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Systematic experimental investigations are reported of charge transport in double-comb and star-shaped planar arrays obtained by coupling superconducting islands via Josephson tunnel junctions. The fabrication of the structures is based on a standard niobium trilayer technology with superconducting transition temperature close to 9 K. Noticeable enhancements of Josephson supercurrents and energy gap are recorded. Complementarity between experimental data and theoretical predictions is employed as a tool to clarify the role of different graph topologies in conditioning the singular behavior of synthetic graph-shaped networks. The predictions of the theoretical models are based on the Bose-Einstein topological condensation and a de Gennes-Alexander approach for granular superconductors. Evidence is shown of the dependence, for both gap and Josephson critical currents, on node-to-node connections in the networks, namely on array topology.

Background: Management of elderly patients with acute myocardial infarction (AMI) is challenging due to lack of knowledge about the link between fragility, outcomes and interventional procedures. Aims: The aim of this study was to establish the prognostic role of the Multidimensional Prognostic Index (MPI) in elderly with AMI. Methods: A total of 241 patients ≥ 65 years old with AMI were continuously enrolled in this prospective study and divided into three groups according to the MPI score. The primary endpoint was 30-day mortality. Secondary endpoints were 6-month mortality and rate of adverse events. Results: In-hospital overall mortality rate was higher in MPI-3 (p= 0.009). Patients of MPI-3 had a significantly higher mortality rate regarding the primary endpoint with 30-day survival of 78.9%, compared to 97.4% and 97.2%, in MPI-1, MPI-2 (p< 0.001), respectively. The survival rate progressively decreased in the three MPI classes of risk with a 6-month survival of 96.5%, 96.3%, 73.7% in groups MPI-1, MPI-2, and MPI-3 (p< 0.001). Longer length of in-hospital stay was observed in MPI-3 group. In-hospital complications were more frequent in higher MPI score. Discussion: Our findings are in agreement with the results of other studies that evaluated the risk of in-hospital complications and mortality in older patients. In our “real-world” population of elderly hospitalized for AMI we observed poorer outcomes in patients belonged to higher MPI groups. Conclusions: In the setting of AMI, MPI may be very useful in the daily clinical practice to manage older patients and predict the risk of in-hospital and follow-up complications.

Since its outbreak in China at the end of 2019, the new coronavirus disease (COVID-19) was characterized by both easy spreading and high mortality. The latter proved to be way more elevated in the North of Italy -with a peak of 18.4% in region Lombardia and even 31% in the city of Bergamo and surrounding county- than in the rest of the world. In an attempt to conceptualize the reasons for such a dramatic situation, four key elements have been identified: COVID-19 itself, old age, lung disease, and heart failure. Their harmful combination has been named “The deadly quartet”. The underlying risk factors, among which a lot of them are distinctive features of the population in northern Italy, have been summarized as “unmodifiable”, “partially modifiable”, and “modifiable”, for the sake of clarity. Up-to-date scientific evidence in this field has been described in the form of a narrative and easy-to-read review.

A structural damage identification technique hinged on the combination of orthogonal empirical mode decomposition and modal analysis is proposed. The output-only technique is based on the comparison between pre- and post-damage free structural vibrations signals. The latter are either kinematic (displacements, velocities or accelerations) or deformation measures (strains or curvatures). The response data are decomposed by means of the orthogonal empirical mode decomposition to derive a finite set of orthogonal intrinsic mode functions; the latter are used as a multi-frequency and data-driven basis to build pseudo-modal shapes. A new damage index, the so-called pseudo-mode index, is introduced to compare the response obtained for the two states of the structural system and detect potential damages. The performance of the devised index in detecting a localised damage is shown through numerical and experimental tests on two structural models, namely a 4-degrees-of-freedom system and a two-hinged parabolic arch.

