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The European Research Roadmap to the Realisation of Fusion Energy foresees that the DEMO reactor is going to succeed ITER in the pathway towards the exploitation of nuclear fusion, achieving long plasma operation time, demonstrating tritium self-sufficiency and producing net electric output on an industrial scale. Therefore, its design must be more oriented towards the Balance of Plant (BoP) than it is in ITER. Since the early pre-conceptual phase of the DEMO project, emphasis has been laid on identifying the main requirements affecting the overall architecture of the BoP. For instance, specific efforts and proper solutions have been envisaged to cope with the pulsed nature of the heat source. Furthermore, the current development of two blanket concepts calls for two separate BoP options to be conceived. This paper summarizes the main alternatives outlined at the end of DEMO pre-conceptual design phase for the BoP concepts based on both the Helium-Cooled Pebble Bed (HCPB) and Water-Cooled Lithium Lead (WCLL) Breeding Blanket (BB) technologies. Then, the assumed reference configurations of both the BoP concepts are described in detail, highlighting the main features and the most relevant engineering aspects. Attention will be focussed on technological challenges, integration constraints and other open issues, highlighting pros and cons of the chosen BoP options to be further investigated in the next design phase. [ABSTRACT FROM AUTHOR]

In the framework of the DEMO Work Package Balance of Plant of EUROfusion consortium, ENEA has been involved in experimental and numerical activities related to the development of a prototypical heat exchanger, suitable as steam generator for the lithium-lead loop of the Dual Coolant Lithium Lead and Water Cooled Lithium Lead breeding blankets. For this purpose, an experimental campaign has been executed on the pool-type liquid metal-cooled facility CIRCE at ENEA Brasimone Research Centre. A dedicated test section named HERO has been designed and installed inside the main vessel of CIRCE. The innovative steam generator consists of a tube bundle with seven double walled bayonet tubes, fed with pressurized water. The selected configuration improves the plant safety, reducing the possibility of water-lead/lead-alloy interaction thanks to a double physical separation and allowing an easier control of eventual leakages from the coolant by pressurizing the separation region with inert gas. A set of tests has been defined to demonstrate technological feasibility and performances of this prototypical steam generator, as well as the suitability of the component for the lithium-lead loop in DEMO. In particular, one of the performed tests is presented and discussed in this paper. The experiment is characterized by a secondary loop feedwater working pressure of 10 MPa and a steam generator inlet temperature of 300 °C. On the primary side, the lead-bismuth eutectic has been used as working fluid with a steam generator inlet temperature of 480 °C. During the test, an experimental sensitivity analysis on the primary coolant mass flow rate has been performed. Furthermore, the results of a post-test analysis realized with two versions of the system thermal-hydraulic code RELAP5 are presented, in order to evaluate their capability in simulating the performances of the component and to support the validation process of the codes for heavy liquid metal applications. The work is concluded presenting a scaling analysis to find the equivalence between LBE and PbLi, recalculating the available experimental data with RELAP5 code using PbLi as working fluid. [ABSTRACT FROM AUTHOR]

In the framework of the EU DEMO fusion reactor technology development, a new steam generator consisting in a helical tube bundle is currently under study for the lithium-lead loop of the Dual Coolant Lithium Lead (DCLL) and Water Cooled Lithium Lead (WCLL) breeding blankets. This solution turns out to be very interesting for high power plants, since the helical geometry is very compact and it assures a high thermal power exchanged, taking up the minimum amount of space. In this framework, the ENEA Brasimone Research Centre supports the development of this innovative component by means of experimental activities, involving CIRCE, a large scale pool-type facility using Lead-Bismuth Eutectic as primary fluid and pressurized water as secondary fluid. The main components of a new test section named THETIS are: a Fuel Pin Simulator, acting as primary heating source, a vertical mechanical pump for the primary fluid circulation inside the main pool and a new prototypical helical coil steam generator mock-up, designed to be relevant for the DCLL and WCLL lithium-lead loop, acting as primary heat sink. In such configuration, the facility will be involved in a set of tests aiming at demonstrating the technological feasibility and thermal-hydraulic performances of this prototypical steam generator, as well as the suitability of the component for the lithium-lead loop in DEMO. The experiments will also provide a database for system thermal-hydraulic codes validation. The aim of this paper is to present the main layout of the CIRCE facility, to describe the preliminary design of the test section and the main features of the helical coil steam generator mock-up. Furthermore, a preliminary test analysis carried out by the system thermal hydraulic code RELAP5/Mod3.3 is presented. A numerical 1-D model of the helical coil steam generator has been set-up in order to test the performance of the component from a thermal-hydraulic point of view. An additional 3D CFD analysis was performed for the flow field of the HCSG to assess the secondary flow behaviour in the component and the pressure losses. [ABSTRACT FROM AUTHOR]

