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We present an efficient approach to quantify the uncertainties associated with the numerical simulations of the laser‐based powder bed fusion of metals processes. Our study focuses on a thermomechanical model of an Inconel 625 cantilever beam, based on the AMBench2018‐01 benchmark proposed by the National Institute of Standards and Technology (NIST). The proposed approach consists of a forward uncertainty quantification analysis of the residual strains of the cantilever beam given the uncertainty in some of the parameters of the numerical simulation, namely the powder convection coefficient and the activation temperature. The uncertainty on such parameters is modelled by a data‐informed probability density function obtained by a Bayesian inversion procedure, based on the displacement experimental data provided by NIST. To overcome the computational challenges of both the Bayesian inversion and the forward uncertainty quantification analysis we employ a multi‐fidelity surrogate modelling technique, specifically the multi‐index stochastic collocation method. The proposed approach allows us to achieve a 33% reduction in the uncertainties on the prediction of residual strains compared with what we would get basing the forward UQ analysis on a‐priori ranges for the uncertain parameters, and in particular the mode of the probability density function of such quantities (i.e., its "most likely value", roughly speaking) results to be in good agreement with the experimental data provided by NIST, even though only displacement data were used for the Bayesian inversion procedure. [ABSTRACT FROM AUTHOR]

Aim: The RESHAPE‐HF2 trial is designed to assess the efficacy and safety of the MitraClip device system for the treatment of clinically important functional mitral regurgitation (FMR) in patients with heart failure (HF). This report describes the baseline characteristics of patients enrolled in the RESHAPE‐HF2 trial compared to those enrolled in the COAPT and MITRA‐FR trials. Methods and results: The RESHAPE‐HF2 study is an investigator‐initiated, prospective, randomized, multicentre trial including patients with symptomatic HF, a left ventricular ejection fraction (LVEF) between 20% and 50% with moderate‐to‐severe or severe FMR, for whom isolated mitral valve surgery was not recommended. Patients were randomized 1:1 to a strategy of delivering or withholding MitraClip. Of 506 patients randomized, the mean age of the patients was 70 ± 10 years, and 99 of them (20%) were women. The median EuroSCORE II was 5.3 (2.8–9.0) and median plasma N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) was 2745 (1407–5385) pg/ml. Most patients were prescribed beta‐blockers (96%), diuretics (96%), angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor–neprilysin inhibitors (82%) and mineralocorticoid receptor antagonists (82%). The use of sodium–glucose cotransporter 2 inhibitors was rare (7%). Cardiac resynchronization therapy (CRT) devices had been previously implanted in 29% of patients. Mean LVEF, left ventricular end‐diastolic volume and effective regurgitant orifice area (EROA) were 31 ± 8%, 211 ± 76 ml and 0.25 ± 0.08 cm2, respectively, whereas 44% of patients had mitral regurgitation severity of grade 4+. Compared to patients enrolled in COAPT and MITRA‐FR, those enrolled in RESHAPE‐HF2 were less likely to have mitral regurgitation grade 4+ and, on average, HAD lower EROA, and plasma NT‐proBNP and higher estimated glomerular filtration rate, but otherwise had similar age, comorbidities, CRT therapy and LVEF. Conclusion: Patients enrolled in RESHAPE‐HF2 represent a third distinct population where MitraClip was tested in, that is one mainly comprising of patients with moderate‐to‐severe FMR instead of only severe FMR, as enrolled in the COAPT and MITRA‐FR trials. The results of RESHAPE‐HF2 will provide crucial insights regarding broader application of the transcatheter edge‐to‐edge repair procedure in clinical practice. [ABSTRACT FROM AUTHOR]

A nationwide survey conducted in Italy by the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition (SIGENP) aimed to analyze the management of food protein-induced allergic proctocolitis (FPIAP). The survey found that there is a lack of standardized guidelines for managing FPIAP, leading to variations in diagnostic and treatment approaches. Milk was identified as the most common trigger for FPIAP, and the survey highlighted the importance of eliminating cow's milk proteins from the mother's diet for breastfeeding infants. The survey also emphasized the need for further research and the development of specific guidelines to improve the management of FPIAP. [Extracted from the article]

This paper is concerned with the well‐posedness of a diffusion–reaction system for a susceptible‐exposed‐infected‐recovered (SEIR) mathematical model. This model is written in terms of four nonlinear partial differential equations with nonlinear diffusions, depending on the total amount of the SEIR populations. The model aims at describing the spatio‐temporal spread of the COVID‐19 pandemic and is a variation of the one recently introduced, discussed, and tested in a paper by Viguerie et al (2020). Here, we deal with the mathematical analysis of the resulting Cauchy–Neumann problem: The existence of solutions is proved in a rather general setting, and a suitable time discretization procedure is employed. It is worth mentioning that the uniform boundedness of the discrete solution is shown by carefully exploiting the structure of the system. Uniform estimates and passage to the limit with respect to the time step allow to complete the existence proof. Then, two uniqueness theorems are offered, one in the case of a constant diffusion coefficient and the other for more regular data, in combination with a regularity result for the solutions. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most frequently primary malignant bone tumor characterized by infiltrative growth responsible for relapses and metastases. Treatment options are limited, and a new therapeutic option is required. Boron neutron capture therapy (BNCT) is an experimental alternative radiotherapy able to kill infiltrative tumor cells spearing surrounding healthy tissues. BNCT studies are performed on 2D in vitro models that are not able to reproduce pathological tumor tissue organization or on in vivo animal models that are expensive, time‐consuming and must follow the 3R's principles. A 3D in vitro model is a solution to better recapitulate the complexity of solid tumors meanwhile limiting the animal's use. Objective of this study is to optimize the technical assessment for developing a 3D in vitro osteosarcoma model as a platform for BNCT studies: printing protocol, biomaterial selection, cell density, and crosslinking process. The best parameters that allow a fully colonized 3D bioprinted construct by rat osteosarcoma cell line UMR‐106 are 6 × 106 cells/ml of hydrogel and 1% CaCl2 as a crosslinking agent. The proposed model could be an alternative or a parallel approach to 2D in vitro culture and in vivo animal models for BNCT experimental study. [ABSTRACT FROM AUTHOR]

