Gender differences with short-term vs 12 months dual antiplatelet therapy in patients with acute coronary syndrome treated with the COMBO dual therapy stent: 2-years follow-up results of the REDUCE trial.

BACKGROUND: Gender differences in the thrombotic and bleeding risk have been suggested to condition the benefits of antithrombotic therapies in Acute Coronary Syndrome (ACS) patients, and mainly among those undergoing percutaneous coronary interventions with drug eluting stents (DES). The impact of gender on the optimal duration of dual antiplatelet therapy (DAPT) in ACS patients is still unexplored and was, therefore, the aim of the present sub-study. METHODS: REDUCE was a prospective, multicenter, randomized investigator-initiated study designed to enroll 1500 ACS patients after treatment with the COMBO Dual Stent Therapy, based on a noninferiority design. Patients were randomized in a 1:1 fashion to either 3 or 12 months of DAPT. Primary study endpoint was a composite of all-cause mortality, myocardial infarction, definite/probable stent thrombosis (ST), stroke, target-vessel revascularization (TVR) and bleedings (BARC II, III, V) at 12 months. Secondary endpoints were cardiovascular mortality and the individual components of the primary endpoint within 24 months. RESULTS: From June 2014 to May 2016 300 women and 1196 men were included in the study. Among them, 43.7% of females and 51.9% of males were assigned to the 3 months DAPT treatment. Baseline characteristics were well matched between the two arms, with the exception of a lower rate of TIMI flow < 3 (p = 0.04), lower systolic blood pressure (p = 0.05) and use of spironolactone (p = 0.006) among women and a more advanced age (p = 0.05) among men receiving a short-term DAPT. At a mean follow-up of 525 (± 198) days, no difference in the primary endpoint was observed according to DAPT duration in both females [6.9% vs 5.9%, HR (95% CI) = 1.19 (0.48-2.9), p = 0.71] and males [8.2% vs 9%, HR (95% CI) = 0.92 (0.63-1.35), p = 0.67; p INT = 0.20]. Results were confirmed after correction for baseline differences [females: adjusted HR (95% CI) = 1.12 (0.45-2.78), p = 0.81; males: adjusted HR (95% CI) = 0.90 (0.61-1.32), p = 0.60]. Comparable rates of survival, thrombotic (MI, stent thrombosis, TVR, stroke) and bleeding events were observed with the two DAPT strategies, with no impact of gender. CONCLUSIONS: The present study shows that among ACS patients randomized in the REDUCE trial, a 3 months DAPT strategy offers comparable results as compared to a standard 12 months DAPT at 2-years follow-up in both male and female gender.

Everolimus-eluting bioresorbable scaffolds and metallic stents in diabetic patients: a patient-level pooled analysis of the prospective ABSORB DM Benelux Study, TWENTE and DUTCH PEERS.

BACKGROUND: Several studies compared everolimus-eluting bioresorbable scaffolds (EE-BRS) with everolimus-eluting stents (EES), but only few assessed these devices in patients with diabetes mellitus. AIM: To evaluate the safety and efficacy outcomes of all-comer patients with diabetes mellitus up to 2 years after treatment with EE-BRS or EES. METHODS: We performed a post hoc pooled analysis of patient-level data in diabetic patients who were treated with EE-BRS or EES in 3 prospective clinical trials: The ABSORB DM Benelux Study (NTR5447), TWENTE (NTR1256/NCT01066650) and DUTCH PEERS (NTR2413/NCT01331707). Primary endpoint of the analysis was target lesion failure (TLF): a composite of cardiac death, target vessel myocardial infarction or clinically driven target lesion revascularization. Secondary endpoints included major adverse cardiac events (MACE): a composite of all-cause death, any myocardial infarction or clinically driven target vessel revascularization, as well as definite or probable device thrombosis (ST). RESULTS: A total of 499 diabetic patients were assessed, of whom 150 received EE-BRS and 249 received EES. Total available follow-up was 222.6 patient years (PY) in the EE-BRS and 464.9 PY in the EES group. The adverse events rates were similar in both treatment groups for TLF (7.2 vs. 5.2 events per 100 PY, p = 0.39; adjusted hazard ratio (HR) = 1.48 (95% confidence interval (CI): 0.77-2.87), p = 0.24), MACE (9.1 vs. 8.3 per 100 PY, p = 0.83; adjusted HR = 1.23 (95% CI: 0.70-2.17), p = 0.47), and ST (0.9 vs. 0.6 per 100 PY, p > 0.99). CONCLUSION: In this patient-level pooled analysis of patients with diabetes mellitus from 3 clinical trials, EE-BRS showed clinical outcomes that were quite similar to EES.