• Experimental data on Heavy Liquid Metal flow in the CIRCE-HERO facility. • Numerical benchmark activity on Heavy Liquid Metal with SYS-TH codes and SYS-TH/CFD codes. • HERO double wall bayonet tube steam genarator thermal–hydraulic characterization. • CIRCE-HERO experimental campaign on protected loss of flow accident scenarios. In the framework of the HORIZON2020 SESAME European project, an experimental campaign has been carried out on the large Lead-Bismuth Eutectic pool integral effect CIRCE facility at ENEA Brasimone Research Center, implementing the HERO test section. This test section is aimed at supporting the development of the ALFRED design. Within the SESAME Project, three protected loss of flow accident tests have been designed and executed, identified as SE-Test1, SE-Test2, and SE-Test3. The third test (SE-Test3) has been selected by the project participants for a benchmark activity involving system thermal-hydraulic codes and coupled system thermalhydraulic/ CFD. This activity has been divided into two phases: a blind phase, and a post-test phase. The present paper illustrates the results achieved during the post-test phase of the CIRCE-HERO benchmark activity. Four participants simulated the experimental test. Three (ENEA, SCKCEN and UNIROMA1) used different versions of RELAP5 code, i.e. RELAP5-3D and RELAP5Mod3.3, and one (NRG) used a coupled approach based on an in-house system thermal-hydraulic code (SPECTRA) and the commercial code ANSYS CFX. The benchmark activity hereafter presented is a relevant exercise for evaluating and comparing the predictive capabilities of system thermal-hydraulic codes, CFD codes and coupled technics, in relation to phenomena occurring during the transition between forced and natural circulation (e.g. loss of flow) in a heavy liquid metals Generation IV system. The results of the numerical exercise showed an adequate capability of the codes to reproduce the relevant phenomena involved during the experiment. The SYS-TH codes have been more accurate than SYS-TH/CFD in predicting the trend of the main parameters during the transient, reproducing them with quite satisfactory accuracy. SYS-TH/CFD simulation, instead, provided a more satisfactory representation of the pool thermal stratification. The results highlighted that the planning and the execution of experiments fully devoted for the code V&V process is needed for the further development of such numerical tools, in particular for SYS-TH/CFD coupled approaches, whose use is more recent respect to SYS-TH codes. [ABSTRACT FROM AUTHOR]

• Experimental campaign on HERO test section is presented to demonstrate technological feasibility of a steam generator bayonet tube. • Steam generator bayonet tube could be used in DCLL and WCLL breeding blanket. • Activity aims at investigating thermal-hydraulic features of the system. • Results will provide a database for thermal-hydraulic system codes validation. • Post-test analysis with RELAP5-3D and RELAP5/Mod3.3 codes are presented. In the frame of the EUROfusion roadmap for the development of the DEMO power plant, a research activity was carried out to develop a Lithium–Lead/water heat exchanger. The component should be capable to remove nuclear heat deposited in the liquid metal of the Dual Coolant Lithium Lead breeding blanket and feeding a steam turbine, ensuring an efficient thermal power conversion to electricity. One of the selected configurations is the steam generator bayonet tube. The HERO test section is an experimental mock-up in a relevant scale of this steam generator, consisting of a bundle of seven double-wall bayonet tubes with a leakage monitoring system. This test section, developed by ENEA at Brasimone Research Center and installed in the main vessel of the CIRCE pool facility, aims to investigate the thermal-hydraulic features of the system, providing a database for thermal-hydraulic system codes validation. An experimental campaign was carried out to demonstrate technological feasibility and performances of the prototypical heat exchanger, suitable as steam generator for the PbLi loop of the Dual Coolant Lithium Lead and Water Cooled Lithium Lead breeding blankets. A post-test analysis has been realized with RELAP5-3D and RELAP5/Mod3.3 codes in order to evaluate code capability in simulating heat transfer in liquid metal side. [ABSTRACT FROM AUTHOR]

• NACIE-UP benchmark activity foreseen inside the EU SESAME Project. • Validation of System Thermal Hydraulic (STH) codes used for Heavy Liquid Metal reactors. • Protected Loss of Flow Accident (PLOFA) scenario of interest for LFRs. • Convective heat transfer in Heavy Liquid Metal systems. This paper illustrates the results obtained in the last phase of the NACIE-UP benchmark activity foreseen inside the EU SESAME Project. The purpose of this research activity, performed by system thermal–hydraulic (STH) codes, is finalized to the improvement, development and validation of existing STH codes for Heavy Liquid Metal (HLM) systems. All the participants improved their modelling of the NACIE-UP facility, respect to the initial blind simulation phase, adopting the actual experimental boundary conditions and reducing as much as possible sources of uncertainty in their numerical model. Four different STH codes were employed by the participants to the benchmark to model the NACIE-UP facility, namely: CATHARE for ENEA, ATHLET for GRS, RELAP5-3D© for the "Sapienza" University of Rome and RELAP5/Mod3.3(modified) for the University of Pisa. Three reference tests foreseen in the NACIE-UP benchmark and carried out at ENEA Brasimone Research Centre were analysed from four participants. The data from the post-test analyses, performed independently by the participant using different STH codes, were compared together and with the available experimental results and critically discussed. [ABSTRACT FROM AUTHOR]