Summary: Within the framework of plane strain nonlinear elasticity, we present a discussion on the stability properties of various Enhanced Assumed Strain (EAS) finite element formulations with respect to physical and artificial (hourglassing) instabilities. By means of a linearized buckling analysis we analyze the influence of element formulations on the geometric stiffness and provide new mechanical insights into the hourglassing phenomenon. Based on these findings, a simple strategy to avoid hourglassing for compression problems is proposed. It is based on a modification of the discrete Green‐Lagrange strain, simple to implement and generally applicable. The stabilization concept is tested for various popular element formulations (namely EAS elements and the assumed stress element by Pian and Sumihara). A further aspect of the present contribution is a discussion on proper benchmarking of finite elements in the context of hourglassing. We propose a simple bifurcation problem for which analytical solutions are readily available in the literature. It is tailored for an in‐depth stability analysis of finite elements and allows a reliable assessment of its stability properties. [ABSTRACT FROM AUTHOR]

Liver gene therapy with adeno‐associated viral (AAV) vectors is under clinical investigation for haemophilia A (HemA), the most common inherited X‐linked bleeding disorder. Major limitations are the large size of the F8 transgene, which makes packaging in a single AAV vector a challenge, as well as the development of circulating anti‐F8 antibodies which neutralise F8 activity. Taking advantage of split‐intein‐mediated protein trans‐splicing, we divided the coding sequence of the large and highly secreted F8‐N6 variant in two separate AAV‐intein vectors whose co‐administration to HemA mice results in the expression of therapeutic levels of F8 over time. This occurred without eliciting circulating anti‐F8 antibodies unlike animals treated with the single oversized AAV‐F8 vector under clinical development. Therefore, liver gene therapy with AAV‐F8‐N6 intein should be considered as a potential therapeutic strategy for HemA. Synopsis: Liver directed AAV‐intein mediated protein trans‐splicing results in stable therapeutic levels of F8 in mice thus representing a novel therapeutic strategy for haemophilia A. Split‐intein mediated protein trans‐splicing (PTS) allows reconstitution of large proteins via adeno‐associated viral (AAV) vectors in mouse liver.The highly secreted and active F8‐N6 (N6) variant has been adapted to fit into AAV intein vectors.A single systemic injection of AAV‐N6 intein targets liver of hemophilic mice resulting in stable therapeutic levels of F8 without eliciting anti‐F8 antibodies at the vector doses used. [ABSTRACT FROM AUTHOR]

Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop progressive constriction of vision fields leading to blindness. Current therapies are unsatisfactory and better treatments are highly needed. In two mouse models of OAT deficiency that recapitulates biochemical and retinal changes of GACR, we investigated the efficacy of an intravenously injected serotype 8 adeno‐associated (AAV8) vector expressing OAT under the control of a hepatocyte‐specific promoter. Following injections, OAT‐deficient mice showed reductions of ornithine concentrations in blood and eye cups compared with control mice injected with a vector expressing green fluorescent protein. AAV‐injected mice showed improved electroretinogram response and partial restoration of retinal structure up to one‐year post‐injection. In summary, hepatic OAT expression by AAV8 vector was effective at correction of hyperornithinemia and improved function and structure of the retina. In conclusion, this study provides proof‐of‐concept of efficacy of liver‐directed AAV‐mediated gene therapy of GACR. Synopsis: Deficiency of ornithine aminotransferase (OAT) results in increased plasma ornithine concentrations and retinal toxicity, especially in the retinal pigment epithelium (RPE). This study investigated liver‐directed gene transfer for OAT deficiency. Intravenous injections of AAV8 vector delivering OAT gene to hepatocytes reduced ornithine concentrations in plasma and eye.The treatment improved function and structure of the retina. [ABSTRACT FROM AUTHOR]

Thoracic endovascular aortic repair (TEVAR) is widespread in clinical practice for treating aortic diseases but it has relevant systemic complications, such as increase of the cardiac workload due to post‐TEVAR aortic stiffening, and local issues such as re‐entry tears due to the tissue damage caused by endograft interaction. The present study aims to elucidate these aortic biomechanical mechanisms by coupling ex vivo and in silico analysis. By ex vivo tests, the pulse wave velocity before and after TEVAR is measured. Uni‐axial tensile tests are performed to measure regional mechanical response of tissue samples, supplied as input data for the in silico analysis. Numerical analysis is finally performed to compute the wall stress induced by the stent‐graft deployment and the arterial pressurization. The ex vivo results highlight an increase of baseline PWV by a mean.78 m/s or 12% after TEVAR with a 100 mm stent‐graft (p <.013). In the in silico analysis, the average von Mises stress in the landing zone increases of about 15% and 20% using, respectively stent‐graft with radial oversizing of 10% and 20%. This work shows the effectiveness of integrated framework to analyze the biomechanical post TEVAR mechanisms. Moreover, the obtained results quantify the effect of prosthesis selection on the stiffening of the aorta after TEVAR and on the local increase of the aortic wall stress that is proportional to the stent‐graft oversizing. [ABSTRACT FROM AUTHOR]

A numerical study of the fused deposition modeling (FDM) process using a boundary‐conforming free‐surface finite element approach is performed. Due to the complexity of the FDM process, among all of its parts, we focus on the deposition and spreading of an individual filament. The polymer behavior, that is, the shear rate dependent and temperature‐dependent viscosity, is included by the Cross‐WLF viscosity model. The moving domain is addressed by the virtual region mesh update method, which, in the present article, is extended to free‐surface problems. The particularity of dividing the mesh domain into an activated and a deactivated domain makes it possible to handle large translatory mesh deformation. In this work, we make use of the level of detail offered by a boundary‐conforming approach regarding both topology accuracy and the imposition of boundary conditions in order to study the deposition of a single filament at a small scale. Parameters with a direct impact on the mechanical properties of the final object can be straightforwardly computed by a boundary‐conforming approach, for instance, the cross‐section, the contact area, the temperature distribution, and the heat fluxes over the surfaces. The presented approach is validated by a two‐dimensional benchmark test case before the numerical results of the three‐dimensional simulation of the filament deposition are shown. [ABSTRACT FROM AUTHOR]

Summary: Background: The effects of early feeding practices on the risk of coeliac disease (CD) remain debated. Aims: To update evidence on these practices on the risk of CD and/or CD‐related autoimmunity (CDA), defined as anti‐transglutaminase or anti‐endomysial antibody positivity Methods: We searched MEDLINE, EMBASE and the Cochrane Library to May 2022 for randomised controlled trials (RCTs) and observational studies. Results: We included 36 publications (30 studies). In the population at genetic risk of developing CD (HLA DQ2/DQ8‐positive), exclusive or any breastfeeding and longer breastfeeding duration did not reduce the risk of developing CD/CDA during childhood. While a meta‐analysis of four case–control studies showed a decreased risk for CD when gluten was introduced during breastfeeding, this was not shown in RCTs and cohort studies. Age at gluten introduction was not associated with cumulative CD/CDA risk, although two RCTs suggested that earlier gluten introduction was associated with earlier CDA appearance. Evidence from six observational studies suggests that consumption of a higher amount of gluten at weaning and/or thereafter may increase CD risk. There is insufficient evidence to determine the amount of gluten associated with an increased CD/CDA risk. Regarding whether infant feeding practices modulate the risk conferred by different HLA genotypes results were inconsistent. Conclusions: For the population at genetic risk of CD, breastfeeding and age at gluten introduction have no effect on its cumulative incidence during childhood. There is some evidence for an effect of the amount of gluten consumed at weaning and/or thereafter on CD/CDA risk. [ABSTRACT FROM AUTHOR]

Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene‐specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR‐181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR‐181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno‐associated viral vector (AAV) that harbors a miR‐181a/b inhibitor (sponge) sequence (AAV2/8‐GFP‐Sponge‐miR‐181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO‐P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR‐181a/b downregulation modulates the level of the mitochondrial fission‐related protein Drp1 and rescues the mitochondrial fragmentation in RHO‐P347S photoreceptors. Overall, these data support the potential use of miR‐181a/b downregulation as an innovative mutation‐independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene‐specific therapeutic approaches. Synopsis: The application of gene‐specific approaches for the treatment of inherited retinal diseases (IRDs) is hampered by their broad genetic heterogeneity. Modulation of the expression of miR‐181a/b in the retina represents a promising gene‐independent therapeutic strategy for these conditions. miR‐181a/b downregulation slows down retinal degeneration in an in vivo model for a dominant form of IRD, i.e., the transgenic RHO‐P347S mouse.miR‐181a/b downregulation ameliorates the retinal phenotype of an animal model for a recessive form of IRD, i.e., the rd10 mouse.Photoreceptor cells of RHO‐P347S mice show an early mitochondrial dysfunction that is counteracted by miR‐181a/b downregulation. [ABSTRACT FROM AUTHOR]

The two‐way shape memory effect is the ability of a material to change its shape between two configurations upon application and removal of a stimulus, and, among shape memory polymers, it is featured only by few systems, such as semicrystalline networks. When studied under tensile conditions, it consists of elongation–contraction cycles along cooling and heating across the crystallization and melting region, typically under the application of a constant load. However, recent studies on crosslinked semicrystalline co‐polymers demonstrate that also a completely stress‐free, or self‐sustained, two‐way effect may be achieved through specific thermomechanical cycles. This effect is currently regarded with interest for the development of intrinsically reversible sensors and actuators, and it may also be displayed by simpler materials, as homopolymer‐based semicrystalline networks. Only seldom articles investigate this possibility, therefore in this work the two‐way shape memory behavior is studied on a poly(ɛ‐caprolactone) system, crosslinked by means of a sol‐gel approach. The effect is studied both under stress‐driven and stress‐free condition, by applying properly set‐up thermo‐mechanical histories. The results allow to describe the effect as a function of temperature, to reveal the dependence on specific testing parameters and to compare the extent of the reversible strain variation under these two conditions. [ABSTRACT FROM AUTHOR]

The valorization of alkenoic acids possibly deriving from biomass (fumaric and citraconic acids) was carried out through conversion in important building blocks, such as γ‐keto acids and succinic acid derivatives. The functionalization was carried out by addition onto the C=C double bond of radicals generated under photocatalyzed conditions from suitable hydrogen donors (mainly aldehydes) and by adopting a decatungstate salt as the photocatalyst. Syntheses were performed under batch (in a glass vessel) and flow (by using 3D‐printed reactors) conditions. The design of the latter reactors allowed for an improved yield and productivity. [ABSTRACT FROM AUTHOR]

Introduction: The changes in ventricular repolarization after cardiac resynchronization therapy (CRT) are poorly understood. This knowledge gap is addressed using a multimodality approach including electrocardiographic and echocardiographic measurements in patients and using patient‐specific computational modeling. Methods: In 33 patients electrocardiographic and echocardiographic measurements were performed before and at various intervals after CRT, both during CRT‐ON and temporary CRT‐OFF. T‐wave area was calculated from vectorcardiograms, and reconstructed from the 12‐lead electrocardiography (ECG). Computer simulations were performed using a patient‐specific eikonal model of cardiac activation with spatially varying action potential duration (APD) and repolarization rate, fit to a patient's ECG. Results: During CRT‐ON T‐wave area diminished within a day and remained stable thereafter, whereas QT‐interval did not change significantly. During CRT‐OFF T‐wave area doubled within 5 days of CRT, while QT‐interval and peak‐to‐end T‐wave interval hardly changed. Left ventricular (LV) ejection fraction only increased significantly increased after 1 month of CRT. Computer simulations indicated that the increase in T‐wave area during CRT‐OFF can be explained by changes in APD following chronic CRT that are opposite to the change in CRT‐induced activation time. These APD changes were associated with a reduction in LV dispersion in repolarization during chronic CRT. Conclusion: T‐wave area during CRT‐OFF is a sensitive marker for adaptations in ventricular repolarization during chronic CRT that may include a reduction in LV dispersion of repolarization. [ABSTRACT FROM AUTHOR]

Additive manufacturing techniques have grown significantly in recent years due to their ability to produce designs almost impossible to obtain with standard production technologies. This growth has in turn led to increased demand for numerical simulation of additive processes. Unfortunately, such simulations are difficult from the computational point of view, since additive problems are characterized by the presence of highly local nonlinearities requiring fine mesh resolutions on small portions of the domain. These difficulties are compounded by the fact that such regions of local high nonlinearities move in the domain with time, and further, by the fact that the physical domain itself evolves with time. Accordingly, the present article addresses these complex computational issues by employing a two‐level technique. The two‐level method provides a natural framework for the resolution of localized nonlinearities while avoiding the need for complex meshing operations, such as refinement‐and‐derefinement algorithms. The proposed approach is validated on a series of one‐ and two‐dimensional problems to establish the viability of the introduced two‐level method for additive manufacturing problems. [ABSTRACT FROM AUTHOR]

4D printing is based on 3D printing of objects that can change their shape upon a proper triggering. Here, a novel approach is reported for fabricating programmable 3D printed objects composed of shape‐memory polymers (SMPs) that are activated by light. The light activation of the movement and shape morphing are based on combining gold nanoparticles (AuNPs) as photothermal converters with acrylate‐based printing compositions that form an SMP with tunable transition temperatures. The shape change of the printed objects is triggered by remote irradiation with a low‐cost LED light at a wavelength specific to the surface plasmon resonance of the embedded AuNPs. The light is converted to heat which enables the shape transition when the temperature reaches the Tg of the polymer. Excellent SMP properties are achieved with shape fixity and recovery ratios over 95%. This material composition and triggering approach enable fabricating programmable light‐activated 3D printed structures with a dual transition while tuning the concentration. Furthermore, numerical simulations performed by finite‐element analysis result in the excellent prediction of the shape‐memory recovery. The presented approach can be applied in remotely controlling morphing, mainly for applications in the fields of actuators and soft robotics. [ABSTRACT FROM AUTHOR]

Background: Although radiofrequency (RF) catheter ablation of cavo‐tricuspid isthmus (CTI) is an established treatment for typical right atrial flutter (RAFL), it remains to be established whether local tissue impedance (LI) is able to predict effective CTI ablation and what LI drop values during ablation should be used to judge a lesion as effective. We aimed to investigate the ability of LI to predict ablation efficacy in patients with RAFL. Methods: RF delivery was guided by the DirectSense™ algorithm. Successful single RF application was defined according to a defragmentation of atrial potentials (DAP), reduction of voltage (RedV) by at least 80% or changes on unipolar electrogram (UPC). The ablation endpoint was the creation of bidirectional conduction block (BDB) across the isthmus. Results: 392 point‐by‐point RF applications were analyzed in 48 consecutive RAFL patients. The mean baseline LI was 105.4 ± 12Ω prior to ablation and 92.0 ± 11Ω after ablation (p < 0.0001). According to validation criteria, absolute drops in impedance were larger at successful ablation sites than at ineffective ablation sites (DAP: 17.8 ± 6Ω vs. 8.7 ± 4Ω; RedV: 17.2 ± 6Ω vs. 7.8 ± 5Ω; UPC: 19.6 ± 6Ω vs. 10.1 ± 5Ω, all p < 0.0001). LI drop values significantly increased according to the number of criteria satisfied (ranging from 7.5Ω to 19.9). BDB was obtained in all cases. No procedure‐related adverse events were reported. Conclusions: A LI‐guided approach to CTI ablation was safe and effective in treating RAFL. The magnitude of LI drop was associated with effective lesion formation and BDB and could be used as a marker of ablation efficacy. Clinical trial registration: Catheter Ablation of Arrhythmias with a High‐Density Mapping System in Real‐World Practice (CHARISMA). URL: http://clinicaltrials.gov/ Identifier: NCT03793998. [ABSTRACT FROM AUTHOR]

Introduction: Microstructural abnormalities at the epicardium of the right ventricular outflow tract (RVOT) may provide the arrhythmia substrate in Brugada syndrome (BrS). Endocardial unipolar electroanatomical mapping allows the identification of epicardial abnormalities. We evaluated the clinical implications of an abnormal endocardial substrate as perceived by high‐density electroanatomical mapping (HDEAM) in patients with BrS. Methods: Fourteen high‐risk BrS patients with aborted sudden cardiac death (SCD) (12 males, mean age: 41.9 ± 11.8 years) underwent combined endocardial‐epicardial HDEAM of the right ventricle/RVOT, while 40 asymptomatic patients (33 males, mean age: 42 ± 10.7 years) underwent endocardial HDEAM. Based on combined endocardial‐epicardial procedures, endocardial HDEAM was considered abnormal in the presence of low voltage areas (LVAs) more than 1 cm2 with bipolar signals less than 1 mV and unipolar signals less than 5.3 mV. Programmed ventricular stimulation (PVS) was performed in all patients. Results: The endocardial unipolar LVAs were colocalized with epicardial bipolar LVAs (p =.0027). Patients with aborted SCD exhibited significantly wider endocardial unipolar (p <.01) and bipolar LVAs (p <.01) compared with asymptomatic individuals. A substrate size of unipolar LVAs more than 14.5 cm2 (area under the curve [AUC]: 0.92, p <.001] and bipolar LVAs more than 3.68 cm2 (AUC: 0.82, p =.001) distinguished symptomatic from asymptomatic patients. Patients with ventricular fibrillation inducibility (23/54) demonstrated broader endocardial unipolar (p <.001) and bipolar LVAs (p <.001) than noninducible patients. The presence of unipolar LVAs more than 13.5 cm2 (AUC: 0.95, p <.001) and bipolar LVAs more than 2.97 cm2 (AUC: 0.78, p <.001) predicted a positive PVS. Conclusion: Extensive endocardial electroanatomical abnormalities identify high‐risk patients with BrS. Endocardial HDEAM may allow risk stratification of asymptomatic patients referred for PVS. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of LDL‐cholesterol and premature cardiovascular disease. We aim to perform a retrospective analysis of a genetically screened population (528 unrelated patients—342 adults and 186 children) to evaluate the biochemical and clinical correlations with the different genetic statuses. Genetic screening was performed by traditional sequencing and some patients were re‐analyzed by next‐generation‐sequencing. Pathogenic variants, mainly missense in the LDLR gene, were identified in 402/528 patients (76.1%), including 4 homozygotes, 17 compound heterozygotes and 1 double heterozygotes. A gradual increase of LDL‐cholesterol was observed from patients without pathogenic variants to patients with a defective variant, to patients with a null variant and to patients with two variants. Six variants accounted for 51% of patients; a large variability of LDL‐cholesterol was observed among patients carrying the same variant. The frequency of pathogenic variants gradually increased from unlikely FH to definite FH, according to the Dutch Lipid Clinic Network criteria. Genetic diagnosis can help prognostic evaluation of FH patients, discriminating between the different genetic statuses or variant types. Clinical suspicion of FH should be considered even if few symptoms are present or if LDL‐cholesterol is only mildly increased. [ABSTRACT FROM AUTHOR]