Informing MS patients on treatment options: a consensus on the process of consent taking.

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. AIMS: The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. RESULTS: The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS.

Re-entrant charge order in overdoped (Bi,Pb)2.12Sr1.88CuO6+δ outside the pseudogap regime.

In the underdoped regime, the cuprate high-temperature superconductors exhibit a host of unusual collective phenomena, including unconventional spin and charge density modulations, Fermi surface reconstructions, and a pseudogap in various physical observables. Conversely, overdoped cuprates are generally regarded as conventional Fermi liquids possessing no collective electronic order. In partial contradiction to this widely held picture, we report resonant X-ray scattering measurements revealing incommensurate charge order reflections for overdoped (Bi,Pb)2.12Sr1.88CuO6+δ (Bi2201), with correlation lengths of 40-60 lattice units, that persist up to temperatures of at least 250 K. The value of the charge order wavevector decreases with doping, in line with the extrapolation of the trend previously observed in underdoped Bi2201. In overdoped materials, however, charge order coexists with a single, unreconstructed Fermi surface without nesting or pseudogap features. The discovery of re-entrant charge order in Bi2201 thus calls for investigations in other cuprate families and for a reconsideration of theories that posit an essential relationship between these phenomena.

Everolimus-eluting bioresorbable scaffolds for treatment of coronary artery disease in patients with diabetes mellitus: the midterm follow-up of the prospective ABSORB DM Benelux study.

BACKGROUND: Percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM) remains challenging even with modern drug-eluting stents (DES) due to high rates of repeat revascularization. Everolimus-eluting bioresorbable scaffolds (EE-BRS) might allow for repeat intervention prolonging the time interval of percutaneous treatment options. METHODS: The ABSORB DM Benelux Study is a dedicated prospective, international study to evaluate the midterm safety and efficacy of EE-BRS in DM patients. All DM patients that received ≥ 1 EE-BRS for any indication were enrolled and prospectively followed. Study endpoints were major adverse cardiac events (MACE): a composite of all-cause death, any myocardial infarction (MI) and ischemic-driven target vessel revascularization (TVR); target lesion failure (TLF): a composite of cardiac death (CD), target vessel MI, and ischemic-driven target lesion revascularization (TLR), as well as definite or probable scaffold thrombosis (ScT). RESULTS: Between April 2015 till March 2017, 150 DM patients and 188 lesions were treated and followed up to 3 years. Device implantation success was 100%. MACE occurred in 15.2% (event rate of 8.8 per 100 PY). TLF was reported in 11.7% (7.0 events per 100 PY). CD, target vessel MI, ischemic-driven TLR occurred in 3.4%, 3.6% and 5.5% respectively, while ScT was observed in 1.4%. There were no occurrences of late or very late ScT. CONCLUSION: EE-BRS treatment in DM patients shows comparable midterm safety and efficacy outcomes when historically compared with modern DES. New-generation EE-BRS might offer an attractive alternative to metallic DES in treatment of fast progressing atherosclerosis population as in DM patients. Trial registration NTR5447. Registered 05 October 2015, retrospectively registered.

Classical de Sitter Solutions of 10-Dimensional Supergravity.

We find four-dimensional de Sitter compactifications of type IIA supergravity by directly solving the 10-dimensional equations of motion. In the simplest examples, the internal space has the topology of a circle times an Einstein manifold of negative curvature. An orientifold acts on the circle with two fixed loci, at which an O8_{-} and an O8_{+} plane sit. These orientifold planes are fully backreacted and localized. While the solutions are numerical, the charge and tension of the orientifold planes can be verified analytically. Our solutions have moduli at tree level and can be made parametrically weakly coupled and weakly curved. Their fate in string theory depends on quantum corrections.

Depolarizing-Field Effects in Epitaxial Capacitor Heterostructures.