• Experimental campaign on Lead-Bismuth Eutectic thermal-hydraulics in the CIRCE-HERO pool-type facility. • Experimental tests on CIRCE-HERO facility in support of MYRRHA primary heat exchanger. • Double Wall Bayonet tube Steam Generator. • CIRCE-HERO experimental tests on Heavy Liquid Metal flow in gas-enhanced circulation regime. In the frame of the MYRRHA ADS technological development, an intense research effort has been undertaken by European Commission, in particular for the Heavy Liquid Metal technology assessment. In this scenario, EURATOM HORIZON2020 funded the SESAME & MYRTE projects, coordinating a series of thermal hydraulics experiments and simulations for the safety assessment of liquid metal fast reactors. In particular, in the MYRTE project, a dedicated activity has been defined, consisting of a low pressure experimental campaign realized at the ENEA Brasimone Research Centre and concerning a double wall Steam Generator Bayonet Tube (SGBT), aiming at supporting the development of the Primary Heat Exchanger (PHX) of MYRRHA. The CIRCE (CIRColazione Eutettico) pool facility hosts a devoted Test Section (TS) named HERO (Heavy liquid mEtal pRessurized water cOoled tubes). HERO consists of seven double wall bayonet tubes, with an active length of 6 m, arranged in a hexagonal geometry. This solution aims at improving the plant safety reducing the possibility of water-lead/leadalloy interaction thanks to a double physical separation between them and allowing an easier control of potential leakages of the coolant by pressurizing the separation region with inert gas. The experimental campaign in CIRCE-HERO has been supported by a pre-test analysis using system thermal-hydraulic codes (i.e. RELAP5). A sensitivity analysis has been performed considering the mass flow rate and HERO inlet temperature for both the water and LBE, fixing the operating pressure at 16 bar. A test matrix, as produced as output of the sensitivity analysis and aimed at reproducing as faithfully as possible the thermal-hydraulic behaviour of the MYRRHA PHX under different operating conditions, is here presented. The experimental results collected from the low pressure tests on HERO test section are reported and discussed. [ABSTRACT FROM AUTHOR]

• Experimental data on Heavy Liquid Metal flow in the CIRCE-HERO loop were presented. • Experimental data on the CIRCE-HERO facility in support of ALFRED design. • Bayonet tube heat exchanger. • CIRCE-HERO protected loss of flow experimental campaign. [ABSTRACT FROM AUTHOR]

Background: Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel-mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2., Methods: Heart rate-corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD 90 ) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model., Results: After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate-corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD 90 by 113 ms, indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test ( r = -0.8; P <0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07-0.14) to 0.04 (95% CI, 0.02-0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16-0.84), reflecting a 60% reduction in the event rate ( P =0.01)., Conclusions: Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2., Competing Interests: None.

Aim: Striatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated., Methods: We studied the role(s) of cardiac Strn gene (STRN) by comparing the functional properties of CMs, generated from Strn-KO and isogenic WT mouse embryonic stem cell lines., Results: The spontaneous beating rate of Strn-KO CMs was faster than WT cells, and this correlated with a larger fast I Na conductance and no changes in I f . Paced (2-8 Hz) Strn-KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in I CaL and I Kr . Motion video tracking analysis highlighted an altered contraction in Strn-KO CMs; this was associated with a global increase in intracellular Ca 2+ , caused by an enhanced late Na + current density (I NaL ) and a reduced Na + /Ca 2+ exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na + channel expression and a more dynamic microtubule network in Strn-KO CMs than in WT. Indeed, incubation of Strn-KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of I Na conductance toward WT levels., Conclusion: Loss of STRN alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn-related multi-protein complexes. This leads to impaired microtubules dynamics and Na + channels trafficking to the plasma membrane, causing a global Na + and Ca 2+ enhancement., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Introduction: Melatonin, a hormone produced by the pineal gland, regulates the sleep-wake cycle and is effective in restoring biological rhythms. Prolonged-release melatonin (PRM) is designed to mimic the natural physiological pattern of melatonin release. In circadian medicine, PRM can be used to treat sleep and circadian rhythm disorders, as well as numerous organic diseases associated with sleep disorders., Evidence Acquisition: This systematic review analyzed 62 studies and adhered to the PRISMA guidelines, examining the effectiveness of PRM in organic pathologies and mental disorders., Evidence Synthesis: The main evidence concerns primary insomnia in subjects over the age of 55, showing significant improvements in sleep quality. In neurodevelopmental disorders, there is evidence of a positive impact on sleep quality and quality of life for patients and their caregivers. PRM shows efficacy in the treatment of sleep disorders in mood disorders, schizophrenia, and neurocognitive disorders, but requires further confirmation. The additional use of PRM is supported for the withdrawal of chronic benzodiazepine therapies. The tolerability and safety of PRM are excellent, with ample evidence supporting the absence of tolerance and dependence., Conclusions: Overall, PRM in circadian medicine is an effective chronopharmaceutical for restoring the sleep-wake rhythm in patients with insomnia disorder. This efficacy may also extend to sleep disorders associated with mood, neurodevelopmental and neurocognitive disorders, suggesting a further potential role in insomnia associated with various organic diseases.

Opportunistic sensors are increasingly used for rainfall measurement. However, their raw data are collected by a variety of systems that are often not primarily intended for rainfall monitoring, resulting in a plethora of different data formats and a lack of common standards. This hinders the sharing of opportunistic sensing (OS) data, their automated processing, and, at the end, their practical usage and integration into standard observation systems. This paper summarises the experiences of the more than 100 members of the OpenSense Cost Action involved in the OS of rainfall. We review the current practice of collecting and storing precipitation OS data and corresponding metadata, and propose new common guidelines describing the requirements on data and metadata collection, harmonising naming conventions, and defining human-readable and machine readable file formats for data and metadata storage. We focus on three sensors identified by the OpenSense community as prominent representatives of the OS of precipitation: Commercial microwave links (CML): fixed point-to-point radio links mainly used as backhauling connections in telecommunication networks Satellite microwave links (SML): radio links between geostationary Earth orbit (GEO) satellites and ground user terminals. Personal weather stations (PWS): non-professional meteorological sensors owned by citizens. The conventions presented in this paper are primarily designed for storing, handling, and sharing historical time series and do not consider specific requirements for using OS data in real time for operational purposes. The conventions are already now accepted by the ever growing OpenSense community and represent an important step towards automated processing of OS raw data and community development of joint OS software packages., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Fencl M et al.)

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide; however, the underlying causes of AF initiation are still poorly understood, particularly because currently available models do not allow in distinguishing the initial causes from maladaptive remodeling that induces and perpetuates AF. Lately, the genetic background has been proven to be important in the AF onset. iPSC-derived cardiomyocytes, being patient- and mutation-specific, may help solve this diatribe by showing the initial cell-autonomous changes underlying the development of the disease. Transcription factor paired-like homeodomain 2 (PITX2) has been identified as a key regulator of atrial development/differentiation, and the PITX2 genomic locus has the highest association with paroxysmal AF. PITX2 influences mitochondrial activity, and alterations in either its expression or function have been widely associated with AF. In this work, we investigate the activity of mitochondria in iPSC-derived atrial cardiomyocytes (aCMs) obtained from a young patient (24 years old) with paroxysmal AF, carrying a gain-of-function mutation in PITX2 (rs138163892) and from its isogenic control (CTRL) in which the heterozygous point mutation has been reverted to WT. PITX2 aCMs show a higher mitochondrial content, increased mitochondrial activity, and superoxide production under basal conditions when compared to CTRL aCMs. However, increasing mitochondrial workload by FCCP or β-adrenergic stimulation allows us to unmask mitochondrial defects in PITX2 aCMs, which are incapable of responding efficiently to the higher energy demand, determining ATP deficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Benzoni, Da Dalt, Elia, Popolizio, Cospito, Giannetti, Dell’Era, Olesen, Bucchi, Baruscotti, Norata and Barbuti.)

Aims: Nfix is a transcription factor belonging to the Nuclear Factor I (NFI) family comprising four members (Nfia, b, c, x). Nfix plays important roles in the development and function of several organs. In muscle development, Nfix controls the switch from embryonic to fetal myogenesis by promoting fast twitching fibres. In the adult muscle, following injury, lack of Nfix impairs regeneration, inducing higher content of slow-twitching fibres. Nfix is expressed also in the heart, but its function has been never investigated before. We studied Nfix role in this organ., Methods: Using Nfix-null and wild type (WT) mice we analyzed: (1) the expression pattern of Nfix during development by qPCR and (2) the functional alterations caused by its absence, by in vivo telemetry and in vitro patch clamp analysis., Results and Conclusions: Nfix expression start in the heart from E12.5. Adult hearts of Nfix-null mice show a hearts morphology and sarcomeric proteins expression similar to WT. However, Nfix-null animals show tachycardia that derives form an intrinsic higher beating rate of the sinus node (SAN). Molecular and functional analysis revealed that sinoatrial cells of Nfix-null mice express a significantly larger L-type calcium current (Cacna1d + Cacna1c). Interestingly, downregulation of Nfix by sh-RNA in primary cultures of neonatal rat ventricular cardiomyocytes induced a similar increase in their spontaneous beating rate and in I CaL current. In conclusion, our data provide the first demonstration of a role of Nfix that, increasing the L-type calcium current, modulates heart rate., (© 2023 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Aims: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2., Methods and Results: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM., Conclusion: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Conducted under the auspices of the Italian Society of Consultation Liaison Psychiatry (SIPC) the aim of this study was to describe the characteristics of Consultation Liaison Psychiatry (CLP) activity in Italy (SIPC-2-2018) over the past 20 years by comparing with data from the first Italian nation-wide study (SIPC-1-1998)., Methods: We collected data on CLP visits of 3,943 patients from 10 Italian hospitals over a period of 1 year. Data were compared with those from the SIPC-1 1998 study (4,183 participants). Patients were assessed with the same ad hoc 60-item Patient Registration Form recording information from five different areas: Sociodemographic, hospitalization-related, consultation-related, interventions and outcome., Results: Compared with participants from the previous study, SIPC-2-2018 participants were significantly older ( d = 0.54) and hospitalized for a longer duration ( d = 0.20). The current study detected an increase in the proportion of referrals from surgical wards and for individuals affected by onco-hematologic diseases. Depressive disorders still represented the most frequent psychiatric diagnosis, followed by adjustment and stress disorders and delirium/dementia. Also, CLP psychiatrists prescribed more often antidepressants (Φ = 0.13), antipsychotics (Φ = 0.09), mood stabilizers (Φ = 0.24), and less often benzodiazepines (Φ = 0.07)., Conclusion: CLP workload has increased considerably in the past 20 years in Italy, with changes in patient demographic and clinical characteristics. A trend toward increase in medication-based patient management was observed. These findings suggest that the psychiatric needs of patients admitted to the general hospital are more frequently addressed by referring physicians, although Italian CLP services still deserve better organization and autonomy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zerbinati, Palagini, Balestrieri, Belvederi Murri, Caruso, D’Agostino, Ferrara, Ferrari, Minervino, Milia, Nanni, Pini, Politi, Porcellana, Rocchetti, Taddei, Toffanin, Grassi and Italian Society of Consultation-Liaison Psychiatry.)

The demand for accurate rainfall rate maps is growing ever more. This paper proposes a novel algorithm to estimate the rainfall rate map from the attenuation measurements coming from both broadcast satellite links (BSLs) and commercial microwave links (CMLs). The approach we pursue is based on an iterative procedure which extends the well-known GMZ algorithm to fuse the attenuation data coming from different links in a three-dimensional scenario, while also accounting for the virga phenomenon as a rain vertical attenuation model. We experimentally prove the convergence of the procedures, showing how the estimation error decreases for every iteration. The numerical results show that adding the BSL links to a pre-existent CML network boosts the accuracy performance of the estimated rainfall map, improving up to 50% the correlation metrics. Moreover, our algorithm is shown to be robust to errors concerning the virga parametrization, proving the possibility of obtaining good estimation performance without the need for precise and real-time estimation of the virga parameters.

A sensorized face mask could be a useful tool in the case of a viral pandemic event, as well as the Covid-19 emergency. In the context of the proposed project "RESPIRE", we have developed a "Smart-Mask" able to collect the signal patterns of body temperature, respiration, and symptoms such as cough, through a set of textile sensors. The signals have been analyzed by Artificial Intelligence algorithms in order to compare them with gold standard measurements, and to recognize the physiological changes associated with a viral infection. This low-cost prototype of a smart face mask is a reliable tool for the estimation of the individual physiological parameters. Moreover, it enables both personal protection and the early and rapid identification and tracking of potentially infected individuals.

In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compounds that could improve the prognosis of symptomatic patients infected by SARS-CoV-2. Hydroxychloroquine (HCQ) was one of the first drugs used to treat COVID-19 due to its supposed capacity of inhibiting SARS-CoV-2 infection and replication in vitro . While its efficacy is debated, HCQ has been associated with QT interval prolongation and potentially Torsades de Pointes, especially in patients predisposed to developing drug-induced Long QT Syndrome (LQTS) as silent carriers of variants associated with congenital LQTS. If confirmed, these effects represent a limitation to the at-home use of HCQ for COVID-19 infection as adequate ECG monitoring is challenging. We investigated the proarrhythmic profile of HCQ with Multi-Electrode Arrays after exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from two healthy donors, one asymptomatic and two symptomatic LQTS patients. We demonstrated that: I) HCQ induced a concentration-dependent Field Potential Duration (FPD) prolongation and halted the beating at high concentration due to the combined effect of HCQ on multiple ion currents. II) hiPSC-CMs from healthy or asymptomatic carriers tolerated higher concentrations of HCQ and showed lower susceptibility to HCQ-induced electrical abnormalities regardless of baseline FPD. These findings agree with the clinical safety records of HCQ and demonstrated that hiPSC-CMs potentially discriminates symptomatic vs. asymptomatic mutation carriers through pharmacological interventions. Disease-specific cohorts of hiPSC-CMs may be a valid preliminary addition to assess drug safety in vulnerable populations, offering rapid preclinical results with valuable translational relevance for precision medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sala, Leonov, Mura, Giannetti, Khudiakov, Moretti, Crotti, Gnecchi and Schwartz.)

Discovered some 40 years ago, the I f current has since been known as the "pacemaker" current due to its role in the initiation and modulation of the heartbeat and of neuronal excitability. But this is not all, the funny current keeps entertaining the researchers; indeed, several data discovering novel and uncanonical roles of f/HCN channel are quickly accumulating. In the present review, we provide an overview of the expression and cellular functions of HCN/f channels in a variety of systems/organs, and particularly in sour taste transduction, hormones secretion, activation of astrocytes and microglia, inhibition of osteoclastogenesis, renal ammonium excretion, and peristalsis in the gastrointestinal and urine systems. We also analyzed the role of HCN channels in sustaining cellular respiration in mitochondria and their participation to mitophagy under specific conditions. The relevance of HCN currents in undifferentiated cells, and specifically in the control of stem cell cycle and in bioelectrical signals driving left/right asymmetry during zygote development, is also considered. Finally, we present novel data concerning the expression of HCN mRNA in human leukocytes. We can thus conclude that the emerging evidence presented in this review clearly points to an increasing interest and importance of the "funny" current that goes beyond its role in cardiac sinoatrial and neuronal excitability regulation., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recent years have witnessed a growing interest in techniques and systems for rainfall surveillance on regional scale, with increasingly stringent requirements in terms of the following: (i) accuracy of rainfall rate measurements, (ii) adequate density of sensors over the territory, (iii) space-time continuity and completeness of data and (iv) capability to elaborate rainfall maps in near real time. The devices deployed to monitor the precipitation fields are traditionally networks of rain gauges distributed throughout the territory, along with weather radars and satellite remote sensors operating in the optical or infrared band, none of which, however, are suitable for full compliance to all of the requirements cited above. More recently, a different approach to rain rate estimation techniques has been proposed and investigated, based on the measurement of the attenuation induced by rain on signals of pre-existing radio networks either in terrestrial links, e.g., the backhaul connections in cellular networks, or in satellite-to-earth links and, among the latter, notably those between geostationary broadcast satellites and domestic subscriber terminals in the Ku and Ka bands. Knowledge of the above rain-induced attenuation permits the retrieval of the corresponding rain intensity provided that a number of meteorological and geometric parameters are known and ultimately permits estimating the rain rate locally at the receiver site. In this survey paper, we specifically focus on such a type of "opportunistic" systems for rain field monitoring, which appear very promising in view of the wide diffusion over the territory of low-cost domestic terminals for the reception of satellite signals, prospectively allowing for a considerable geographical capillarity in the distribution of sensors, at least in more densely populated areas. The purpose of the paper is to present a broad albeit synthetic overview of the numerous issues inherent in the above rain monitoring approach, along with a number of solutions and algorithms proposed in the literature in recent years, and ultimately to provide an exhaustive account of the current state of the art. Initially, the main relevant aspects of the satellite link are reviewed, including those related to satellite dynamics, frequency bands, signal formats, propagation channel and radio link geometry, all of which have a role in rainfall rate estimation algorithms. We discuss the impact of all these factors on rain estimation accuracy while also highlighting the substantial differences inherent in this approach in comparison with traditional rain monitoring techniques. We also review the basic formulas relating rain rate intensity to a variation of the received signal level or of the signal-to-noise ratio. Furthermore, we present a comprehensive literature survey of the main research issues for the aforementioned scenario and provide a brief outline of the algorithms proposed for their solution, highlighting their points of strength and weakness. The paper includes an extensive list of bibliographic references from which the material presented herein was taken.

Aims: PCSK9 is secreted into the circulation, mainly by the liver, and interacts with low-density lipoprotein receptor (LDLR) homologous and non-homologous receptors, including CD36, thus favouring their intracellular degradation. As PCSK9 deficiency increases the expression of lipids and lipoprotein receptors, thus contributing to cellular lipid accumulation, we investigated whether this could affect heart metabolism and function., Methods and Results: Wild-type (WT), Pcsk9 KO, Liver conditional Pcsk9 KO and Pcsk9/Ldlr double KO male mice were fed for 20 weeks with a standard fat diet and then exercise resistance, muscle strength, and heart characteristics were evaluated. Pcsk9 KO presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with lipid accumulation. A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice. Heart function profiling of the liver selective Pcsk9 KO model further excluded the involvement of circulating PCSK9 in the development of HFpEF, pointing to a possible role locally produced PCSK9. Concordantly, carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects., Conclusion: PCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

miR-1, the most abundant miRNA in the heart, modulates expression of several transcription factors and ion channels. Conditions affecting the heart rate, such as endurance training and cardiac diseases, show a concomitant miR-1 up- or down-regulation. Here, we investigated the role of miR-1 overexpression in the development and function of sinoatrial (SAN) cells using murine embryonic stem cells (mESC). We generated mESCs either overexpressing miR-1 and EGFP (miR1OE) or EGFP only (EM). SAN-like cells were selected from differentiating mESC using the CD166 marker. Gene expression and electrophysiological analysis were carried out on both early mES-derived cardiac progenitors and SAN-like cells and on beating neonatal rat ventricular cardiomyocytes (NRVC) over-expressing miR-1. miR1OE cells increased significantly the proportion of CD166 + SAN precursors compared to EM cells (23% vs 12%) and the levels of the transcription factors TBX5 and TBX18, both involved in SAN development. miR1OE SAN-like cells were bradycardic (1,3 vs 2 Hz) compared to EM cells. In agreement with data on native SAN cells, EM SAN-like cardiomyocytes show two populations of cells expressing either slow- or fast-activating I f currents; miR1OE SAN-like cells instead have only fast-activating I f with a significantly reduced conductance. Western Blot and immunofluorescence analysis showed a reduced HCN4 signal in miR-1OE vs EM CD166+ precursors. Together these data point out to a specific down-regulation of the slow-activating HCN4 subunit by miR-1. Importantly, the rate and I f alterations were independent of the developmental effects of miR-1, being similar in NRVC transiently overexpressing miR-1. In conclusion, we demonstrated a dual role of miR-1, during development it controls the proper development of sinoatrial-precursor, while in mature SAN-like cells it modulates the HCN4 pacemaker channel translation and thus the beating rate., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Properties of the funny current (I f ) have been studied in several animal and cellular models, but so far little is known concerning its properties in human pacemaker cells. This work provides a detailed characterization of I f in human-induced pluripotent stem cell (iPSC)-derived pacemaker cardiomyocytes (pCMs), at different time points. Patch-clamp analysis showed that I f density did not change during differentiation; however, after day 30, it activates at more negative potential and with slower time constants. These changes are accompanied by a slowing in beating rate. I f displayed the voltage-dependent block by caesium and reversed (E rev ) at - 22 mV, compatibly with the 3:1 K + /Na + permeability ratio. Lowering [Na + ] o (30 mM) shifted the E rev to - 39 mV without affecting conductance. Increasing [K + ] o (30 mM) shifted the E rev to - 15 mV with a fourfold increase in conductance. pCMs express mainly HCN4 and HCN1 together with the accessory subunits CAV3, KCR1, MiRP1, and SAP97 that contribute to the context-dependence of I f . Autonomic agonists modulated the diastolic depolarization, and thus rate, of pCMs. The adrenergic agonist isoproterenol induced rate acceleration and a positive shift of I f voltage-dependence (EC 50 73.4 nM). The muscarinic agonists had opposite effects (Carbachol EC 50 , 11,6 nM). Carbachol effect was however small but it could be increased by pre-stimulation with isoproterenol, indicating low cAMP levels in pCMs. In conclusion, we demonstrated that pCMs display an I f with the physiological properties expected by pacemaker cells and may thus represent a suitable model for studying human I f -related sinus arrhythmias.