Introduction: Filamin C (FLNC) gene variants associated with atrial cardiomyopathies have not been reported so far. The aim of this study was to assess the genetics of two siblings presenting with recurrent right atrial arrhythmias, severe right atrial dilatation, and skeletal myopathy. Methods: A family with subjects affected by recurrent atrial arrhythmias and skeletal myopathy was extensively evaluated by the means of electrocardiographic recordings, magnetic resonance, intracardiac high‐density mapping, and genetic testing. Results: Two siblings with right atrial arrhythmias and severe right atrial disease were found to be heterozygous carriers of the variant FLNC‐c.925G>A p.(Glu309Lys), previously reported as a variant of uncertain significance. Despite the presence of a severe dilatation of the right atrium in both patients, one presented with skeletal muscle myopathy and an atrial arrhythmia refractory to pharmacological and invasive treatment, while the other one did not have any myopathy, and rhythm control was easily achieved by drugs. Conclusion: Filamin C missense variant c.925G>A p.(Glu309Lys) is associated with the severe right atrial disease. Considering cosegregation with the disease (PP1 supporting), this variant should be classified as likely pathogenic. [ABSTRACT FROM AUTHOR]

In this contribution, we apply adaptive isogeometric analysis to a diffuse interface model for topology optimization. First, the influence of refinement and coarsening parameters on the optimization procedure are evaluated and discussed on a two‐dimensional problem and a possible workflow to convert smooth isogeometric solutions into 3D printed products is described. Second, to assess the required numerical accuracy of the proposed simulation framework, numerical results obtained adopting different stopping criteria are experimentally evaluated for a three‐dimensional benchmark problem. [ABSTRACT FROM AUTHOR]

Objectives: We designed this study to identify laboratory and radiological parameters, which could be useful to guide the clinician, in the evaluation of a suspected case of coronavirus disease 19 (COVID‐19). Methods: This retrospective, observational, single‐center‐study recruited patients with a suspect of COVID‐19 data were extracted from electronic medical records using a standardized data collection form. Results: A total of 566 patients with suspect COVID‐19 infection were enrolled (280 were COVID‐19+). The COVID‐19 population was characterized with bilateral‐pneumonia, a lower count of neutrophil, lymphocyte and monocyte, a lower neutrophil to lymphocyte‐ratio (NLR). Lower of platelet count, d‐dimer, troponin I, and serum calcium were in COVID‐19 patients. The occurrence of COVID‐19 diagnosis increased, independently of other variables, with pneumonia (odds ratio [OR]: 3.60; p <.001), neutrophil below normal range (OR: 4.15; p <.05), lactate dehydrogenase (OR: 2.09; p <.01) and sodium above normal range (OR: 2.34; p <.01). In patients with possible respiratory acute affections we found a higher neutrophil, higher monocyte, a higher NLR and a more elevation in d‐dimer. In the Sepsis group showed higher level of white blood cell, C‐reactive protein, d‐dimer, and procalcitonin. Conclusions: Our study confirms that patients with COVID‐19 have typical radiological and laboratory characteristics. The parameters highlighted in the study can help identify COVID‐19 patients, also highlighting which are the main differential diagnoses to be made and the parameters that facilitate the differential diagnosis. [ABSTRACT FROM AUTHOR]

Permanent His bundle pacing is a physiological alternative to right ventricular pacing, resulting in a lower probability of pacing- induced cardiomyopathy and left ventricular ejection fraction deterioration. The combined use of UHD mapping systems allows precise and detailed information on the His bundle location, possibly providing more pacing option locations. [ABSTRACT FROM AUTHOR]

Background: Clinicians all around the world are currently experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Several therapeutic strategies have been used until now but, to date, there is no specific therapy to treat SARS‐CoV‐2 infection. In this study, we used canakinumab, a human monoclonal antibody targeting interleukin‐1 beta to improve respiratory function and laboratory parameters compared with standard therapy (hydroxycloroquine plus lopinavir/ritonavir). Methods: We enrolled 34 patients with mild or severe non intensive care unit (ICU) coronavirus disease 2019 (COVID‐19): 17 patients treated with standard therapy and 17 patients treated with a subcutaneous single dose of canakinumab 300 mg. We collected data about oxygen supports and laboratory parameters such as inflammation indices and hemogasanalysis. We compared the data collected before the administration of canakinumab (T0), 3 days after T0 (T1) and 7 days after T0 (T2) with the same data from patients taking the standard therapy. Results: We observed a reduction in inflammation indices and a significant and rapid increase in P/F ratio in canakinumab group, with improvement of 60.3% after the administration. We reported a significant reduction in oxygen flow in patients treated with canakinumab (−28.6% at T1 vs. T0 and −40.0% at T2 vs. T1). Conversely, the standard group increased the supply of high oxygen at T1 versus T0 (+66.7%), but reduced oxygen flows at T2 versus T1 (−40.0%). Conclusion: In hospitalized adult patients with mild or severe non ICU COVID‐19, canakinumab could be a valid therapeutic option. Canakinumab therapy causes rapid and long‐lasting improvement in oxygenation levels in the absence of any severe adverse events. [ABSTRACT FROM AUTHOR]

Aims: The implantable cardiac defibrillator/cardiac resynchronization therapy with defibrillator‐based HeartLogic™ algorithm has recently been developed for early detection of impending decompensation in heart failure (HF) patients; but whether this novel algorithm can reduce HF hospitalizations has not been evaluated. We investigated if activation of the HeartLogic algorithm reduces the number of hospital admissions for decompensated HF in a 1 year post‐activation period as compared with a 1 year pre‐activation period. Methods and results: Heart failure patients with an implantable cardiac defibrillator/cardiac resynchronization therapy with defibrillator with the ability to activate HeartLogic and willingness to have remote device monitoring were included in this multicentre non‐blinded single‐arm trial with historical comparison. After a HeartLogic alert, the presence of HF symptoms and signs was evaluated. If there were two or more symptoms and signs apart from the HeartLogic alert, lifestyle advices were given and/or medication was adjusted. After activation of the algorithm, patients were followed for 1 year. HF events occurring in the 1 year prior to activation and in the 1 year after activation were compared. Of the 74 eligible patients (67.2 ± 10.3 years, 84% male), 68 patients completed the 1 year follow‐up period. The total number of HF hospitalizations reduced from 27 in the pre‐activation period to 7 in the post‐activation period (P = 0.003). The number of patients hospitalized for HF declined from 21 to 7 (P = 0.005), and the hospitalization length of stay diminished from average 16 to 7 days (P = 0.079). Subgroup analysis showed similar results (P = 0.888) for patients receiving cardiac resynchronization therapy during the pre‐activation period or not receiving cardiac resynchronization therapy, meaning that the effect of hospitalizations cannot solely be attributed to reverse remodelling. Subanalysis of a single‐centre Belgian subpopulation showed important reductions in overall health economic costs (P = 0.025). Conclusion: Activation of the HeartLogic algorithm enables remote monitoring of HF patients, coincides with a significant reduction in hospitalizations for decompensated HF, and results in health economic benefits. [ABSTRACT FROM AUTHOR]

This article presents a novel 3D‐printed cavity resonator, adopted for the extraction of complex dielectric permittivity of liquid chemicals. The proposed structure consists of a spherical cavity slightly compressed at the poles (similar to a pumpkin), which embeds a thin pipe, where the liquid material under test flows. When the liquid is injected into the pipe, the resonance frequency and the quality factor of the fundamental cavity mode change, and their measurement allows retrieving the complex dielectric permittivity of the liquid. The device is entirely realized by 3D‐printing and subsequently metalized by electroplating. The flexibility of the 3D‐printing technique allows to implement cavities with unconventional shapes. In this case, the shape is selected to achieve a high quality factor, and it permits to find a good compromise between high sensitivity and good accuracy in the determination of the complex dielectric permittivity. The device was tested with several liquids, and the results were compared to characterizations performed using a commercial coaxial probe. [ABSTRACT FROM AUTHOR]

Background: His bundle pacing (HBP) is an alternative to biventricular pacing (BVP) for delivering cardiac resynchronization therapy (CRT) in patients with heart failure and left bundle branch block (LBBB). It is not known whether ventricular activation times and patterns achieved by HBP are equivalent to intact conduction systems and not all patients with LBBB are resynchronized by HBP. Objective: To compare activation times and patterns of His‐CRT with BVP‐CRT, LBBB and intact conduction systems. Methods: In patients with LBBB, noninvasive epicardial mapping (ECG imaging) was performed during BVP and temporary HBP. Intrinsic activation was mapped in all subjects. Left ventricular activation times (LVAT) were measured and epicardial propagation mapping (EPM) was performed, to visualize epicardial wavefronts. Normal activation pattern and a normal LVAT range were determined from normal subjects. Results: Forty‐five patients were included, 24 with LBBB and LV impairment, and 21 with normal 12‐lead ECG and LV function. In 87.5% of patients with LBBB, His‐CRT successfully shortened LVAT by ≥10 ms. In 33.3%, His‐CRT resulted in complete ventricular resynchronization, with activation times and patterns indistinguishable from normal subjects. EPM identified propagation discontinuity artifacts in 83% of patients with LBBB. This was the best predictor of whether successful resynchronization was achieved by HBP (logarithmic odds ratio, 2.19; 95% confidence interval, 0.07–4.31; p =.04). Conclusion: Noninvasive electrocardiographic mapping appears to identify patients whose LBBB can be resynchronized by HBP. In contrast to BVP, His‐CRT may deliver the maximum potential ventricular resynchronization, returning activation times, and patterns to those seen in normal hearts. [ABSTRACT FROM AUTHOR]

In this contribution, we apply adaptive isogeometric analysis to a phase‐field model for topology optimization. To increase the efficiency of the computation, we perform local mesh refinement and coarsening between the time increments of the simulation. To provide a trial solution for the iterative solver of the next increment, state variables have to be transferred from the old to the new mesh. We therefore compare the application of a discrete least squares fit with an L2‐projection in well known two‐ and three‐dimensional benchmarks and analyze the influence of these methods on the quality of the results. [ABSTRACT FROM AUTHOR]

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heart failure hospitalization rates and all-cause mortality. Nevertheless, up to two-thirds of eligible patients are not referred for CRT. Furthermore, post-implantation follow-up is often fragmented and suboptimal, hampering the potential maximal treatment effect. This joint position statement from three European Society of Cardiology Associations, Heart Failure Association (HFA), European Heart Rhythm Association (EHRA) and European Association of Cardiovascular Imaging (EACVI), focuses on optimized implementation of CRT. We offer theoretical and practical strategies to achieve more comprehensive CRT referral and post-procedural care by focusing on four actionable domains: (i) overcoming CRT under-utilization, (ii) better understanding of pre-implant characteristics, (iii) abandoning the term 'non-response' and replacing this by the concept of disease modification, and (iv) implementing a dedicated post-implant CRT care pathway. [ABSTRACT FROM AUTHOR]

In the last two decades, great efforts have been made in the development of 3D cadmium–zinc–telluride (CZT) detectors operating at room temperature for gamma‐ray spectroscopic imaging. This work presents the spectroscopic performance of new high‐resolution CZT drift strip detectors, recently developed at IMEM‐CNR of Parma (Italy) in collaboration with due2lab (Italy). The detectors (19.4 mm × 19.4 mm × 6 mm) are organized into collecting anode strips (pitch of 1.6 mm) and drift strips (pitch of 0.4 mm) which are negatively biased to optimize electron charge collection. The cathode is divided into strips orthogonal to the anode strips with a pitch of 2 mm. Dedicated pulse processing analysis was performed on a wide range of collected and induced charge pulse shapes using custom 32‐channel digital readout electronics. Excellent room‐temperature energy resolution (1.3% FWHM at 662 keV) was achieved using the detectors without any spectral corrections. Further improvements (0.8% FWHM at 662 keV) were also obtained through a novel correction technique based on the analysis of collected‐induced charge pulses from anode and drift strips. These activities are in the framework of two Italian research projects on the development of spectroscopic gamma‐ray imagers (10–1000 keV) for astrophysical and medical applications. [ABSTRACT FROM AUTHOR]

The study aims to investigate a novel bioink made from Chitosan (Cs)/ poly(gamma‐glutamic acid) (Gamma‐PGA) hydrogel that takes advantage of the two biodegradable and biocompatible polymers meeting most of the requirements for biomedical applications. The bioink could be an alternative to other materials commonly used in 3D‐bioprinting such as gelatin or alginate. Cs/ Gamma‐PGA hydrogel was prepared by double extrusion of Gamma‐PGA and Cs solutions, where 2 × 105 human adult fibroblasts per ml Cs solution had been loaded, through Cellink 3D‐Bioprinter at 37°C. A computer aided design model was used to get 3D‐bioprinting of a four layers grid hydrogel construct with 70% infill. Hydrogel characterization involved rheology, FTIR analysis, stability study (mass loss [ML], fluid uptake [FU]), and cell retaining ability into hydrogel. 3D‐bioprinted hydrogel gelation time resulted to be <60 s, hydrogel structure was maintained up to 36.79 Pa shear stress, FTIR analysis demonstrated Gamma‐PGA/Cs interpolyelectrolyte complex formation. The 3D‐bioprinted hydrogel was stable for 35 days (35% ML) in cell culture medium, with increasing FU. Cell loaded 3D‐bioprinted Cs 6% hydrogel was able to retain 70% of cells which survived to printing process and cell viability was maintained during 14 days incubation. [ABSTRACT FROM AUTHOR]

Background: Endocardial pacing may be beneficial in patients who fail to improve following conventional epicardial cardiac resynchronization therapy (CRT). The potential to pace anywhere inside the left ventricle thus avoiding myocardial scar and targeting the latest activating segments may be particularly important. The WiSE‐CRT system (EBR systems, Sunnyvale, CA) reliably produces wireless, endocardial left ventricular (LV) pacing. The purpose of this analysis was to determine whether this system improved symptoms or led to LV remodeling in patients who were nonresponders to conventional CRT. Method: An international, multicenter registry of patients who were nonresponders to conventional CRT and underwent implantation with the WiSE‐CRT system was collected. Results: Twenty‐two patients were included; 20 patients underwent successful implantation with confirmation of endocardial biventricular pacing and in 2 patients, there was a failure of electrode capture. Eighteen patients proceeded to 6‐month follow‐up; endocardial pacing resulted in a significant reduction in QRS duration compared with intrinsic QRS duration (26.6 ± 24.4 ms; P =.002) and improvement in left ventricular ejection fraction (LVEF) (4.7 ± 7.9%; P =.021). The mean reduction in left ventricular end‐diastolic volume was 8.3 ± 42.3 cm3 (P =.458) and left ventricular end‐systolic volume (LVESV) was 13.1 ± 44.3 cm3 (P =.271), which were statistically nonsignificant. Overall, 55.6% of patients had improvement in their clinical composite score and 66.7% had a reduction in LVESV ≥15% and/or absolute improvement in LVEF ≥5%. Conclusion: Nonresponders to conventional CRT have few remaining treatment options. We have shown in this high‐risk patient group that the WiSE‐CRT system results in improvement in their clinical composite scores and leads to LV remodeling. [ABSTRACT FROM AUTHOR]

Drawing stimulus from interpersonal acceptance‐rejection theory, this multicultural study examined relations between men's versus women's remembrances of maternal and paternal acceptance‐rejection in childhood and their current level of loneliness, as mediated by adults' self‐reported psychological maladjustment. Adults (N = 899) from five nations (Iraq, Italy, the Netherlands, Pakistan, and the United States) responded to the Adult version of the Parental Acceptance‐Rejection Questionnaire‐short form for mothers and fathers, the Adult version of the Personality Assessment Questionnaire‐short form, and the Interpersonal Acceptance‐Rejection Loneliness Scale. Adults' remembrances of maternal and paternal rejection in childhood significantly and independently predicted feelings of loneliness but remembered paternal rejection was more strongly related to these feelings than were remembrances of maternal rejection. Psychological maladjustment fully mediated the effect of remembered maternal rejection but only partially mediated the effect of remembered paternal rejection on loneliness. There were no significant differences in these results across the five countries or genders. Overall, the results suggest that adults' remembrances of parental rejection in childhood—along with the theoretically expected development of psychological maladjustment—are likely to be associated panculturally with the experience of loneliness in adulthood. [ABSTRACT FROM AUTHOR]

We propose a Bayesian spatiotemporal statistical model for predicting out‐of‐hospital cardiac arrests (OHCAs). Risk maps for Ticino, adjusted for demographic covariates, are built for explaining and forecasting the spatial distribution of OHCAs and their temporal dynamics. The occurrence intensity of the OHCA event in each area of interest, and the cardiac risk‐based clustering of municipalities are efficiently estimated, through a statistical model that decomposes OHCA intensity into overall intensity, demographic fixed effects, spatially structured and unstructured random effects, time polynomial dependence, and spatiotemporal random effect. In the studied geography, time evolution and dependence on demographic features are robust over different categories of OHCAs, but with variability in their spatial and spatiotemporal structure. Two main OHCA incidence‐based clusters of municipalities are identified. [ABSTRACT FROM AUTHOR]

Vertebrate vision relies on the daily phagocytosis and lysosomal degradation of photoreceptor outer segments (POS) within the retinal pigment epithelium (RPE). However, how these events are controlled by light is largely unknown. Here, we show that the light‐responsive miR‐211 controls lysosomal biogenesis at the beginning of light–dark transitions in the RPE by targeting Ezrin, a cytoskeleton‐associated protein essential for the regulation of calcium homeostasis. miR‐211‐mediated down‐regulation of Ezrin leads to Ca2+ influx resulting in the activation of calcineurin, which in turn activates TFEB, the master regulator of lysosomal biogenesis. Light‐mediated induction of lysosomal biogenesis and function is impaired in the RPE from miR‐211−/− mice that show severely compromised vision. Pharmacological restoration of lysosomal biogenesis through Ezrin inhibition rescued the miR‐211−/− phenotype, pointing to a new therapeutic target to counteract retinal degeneration associated with lysosomal dysfunction. Synopsis: MicroRNA‐204/211 (miR‐211) are expressed in murine retinal pigment epithelium (RPE) and regulate eye differentiation and function. Light‐activated miR‐211 targets the membrane/cytoskeleton‐crosslinking protein Ezrin to activate the calcineurin/TFEB pathway in the RPE, thereby inducing lysosomal biogenesis and the degradation of photoreceptor outer segments (POS). Light‐responsive miR‐211 is required for daily lysosomal biogenesis and function in the RPE by targeting Ezrin.miR‐211‐induced downregulation of Ezrin promotes the release of lysosomal Ca2+ through TRPML1, which triggers TFEB nuclear translocation and Calcineurin‐mediated activation of CLEAR network.miR‐211−/− mice show impaired lysosomal degradation of POS and a progressive accumulation of lipofuscin in the RPE that resembles human age‐related macular degeneration (AMD) disease.Pharmacological inhibition of Ezrin in miR‐211−/− mice rescues these defects, pointing to a new therapeutic target to counteract AMD onset and progression. [ABSTRACT FROM AUTHOR]

Background: Contemporary implantable cardioverter‐defibrillator (ICD) programming involving delayed high‐rate detection and use of supraventricular tachycardia (SVT) discriminators has significantly reduced the rate of inappropriate shocks. The extent to which SVT algorithms alone reduce inappropriate therapies is poorly understood. Methods and Results: PainFree SST enrolled 2770 patients with a single‐ or dual‐chamber ICD or cardiac resynchronization defibrillator. Patients were followed for 22 ± 9 months with SVT discriminators on in 96% of patients. Sustained ventricular tachyarrhythmias and SVT episodes were adjudicated by an independent physician committee. For this analysis, all episodes were subjected to postprocessing computer simulation with SVT discriminators off with and without delayed high‐rate detection criteria (ventricular fibrillation zone only, 30/40 at 320 ms). There were 3282 adjudicated SVT episodes of which 115 resulted in an ICD shock and 113 received only ATP (2‐year inappropriate shock and therapy rates of 3.1% and 4.1%). Therapy was appropriately withheld for the remaining 3054 SVT episodes. With both SVT discriminators and delayed high‐rate detection simulated off, the 2‐year inappropriate therapy rate would have been 22.9% (hazard ratio [HR] = 6.24; 95% confidence interval [CI]: 5.20‐7.49). With SVT discriminators simulated off and delayed high‐rate detection simulated on in all patients, the 2‐year rate would have been 6.4% (HR = 1.63; CI: 1.44‐1.85). Conclusions: The use of SVT discriminators has a significant role in reducing the rate of inappropriate ICD therapy even in the setting of delayed high‐rate detection settings. Deactivating SVT discriminators would have resulted in an overall increase in the inappropriate ICD therapy rate by 63% and 524% with and without delayed high‐rate detection programming, respectively. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is characterized by a spectrum of intestinal inflammatory lesions. Most patients have villous atrophy (overt‐CD), while others have a morphologically normal mucosa, despite the presence of CD‐specific autoantibodies (potential‐CD). As the mechanism responsible for villous atrophy is not completely elucidated, we investigated biomarkers specific for the different celiac lesions. Phenotype and cytokine production of intestinal mucosa cells were analyzed by flow cytometry in gut biopsies of children with overt‐ or potential‐CD and in healthy controls. Density of TCRγδ+ T cells was found markedly enhanced in intestinal mucosa of children with overt‐CD compared to potential‐CD or controls. By contrast, very few IL4+ T cells infiltrated the mucosa with villous atrophy compared to morphologically normal mucosa. IL4+ T cells were classical CD4+ T‐helper cells (CD161−), producing or not IFN‐γ, and negative for IL17A. Our study demonstrated that the transition to villous atrophy in CD patients is characterized by increased density of TCRγδ+ T cells, and concomitant disappearance of IL4+ cells. These findings suggest that immunomodulatory mechanisms are active in potential‐CD to counteract the inflammatory cascade responsible of villous atrophy. Further studies are required to validate the use of IL4+ and TCRγδ+ T cells as biomarkers of the different CD forms. [ABSTRACT FROM AUTHOR]