We identify a transient enhancement of the depolarizing field, leading to an unexpected quench of net polarization, during the growth of a prototypical metal-ferroelectric-metal epitaxial system made of BaTiO_{3} and SrRuO_{3}. Reduced conductivity and, hence, charge screening efficiency in the early growth stage of the SrRuO_{3} top electrode promotes a breakdown of ferroelectric BaTiO_{3} into domains. We demonstrate how a thermal annealing procedure can recover the single-domain state. By tracking the polarization state in situ, using optical second harmonic generation, we bring new understanding to interface-related electrostatic effects in ferroelectric capacitors.

Gender differences in clinical presentation and vascular pattern in patients with Takayasu arteritis.

Objective: To compare clinical characteristics and pattern of vascular involvement at disease onset according to gender specificity in patients with Takayasu arteritis (TA).Methods: Data from 117 TA patients (11 male, 106 female), diagnosed according to the American College of Rheumatology criteria, from our centre were retrospectively collected. Differences between men and women regarding demographic features, diagnostic delay, signs and symptoms attributed to TA, and arteries involved at diagnosis were compared. Data were obtained from three published articles describing gender differences in TA. A global analysis of these three cohorts plus ours (a total of 578 patients; 108 men, 470 women) was performed.Results: In our TA cohort, age at disease onset and age at diagnosis were not significantly different between genders. Diagnostic delay was higher in men. Male patients showed higher involvement of iliac arteries (right, p = 0.016; left, p = 0.021); females suffered more frequently from upper limb claudication (p = 0.026). In the overall analysis, men had higher prevalence of arterial hypertension (p = 0.007) and more frequent involvement of abdominal aorta (p = 0.026), renal arteries (right, p < 0.001; left, p < 0.001), and iliac arteries (right, p = 0.009; left, p = 0.002). Women more frequently exhibited upper limb claudication (p = 0.042) and involvement of left subclavian artery (p = 0.005), carotid arteries (right, p < 0.001; left, p < 0.001), and supradiaphragmatic aorta (ascending, p = 0.050; arch, p < 0.001; descending, p = 0.003). Inflammatory markers were more frequently raised in women (p = 0.005).Conclusions: In TA patients, gender has a strong influence on pattern of vascular involvement and consequently on clinical presentation. Specifically, women have a higher involvement of the supradiaphragmatic vessels, whereas in men the abdominal vessels are more frequently affected.

Molecular detection of Chlamydia abortus in a stranded Mediterranean striped dolphin Stenella coeruleoalba.

This study reports gross, histopathological, and molecular features of a Chlamydia abortus infection in a stranded female striped dolphin Stenella coeruleoalba from the Tyrrhenian coast of southern Italy. Post-mortem examination revealed liver congestion, splenic lymphoid depletion with capsular petechiae, and pneumonia. Histology revealed disseminated intravascular coagulation with vasculitis and congestion. Hepatocellular and acute myocardial degeneration were also observed. Basophilic, coccobacillary inclusions consistent with Chlamydia spp. were observed histologically in the type II pneumocytes, myocardial fibers, and hepatocytes, and in macrophages and plasma cells of liver, spleen, and prescapular lymph nodes. Chlamydial antigen was detected by immunofluorescence assay using genus-specific anti-Chlamydia antibodies. PCR assay revealed C. abortus in spleen, liver, heart, and lungs. C. abortus was the only pathogen detected. The main pathological changes suggest that Chlamydia infection may have been the cause of stranding and death of the striped dolphin. This case represents the first molecular detection of a member of the Chlamydiaceae in a marine mammal.

The 1­year safety and efficacy outcomes of Absorb bioresorbable vascular scaffolds for coronary artery disease treatment in diabetes mellitus patients: the ABSORB DM Benelux study.

