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Graphical AbstractSudden cardiac death after early-onset myocardial infarction. MI, myocardial infarction; SCD, sudden cardiac death.

1H-detected dynamic nuclear polarization (DNP)-enhanced fast magic angle spinning (MAS) NMR experiments provide unprecedented sensitivity to study the structure and dynamics in advanced materials and biomolecules. However, in relayed DNP experiments, DNP enhancements decrease with faster MAS rates, which is detrimental for sensitivity. The decrease is because 1H-1H spin diffusion rates are significantly reduced at fast MAS frequencies. To improve sensitivity at these fast MAS rates, here, we propose to combine fast polarization build-up by relay at slow MAS rate with high-resolution 1H NMR at fast MAS for acquisition. We perform experiments on l-histidine·HCl·H2O with MAS rates of up to 65 kHz using a 0.7 mm DNP probe at 18.8 T and 100 K. We obtain a 35% improvement in sensitivity in experiments where the sample is polarized at 20 kHz MAS and where the signal is acquired at 60 kHz MAS.

Superconducting magnet coils are subject to large thermo-mechanical loads applied during magnet assembly, cooldown and operation. These loads can cause the reduction of their critical current due to mechanical strains or local filament failures. Measurements on longitudinally stretched strands and Rutherford cables under transverse pressure have allowed exploration of material limits in two directions. However, no systematic study of the effect of multi-axial loading conditions has been done. Finite Element (FE) models show that, indeed, the actual limits of the material are strongly dependent on the nature of the applied load and that the strength under multi-axial loading can be significantly higher with respect to uniaxial loading conditions. In this paper, we try, for the first time, to measure the effect of multi-direction loading conditions on Nb3Sn Rutherford cables. The experiments are performed on impregnated cable stacks under transverse, lateral, and longitudinal constraints. The integrity of the cables is verified by destructive metallography inspection, evaluating the damage as a function of the applied loading condition.

Nucleotide repeat expansions in the C9orf72gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Unconventional translation (RAN translation) of C9orf72repeats generates dipeptide repeat proteins that can cause neurodegeneration. We performed a genetic screen for regulators of RAN translation and identified small ribosomal protein subunit 25 (RPS25), presenting a potential therapeutic target for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia and other neurodegenerative diseases caused by nucleotide repeat expansions. A nucleotide repeat expansion in the C9orf72gene is the most common cause of amyotrophic lateral sclerosis. The mutation causes production of aberrant proteins by an enigmatic form of translation. Yamada et al. identify that RPS25 is required for this form of translation.

Dipeptide repeat proteins are a major pathogenic feature of C9orf72amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophilaexacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.

Shape memory alloy (SMA)-based fasteners and connectors represent a class of successful SMA components that are increasingly used especially in marine or aerospace applications. The present paper aims to investigate novel C-Shaped SMA connectors for room-temperature vacuum pipes within particle accelerators. The proposed connectors exhibit the two-way shape memory effect (TW-SME), so they can generate significant axial recovery forces and they can be dismounted by temperature variations. Proper thermo-mechanical training procedures were performed to tune the mechanical and functional response of the connectors to make them suitable for the investigated application. The thermo-mechanical and functional response of the SMA fasteners in both free and constrained recovery conditions were assessed by strain gauge and extensometer tests as well as by finite element analyses based on a constitutive model, recently developed by the authors, accounting for TW-SME and plasticity. Comparison between experimental and numerical results validates the proposed model. Moreover, results give useful, important information in terms of SMA transformation temperatures, generated recovery forces as well as shape recovery capabilities.

Neuroendocrine tumors (NETs) belong to a rare family of tumors whose incidence has increased significantly over the past 50 years.

Despite prompt epicardial recanalization in patients presenting with ST-segment elevation myocardial infarction (STEMI), coronary microvascular obstruction and dysfunction (CMVO) is still fairly common and is associated with poor prognosis. Various pharmacological and mechanical strategies to treat CMVO have been proposed, but the positive results reported in preclinical and small proof-of-concept studies have not translated into benefits in large clinical trials conducted in the modern treatment setting of patients with STEMI. Therefore, the optimal management of these patients remains a topic of debate. In this Review, we appraise the pathophysiological mechanisms of CMVO, explore the evidence and provide future perspectives on strategies to be implemented to reduce the incidence of CMVO and improve prognosis in patients with STEMI.

Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application.