Measuring rainfall is complex, due to the high temporal and spatial variability of precipitation, especially in a changing climate, but it is of great importance for all the scientific and operational disciplines dealing with rainfall effects on the environment, human activities, and economy. Microwave (MW) telecommunication links carry information on rainfall rates along their path, through signal attenuation caused by raindrops, and can become measurements of opportunity, offering inexpensive chances to augment information without deploying additional infrastructures, at the cost of some smart processing. Processing satellite telecom signals bring some specific complexities related to the effects of rainfall boundaries, melting layer, and non-weather attenuations, but with the potential to provide worldwide precipitation data with high temporal and spatial samplings. These measurements have to be processed according to the probabilistic nature of the information they carry. An EnKF-based (Ensemble Kalman Filter) method has been developed to dynamically retrieve rainfall fields in gridded domains, which manages such probabilistic information and exploits the high sampling rate of measurements. The paper presents the EnKF method with some representative tests from synthetic 3D experiments. Ancillary data are assumed as from worldwide-available operational meteorological satellites and models, for advection, initial and boundary conditions, rain height. The method reproduces rainfall structures and quantities in a correct way, and also manages possible link outages. It results computationally viable also for operational implementation and applicable to different link observation geometries and characteristics.

Different forest types based on different tree species composition may have similar spectral signatures if observed with traditional multispectral satellite sensors. Hyperspectral imagery, with a more continuous representation of their spectral behavior may instead be used for their classification. The new hyperspectral Precursore IperSpettrale della Missione Applicativa (PRISMA) sensor, developed by the Italian Space Agency, is able to capture images in a continuum of 240 spectral bands ranging between 400 and 2500 nm, with a spectral resolution smaller than 12 nm. The new sensor can be employed for a large number of remote sensing applications, including forest types discrimination. In this study, we compared the capabilities of the new PRISMA sensor against the well-known Sentinel-2 Multi-Spectral Instrument (MSI) in recognition of different forest types through a pairwise separability analysis carried out in two study areas in Italy, using two different nomenclature systems and four separability metrics. The PRISMA hyperspectral sensor, compared to Sentinel-2 MSI, allowed for a better discrimination in all forest types, increasing the performance when the complexity of the nomenclature system also increased. PRISMA achieved an average improvement of 40% for the discrimination between two forest categories (coniferous vs. broadleaves) and of 102% in the discrimination between five forest types based on main tree species groups.

GNB5 loss-of-function pathogenic variants cause IDDCA, a rare autosomal recessive human genetic disease characterized by infantile onset of intellectual disability, sinus bradycardia, hypotonia, visual abnormalities, and epilepsy. We generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of a patient with the homozygous c.136delG frameshift variant, and a GNB5 knock-out (KO) line by CRISPR/Cas9 editing. hiPSCs express common pluripotency markers and differentiate into the three germ layers. These lines represent a powerful cellular model to study the molecular basis of GNB5-related disorders as well as offer an in vitro model for drug screening., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

We present the NEFOCAST project (named by the contraction of "Nefele", which is the Italian spelling for the mythological cloud nymph Nephele, and "forecast"), funded by the Tuscany Region, about the feasibility of a system for the detection and monitoring of precipitation fields over the regional territory based on the use of a widespread network of new-generation Eutelsat "SmartLNB" (smart low-noise block converter) domestic terminals. Though primarily intended for interactive satellite services, these devices can also be used as weather sensors, as they have the capability of measuring the rain-induced attenuation incurred by the downlink signal and relaying it on an auxiliary return channel. We illustrate the NEFOCAST system architecture, consisting of the network of ground sensor terminals, the space segment, and the service center, which has the task of processing the information relayed by the terminals for generating rain field maps. We discuss a few methods that allow the conversion of a rain attenuation measurement into an instantaneous rainfall rate. Specifically, we discuss an exponential model relating the specific rain attenuation to the rainfall rate, whose coefficients were obtained from extensive experimental data. The above model permits the inferring of the rainfall rate from the total signal attenuation provided by the SmartLNB and from the link geometry knowledge. Some preliminary results obtained from a SmartLNB installed in Pisa are presented and compared with the output of a conventional tipping bucket rain gauge. It is shown that the NEFOCAST sensor is able to track the fast-varying rainfall rate accurately with no delay, as opposed to a conventional gauge., Competing Interests: The authors declare no conflict of interest.

Ozone-like visible injury was detected on Hibiscus syriacus plants used as ornamental hedges. Weekly spray of the antiozonant ethylenediurea (EDU, 300ppm) confirmed that the injury was induced by ambient ozone. EDU induced a 75% reduction in visible injury. Injury was more severe on the western than on the eastern exposure of the hedge. This factor of variability should be considered in ozone biomonitoring programmes. Seeds were collected and seedlings were artificially exposed to ozone in filtered vs. not-filtered (+30ppb) Open-Top Chambers. The level of exposure inducing visible injury in the OTC seedlings was lower than that in the ambient-grown hedge. The occurrence of visible injury in the OTC confirmed that the ozone sensitivity was heritable and suggested that symptomatic plants of this deciduous shrub population can be successfully used as ozone bioindicators. EDU is recommended as a simple tool for diagnosing ambient ozone visible injury on field vegetation.