/honoraria from AstraZeneca, Daiichi-Sankyo, Bayer, Pfizer, Boehringer Ingelheim, Servier, Amgen, Sanofi, Piam, Alvi Medica, Teleflex, and Stenty. Dr. Caporale has received an Advisory Board fee from AstraZeneca. Dr. Rigattieri has received a consulting fee from AstraZeneca; and has received a Speakers Bureau fee from Eli Lilly. Dr. Andò has received individual payments as a consultant, for serving on the Advisory Board, or as a speaker at scientific congresses from AstraZeneca, Daiichi-Sankyo, Chiesi Farmaceutici, Pfizer–Bristol Myers Squibb, Boehringer Ingelheim, and Biosensors. Dr. Saia has received Speakers Bureau fees from AstraZeneca and Daiichi-Sankyo. Dr. Ferlini has received individual payment as a consultant, for serving on the Advisory Board, or as a speaker at scientific congresses from AstraZeneca, Chiesi Farmaceutici, Bayer, Biosensors, Sanofi, and Boehringer Ingelheim. Dr. Angiolillo has received consulting fees or honoraria as an individual from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has received payment as an individual for participation in review activities from CeloNova and St. Jude Medical; and has received institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. All rights reserved.)

The biomechanics of the abdominal wall depends on muscular activation, tissue mechanical behavior and Intra-Abdominal Pressure (IAP). In this work, a numerical model of a human abdomen is presented, based on abdominal wall geometry from medical images. Specific constitutive formulations describe tissues mechanical behavior. Connective tissues are modelled as hyperelastic fiber-reinforced materials, while muscular tissues are described by means of a three-element Hill's model. The abdominal cavity is represented by a volume region interacting with the abdominal wall. Numerical analyses are developed by applying a muscular contraction, inducing a volume reduction of the abdominal cavity and a simultaneous IAP increase. Numerical results of abdomen displacement at IAP corresponding to an abdominal crunch are compared with experimental results acquired via 3D laser scanning on a healthy subject. Numerical and experimental results are mutually consistent and show that muscular activation induces a raising in the region adjacent to linea alba along the posterior-anterior direction and a lowering along lateral-medial direction of the abdominal wall sides. The numerical model developed in this work allows a coherent representation of the abdominal wall mechanics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Objective: The biomechanical analysis of the abdominal wall should take into account muscle activation and related phenomena, such as intra-abdominal pressure variation and abdomen surface deformation. The geometry of abdominal surface and its deformation during contraction have not been extensively characterized, while represent a key issue to be investigated., Methods: In this work, the antero-lateral abdominal wall surface of ten healthy volunteers in supine position is acquired via laser scanning in relaxed conditions and during abdominal muscles contraction, repeating each acquisition six times. The average relaxed and contracted abdominal surfaces are compared for each subject and displacements measured., Results: Muscular activation induces raising in the region adjacent to linea alba along the posterior-anterior direction and a simultaneous lowering along lateral-medial direction of the abdominal wall sides. Displacements reach a maximum value of 12.5 mm for the involved subjects. The coefficient of variation associated to the abdomen surface measurements in the same configuration (relaxed or contracted) is below 0.75%. Non-parametric Mann-Whitney U test highlights that the differences between relaxed and contracted abdominal wall surfaces are significant (p < 0.01)., Conclusions: Laser scanning is an accurate and reliable method to evaluate surface changes on the abdominal wall during muscular contraction. The results of this experimental activity can be useful to validate numerical models aimed at describing abdominal wall biomechanics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Bariatric surgery is performed on obese people aiming at reducing the capacity of the stomach and/or the absorbing capability of the gastrointestinal tract. A more reliable and effective approach to bariatric surgery may integrate different expertise, in the areas of surgery, physiology and biomechanics, availing of a strong cooperation between clinicians and engineers. This work aimed at developing a computational model of the stomach, as a computational tool for the physio-mechanical investigation of stomach functionality and the planning of bariatric procedures. In this sense, coupled experimental and numerical activities were developed. Experimental investigations on pig and piglet stomachs aimed at providing information about stomach geometrical configuration and structural behavior. The computational model was defined starting from the analysis of data from histo-morphometric investigations and mechanical tests. A fiber-reinforced visco-hyperelastic constitutive model was developed to interpret the mechanical response of stomach tissues; constitutive parameters were identified considering mechanical tests at both tissue and structure levels. Computational analyses were performed to investigate the pressure-volume behavior of the stomach. The developed model satisfactorily interpreted results from experimental activities, suggesting its reliability. Furthermore, the model was exploited to investigate stress and strain fields within gastric tissues, as the stimuli for mechanoreceptors that interact with the central nervous system leading to the feeling of satiety. In this respect, the developed computational model may be employed to evaluate the influence of bariatric intervention on the stimulation of mechanoreceptors, and the following meal induced satiety.

Congenital diaphragmatic hernia (CDH) is a neonatal defect in which the diaphragm muscle does not develop properly, thereby raising abdominal organs into the thoracic cavity and impeding lung development and function. Large diaphragmatic defects require correction with prosthetic patches to close the malformation. This treatment leads to a consequent generation of unwelcomed mechanical stress in the repaired diaphragm and hernia recurrences, thereby resulting in high morbidity and significant mortality rates. We proposed a specific diaphragm-derived extracellular matrix (ECM) as a scaffold for the treatment of CDH. To address this strategy, we developed a new surgical CDH mouse model to test the ability of our tissue-specific patch to regenerate damaged diaphragms. Implantation of decellularized diaphragmatic ECM-derived patches demonstrated absence of rejection or hernia recurrence, in contrast to the performance of a commercially available synthetic material. Diaphragm-derived ECM was able to promote the generation of new blood vessels, boost long-term muscle regeneration, and recover host diaphragmatic function. In addition, using a GFP + Schwann cell mouse model, we identified re-innervation of implanted patches. These results demonstrated for the first time that implantation of a tissue-specific biologic scaffold is able to promote a regenerating diaphragm muscle and overcome issues commonly related to the standard use of prosthetic materials. STATEMENT OF SIGNIFICANCE: Large diaphragmatic hernia in paediatric patients require application of artificial patches to close the congenital defect. The use of a muscle-specific decellularized scaffold in substitution of currently used synthetic materials allows new blood vessel growth and nerve regeneration inside the patch, supporting new muscle tissue formation. Furthermore, the presence of a tissue-specific scaffold guaranteed long-term muscle regeneration, improving diaphragm performance to almost complete functional recovery. We believe that diaphragm-derived scaffold will be key player in future pre-clinical studies on large animal models., (Copyright © 2019 Acta Materialia Inc. All rights reserved.)

Background: The impact of coronary artery disease (CAD) extension/complexity on outcomes and on the comparative benefits/risks of zotarolimus-eluting stent (ZES) versus bare-metal stents (BMS) remains unclear in patients at high risk of bleeding or thrombosis or at low restenosis risk., Methods: We performed a post-hoc analysis of the ZEUS trial. The impact of coronary anatomic complexity measured by the SYNTAX score on the differences in outcomes following ZES and BMS was assessed at 1 year., Results: The mean SYNTAX score was 16.3 ± 13.1 with a median of 12 (IQR: 7 to 22). We stratified patients according to SYNTAX tertiles (0-8: n = 563; >8-19 n = 532; >19: n = 511), and observed that the higher the score, the correspondingly higher was the rate of the primary endpoint of major adverse cardiovascular events (MACE) and other ischemic events, but not bleeding after adjustment. The superior efficacy of ZES versus BMS for MACE was consistent across SYNTAX tertiles (tertile 1: HR 0.71, 95% CI 0.44-1.13; tertile 2: HR 0.71, 95% CI 0.46-1.09; tertile 3: HR 0.83, 95% CI 0.61-1.10) without significant heterogeneity (p for trend = 0.55). This between-groups difference mainly reflected a reduction in MI and TVR without effect on mortality. There was no significant interaction between the SYNTAX score and allocated stent type with respect to ischemic and bleeding endpoints., Conclusions: The SYNTAX score was predictor of major adverse cardiovascular events but not bleeding and ZES provided superior efficacy and safety than BMS across the whole spectrum of CAD complexity. SYNTAX score may be routinely used for the assessment of the ischemic risk (but not bleeding) after PCI and should not guide the decision-making for DES versus BMS in patients undergoing PCI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The diaphragm is a mammalian skeletal muscle that plays a fundamental role in the process of respiration. Alteration of its mechanical properties due to a diaphragmatic hernia contributes towards compromising its respiratory functions, leading to the need for surgical intervention to restore the physiological conditions by means of implants. This study aims to assess via numerical modeling biomechanical differences between a diaphragm in healthy conditions and a herniated diaphragm surgically repaired with a polymeric implant, in a mouse model. Finite Element models of healthy and repaired diaphragms are developed from diagnostic images and anatomical samples. The mechanical response of the diaphragmatic tendon is described by assuming an isotropic hyperelastic model. A similar constitutive model is used to define the mechanical behavior of the polymeric implant, while the muscular tissue is modeled by means of a three-element Hill's model, specifically adapted to mouse muscle fibers. The Finite Element Analysis is addressed to simulate diaphragmatic contraction in the eupnea condition, allowing the evaluation of diaphragm deformation in healthy and herniated-repaired conditions. The polymeric implant reduces diaphragm excursion compared to healthy conditions. This explains the possible alteration in the mechanical functionality of the repaired diaphragm. Looking to the surgical treatment of diaphragmatic hernia in human neonatal subjects, this study suggests the implementation of alternative approaches based on the use of biological implants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) programme was designed to assess the comparative safety and effectiveness of radial versus femoral access and of bivalirudin versus unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients with the whole spectrum of acute coronary syndrome undergoing invasive management. Here we describe the prespecified final 1-year outcomes of the entire programme., Methods: MATRIX was a programme of three nested, randomised, multicentre, open-label, superiority trials in patients with acute coronary syndrome in 78 hospitals in Italy, the Netherlands, Spain, and Sweden. Patients with ST-elevation myocardial infarction were simultaneously randomly assigned (1:1) before coronary angiography to radial or femoral access and to bivalirudin, with or without post-percutaneous coronary intervention infusion or unfractionated heparin (one-step inclusion). Patients with non-ST-elevation acute coronary syndrome were randomly assigned (1:1) before coronary angiography to radial or femoral access and, only if deemed eligible to percutaneous coronary intervention after angiography (two-step inclusion), entered the antithrombin type and treatment duration programmes. Randomisation sequences were computer generated, blocked, and stratified by intended new or current use of P2Y12 inhibitor (clopidogrel vs ticagrelor or prasugrel), and acute coronary syndrome type (ST-elevation myocardial infarction, troponin-positive, or troponin-negative non-ST-elevation acute coronary syndrome). Bivalirudin was given as a bolus of 0·75 mg/kg, followed immediately by an infusion of 1·75 mg/kg per h until completion of percutaneous coronary intervention. Heparin was given at 70-100 units per kg in patients not receiving glycoprotein IIb/IIIa inhibitors, and at 50-70 units per kg in patients receiving glycoprotein IIb/IIIa inhibitors. Clinical follow-up was done at 30 days and 1 year. Co-primary outcomes for MATRIX access and MATRIX antithrombin type were major adverse cardiovascular events, defined as the composite of all-cause mortality, myocardial infarction, or stroke up to 30 days; and net adverse clinical events, defined as the composite of non-coronary artery bypass graft-related major bleeding, or major adverse cardiovascular events up to 30 days. The primary outcome for MATRIX treatment duration was the composite of urgent target vessel revascularisation, definite stent thrombosis, or net adverse clinical events up to 30 days. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01433627., Findings: Between Oct 11, 2011, and Nov 7, 2014, we randomly assigned 8404 patients to receive radial (4197 patients) or femoral (4207 patients) access. Of these 8404 patients, 7213 were included in the MATRIX antithrombin type study and were randomly assigned to bivalirudin (3610 patients) or heparin (3603 patients). Patients assigned to bivalirudin were included in the MATRIX treatment duration study, and were randomly assigned to post-procedure infusion (1799 patients) or no post-procedure infusion (1811 patients). At 1 year, major adverse cardiovascular events did not differ between patients assigned to radial access compared with those assigned to femoral access (14·2% vs 15·7%; rate ratio 0·89, 95% CI 0·80-1·00; p=0·0526), but net adverse clinical events were fewer with radial than with femoral access (15·2% vs 17·2%; 0·87, 0·78-0·97; p=0·0128). Compared with heparin, bivalirudin was not associated with fewer major adverse cardiovascular (15·8% vs 16·8%; 0·94, 0·83-1·05; p=0·28) or net adverse clinical events (17·0% vs 18·4%; 0·91, 0·81-1·02; p=0·10). The composite of urgent target vessel revascularisation, stent thrombosis, or net adverse clinical events did not differ with or without post-procedure bivalirudin infusion (17·4% vs 17·4%; 0·99, 0·84-1·16; p=0·90)., Interpretation: In patients with acute coronary syndrome, radial access was associated with lower rates of net adverse clinical events compared with femoral access, but not major adverse cardiovascular events at 1 year. Bivalirudin with or without post-procedure infusion was not associated with lower rates of major adverse cardiovascular events or net adverse clinical events. Radial access should become the default approach in acute coronary syndrome patients undergoing invasive management., Funding: Italian Society of Invasive Cardiology, The Medicines Company, Terumo, amd Canada Research Chairs Programme., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Contrasting evidence exists on the comparative efficacy and safety of bivalirudin and unfractionated heparin (UFH) in relation to the planned use of glycoprotein IIb/IIIa inhibitors (GPIs)., Objectives: This study assessed the efficacy and safety of bivalirudin compared with UFH with or without GPIs in patients with acute coronary syndrome (ACS) who underwent invasive management., Methods: In the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX) program, 7,213 patients were randomly assigned to receive either bivalirudin or UFH with or without GPIs at discretion of the operator. The 30-day coprimary outcomes were major adverse cardiovascular events (MACEs) (a composite of death, myocardial infarction, or stroke), and net adverse clinical events (NACEs) (a composite of MACEs or major bleeding)., Results: Among 3,603 patients assigned to receive UFH, 781 (21.7%) underwent planned treatment with GPI before coronary intervention. Bailout use of GPIs was similar between the bivalirudin and UFH groups (4.5% and 5.4%) (p = 0.11). At 30 days, the 2 coprimary endpoints of MACEs and NACEs, as well as individual endpoints of mortality, myocardial infarction, stent thrombosis or stroke did not differ among the 3 groups after adjustment. Compared with the UFH and UFH+GPI groups, bivalirudin reduced bleeding, mainly the most severe bleeds, including fatal and nonaccess site-related events, as well as transfusion rates and the need for surgical access site repair. These findings were not influenced by the administered intraprocedural dose of UFH and were confirmed at multiple sensitivity analyses, including the randomly allocated access site., Conclusions: In patients with ACS, the rates of MACEs and NACEs were not significantly lower with bivalirudin than with UFH, irrespective of planned GPI use. However, bivalirudin significantly reduced bleeding complications, mainly those not related to access site, irrespective of planned use of GPIs. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX [MATRIX]; NCT01433627)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: To assess whether radial compared with femoral access is associated with consistent outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation acute coronary syndrome (NSTE-ACS)., Methods and Results: In the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) programme patients were randomized to radial or femoral access, stratified by STEMI (2001 radial, 2009 femoral) and NSTE-ACS (2196 radial, 2198 femoral). The 30-day co-primary outcomes were major adverse cardiovascular events (MACE), defined as death, myocardial infarction, or stroke, and net adverse clinical events (NACE), defined as MACE or major bleeding In the overall study population, radial access reduced the NACE but not MACE endpoint at the prespecified 0.025 alpha. MACE occurred in 121 (6.1%) STEMI patients with radial access vs. 126 (6.3%) patients with femoral access [rate ratio (RR) = 0.96, 95% CI = 0.75-1.24; P = 0.76] and in 248 (11.3%) NSTE-ACS patients with radial access vs. 303 (13.9%) with femoral access (RR = 0.80, 95% CI = 0.67-0.96; P = 0.016) (Pint = 0.25). NACE occurred in 142 (7.2%) STEMI patients with radial access and in 165 (8.3%) patients with femoral access (RR = 0.86, 95% CI = 0.68-1.08; P = 0.18) and in 268 (12.2%) NSTE-ACS patients with radial access compared with 321 (14.7%) with femoral access (RR = 0.82, 95% CI = 0.69-0.97; P = 0.023) (Pint = 0.76). All-cause mortality and access site-actionable bleeding favoured radial access irrespective of ACS type (Pint = 0.11 and Pint = 0.36, respectively)., Conclusion: Radial as compared with femoral access provided consistent benefit across the whole spectrum of patients with ACS, without evidence that type of presenting syndrome affected the results of the random access allocation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study sought to investigate the ischemic and bleeding outcomes of patients fulfilling high bleeding risk (HBR) criteria who were randomized to zotarolimus-eluting Endeavor Sprint stent (E-ZES) or bare-metal stent (BMS) implantation followed by an abbreviated dual antiplatelet therapy (DAPT) duration for stable or unstable coronary artery disease., Background: DES instead of BMS use remains controversial in HBR patients, in whom long-term DAPT poses safety concerns., Methods: The ZEUS (Zotarolimus-Eluting Endeavor Sprint Stent in Uncertain DES Candidates) is a multinational, randomized single-blinded trial that randomized among others, in a stratified manner, 828 patients fulfilling pre-defined clinical or biochemical HBR criteria-including advanced age, indication to oral anticoagulants or other pro-hemorrhagic medications, history of bleeding and known anemia-to receive E-ZES or BMS followed by a protocol-mandated 30-day DAPT regimen. The primary endpoint of the study was the 12-month major adverse cardiovascular event rate, consisting of death, myocardial infarction, or target vessel revascularization., Results: Compared with patients without, those with 1 or more HBR criteria had worse outcomes, owing to higher ischemic and bleeding risks. Among HBR patients, major adverse cardiovascular events occurred in 22.6% of the E-ZES and 29% of the BMS patients (hazard ratio: 0.75; 95% confidence interval: 0.57 to 0.98; p = 0.033), driven by lower myocardial infarction (3.5% vs. 10.4%; p < 0.001) and target vessel revascularization (5.9% vs. 11.4%; p = 0.005) rates in the E-ZES arm. The composite of definite or probable stent thrombosis was significantly reduced in E-ZES recipients, whereas bleeding events did not differ between stent groups., Conclusions: Among HBR patients with stable or unstable coronary artery disease, E-ZES implantation provides superior efficacy and safety as compared with conventional BMS. (Zotarolimus-Eluting Endeavor Sprint Stent in Uncertain DES Candidates [ZEUS]; NCT01385319)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Whether cyclosporine A (CsA) has beneficial effects in reperfused myocardial infarction (MI) is debated., Objectives: This study investigated whether CsA improved ST-segment resolution in a randomized, multicenter phase II study., Methods: The authors randomly assigned 410 patients from 31 cardiac care units, age 63 ± 12 years, with large ST-segment elevation MI within 6 h of symptom onset, Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1 in the infarct-related artery, and committed to primary percutaneous coronary intervention, to 2.5 mg/kg intravenous CsA (n = 207) or control (n = 203) groups. The primary endpoint was incidence of ≥70% ST-segment resolution 60 min after TIMI flow grade 3. Secondary endpoints included high-sensitivity cardiac troponin T (hs-cTnT) on day 4, left ventricular (LV) remodeling, and clinical events at 6-month follow-up., Results: Time from symptom onset to first antegrade flow was 180 ± 67 min; a median of 5 electrocardiography leads showed ST-segment deviation (quartile [Q]1 to Q3: 4 to 6); 49.8% of MIs were anterior. ST-segment resolution ≥70% was found in 52.0% of CsA patients and 49.0% of controls (p = 0.55). Median hs-cTnT on day 4 was 2,160 (Q1 to Q3: 1,087 to 3,274) ng/l in CsA and 2,068 (1,117 to 3,690) ng/l in controls (p = 0.85). The 2 groups did not differ in LV ejection fraction on day 4 and at 6 months. Infarct site did not influence CsA efficacy. There were no acute allergic reactions or nonsignificant excesses of 6-month mortality (5.7% CsA vs. 3.2% controls, p = 0.17) or cardiogenic shock (2.4% CsA vs. 1.5% controls, p = 0.33)., Conclusions: In the CYCLE (CYCLosporinE A in Reperfused Acute Myocardial Infarction) trial, a single intravenous CsA bolus just before primary percutaneous coronary intervention had no effect on ST-segment resolution or hs-cTnT, and did not improve clinical outcomes or LV remodeling up to 6 months. (CYCLosporinE A in Reperfused Acute Myocardial Infarction [CYCLE]; NCT01650662; EudraCT number 2011-002876-18)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Conflicting evidence exists on the efficacy and safety of bivalirudin administered as part of percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome., Methods: We randomly assigned 7213 patients with an acute coronary syndrome for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin. Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion. Primary outcomes for the comparison between bivalirudin and heparin were the occurrence of major adverse cardiovascular events (a composite of death, myocardial infarction, or stroke) and net adverse clinical events (a composite of major bleeding or a major adverse cardiovascular event). The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events., Results: The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (10.3% and 10.9%, respectively; relative risk, 0.94; 95% confidence interval [CI], 0.81 to 1.09; P=0.44), nor was the rate of net adverse clinical events (11.2% and 12.4%, respectively; relative risk, 0.89; 95% CI, 0.78 to 1.03; P=0.12). Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (11.0% and 11.9%, respectively; relative risk, 0.91; 95% CI, 0.74 to 1.11; P=0.34)., Conclusions: In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin. The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion. (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrials.gov number, NCT01433627.).

The Accelerator Mass Spectrometry (AMS) is the most sensitive technique, compared either to the Inductively Coupled Plasma (ICP-MS) or Thermal Ionization (TI-MS) mass spectrometer, for the actinide (e.g. (236)U, (x)Pu isotopes) measurements. They are present in environmental samples at the ultra trace level since atmospheric tests of Nuclear Weapons (NWs) performed in the past, deliberate dumping of nuclear waste, nuclear fuel reprocessing, on a large scale, and operation of Nuclear Power Plants (NPPs), on a small scale, have led to the release of a wide range of radioactive nuclides in the environment. At the Center for Isotopic Research on Cultural and Environmental heritage (CIRCE) in Caserta, Italy, an upgraded actinide AMS system, based on a 3-MV pelletron tandem accelerator, has been developed and routinely operated. At CIRCE a charge state distribution as a function of terminal voltage, the beam emittance, measured in the 20° actinides dedicated beam line, as well as the energy and position validation of the U ions were performed in order to determine the best measurement conditions. A (236)U/(238)U isotopic ratio background level of about 5×10(-12) or 3×10(-13), depending on the Time of Flight-Energy (TOF-E) configurations, as well as the spatial distribution of the (235)U, (238)U interferences ions and a (236)U contamination mass of about 0.5 fg have been determined., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: It is unclear whether radial compared with femoral access improves outcomes in unselected patients with acute coronary syndromes undergoing invasive management., Methods: We did a randomised, multicentre, superiority trial comparing transradial against transfemoral access in patients with acute coronary syndrome with or without ST-segment elevation myocardial infarction who were about to undergo coronary angiography and percutaneous coronary intervention. Patients were randomly allocated (1:1) to radial or femoral access with a web-based system. The randomisation sequence was computer generated, blocked, and stratified by use of ticagrelor or prasugrel, type of acute coronary syndrome (ST-segment elevation myocardial infarction, troponin positive or negative, non-ST-segment elevation acute coronary syndrome), and anticipated use of immediate percutaneous coronary intervention. Outcome assessors were masked to treatment allocation. The 30-day coprimary outcomes were major adverse cardiovascular events, defined as death, myocardial infarction, or stroke, and net adverse clinical events, defined as major adverse cardiovascular events or Bleeding Academic Research Consortium (BARC) major bleeding unrelated to coronary artery bypass graft surgery. The analysis was by intention to treat. The two-sided α was prespecified at 0·025. The trial is registered at ClinicalTrials.gov, number NCT01433627., Findings: We randomly assigned 8404 patients with acute coronary syndrome, with or without ST-segment elevation, to radial (4197) or femoral (4207) access for coronary angiography and percutaneous coronary intervention. 369 (8·8%) patients with radial access had major adverse cardiovascular events, compared with 429 (10·3%) patients with femoral access (rate ratio [RR] 0·85, 95% CI 0·74-0·99; p=0·0307), non-significant at α of 0·025. 410 (9·8%) patients with radial access had net adverse clinical events compared with 486 (11·7%) patients with femoral access (0·83, 95% CI 0·73-0·96; p=0·0092). The difference was driven by BARC major bleeding unrelated to coronary artery bypass graft surgery (1·6% vs 2·3%, RR 0·67, 95% CI 0·49-0·92; p=0·013) and all-cause mortality (1·6% vs 2·2%, RR 0·72, 95% CI 0·53-0·99; p=0·045)., Interpretation: In patients with acute coronary syndrome undergoing invasive management, radial as compared with femoral access reduces net adverse clinical events, through a reduction in major bleeding and all-cause mortality., Funding: The Medicines Company and Terumo., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The use of drug-eluting stents (DES) in patients at high risk of bleeding or thrombosis has not been prospectively studied; limited data are available in patients who have a low restenosis risk., Objectives: This study sought to compare a hydrophilic polymer-based, second-generation zotarolimus-eluting stent (ZES) with a unique drug fast-release profile versus bare-metal stents (BMS) under similar durations of dual-antiplatelet therapy (DAPT)., Methods: We randomly assigned 1,606 patients with stable or unstable symptoms, and who on the basis of thrombotic bleeding or restenosis risk criteria, qualified as uncertain candidates for DES, to receive ZES or BMS. DAPT duration was on the basis of patient characteristics, rather than stent characteristics, and allowed for a personalized 1-month dual antiplatelet regimen. The primary endpoint was the risk of 1-year major adverse cardiovascular events (MACE), which included death, myocardial infarction (MI), or target vessel revascularization (TVR)., Results: Median DAPT duration was 32 days (interquartile range [IQR]: 30 to 180 days) and did not differ between the groups. In the ZES group, 140 patients (17.5%) reached the primary endpoint, compared with 178 patients (22.1%) in the BMS group (hazard ratio: 0.76; 95% confidence interval: 0.61 to 0.95; p = 0.011) as a result of lower MI (2.9% vs. 8.1%; p < 0.001) and TVR rates (5.9% vs.10.7%; p = 0.001) in the ZES group. Definite or probable stent thrombosis was also significantly reduced in ZES recipients (2.0% vs. 4.1%; p = 0.019)., Conclusions: Compared with BMS, DES implantation using a stent with a biocompatible polymer and fast drug-eluting characteristics, combined with an abbreviated, tailored DAPT regimen, resulted in a lower risk of 1-year MACE in uncertain candidates for DES implantation. (Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES Candidates [ZEUS] Study; NCT01385319)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The use of drug-eluting stent (DES) instead of bare-metal stent (BMS) in patients at high stent thrombosis or bleeding risk as well as in those at low restenosis risk (ie, uncertain DES candidates) remains a matter of debate. Zotarolimus-Eluting Endeavor Sprint stent (E-ZES) (Santa Rosa, CA) is a hydrophilic polymer-based second-generation device with unique drug fast-release profile, which may allow for a shorter dual antiplatelet therapy (DAPT) duration without safety concerns., Hypothesis: The primary objective is to assess whether E-ZES implantation followed by a shorter than currently recommended course of DAPT will decrease the incidence of 12-month major adverse cardiovascular events as compared with BMS in undefined DES recipients. Actual duration of DAPT regimen will be dictated by patients' characteristics and not by stent type and, as such, can be as short as 30 days after intervention in both stent groups., Study Design: The ZEUS study is an open-label randomized clinical trial conducted at 20 clinical sites in Italy, Switzerland, Portugal, and Hungary. With 1,600 individuals, this study will have 85% power to detect a 33% difference in the primary end point consisting of the composite of death, nonfatal myocardial infarction, or target vessel revascularization., Summary: The ZEUS trial aims to assess whether the use of E-ZES, followed by a DAPT duration regimen based on patients' characteristics and not by stent type, is superior to conventional BMS implantation in undefined DES recipients who qualify for the presence of high thrombosis, bleeding, or low restenosis risk criteria., (© 2013.)

Background: The Multicentre Evaluation of Single high-dose Bolus TiRofiban versus Abciximab with Sirolimus-eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study [MULTISTRATEGY]) randomised 745 patients with ST-elevation myocardial infarction to receive high-dose bolus (HDB) tirofiban or abciximab infusion and sirolimus-eluting (SES) or uncoated-stent (BMS) implantation. Tirofiban was non-inferior to abciximab in terms of ST-segment resolution after intervention, whereas 8 month-major adverse cardiac events occurred in 14.5% in the BMS and 7.8% in the SES groups (P = 0.0039), reflecting a reduction of reintervention rates (10.2% vs. 3.2%). A three-year follow-up was performed to extend previous short- to mid-term findings., Methods and Results: Complete data at 3 years was available for 736 patients (99%). All-cause mortality was 6.7% in the tirofiban and 7.8% in the abciximab (P = 0.56) and 7.5% in the BMS vs 7.0 in the SES groups, P = 0.79. The composite of all-cause death or MI was identical at 12.9% in tirofiban and abciximab groups, P = 0.99 and it occurred in 13.2% in the BMS vs. 12.6% in the SES groups (P = 0.83). The need for reintervention remained more than twice as common with BMS (13.7%; versus 6.2%, P = 0.0006). The cumulative rate of stent thrombosis (ST) did not differ. This is inspite of a higher very late definite, probable or possible ST thrombosis rate in the SES group., Conclusions: The 3-year follow-up of MULTISTRATEGY demonstrated comparable outcomes with HDB Tirofiban or abciximab and a sustained efficacy of SES to reduce reintervention with no difference in death, repeat MI or ST., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Identification of high-risk patients with ST-segment elevation acute myocardial infarction (STEMI) is of the utmost importance for adequate patient stratification and evaluation of additive treatments. However, there is no consensus on the optimal definition of high-risk patients., Methods: We therefore compared 5 scoring systems in the assessment of the risk of 30-day mortality in 3214 patients with STEMI treated with primary percutaneous coronary intervention (PCI)., Results: Clinical scores showed a large variability in risk stratifying patients. Identification of high-risk patients ranged from 15% (PAMI score ≥ 9) to 66% (McNamara definition). McNamara, Antoniucci and Brodie definitions had the best sensitivity (0.87-0.88 and 95% confidence intervals (CI) ranging from 0.82-0.93) while PAMI ≥ 9 had the best specificity (0.87 with 95% CI of 0.86-0.88), while its sensitivity was quite low (0.42). In a sample size simulation of a trial aimed at demonstrating a 33% difference in 30-day mortality between two hypothetical treatments, the number of STEMI patients needed to be screened varied from 4712 for the Brodie definition to 9038 for the PAMI ≥ 9 score., Conclusions: There is a large variability in risk stratification, sensitivity, specificity and predictive values among different scoring systems. These considerations should be taken into account when designing randomised trials., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We assessed the relation between female sex and sirolimus-eluting stent (SES) use on long-term outcomes in acute myocardial infarction., Background: There are no data on sex-specific differences in long-term benefit of SES use compared with bare-metal stent (BMS) use among patients undergoing primary percutaneous coronary interventions., Methods: We performed a post hoc analysis of the MULTISTRATEGY trial. Hazard ratios (HRs) of events with 95% CI for sex and stent type were computed using Cox proportional regression with adjustment for confounders., Results: A total of 744 patients, 64 years old (55-73 years old), 179 (24.1%) women, were enrolled. After a follow-up of 1,080 days, SES use was associated with a significant reduction of major adverse cardiovascular events, that is, the composite of all-cause death, reinfarction, or clinically driven target vessel revascularization (TVR) (13.9% vs 23.6%, adjusted HR 0.62, 95% CI 0.41-0.94, P = .026) and of TVR (6.1% vs 15.1%, adjusted HR 0.35, 95% CI 0.19-0.63, P < .001) in men. Conversely, SES use was not associated to a better outcome among women (major adverse cardiovascular events 21.9% in SES vs 18.2% in the BMS group, adjusted HR 1.27, 95% CI 0.53-3.02, P = .59; TVR 6.6% vs 9.1%, adjusted HR 0.62, 95% CI 0.17-2.21, P = .46)., Conclusions: In this analysis, the clinical benefit of SES use, over BMS, at 3-year follow-up was restricted to men and was not observed among women., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Evidence of prehistoric dentistry has been limited to a few cases, the most ancient dating back to the Neolithic. Here we report a 6500-year-old human mandible from Slovenia whose left canine crown bears the traces of a filling with beeswax. The use of different analytical techniques, including synchrotron radiation computed micro-tomography (micro-CT), Accelerator Mass Spectrometry (AMS) radiocarbon dating, Infrared (IR) Spectroscopy and Scanning Electron Microscopy (SEM), has shown that the exposed area of dentine resulting from occlusal wear and the upper part of a vertical crack affecting enamel and dentin tissues were filled with beeswax shortly before or after the individual's death. If the filling was done when the person was still alive, the intervention was likely aimed to relieve tooth sensitivity derived from either exposed dentine and/or the pain resulting from chewing on a cracked tooth: this would provide the earliest known direct evidence of therapeutic-palliative dental filling.

Background: The purpose of this study is to present data on the effects of pre-hospital electrocardiogram (PH-ECG) on the outcome of ST elevation myocardial infarction (STEMI) patients treated with percutaneous coronary angioplasty (PCI) included in a registry undertaken in the Italian region of Lombardy. Pre-hospital 12-lead electrocardiogram is recommended by current guidelines in order to achieve faster times to reperfusion in patients with STEMI., Methods: The registry includes 3901 STEMI patients who underwent primary PCI over an 18-month period., Results: Mean age was 63 ± 12 years. Admission through the emergency medical system (EMS) occurred in 1603 patients (40%): they were older, more frequently had previous MI, TIMI flow = 0 at entry and were more frequently in Killip class >1 than patients who were not admitted through the EMS. Among the patients admitted through the EMS, PH-ECG was obtained in 475 patients (12%). These patients had less frequently an anterior MI, but more frequently had absence of TIMI flow at entry than patients whose ECG was not teletransmitted. Moreover, they had a significantly shorter first medical contact-to-balloon time and a trend toward a lower 30-day death rate (5.3% vs 7.9 %, p = 0.06). However, only patients in Killip class 2-3 had a significantly lower mortality when the diagnostic ECG was transmitted, whereas no difference was found in Killip class 1 or Killip class 4 patients., Conclusions: In this registry, PH-ECG significantly decreased first medical contact-to-balloon time. Attempts to achieve faster reperfusion times should be undertaken, as this may result in improved outcome, particularly in patients with mild to moderate symptoms of heart failure.

Objectives: These studies sought to investigate the impact on mortality of coronary flow after passage of the wire through the culprit vessel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing mechanical reperfusion., Background: Reduced spontaneous coronary flow before percutaneous coronary intervention influences mortality in patients with STEMI. Response to vessel wiring in patients with an occluded coronary artery before intervention might further discriminate outcomes irrespective of pre- and post-intervention coronary flow., Methods: Data from the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials were pooled: of 919 index procedures, 902 films (98%) were technically adequate for core laboratory TIMI (Thrombolysis In Myocardial Infarction) flow determination., Results: TIMI flow grade 0 was present before percutaneous coronary intervention in 59% of infarct vessels, TIMI flow grade 1 to 2 was found in 21%, whereas the remainder of infarct arteries presented with TIMI flow grade 3. In 49% of patients who showed persistent TIMI flow grade 0 after wire insertion (AWI), mortality was higher at 30 days (5.3%) and 1 year (9.4%) compared with patients in whom TIMI flow grade before percutaneous coronary intervention was either >0 (0.8%; p < 0.003 and 3.6%, p < 0.008) or improved from 0 AWI (1.5%, p < 0.04 and 3.6%, p < 0.02). After correcting for multiple imbalances, including baseline and final flow, persistent TIMI flow grade 0 AWI remained associated at 30 days to 2-fold (risk ratio [RR]: 2.1, 95% confidence interval [CI]: 1.08 to 5.00; p = 0.038) and at 1 year to almost 3-fold increases of mortality (RR: 2.7, 95% CI: 1.3 to 5.6; p = 0.008)., Conclusions: STEMI patients displaying persistent no-flow AWI have a lower survival rate despite an apparently successful mechanical intervention. As an early marker for high residual mortality risk, persistent no-flow AWI may qualify STEMI patients for dedicated pharmacomechanical treatment strategies., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate the impact of SYNTAX score (SXscore), and compare its performance in isolation and combination with the PAMI (The Primary Angioplasty in Myocardial Infarction Study) score, for the prediction of 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention., Background: Patients with STEMI were excluded from the original SYNTAX score (SXscore) algorithm. Therefore, the utility of using the SXscore in this patient group remains undefined., Methods: SXscore was calculated retrospectively in 807 patients with STEMI enrolled in the randomized STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) clinical trials. Clinical outcomes of all-cause death, reinfarction, and clinically driven target vessel revascularization were subsequently stratified according to SXscore tertiles: SX(LOW) ≤ 9 (n = 311), 9 < SX(MID) ≤ 16 (n = 234), SX(HIGH) >16 (n = 262)., Results: At 1-year follow-up, all clinical outcomes including mortality, mortality/reinfarction, major adverse cardiac events (MACE) (a composite of all-cause death, reinfarction and target vessel revascularization), and definite, definite/probable, and any stent thrombosis were all significantly higher in patients in the highest SXscore tertile. SXscore was identified as an independent predictor of mortality, MACE, and stent thrombosis out to 1-year follow-up. The combination SYNTAX-PAMI score led to a net reclassification improvement of 15.7% and 4.6% for mortality and MACE, respectively. The C-statistics for the SXscore, PAMI score, and the combined SYNTAX-PAMI score were 0.65, 0.81, and 0.73 for 1-year mortality, and 0.68, 0.64, and 0.69 for 1-year MACE, respectively., Conclusions: SXscore does have a role in the risk stratification of patients with STEMI having primary percutaneous coronary intervention; however, this ability can be improved through a combination with clinical variables. (Multicentre 2×2 Factorial Randomised Study Comparing Tirofiban Versus Abciximab and SES Versus BMS in AMI; NCT00229515)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Percutaneous coronary intervention (PCI) has been shown to be the best reperfusion therapy for acute myocardial infarction with ST-elevation (STEMI), but data from registries show differences in patient populations and outcomes between randomized trials and real life., Objectives: We sought to provide information about the current status of this treatment with a registry collecting data in Lombardy, the most densely populated region in Italy, with widespread availability of cathlabs and a well-established network for the treatment of STEMI., Methods and Results: Patient enrollment was performed by 32 hub centres recruiting 3901 STEMI patients who underwent PCI procedures within 12 h of the onset of symptoms, of whom 3317 patients underwent primary PCI, 376 'facilitated' PCI, and 208 rescue PCI in cathlabs located, in 77% of cases, in the same hospital of admission. In-hospital and 30-day total death were 4.4 and 6.6%, respectively. At multivariate analysis independent negative predictors of 30-day mortality were Killip class 3-4, number of involved ECG leads, chronic renal failure and age, whereas positive predictors were ST resolution more than 50% and postprocedural grade 3 thrombolysis in myocardial infarction flow., Conclusions: LombardIMA PCI registry enrolled STEMI patients representing a real-world population treated with PCI. Findings presented in this study may provide a benchmark for similar registries undertaken in other Italian regions and may be helpful to assess future possible developments of care for STEMI patients.

Objectives: The purpose of this study was to investigate the long-term outcome after elective percutaneous coronary intervention in low-risk patients screened for aspirin and/or clopidogrel responsiveness in the 3T/2R (Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel) trial., Background: The impact of aspirin and/or clopidogrel poor response on long-term outcome is debated., Methods: Aspirin and clopidogrel response was measured with the VerifyNow system aspirin and P2Y12 assays. After percutaneous coronary intervention (PCI), death, stroke, and myocardial infarction were assessed up to 1 year., Results: Overall, 1,277 patients were screened, and 826 (65%) were treated with PCI. In all, 124 patients were found to be aspirin poor responders, and there were 179 clopidogrel poor responders (totally, 278 poor responders). The 1-year end point was significantly higher in poor responders as compared to full responders (15.8% vs. 8.6%, p=0.002), which is principally due to more myocardial infarction occurrence. At multivariable analysis, clopidogrel poor response emerged as an independent predictor (hazard ratio: 1.15, 95% confidence interval: 1.03 to 1.28). Receiver-operator characteristic analysis identifies≤23 of percentage of platelet inhibition and ≥208 of P2Y12 reactivity units as optimal cut offs to predict 1-year end point. Excluding periprocedural events, also peri-PCI myocardial infarction, which is strongly related to aspirin/clopidogrel poor response, was an independent predictor (hazard ratio: 1.25, 95% confidence interval: 1.14 to 1.37). Glycoprotein IIb/IIIa inhibitor administration reduces this risk in poor responders (21.2% vs. 34.7%, p=0.02), but not in full responders (6.3% vs. 6.5%, p=0.8)., Conclusions: Poor response to clopidogrel is an independent predictor of periprocedural myocardial infarction and worse 1-year outcome in low-risk patients undergoing PCI, whereas poor response to aspirin failed to predict a worse outcome. Contrary to what was observed in poor responders, glycoprotein IIb/IIa inhibitor therapy failed to provide a benefit in aspirin and/or clopidogrel full responders., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Scant data are available on the relation between ST-segment elevation (STE) resolution and 30-day mortality in patients with STE acute myocardial infarction treated with percutaneous coronary intervention in contemporary, real world, clinical practice. Furthermore, whether the prognostic value of STE resolution is influenced by the patient clinical risk profile or postprocedural Thrombolysis In Myocardial Infarction (TIMI) flow has never been investigated. Lombardima was an observational registry implemented in Lombardy, a Northern Italian region. The clinical characteristics, electorcardiographic parameters, and procedural data were prospectively entered into a Web-based database. In the present study, we enrolled 3,403 patients. STE resolution occurred in 2,452 patients (group 1) and did not in 951 patients (group 2). The mortality rate was 2.4% in group 1 and 11.3% in group 2 (p <0.001). After stratifying patients according to their TIMI risk index, we observed that STE resolution was an independent predictor of 30-day mortality across all spectrum of clinical risk. Furthermore, in patients with TIMI 3 flow, STE resolution remained an independent predictor of 30-day mortality (p <0.0001). In conclusion, STE resolution was a strong and independent predictor of 30-day mortality in patients with STE acute myocardial infarction undergoing percutaneous coronary intervention across all spectrum of clinical risk., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients, and previous studies have suggested that poor response to oral antiplatelet agents may increase the risk of thrombotic events, especially after coronary angioplasty. Whether this reflects suboptimal platelet inhibition per se, which might benefit from more potent antiplatelet agents such as tirofiban, is unknown., Methods and Results: We screened 1277 patients to enroll 93 aspirin, 147 clopidogrel, and 23 dual poor responders, based on a point-of-care assay, who underwent elective coronary angioplasty at 10 European sites for stable or low-risk unstable coronary artery disease. Patients were randomly assigned in a double-blind manner to receive either tirofiban (n=132) or placebo (n=131) on top of standard aspirin and clopidogrel therapy. The primary end point, consisting of troponin I/T elevation at least 3 times the upper limit of normal, was attained in 20.4% (n=27) in the tirofiban group compared with 35.1% (n=46) in the placebo group (relative risk, 0.58; 95% confidence interval, 0.39 to 0.88; P=0.009). The rate of major adverse cardiovascular events within 30 days in the tirofiban group also was reduced (3.8% versus 10.7%; P=0.031). The overall incidence of bleeding was low, likely explained by a substantial use of the transradial approach, and did not differ between the 2 groups., Conclusions: In low-risk patients according to clinical presentation who had poor responsiveness to standard oral platelet inhibitors via a point-of-care assay, intensified platelet inhibition with tirofiban lowers the incidence of myocardial infarction after elective coronary intervention.

The 3He(alpha,gamma)7Be reaction presently represents the largest nuclear uncertainty in the predicted solar neutrino flux and has important implications on the big bang nucleosynthesis, i.e., the production of primordial 7Li. We present here the results of an experiment using the recoil separator ERNA (European Recoil separator for Nuclear Astrophysics) to detect directly the 7Be ejectiles. In addition, off-beam activation and coincidence gamma-ray measurements were performed at selected energies. At energies above 1 MeV a large discrepancy compared to previous results is observed both in the absolute value and in the energy dependence of the cross section. Based on the available data and models, a robust estimate of the cross section at the astrophysical relevant energies is proposed.

Background: Steroids have known powerful anti-inflammatory effects. This study was designed to assess the possible antiproliferative action of the Dexamet(R)dexamethasone-loaded stent., Methods: This was a prospective, controlled registry performed in 20 Italian centers that enrolled 332 patients with acute coronary syndromes (ACS) treated according to an early-invasive approach with the implantation of 420 dexamethasone-eluting stents in 387 coronary lesions. Six of the enrolling centers participated in the angiographic substudy: elective 6-month follow-up angiography was performed in 140/151 patients (92.7%). Quantitative coronary analysis (QCA) was performed at a centralized core laboratory on 156 lesions treated with the Dexamet stent., Results: One hundred forty patients (156 lesions) underwent elective QCA. Patients presented with either unstable angina (80%) or Non-ST-elevation myocardial infarction (20%); 70 patients (50%) had ST-T segment changes, 81 (58%) had troponin elevation and 31 (22.1%) were diabetic. One hundred twenty-five patients had a single lesion, 117 of which were treated with a single stent, while 8 received multiple stents. Mean lesion and stent lengths were 11.94 +/- 6.30 and 17.30 +/- 6.08 mm, respectively. In-segment binary restenosis (percent [%] diameter stenosis >/= 50%) was 34.3% per patient (48/140), or 33.3% per lesion (52/156); the mean late lumen loss was 0.95 +/- 0.64 mm in-stent and 1.02 +/- 0.59 mm in-segment. At multivariate analysis, baseline minimum luminal diameter (MLD) (MLD - odds ratio [OR] = 0.18; 95% confidence interval [CI] = 0.04-0.72; p = 0.01) and lesion length (OR = 1.12; 95% CI = 1.04-1.2; p < 0.01) were independent predictors of 6-months binary restenosis, Conclusions: This is the first large, multicenter analysis of the angiographic outcome obtained with Dexamet. Our results do not support any effective antiproliferative action of this device implanted in patients with ACS.

Background: The role of emergency reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI) resuscitated after an out-of-hospital cardiac arrest (OHCA) has not been clearly established yet. The aim of this study was to evaluate the in-hospital and postdischarge outcomes of STEMI patients surviving OHCA and undergoing emergency angioplasty (percutaneous coronary intervention [PCI]) within an established regional network., Methods: We prospectively collected data on 2,617 consecutive patients with STEMI treated with emergency PCI in 2005; in-hospital and 6-month outcomes of 99 patients who had experienced OHCA were compared with those of 2,518 patients without OHCA. The OHCA patients also underwent a cerebral performance evaluation after 12 months., Results: OHCA patients were at higher clinical risk at presentation (cardiogenic shock 26% vs 5%, P < .0001). Percutaneous coronary intervention was successful in 80% of the OHCA and 89% of the non-OHCA patients (P = NS). In-hospital mortality rates were 22% and 3%, respectively (P < .0001). Independent predictors of in-hospital mortality among OHCA patients were longer delay between the call to the emergency medical system and the start of cardiopulmonary resuscitation (odds ratio [OR] 3.5, P = .03), nonshockable initial rhythms (OR 10.5, P = .002), cardiogenic shock (OR 3.05, P = .035), and a Glasgow Coma Scale score of 3 on admission (OR 2.9, P = .032). The 6-month composite rate of death, myocardial infarction, and revascularization among OHCA patients surviving the acute phase was comparable to that of non-OHCA patients (16% vs 13.9%, P = NS), and 87% of them showed a favorable neurologic recovery after 1 year., Conclusions: Resuscitated OHCA patients undergoing emergency PCI for STEMI have worse clinical presentation and higher in-hospital mortality compared to those without OHCA. However, subsequent cardiac events are similar, and neurologic recovery is more favorable than reported in most previous series.

Purpose: To assess whether glycoprotein IIb/IIIa inhibition using tirofiban in low risk patients undergoing percutaneous coronary intervention (PCI) may reduce the risk of periprocedural myocardial infarction compared to standard care in poor responders to aspirin and/or clopidogrel., Methods: We will enroll patients at ten European sites or more to participate in the Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel (3T/2R) study with a pre-specified sample size of 240 patients out of 1,100 or more who will undergo screening. The primary outcome measure is troponin I or T elevation ratio at least three times the upper limit of normal within 48 h after completion of the PCI., Conclusion: The results of 3T/2R study will evaluate whether tailored intensification of anti-platelet treatment based on poor individual response to oral anti-platelet agents may modulate the risk of periprocedural myocardial infarction during PCI. Our findings attempt at unraveling a new era of individualized anti-platelet treatment through the use of point-of-care assessment.

Context: Abciximab infusion and uncoated-stent implantation is a complementary treatment strategy to reduce major adverse cardiac events in patients undergoing angioplasty for ST-segment elevation myocardial infarction (STEMI). It is uncertain whether there may be similar benefits in replacing abciximab with high-dose bolus tirofiban. Similarly, the use of drug-eluting stents in this patient population is currently discouraged because of conflicting results on efficacy reported in randomized trials and safety concerns reported by registries., Objective: To evaluate the effect of high-dose bolus tirofiban and of sirolimus-eluting stents as compared with abciximab infusion and uncoated-stent implantation in patients with STEMI undergoing percutaneous coronary intervention., Design, Setting, and Patients: An open-label, 2 x 2 factorial trial of 745 patients presenting with STEMI or new left bundle-branch block at 16 referral centers in Italy, Spain, and Argentina between October 2004 and April 2007., Interventions: High-dose bolus tirofiban vs abciximab infusion and sirolimus-eluting stent vs uncoated stent implantation., Main Outcome Measures: For drug comparison, at least 50% ST-segment elevation resolution at 90 minutes postintervention with a prespecified noninferiority margin of 9% difference (relative risk, 0.89); for stent comparison, the rate of major adverse cardiac events, defined as the composite of death from any cause, reinfarction, and clinically driven target-vessel revascularization within 8 months., Results: ST-segment resolution occurred in 302 of 361 patients (83.6%) who had received abciximab infusion and 308 of 361 (85.3%) who had received tirofiban infusion (relative risk, 1.020; 97.5% confidence interval, 0.958-1.086; P < .001 for noninferiority). Ischemic and hemorrhagic outcomes were similar in the tirofiban and abciximab groups. At 8 months, major adverse cardiac events occurred in 54 patients (14.5%) with uncoated stents and 29 (7.8%) with sirolimus stents (P = .004), predominantly reflecting a reduction of revascularization rates (10.2% vs 3.2%). The incidence of stent thrombosis was similar in the 2 stent groups., Conclusions: In patients with STEMI undergoing percutaneous coronary intervention, compared with abciximab, tirofiban therapy was associated with noninferior resolution of ST-segment elevation at 90 minutes following coronary intervention, whereas sirolimus-eluting stent implantation was associated with a significantly lower risk of major adverse cardiac events than uncoated stents within 8 months after intervention., Trial Registration: clinicaltrials.gov Identifier: NCT00229515.

Background: Current treatment standards for patients undergoing primary percutaneous coronary intervention support early infusion of abciximab, followed by bare-metal stent (BMS) implantation. Whether the use of sirolimus-eluting stent (SES) would result in a further improvement of clinical outcomes remains to be proven. Similarly, whether tirofiban administered at high-bolus dose (HBD) followed by standard infusion is a valuable alternative to abciximab in the setting of ST-segment elevation myocardial infarction remains uncertain., Study Design: Multicentre evaluation of single high-bolus dose tirofiban versus abciximab and sirolimus-eluting versus bare metal stent in acute myocardial infarction (MULTI-STRATEGY) is a phase III, open-label, multinational investigator-driven clinical trial evaluating, with a 2-by-2 factorial design, the safety/efficacy profile of 4 interventional strategies of reperfusion: tirofiban given at HBD (bolus of 25 microg/kg over 3 minutes), followed by an infusion of 0.15 microg/kg per minute for 18 to 24 hours versus abciximab and SES, as compared to BMS implantation in primary percutaneous coronary intervention. The coprimary objectives are (i) the evaluation of the effect of SES versus BMS on the incidence of major adverse cardiac events within 8 months of the index procedure and (ii) the degree of ST-segment resolution obtained after the mechanical intervention for the comparison of HBD tirofiban versus abciximab. The protocol mandates clinical follow-up for 5 years., Conclusions: MULTI-STRATEGY will evaluate the role of SES and HBD tirofiban versus BMS and abciximab in the acute management of patients presenting with ST-segment elevation myocardial infarction.

Objective: To assess immediate and mid-term clinical and angiographic outcomes of the dexamethasone drug-eluting stent (D-DES) in patients with acute coronary syndrome (ACS)., Patients and Methods: A prospective, nationwide, controlled, registry. Inflammation plays a key role in ACS, and the anti-inflammatory effects of local elution of dexamethasone in unstable plaques may represent a valid therapeutic approach. All patients had ACS on admission (n = 332). 81.5% of the patients had unstable angina and 18.5% had non-ST elevation myocardial infarction (MI). 47% had ST-T segment changes, 59% had troponin elevation, 77% had elevated C-reactive protein levels and 48% had intermediate-high Thrombolysis in Myocardial Infarction risk score. Patients were treated according to an early invasive approach with 420 D-DES in 387 coronary lesions. Primary end point was the cumulative incidence of death, MI and ischaemia-driven target vessel revascularisation (TVR) at 6 months., Results: At 30 days, 2 (0.6%) patients died, and sub-acute stent thrombosis occurred in 2 patients. At 6 months, 328 (98.8%) patients were controlled, 3 (0.9%) patients had died, 7 (2.1%) had MI and 28 (8.5%) underwent ischaemia-driven TVR. Therefore, the primary end point occurred in 11.5% of patients. At multivariate analysis, multi-vessel coronary artery disease (odds ratio (OR) = 2.16, 95% CI = 1.47 to 3.17, p = 0.0001) and vessel diameter < or =2.75 mm (OR = 1.64, 95% CI = 1.08 to 2.49, p = 0.02) were independent predictors of 6-month clinical events. Global angiographic restenosis rate was 33.3%., Conclusion: This is the first large, multicentre analysis of the clinical and angiographic outcomes obtained with D-DES implanted in ACS. D-DES offers a low rate of clinical events at 6 months, but has no anti-restenosis effect.

Human bones recovered from the archaeological site of Pontecagnano (Salerno, Italy) have been studied to reconstruct the diet of an Etrurian population. Two different areas were investigated, named Library and Sant' Antonio, with a total of 44 tombs containing human skeletal remains, ranging in age from the 8th to the 3rd century B.C. This time span was confirmed by 14C dating obtained using Accelerator Mass Spectrometry (AMS) on one bone sample from each site. Atomic Absorption Spectrometry (AAS) was used to extract information about the concentration of Sr, Zn, Ca elements in the bone inorganic fraction, whilst stable isotope ratio measurements (IRMS) were carried out on bone collagen to obtain the delta13C and delta15N. A reliable technique has been used to extract and separate the inorganic and organic fractions of the bone remains. Both IRMS and AAS results suggest a mixed diet including C3 plant food and herbivore animals, consistent with archaeological indications.

Stents increase smooth muscle cell proliferation, which may also lead to in-stent restenosis. A local delivery strategy provides higher drug concentration at the angioplasty site and may limit the proliferative response following stenting. Local heparin delivery was attempted in 35 patients following balloon angioplasty using an "over-the-balloon" style catheter (infusion sleeve). The infusion sleeve was successfully tracked and heparin was delivered in 33 (94%) patients. Heparin (1,000 IU/ml) was delivered under low (45 psi, 2 ml, n = 4), intermediate (75 psi, 4 ml, n = 11), and high (100 psi, 4 ml, n = 18) proximal infusion pressures. Stent placement was successful in all cases. Acute and in-hospital complications were a severe arterial spasm after heparin delivery, a non Q-wave myocardial infarction, and two vascular complications. Ten dissections were observed after PTCA and prior to heparin delivery. Of these dissections, 7 remained unchanged, 2 worsened, and 1 improved with local delivery. When heparin was delivered in the absence of dissection, no new dissections were observed. Of the 33 patients who received heparin, 30 (91%) had no symptoms and a negative exercise test at clinical follow-up. QCA analysis of 6-month follow-up angiograms, performed in 32 of 33 (97%) patients, demonstrated an acute gain of 1.98 +/- 0.67 mm, a late loss of 0.94 +/- 0.78 mm, a net gain of 1.04 +/- 0.78 mm, and a loss index of 0.48 +/- 0.32. Restenosis (> or = 50% stenosis) was observed in 4 of 32 (12%) patients. Local delivery of heparin via the infusion sleeve following PTCA and prior to stent deployment is feasible with an acceptable safety profile and a low clinical and angiographic restenosis rate at 6 months.

Because systemic factors, such as lipoproteins, autoantigens, infectious agents, may facilitate plaque rupture, thrombus formation and coronary occlusion, the question may arise of whether thrombosis be only a local plaque event or the consequence of an acute activity of the entire coronary tree. Taking changes at the narrowest point of non culprit lesions as reflecting progression or regression of the disease when > 0.27 mm, early (within a few days) and late (within 1 month) coronarographic findings in 23 patients with first infarction were compared with those of patients with stable angina, in whom coronary angiography was performed for diagnostic purposes and was repeated 1 month later, before angioplasty. Sixteen infarction patients had progression, 4 had regression, 1 had both, and 2 had steadiness; corresponding values in stable angina group were 2 (p < 0.001), 1 (NS), 0 (NS) and 20 (p < 0.001). In the infarction group, 17 out of the 45 non culprit lesions progressed and 5 regressed; corresponding figures in stable angina group were 2 (p < 0.001) and 1 (p < 0.05). Three of the infarction patients developed interim angina at rest that was associated with progression of a culprit lesion in each of them. These results support the hypothesis that in a number of cases infarction may not reflect an arbitrary plaque event but rather a systemic coronary disease activity with maximal expression at the level of the offending plaque.

Aim: Transient coronary artery occlusion during percutaneous transluminal coronary angioplasty may cause left ventricular diastolic dysfunction. The aim of this study was to evaluate the effect of left anterior descending, left circumflex and right coronary artery balloon occlusion on right ventricular diastolic function., Methods: Thirty-five patients with single-vessel coronary artery disease and no previous myocardial infarction were selected. Left and right ventricular filling pressures were monitored by Doppler echocardiography and haemodynamic monitoring. This was performed during and immediately after 60 s of coronary balloon occlusion of the left anterior descending artery in 21 cases (Group 1), the left circumflex artery in eight cases (Group 2) and the right coronary artery in six cases (Group 3). Doppler analysis of left and right ventricular filling included peak velocity of early (PFVE) and late ventricular filling (PFVA) and PFVE to PFVA ratio (PFVE/PFVA)., Results: In all three groups, balloon inflation induced a significant increase in left and right filling pressures (P < 0.05). No qualitative difference in haemodynamic changes was found between groups during inflation. Significant impairment in the Doppler pattern of left and right ventricular filling occurred after 20 s of coronary occlusion: PFVE values in mitral and tricuspid valves decreased by 14% and 25% in Group 1, 13% and 25% in Group 2, and 10% and 21% in Group 3, respectively, as PFVA remained unchanged in all groups, the PFVE/PFVA ratio of mitral and tricuspid valve flows significantly decreased (Group 1: -12% and -20%, Group 2: -10% and -21%, Group 3: -14% and -21%, respectively). All parameters returned to baseline within 30 s after each balloon deflation., Conclusion: Our data suggest that brief episodes of acute myocardial ischaemia, such as those induced by 60 s of coronary artery occlusion during percutaneous transluminal coronary angioplasty, elicit simultaneous diastolic dysfunction of both ventricles, independent of the coronary artery involved.

Recent evidence suggests that higher restenosis rate is observed after coronary angioplasty of an infarct-related artery. Furthermore, angiographic restenosis seems associated with a deterioration of left ventricular function at follow-up. The aim of this study was to assess the acute results and angiographic restenosis following coronary artery stenting of infarct-related (Group 1) and non infarct-related coronary arteries (Group 2). We retrospectively analyzed the results of 381 consecutive patients treated with Palmaz-Schatz coronary stent implantation between May 1992 and January 1996. Stenting of the infarct-related artery was performed in 154 patients (Group 1), while 227 patients (Group 2) received stenting of the non infarct-related artery. Both groups had similar age, gender, clinical conditions and coronary angiographic pattern. There were no significant differences between groups, concerning type of stented coronary vessel (left anterior descending-LAD 52.4% vs non-LAD 47.6%, Group 1, LAD 59.5% vs non-LAD 40.5%, Group 2) and number of stents per patient (1.31 +/- 0.48 in Group 1, 1.18 +/- 0.56 in Group 2) and per coronary vessel (1.17 +/- 0.54 in Group 1, 1.09 +/- 0.46 in Group 2). The procedure was performed using similar maximal inflation pressures in both groups (13.3 +/- 2.9 atm in Group 1, 13.40 +/- 3.17 atm in Group 2). Technical success was achieved in 96.8% of Group 1 and in 96% of Group 2 patients. Acute coronary stenting success and major adverse events (acute myocardial infarction, emergency bypass, death) were similar in both groups of patients. No difference was found in restenosis rate at 6-month angiographic follow-up (Group 1 = 29.8%, Group 2 = 27%). In conclusion, this study indicates that stenting of infarct and non infarct-related coronary arteries has similar success and 6-month restenosis rates.

Background: Destabilization of the fibrous cap facilitates plaque rupture, thrombus formation, and myocardial infarction. Because systemic stimuli, such as lipoproteins, infectious agents, and autoantigens, may incite this reaction, one may wonder whether disruption mechanisms are only local or systemic and infarction is caused by an arbitrary plaque event or by a systemic, acute activity of the coronary disease., Methods and Results: Early (3 to 5 days) and late (1 month) peri-infarction coronary angiographic data in 23 patients with first infarction were compared with that in 23 similar patients, with angiography performed because of stable angina and repeated after 1 month before angioplasty. Nonculprit lesion changes at the narrowest point defined progression or regression when exceeding 0.27 mm. In patients with recent infarction we found that 16 had progression, 4 had regression, 1 had both, 2 were steady (values in patients with stable angina being 2 [P<.0011, 1 [NS], 0 [NS], and 20 [P<.001]); 27 lesions were infarct related; 17 of the 45 nonculprit lesions progressed and 5 regressed (values in stable angina being 2 [P<.001] and 1 [P<.05] out of 78); minimal diameter reduction of progressing stenoses averaged 0.39 mm; lumen increase of regressing lesions averaged 0.30 mm; 3 patients developed interim rest angina associated with progression of a nonculprit lesion., Conclusions: A greater proportion of subjects and lesions with progression or regression (in infarction versus stable angina) supports the hypothesis that infarction is a hallmark of systemic coronary disease activity. Changes might vary according to the "maturation" stage of an atheroma, and maximal expression would be at the level of the offending plaque. Shrinkage, thrombolysis, or vascular remodeling would determine the residual plaque morphology.