ABSTRACTIntroductionIn 2015, the Italian board for the TAilored BIOlogic therapy (ITABIO) proposed evidence-based decisional statements for first-line tailored biologic therapy in patients with rheumatoid arthritis (RA). Taking into account the new licensed drugs, the aim of the present review was to update the previous statements.Areas coveredA narrative review of the most recent evidence on the efficacy and safety of old and newly licensed drugs for the treatment of articular and extra-articular RA was performed. In addition, host-related variables potentially driving the therapy choice, such as the infection risk, the cardiovascular risk, the risk of deep vein thrombosis, thromboembolism, pregnancy, and obesity were analyzed. Consequently, several statements for personalized therapy were formulated, thus providing a decisional algorithm useful for proper personalized therapy of RA patients in clinical practice.Expert opinionSeveral clinical variables related to specific drug and host characteristics may drive the choice toward anti-TNF and non-anti-TNF biologics, or anti-JAKs, thus allowing to personalize the therapy. Consequently, the right therapy for the right patient would ensure a successful therapeutic intervention.

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We report a case of left pericardial agenesis in a 61 year old man presenting palpitations, without syncope. Clinical picture was not specific on clinical field: atypical chest pain, systolic murmur 2/6 Levine on the second left interspace were found. ECG showed sinus rhythm, clockwise deviation of axis in the precordial leads and incomplete right bundle branch block. Frequent isolated polymorphic premature extrabeats. Holter ecg was perfomed: frequent polymorphic extrabeats (9834/24 ore) with some couplets and triplets, without sustained ventricular tachycardia episodes. Starting metoprololo 100 mg per day the arrhythmic burden decreases significantly. Chest X–ray showed marked levocardia and dilatation of pulmonary trunk. Levocardia increased with the patient on the left side. Levoposition of the heart, lung interposition between the diaphragm and the base of the heart and between the aorta and pulmonary artery Echocardiography showed a classic abnormal swinging motion of the heart in the chest, a paradoxical interventricular septal movement, apparent right–sided heart enlargement, with unusual bulging of the apex of the right ventricle. Magnetic resonance imaging (currently the gold standard for diagnosing) confirmed the absence of the left pericardium, and a left pericardial agenesia diagnosis was performed Patients have a similar life expectancy to those without pericardial defects; however in certain cases, herniation and strangulation of cardiac chambers can be life threatening and lead to sudden cardiac death. We analyze the diagnostic problems and the prognostic doubts of this rare congenital anomaly.

Fatigue crack growth of austenitic and martensitic NiTi shape memory alloys was analyzed, with the purpose of capturing the effects of distinct stress-induced transformation mechanics in the two crystal structures. Mode I crack growth experiments were carried out, and near-crack-tip displacements were captured by in-situdigital image correlation (DIC). A special fitting procedure, based on the William’s solution, was used to estimate the effective stress intensity factor (SIF). The SIF was also computed by linear elastic fracture mechanics (LEFM) as well as by a special analytical model that takes into account the unique thermomechanical response of SMAs. A significant difference in the crack growth rate for the two alloys was observed, and it has been attributed to dissimilar dissipative phenomena and different crack-tip stress–strain fields, as also directly observed by DIC. Finally, it was shown that the predictions of the analytical method are in good agreement with effective results obtained by DIC, whereas a very large mismatch was observed with LEFM. Therefore, the proposed analytical model can be actually used to analyze fatigue crack propagation in both martensitic and austenitic NiTi.

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ABSTRACTIntroductionJanus kinases inhibitors (anti-JAKs), including tofacitinib, baricitinib, upadacitinib, and filgotinib, represent a new class of synthetic targeted drugs for the treatment of rheumatoid arthritis (RA). In this review, the risk of active tuberculosis (TB) occurrence in patients receiving anti-JAKs was assessed. The literature on this topic, updated to 29 February 2020 was reviewed. Overall, 40 reports (22 tofacitinib, 10 baricitinib, 5 upadacitinib, 3 filgotinib) were examined. A low frequency, not exceeding 0.25%, of active TB cases in patients were exposed to anti-JAKs. Only 1 of 89 recorded cases in tofactinib and baricitinib exposure occurred in countries at intermediate or high TB risk, and most of the cases probably were due to first mycobacterium tuberculosis (Mtb) exposure. Although no cases were observed in patients receiving upadacitinib and filgotinib, long-term trials and data from real-life are required to more precisely address the TB risk associated with the two drugs.Areas coveredDiscussion on the TB risk associated with anti-JAKs, and on the need for accurate evaluation of host-related risk factors in high risk countries.Expert opinionAvailable data on anti-JAKs suggest a negligible risk of active TB occurrence in low endemic areas.