Background Environmental pollution and weather changes unfavorably impact on cardiovascular disease. However, limited research has focused on ST-elevation myocardial infarction (STEMI), the most severe yet distinctive form of acute coronary syndrome.Methods and results We appraised the impact of environmental and weather changes on the incidence of STEMI, analysing the bivariate and multivariable association between several environmental and atmospheric parameters and the daily incidence of STEMI in two large Italian urban areas. Specifically, we appraised: carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NOX), ozone, particulate matter smaller than 10 μm (PM10) and than 2.5 μm (PM2.5), temperature, atmospheric pressure, humidity and rainfall. A total of 4285 days at risk were appraised, with 3473 cases of STEMI. Specifically, no STEMI occurred in 1920 (44.8%) days, whereas one or more occurred in the remaining 2365 (55.2%) days. Multilevel modelling identified several pollution and weather predictors of STEMI. In particular, concentrations of CO (p=0.024), NOX (p=0.039), ozone (p=0.003), PM10 (p=0.033) and PM2.5 (p=0.042) predicted STEMI as early as three days before the event, as well as subsequently, and NO predicted STEMI one day before (p= 0.010), as well as on the same day. A similar predictive role was evident for temperature and atmospheric pressure (all p< 0.05).Conclusions The risk of STEMI is strongly associated with pollution and weather features. While causation cannot yet be proven, environmental and weather changes could be exploited to predict STEMI risk in the following days.

IMPORTANCE: Takotsubo syndrome (TTS) is an acute, reversible heart failure syndrome featured by significant rates of in-hospital complications. There is a lack of data for risk stratification during hospitalization. OBJECTIVE: To derive a simple clinical score for risk prediction of in-hospital complications among patients with TTS. DESIGN, SETTING, AND PARTICIPANTS: In this prognostic study, 1007 consecutive patients were enrolled in the German and Italian Stress Cardiomyopathy (GEIST) registry from July 1, 2007, through December 31, 2017, and identified as the derivation cohort; 946 patients were enrolled in the Spanish Registry for Takotsubo Cardiomyopathy (RETAKO) as the external score validation. An admission risk score was developed using a stepwise multivariable regression analysis from 2 registries. Data analysis was performed from March 1, 2018, through July 31, 2018. MAIN OUTCOMES AND MEASURES: In-hospital complications were defined as death, pulmonary edema, need for invasive ventilation, and cardiogenic shock. Four variables were identified as independent predictors of in-hospital complications and were used for the score: male sex, history of neurologic disorder, right ventricular involvement, and left ventricular ejection fraction (LVEF). RESULTS: Of the 1007 patients enrolled in the GEIST registry, 107 (10.6%) were male, with mean (SD) age of 69.8 (11.4) years. Overall rate of in-hospital complications was 23.3% (235 of 1007) (death, 4.0%; pulmonary edema, 5.8%; invasive ventilation, 6.4%; and cardiogenic shock, 9.1%). The GEIST prognosis score was derived by providing 20 points each for male sex and history of neurologic disorders and 30 points for right ventricular involvement and then subtracting the value in percent of LVEF (decimal values between 0.15 and 0.70). Score accuracy on area under the receiver operating characteristic curve analysis was 0.71, with a negative predictive power of 87% with scores less than 20. External validation in the RETAKO population (124 [13.1%] male; mean [SD] age, 69.5 [14.9] years) revealed an area under the curve of 0.73 (P = .46 vs GEIST derivation cohort). Stratification into 3 risk groups (&lt;20, 20-40, and >40 points) classified 316 patients (40.9%) as having low risk; 342 (44.3%) as having intermediate risk, and 114 (14.8%) as having high risk of complications. The observed in-hospital complication rates were 12.7% for low-risk patients, 23.4% for intermediate-risk patients, and 58.8% for high-risk patients (P &lt; .001 for trend). After 2.6 years of follow-up, patients with in-hospital complications had significantly higher rates of mortality than those without complications (40% vs 10%, P = .01). CONCLUSIONS AND RELEVANCE: The GEIST prognostic score may be useful in early risk stratification for TTS. High-risk patients with TTS may require an intensive care unit stay, and low-risk patients with TTS could be discharged within a few days. In-hospital complications in patients with TTS may be associated with increased risk of long-term mortality.

Erythrocytosis is one of the most common side effects occurring during testosterone replacement therapy (TRT) in male hypogonadism. It is well known that all testosterone formulations may cause Hb and hematocrit increase, especially with short-acting injectable formulations. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a new class of glucose-lowering agents that reduce hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by inhibition of renal glucose reabsorption, leading to increased urinary glucose excretion. The co-occurrence of T2DM and hypogonadism is known to be increasingly frequent. However, to date, no adverse events with the concomitant use of TRT and SGLT2is are reported.

Single molecules can be coupled to metallic electrodes when the latter are in the superconducting state. In such emerging hybrid molecular devices, the possibility of the Josephson effect, that is, the dissipation-less transport of Cooper-paired electrons from one electrode to the other, arises. In this theoretical study, we demonstrate that a junction formed by two superconductors linked by an annular molecule, of which benzene (phenylene group) is a prototype, can sustain indeed a supercurrent and work as a “single molecule superconducting field-effect transistor (SMoSFET)”. In this device, Cooper-paired electrons are transmitted via the molecule in the presence of quantum interference. Through the presented model, we show that the resonant nontrivial modulation of the critical current with an external gate voltage may be strongly modified by choosing a paracoupled, a metacoupled, or an orthocoupled molecular ring. These features are directly related to the possibility of obtaining a SMoSFET controlled by quantum interference.

Within the current global challenges, energy plays a key role for the achievement of basic human needs, socio-economic development, environmental protection and global security. At the light of this interconnection, a proper impact evaluation metric able to assess the main effects of energy projects at local level becomes necessary in order to highlight successful strategies. Relying on the Sustainable Livelihoods concept, this study proposes an Impact Evaluation Framework (IEF) to measure project impact as changes of target community’s livelihoods. First, the IEF establishes a Capitals-Based Evaluation Hierarchy, taking its rationale from the literature: this first step responds to the needs of providing a standard and harmonized structure applicable to different projects. Secondly, the IEF develops a further Five-Step Procedure to respond to the concurrent need of flexibility and customization of specific projects. The conceptual methodology of the IEF might be used at different stages of project design: as a supportive methodology donors use in their programme of funds allocation or as an instrument experts use to quantitatively support their ex-post project evaluation. In the paper, the IEF is presented in the light of this second application and the procedure applied to a real project in Ethiopia. The set of information obtained with the IEF is compared to the final expert evaluation, commissioned by the donor and performed at the end of the project, showing the usefulness of IEF as a supportive methodology in the evaluation process.

The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes.

Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitroand in vivoto elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.

ABSTRACTHuman centromeres contain large amounts of repetitive DNA sequences known as α satellite DNA, which can be difficult to replicate and whose functional role is unclear. Recently, we have characterized protein composition, structural organization and checkpoint response to stalled replication forks of centromeric chromatin reconstituted in Xenopus laevisegg extract. We showed that centromeric DNA has high affinity for SMC2-4 subunits of condensins and for CENP-A, it is enriched for DNA repair factors and suppresses the ATR checkpoint to ensure its efficient replication. We also showed that centromeric chromatin forms condensins enriched and topologically constrained DNA loops, which likely contribute to the overall structure of the centromere. These findings have important implications on how chromosomes are organized and genome stability is maintained in mammalian cells.

We study nonequilibrium properties of an atomic quantum dot (AQD) coupled to a Bose-Einstein condensate (BEC) within Keldysh-Green's function formalism when the AQD level is varied harmonically in time. Nonequilibrium features in the AQD energy absorption spectrum are the side peaks that develop as an effect of photon absorption and emission. We show that atoms can be efficiently transferred from the BEC into the AQD for the parameter regime of current experiments with cold atoms.

Subclinical rejection (SCR) has been variably associated with reduced graft survival, development and progression of interstitial fibrosis/tubular atrophy and chronic allograft nephropathy, but data are controversial concerning SCR treatment in terms of graft survival improvement. In this single-center retrospective study, we enrolled 174 adult kidney transplant recipients with a protocol biopsy performed at 30 days after transplantation to evaluate the incidence rate and risk factors for early SCR and its impact on 10-year graft survival. Five patients showed primary non function and were excluded. Among 159/169 (94.08 %) patients with stable graft function who underwent protocol biopsy, 17 (10.7 %) showed signs of SCR and were treated with low-dose intravenous (i.v.) steroids. Ten patients showed functional impairment, 8 (4.73 %) resulting as acute rejection. At multivariate analysis, donor age [odds ratio (OR) 1.04, 95 % confidence interval (CI) 1.01–1.09], and delayed graft function (DGF) (OR 1.08, 95 % CI 1.03–1.12) were significantly associated with SCR. The 10-year graft survival rate in the SCR group was similar to that in the normal-findings group (76.5 vs. 74.9 % respectively; p = 0.61). At multivariate Cox regression, acute [hazard ratio (HR) 5.22, 95 % CI 1.70–16.01], but not sub-clinical, rejection was independently associated with long-term graft failure. In conclusion, early protocol biopsy is a useful and safe tool to detect early SCR which seems not to affect the long-term survival. We suggest that this could be, probably, linked to early SCR treatment with low dose i.v. steroids.

The most recent results from searches of leptoquark-like signatures are presented using 1.03 and 4.7 fb−1of pp collision data collected by the ATLAS detector with s=7 TeVand 19.6 fb−1of pp collision data collected by the CMS detector with s=8 TeVat the LHC. First- and second-generation scalar leptoquarks are looked for in the final states with either two leptons and two jets (ℓℓ+jj, ℓ=e, μ) or one lepton, missing transverse energy, and two jets (ℓν+jj, ℓ=e, μ). Apart from leptoquark investigations, the ℓℓ+jjfinal states are further studied in a search for W bosons with right-handed couplings that arise in left-right models. Third-generation scalar leptoquarks are looked for in the final state with two tau leptons and two b quarks or two top quarks (ττ+bband ττ+tt). The ττ+bbfinal state is also sensitive to stop pairs decaying through R-parity violating and conserving processes that are foreseen in some models of supersymmetry. In addition, results are shown for third-generation scalar leptoquarks in the final states bb+ννand tt+νν, reinterpreting searches for bottom and top squark pair production. 95% confidence level upper limits are set on the scalar leptoquark pair production cross section times branching fraction in each decay channel as a function of the leptoquark mass and the branching ratio of decay.

Percutaneous valve-in-valve therapy has become an important treatment option for failing bioprosthetic heart valves. Accurate assessment of valve internal diameter (ID) is essential for effective and safe treatment. These data may not be available in an individual patient, or the manufacturer-supplied dimensions may be incorrect because they do not allow for the space occupied by valve leaflet material.

The forced dynamics of chains of linearly coupled mechanical oscillators characterized by on-site cubic nonlinearity is investigated. The study aims to highlight the role played by the harmonic excitation on the nonlinear spatially localised dynamics of the system. Towards this goal, a map approach is employed in order to identify the chain nonlinear propagation regions under 1:1 resonance conditions. Given the latter assumption, the governing second-order difference equation refers to a perturbation of the stationary resonant response. Softening and hardening type of nonlinearities are considered and the associated unstaggered and staggered discrete breathers (DB), respectively, are discussed. Stationary DBs obtained as soliton-like solutions are identified either with sequences of the nonlinear map homoclinic primary intersection points and with an ad hoc analytic approximation; the latter is based on the idea that the nonlinearity is taken into account only in the central part of the breather whilst the tails are treated as linear excitations.

Arrhythmia-induced cardiomyopathy is a partially or completely reversible form of myocardial dysfunction due to sustained supraventricular and ventricular arrhythmias. Asynchrony, rapid cardiac rates and rhythm irregularities are the main factors involved in the development of the disease. The reversible nature of arrhythmia-induced cardiac dysfunction allows only for a retrospective diagnosis of the disease once cardiac function is restored following heart rate control. A high level of suspicion is needed to make a diagnosis at an early stage and prevent further progression of the disease. Although reversible, arrhythmia-induced cellular and molecular changes may remain, increasing the risk for sudden death even when normal ejection fraction is restored as well as causing rapid deterioration of cardiac function and development of heart failure symptoms if arrhythmia recurs. Appropriate management based on a combination of pharmacologic and nonpharmacologic strategies to achieve rate control and prevent arrhythmia recurrence is pivotal to avoid further cardiac function deterioration and to control symptoms, significantly reducing the risk of heart failure and sudden cardiac death.

Growth of atherosclerotic plaque requires neovascularization (angiogenesis). To elucidate the involvement of angiotensin II (Ang II) in angiogenesis, we performed gene microarray and microRNA (miRNA) polymerase chain reaction array analyses on human coronary artery endothelial cells exposed to moderate concentration of Ang II for 2 and 12 hours. At 12, but not 2, hours, cultures treated with Ang II exhibited shifts in transcriptional activity involving 267 genes (>1.5-fold difference; P< 0.05). Resulting transcriptome was most significantly enriched for genes associated with blood vessel development, angiogenesis, and regulation of proliferation. Majority of upregulated genes implicated in angiogenesis shared a commonality of being either regulators (HES1, IL-18, and CXCR4) or targets (ADM, ANPEP, HES1, KIT, NOTCH4, PGF, and SOX18) of STAT3. In line with these findings, STAT3 inhibition attenuated Ang II–dependent stimulation of tube formation in Matrigel assay. Expression analysis of miRNAs transcripts revealed that the pattern of differential expression for miRNAs was largely consistent with proangiogenic response with a prominent theme of upregulation of miRs targeting PTEN (miR-19b-3p, miR-21-5p, 23b-3p, and 24-3p), many of which are directly or indirectly STAT3 dependent. We conclude that STAT3 signaling may be an intrinsic part of Ang II–mediated proangiogenic response in human endothelial cells.

We present a conjecture about the reduced Hilbert series of the coordinate ring of a simple polyomino in terms of particular arrangements of non-attacking rooks that can be placed on the polyomino. By using a computational approach, we prove that the above conjecture holds for all simple polyominoes up to rank 11. In addition, we prove that the conjecture holds true for the class of parallelogram polyominoes, by looking at those as simple planar distributive lattices. Finally, we give a combinatorial interpretation of the Gorensteinness of parallelogram polyominoes.

The amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). Two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53. Here, we show that the p53 family member TAp73 also drives the expression of GLS2. Specifically, we demonstrate that TAp73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells, and overexpression or inhibition of GLS2 modulates neuronal differentiation and intracellular levels of ATP. Moreover, inhibition of GLS activity, by removing Glutamine from the growth medium, impairs in vitro differentiation of cortical neurons. Finally, expression of GLS2 increases during mouse cerebellar development. Although, p73 is dispensable for the in vivo expression of GLS2, TAp73 loss affects GABA and Glutamate levels in cortical neurons. Together, these findings suggest a role for GLS2 acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible role of p73 in regulating neurotransmitter synthesis.

The role of the Forkhead box class O (FoxO)3a transcription factor in breast cancer migration and invasion is controversial. Here we show that FoxO3a overexpression decreases motility, invasiveness, and anchorage-independent growth in estrogen receptor α-positive (ERα+) cancer cells while eliciting opposite effects in ERα-silenced cells and in ERα-negative (ERα−) cell lines, demonstrating that the nuclear receptor represents a crucial switch in FoxO3a control of breast cancer cell aggressiveness. In ERα+ cells, FoxO3a-mediated events were paralleled by a significant induction of Caveolin-1 (Cav1), an essential constituent of caveolae negatively associated to tumor invasion and metastasis. Cav1 induction occurs at the transcriptional level through FoxO3a binding to a Forkhead responsive core sequence located at position −305/−299 of the Cav1 promoter. 17β-estradiol (E2) strongly emphasized FoxO3a effects on cell migration and invasion, while ERα and Cav1 silencing were able to reverse them, demonstrating that both proteins are pivotal mediators of these FoxO3a controlled processes. In vivo, an immunohistochemical analysis on tissue sections from patients with ERα+ or ERα− invasive breast cancers or in situ ductal carcinoma showed that nuclear FoxO3a inversely (ERα+) or directly (ERα−) correlated with the invasive phenotype of breast tumors. In conclusion, FoxO3a role in breast cancer motility and invasion depends on ERα status, disclosing a novel aspect of the well-established FoxO3a/ERα interplay. Therefore FoxO3a might become a pursuable target to be suitably exploited in combination therapies either in ERα+ or ERα− breast tumors.

Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disorder characterized by venous and arterial thromboembolic (TE) disease, and/or pregnancy morbidity, associated with persistent elevated antiphospholipid antibodies (lupus anticoagulant, LA, anticardiolipin, aCL, and anti-beta2-glycoprotein I, anti-β2GPI). A 51 year-old man, smoker, presented to our ER with chest pain. EKG showed Q waves and STE in the anterior leads, with increased troponin levels. A diagnosis of anterior STEMI was made and he was taken into our catheterization laboratory, where a high burden thrombotic plaque determining LM and ostial LAD subocclusion was treated with PPCI and a DES implantation; in addition, multiple failed PCI attempts were performed on a distal LAD occlusion, and an integrilin bolus was administered. The patient was admitted to our CICU and a DAPT with ASA and Ticagrelor was started. TTE showed LVEF 40%, apical akinesis, septal and anterior hypokinesis, and no significant valve disease. An aPTT abnormal value (100.5 s; reference range 25–38.5 s) was detected, not corrected by aPTT mixing study. Given suspected autoimmune prothrombotic state, normal Hb and PLT values and low bleeding risk, LMWH 100 IU/kg every 12 h was started, in addition to DAPT with switch from Ticagrelor to Clopidogrel. LA and aCL and anti-β2GPI IgG were positive, with negativity of others rheumatologic tests, confirming primary APS diagnosis. Repeat TTE showed EF 50%. The patient was discharged in ‘triple therapy’ (DAPT plus LMWH), and referred to the rheumatology clinic. LA, aCL, and anti-β2GPI tests 12 weeks later were positive, confirming a triple positive APS and satisfying revised Sapporo criteria. The rheumatologist switched therapy to Clopidogrel plus Warfarin. At 3 months follow-up, the patient, former smoker, was asymptomatic and TTE confirmed EF 50%, so he was recommended to continue with his medical therapy. APS is rarely associated with AMI (∼5.5%) and in only 2.8% cases AMI represents the onset of the disease. AMI pathogenesis in APS is considered to be acute thrombosis of coronary arteries, in contrast with atherosclerotic plaque rupture in typical AMI. Key discriminators to identify APS as potential underlying cause of AMI include young age, previous unprovoked thromboses, low platelets count (they are consumed in the thrombotic process), high aPTT value (LA may interfere with assembly of the prothrombinase complex on phospholipids), coronary artery thromboses in the setting of otherwise normal otherwise appearing coronary arteries. APS antibodies have also pro-inflammatory activity on vascular endothelial cells, leading to accelerated atherosclerosis. aGAPSS score (high risk ≥10) is useful for risk stratification of recurrent thrombosis and AMI in young patients with APS. The treatment of AMI in APS is therefore a clinical challenge. Strict management of additional CV risk factors is crucial. VKA (INR >3 with Warfarin, INR2–3 with Warfarin and ASA) should be provided for life, because of the very high risk of recurrent TE. DOACs are less effective and less safe than VKAs for TE prevention in APS. The role of coronary stents, considering higher rates of stent thrombosis after PCI in APS patients triple therapy concomitant risks, requires further studies. Due to lack of large, randomized, prospective studies, there is no clear experts consensus about optimal antithrombotic therapy in secondary prevention after arterial TE. APS patients with STEMI should undergo PCI, usually associated with thrombus aspiration, and in selected cases DES implantation in culprit lesion followed by triple antithrombotic therapy with short-term DAPT and long-term VKA.

Mitral regurgitation (MR) is the second most frequent valve heart disease in Europe and its underlying mechanism primary-organic (due to disease of the mitral leaflets), or secondary-functional (where valve leaflets and chordae are structurally normal and MR results from alterations in left ventricle and left atrium geometry), determines the therapeutic approach. Transcatheter Edge-to-Edge Repair (TEER) with MitraClip implantation is a minimal-invasive treatment that according to 2021 ESC Guidelines should be considered (class indication IIa) in selected symptomatic patients with severe MR despite optimal medical therapy, not eligible for surgery and fulfilling COAPT trial inclusion criteria, suggesting an increased chance of responding to treatment. Optimal valve morphology features for TEER are central pathology (second scallop), no leaflet calcifications, mitral valve area >4 cm2, mobile length of posterior leaftel >10 mm, coaptation depth <11mm, normal leaflet strength and mobility, flail width <15 mm, flail gap <10 mm. TEER may be considered (class IIb) only in selected cases when the COAPT criteria are not fulfilled with the aim of improving symptoms and quality of life. MR occurs during systole, that at normal heart rates represents 30–50% of the cardiac cycle. As such, marked left atrial (LA) pressure elevation is present only transiently, representing less of a drive to development of secondary pulmonary hypertension compared to chronic LA pressure elevation seen in severe mitral stenosis. Anyway, in patients with severe MR echocardiography often reveals elevated systolic pulmonary artery pressure (PAPs) and MitraClip implantation usually is associated with a slight increase of the trans-mitral gradient with possible repercussions on pulmonary pressures. To better describe the effect of MitraClip implantation on pulmonary pressures and clinical outcomes we did a retrospective study enrolling in the period 2012–2021 25 patients with severe mitral regurgitation treated with TEER. We aimed to evaluate the clinical outcomes (symptoms, signs of heart failure, NYHA functional class) and the pulmonary pressures assessed by an echocardiographic examination before and after the intervention. At 6-month follow-up all patients with repaired mitral regurgitation showed an improvement in the NYHA class (from IV to II) and no need for re-hospitalization. We observed a trend in the reduction of the mean sistolic pulmonary arterial pressure of 2.68 mmHg ± 15 mmHg (P0.39, 95% C.I. −9.03 to 3.67) with an unchanged left ventricle ejection fraction. Moreover, the echocardiographic exam showed a normalization of the S and D waves pattern in the pulmonary veins at the PW Doppler evaluation. We can assume that the clinical improvement and the reduction of dyspnoea in these patients underwent TEER is related to a reduction of pressures in the pulmonary circulation regardless of the ejection fraction. This finding could be used as a tool that the cardiologist has to evaluate in the echocardiography lab to reveal a new mitral valve disfunction. Considering the small sample, a greater number of patients will be enrolled to highlight the statistical significance.

The human lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that has been implicated in the pathogenesis of atherosclerosis. LOX-1 activation is an important mechanism that contributes to plaque instability and subsequent development of acute coronary syndromes. Association studies have implicated OLR1 gene variants in myocardial infarction (MI) susceptibility. In particular, previously we demonstrated that intronic SNPs associated to susceptibility to myocardial infarction, regulate the expression of a new functional splicing isoform of the OLR1 gene, called LOXIN. The ratio OLR1/LOXIN mRNA is increased in subjects carrying the risk haplotype. On this basis, we developed a genetic kit named “LOXIN test” that allows the rapid identification of ORL1 genotypes and therefore establish the susceptibility risk to atherosclerosis and myocardial infarction. The recent patents related to OLR1, SNPs and LOXIN are also discussed in this article.

Percutaneous coronary intervention with drug-eluting stents is currently the preferred approach to the treatment of obstructive coronary stenoses. Large, randomized trials have demonstrated a significant reduction in the incidence of restenosis after drug-eluting stent placement compared with balloon angioplasty or bare metal stents across a wide range of lesions. Furthermore, these stents have appeared to be effective in maintaining the luminal patency at follow up for up to 2–4 years. Concerns regarding the potential adverse effects of drug-eluting stents, such as aneurysm formation in arteries secondary to drug toxicity or hypersensitivity, as well as the overdependence on antiplatelet therapy for a protracted period to prevent subacute thrombosis, have been raised. However, evidence from large studies has not demonstrated any significant increase in the incidence of such adverse events. Future approaches to treating coronary stenoses involve technical modifications, such as direct stenting, accelerating endothelialization with gene delivery of nitric oxide donors, smooth muscle cell growth inhibitors after stent placement, biodegradable stents and concurrent use of local molecule delivery and oral chemotherapy. Ongoing large-scale postmarketing surveillance studies are expected to provide credible answers to the concerns regarding the safety of these stents.

Abstract: Free wave propagation properties in one-dimensional chains of nonlinear oscillators are investigated by means of nonlinear maps. In this realm, the governing difference equations are regarded as symplectic nonlinear transformations relating the amplitudes in adjacent chain sites (n, n +1) thereby considering a dynamical system where the location index n plays the role of the discrete time. Thus, wave propagation becomes synonymous of stability: finding regions of propagating wave solutions is equivalent to finding regions of linearly stable map solutions. Mechanical models of chains of linearly coupled nonlinear oscillators are investigated. Pass- and stop-band regions of the mono-coupled periodic system are analytically determined for period-q orbits as they are governed by the eigenvalues of the linearized 2D map arising from linear stability analysis of periodic orbits. Then, equivalent chains of nonlinear oscillators in complex domain are tackled. Also in this case, where a 4D real map governs the wave transmission, the nonlinear pass- and stop-bands for periodic orbits are analytically determined by extending the 2D map analysis. The analytical findings concerning the propagation properties are then compared with numerical results obtained through nonlinear map iteration. [Copyright &y& Elsevier]

Pharmacogenomics is the study of how an individual’s genetic inheritance affects the body’s response to drugs. Pharmacogenomics holds the promise that drugs might one day be tailor-made for individuals and adapted to an individual’s genetic makeup. Several studies have shown that both adverse and beneficial responses to cardiovascular drugs can be influenced by single nucleotide polymorphisms in genes coding for metabolising enzymes, drug transporters and drug targets. Despite the large amount of data about gene–drug interactions, the translation of pharmacogenomics in clinical practise is slow. To improve this, there is a need of new technology and large prospective trials allowing for simultaneous analysis of multiple genetic variants in molecular pathways that could affect drug disposition and action.