BACKGROUND: Diabetes mellitus (DM) patients show higher rates of repeat revascularisation even in the era of modern drug-eluting stents (DES). The concept of bioresorbable scaffolds is becoming captivating, as it might allow for repeat interventions, prolonging the time span during which patients can be treated by percutaneous coronary intervention (PCI). AIMS: We intend to evaluate the short- and long-term safety and efficacy of Absorb bioresorbable vascular scaffolds (Absorb BVS) in the treatment of coronary artery disease (CAD) in DM patients for any indication. METHODS: The ABSORB DM Benelux is an international prospective study in DM patients who have undergone PCI with ≥1 Absorb BVS. Major adverse cardiac events (MACE) at 1 year was the primary endpoint, defined as a composite of all-cause death, any myocardial infarction (MI) and ischaemia-driven target vessel revascularisation (TVR). Secondary endpoints were target lesion failure (TLF) and definite or probable scaffold thrombosis (ScT). RESULTS: Between April 2015 and March 2017, 150 DM patients and 188 non-complex lesions were treated. Device implantation was successful in 100%. MACE occurred in 14 (9.5%) patients, with all-cause death occurring in 4 (2.7%), any MI in 6 (4.1%) and ischaemia-driven TVR in 7 (4.8%) respectively. TLF was reported in 11 (7.5%). Definite and probable ScT was observed in 2 (1.4%). CONCLUSION: Absorb BVS for treatment of anatomically low-risk patients with DM show acceptable safety and efficacy outcomes at 1 year. If these promising results are confirmed after a longer follow-up period, new-generation bioresorbable scaffolds combined with refinement of implantation techniques might open new horizons for CAD treatment in DM patients.

Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Interactions between Proteins and the Membrane Surface in Multiscale Modeling of Organic Fouling.

In the present paper, an improved multiscale modeling aimed at describing membrane fouling in the UltraFiltration (UF) process was proposed. Some of the authors of this work previously published a multiscale approach to simulate ultrafiltration of Bovine Serum Albumin (BSA) aqueous solutions. However, the noncovalent interactions between proteins and the membrane surface were not taken into account in the previous formulation. Herein, the proteins-surface interactions were accurately computed by first-principle-based calculations considering also the effect of pH. Both the effective surface of polysulfone (PSU) and the first layer of proteins adsorbed on the membrane surface were accurately modeled. Different from the previous work, the equilibrium distance between proteins was calculated and imposed as lower bound to the protein-protein distances in the compact deposit accumulated on the membrane surface. The computed BSA surface charges were used to estimate the protein potential and the charge density, both necessary to formulate a forces balance at microscopic scale. The protein surface potential was compared with Z-potential measurements of BSA aqueous solution, and a remarkable agreement was found. Finally, the overall additional resistance, as due to both the compact and loose layers of the deposit, was computed, thus allowing the final transition to a macroscopic scale, where an unsteady-state mass transfer model was formulated to describe the behavior of a typical dead-end UF process. A good agreement between simulated and experimental permeate flux decays was observed.

Selective synthesis of turbostratic polyhedral carbon nano-onions by arc discharge in water.

Carbon nano-onions (CNOs), in their spherical or polyhedral forms, represent an important class of nanomaterials, due to their peculiar physical and electrochemical properties. Among the different methods of production, arc discharge between graphite electrodes sustained by deionized water is one of the most promising to obtain good quality CNOs in gram quantities. We applied the method with the aim to optimize the production of CNOs, using an innovative experimental arrangement. The discharges generate dispersed nanomaterials and a black hard cathodic deposit, which were studied by transmission electron microscopy-high-resolution TEM, scanning electron microscopy, Raman, thermogravimetric analysis and energy-dispersive x-ray spectroscopy. A simple mechanical grinding of the deposits permitted us to obtain turbostratic polyhedral CNOs that exhibited higher stability towards burning in air, compared to CNOs found in water. We propose a mechanism for the formation of the CNOs present in the deposit, in which the crystallization is driven by a strong temperature gradient existing close to the cathode surface at the beginning of the process, and subsequently close to the deposit surface whenever it is growing.

Tunable spin polarization and superconductivity in engineered oxide interfaces.

Advances in growth technology of oxide materials allow single atomic layer control of heterostructures. In particular delta doping, a key materials' engineering tool in today's semiconductor technology, is now also available for oxides. Here we show that a fully electric-field-tunable spin-polarized and superconducting quasi-2D electron system (q2DES) can be artificially created by inserting a few unit cells of delta doping EuTiO3 at the interface between LaAlO3 and SrTiO3 oxides. Spin polarization emerges below the ferromagnetic transition temperature of the EuTiO3 layer (TFM = 6-8 K) and is due to the exchange interaction between the magnetic moments of Eu-4f and of Ti-3d electrons. Moreover, in a large region of the phase diagram, superconductivity sets in from a ferromagnetic normal state. The occurrence of magnetic interactions, superconductivity and spin-orbit coupling in the same q2DES makes the LaAlO3/EuTiO3/SrTiO3 system an intriguing platform for the emergence of novel quantum phases in low-dimensional materials.

Configurations of the Re-scan Confocal Microscope (RCM) for biomedical applications.

The new high-sensitive and high-resolution technique, Re-scan Confocal Microscopy (RCM), is based on a standard confocal microscope extended with a re-scan detection unit. The re-scan unit includes a pair of re-scanning mirrors that project the emission light onto a camera in a scanning manner. The signal-to-noise ratio of Re-scan Confocal Microscopy is improved by a factor of 4 compared to standard confocal microscopy and the lateral resolution of Re-scan Confocal Microscopy is 170 nm (compared to 240 nm for diffraction limited resolution, 488 nm excitation, 1.49 NA). Apart from improved sensitivity and resolution, the optical setup of Re-scan Confocal Microscopy is flexible in its configuration in terms of control of the mirrors, lasers and filters. Because of this flexibility, the Re-scan Confocal Microscopy can be configured to address specific biological applications. In this paper, we explore a number of possible configurations of Re-scan Confocal Microscopy for specific biomedical applications such as multicolour, FRET, ratio-metric (e.g. pH and intracellular Ca2+ measurements) and FRAP imaging.

Impact of polymorphism rs7041 and rs4588 of Vitamin D Binding Protein on the extent of coronary artery disease.

BACKGROUND AND AIM: 25-hydroxyvitamin D deficiency represents a widespread social problem but also an emerging risk factor for cardiovascular disease. Genetic variants of the Vitamin D Binding Protein (VDBP), the main transporter of vitamin D in the bloodstream, have been shown to account for a significant variability in the levels and systemic effects of vitamin D. We investigated whether the single nucleotide polymorphisms, rs7041 and rs4588, of VDBP are associated to the prevalence and extent of coronary artery disease. METHODS AND RESULTS: A consecutive cohort of patients undergoing coronary angiography in a single centre were included. Significant CAD was defined as at least 1 stenosis >50%, severe CAD for as left main and/or three-vessel disease. VDBP genetic status was assessed by polymerase chain reaction and restriction fragment length polymorphism technique. We included 1080 patients, 57% carried the mutated G allele of rs7041, whereas 22% carried the A allele of rs4588. Higher levels of C- reactive protein were observed in the carriers of G allele of rs7041 (p = 0.02), whereas 25-hydroxyvitamin D levels were similar across groups. A higher prevalence of lesions in the left anterior descending artery and a longer lesion length were observed in "A" carriers for rs4588 (p = 0.04 and p = 0.03, respectively). On the contrary, a higher prevalence of bifurcation lesions and chronic occlusions was observed in G carriers (p = 0.002 and p = 0.01 respectively). Both polymorphisms of VDBP did not affect the prevalence of CAD (rs7041: 79.1% TT vs 80.3% TG vs 78.5% GG, p = 0.81; rs4588 = 80.3% CC vs 78.5% AC + AA, p = 0.49) and severe CAD, (rs7041: 31.1% TT % vs 31.3% TG vs 30.6% GG, p = 0.88; rs4588: 32.2% CC vs 29.3% AC + AA, p = 0.31). Results were confirmed at multivariate analysis, for both rs7041 and rs4588. However, when including the levels of 25-hydroxyvitamin D in the multivariate model, we observed that 25(OH)D status and not genetic variants of VDBP were significantly associated with CAD (25-hydroxyvitamin D OR [95% CI] = 0.99 [0.97-1.0], p = 0.05; rs7041 TG: OR [95% CI] = 1.26 [0.73-2.19], p = 0.41; rs7041 GG: OR [95% CI] = 1.25 [0.82-1.91], p = 0.30; rs4588 AC + AA: OR [95% CI] = 0.76 [0.51-1.13], p = 0.18). CONCLUSION: This study showed in a large cohort of patients undergoing coronary angiography, that the polymorphisms rs7041 and rs4588 of VDBP are not associated with the levels of 25-hydroxyvitamin D nor with the prevalence and extent of CAD. In fact, 25-hydroxyvitamin D levels but not VDBP genetic status independently predicted the occurrence of coronary lesions at angiography.