Pleural effusions are among the first clinical manifestations of malignant pleural mesothelioma (MPM) and often constitute the only available material for diagnosis. Although an MPM diagnosis can be reliable on cytology, the reported sensitivity is low (30% to 75%). Particularly, it can be hard to discriminate epithelioid MPM, the most common histotype, from reactive mesothelial hyperplasia (MH). Currently, BRCA1-associated protein 1 (BAP1) and CDKN2A(p16), evaluated by immunohistochemistry and fluorescent in situhybridization, respectively, are the most valuable markers to discriminate MPM and MH. Both markers have a high specificity, but their sensitivity is not always satisfying, even when used together. We have recently developed a 117-gene expression panel, based on Nanostring technology, able to differentiate epithelioid MPM from MH pleural tissues better than BAP1 and p16. Herein, we evaluated the efficacy of the same panel on an independent retrospective cohort of 23 MPM and 11 MH pleural effusions (cell blocks and smears). The overall sensitivity and specificity of the panel were equal to 0.9565 and 1, respectively. Moreover, the panel performance was compared with BAP1 and p16 on 25 cell blocks. Sensitivity levels of gene panel, BAP1 alone, p16 alone, and BAP1 plus p16 were 1, 0.5882, 0.4706, and 0.7647, respectively. Specificity was always 1. Although further validation is needed, this gene panel could really facilitate patients' management, allowing a definitive MPM diagnosis directly on pleural effusions.

ObjectivePatients with Takotsubo syndrome (TTS) present an acute microvascular dysfunction that leads to an impaired myocardial perfusion and, in more severe forms, an impaired epicardial flow. However, clinical relevance of a delayed coronary flow, the coronary slow flow (CSF), has never been investigated. We studied the prognostic value of CSF occurring in the acute phase of TTS.MethodsThis cohort study prospectively evaluated patients with a diagnosis of TTS. CSF was defined as angiographically non-obstructive coronary arteries with thrombolysis in myocardial infarction-2 flow. The incidence of overall mortality and major adverse cardiovascular events (MACEs), defined as the composite of TTS recurrence, cardiac rehospitalisation, cerebrovascular events and mortality, was assessed at follow-up.ResultsWe enrolled 101 patients (mean age 71.0±11.1 years, 86 (85.1%) female); CSF occurred in 18 (17.8%) patients. At admission, patients with CSF presented more frequently with Killip class III/IV, moderate-to-severe left ventricle systolic dysfunction and right ventricle dysfunction. During the index admission, patients with CSF had a higher rate of intrahospital complications (12 (66.7%) vs 28 (33.7%), p=0.01). At long-term follow-up, patients with CSF had a significantly higher occurrence of overall mortality (9 (50%) vs 19 (22.9%), p=0.011), mainly due to non-cardiac causes (89.3%), and a higher rate of MACE (10 (55.5%) vs 27 (32.5%), p=0.06). At multivariable Cox regression, CSF was independently associated with death from any causes.ConclusionsPatients with TTS presenting with CSF have a worse clinical presentation with a higher rate of intrahospital complications and a poor long-term clinical outcome.

Background: The recurrence of angina after percutaneous coronary intervention affects 20–35% of patients with stable coronary artery disease; however, few data are available in the setting of ST-segment elevation myocardial infarction. We evaluated the relation between coronary microvascular obstruction and the recurrence of angina at follow-up.Methods: We prospectively enrolled patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Microvascular obstruction was defined as thrombolysis in myocardial infarction flow less than 3 or 3 with myocardial blush grade less than 2. The primary endpoint was the recurrence of angina at follow-up. Moreover, angina status was evaluated by the Seattle angina questionnaire summary score (SAQSS). Therapy at follow-up and the occurrence of major adverse cardiovascular events were also collected.Results: We enrolled 200 patients. Microvascular obstruction occurred in 52 (26%) of them. Follow-up (mean time 25.17±9.28 months) was performed in all patients. Recurrent angina occurred in 31 (15.5%) patients, with a higher prevalence in patients with microvascular obstruction compared with patients without microvascular obstruction (13 (25.0%) vs. 18 (12.2%), P=0.008). Accordingly, SAQSS was lower and the need for two or more anti-anginal drugs was higher in patients with microvascular obstruction compared with patients without microvascular obstruction. At multiple linear regression analysis a history of previous acute coronary syndrome and the occurrence of microvascular obstruction were the only independent predictors of a worse SAQSS. Finally, the occurrence of major adverse cardiovascular events was higher in patients with microvascular obstruction compared with patients without microvascular obstruction.Conclusions: The recurrence of angina in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention is an important clinical issue. The occurrence of microvascular obstruction portends a worse angina status and is associated with the use of more anti-anginal drugs.

No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas.