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Background The multiorgan involvement of heart failure is similar to the spread observed in cancer. We proposed a new score, named HLM, analogous to TNM classification used in oncology. HLM refers to (i) H: heart damage, instead of “T” for tumor; (ii) L: lung involvement, instead of “N” for lymph nodes; (iii) M: systemic multiorgan involvement, instead of “M” for metastasis. Objectives to compare HLM score to NYHA class, ACC/AHA stages and left ventricular ejection fraction (LVEF) classification, to assess the most accurate prognostic tool for HF patients. Methods We performed a multicentric, observational, prospective study of consecutive patients admitted for HF, or at risk for HF. Parameters for heart, lungs and organs’ function were collected. Each patient was classified according to HLM, NYHA, ACC/AHA stages and LVEF classification. Patients were followed up for 12 months. The primary composite endpoint was all-cause death and rehospitalization due to HF. Results We enrolled 1720 patients who completed the 12-month follow-up. As shown by Kaplan Meier curves, HLM was the most accurate score to predict primary endpoint at 12- month. The area under the ROC curve (AUC) was greater for HLM score than NYHA, ACC/AHA stages and LVEF classification, regarding the composite endpoint (HLM=0.645; NYHA=0.580; ACC/AHA=0.589; LVEF=0.572) (Figure 1). HLM score related AUC showed statistically significant differences compared to LVEF (p=0.002), ACC/AHA (p=0.029) and NYHA (p=0.009). Conclusions HLM score has a greater prognostic power compared to other nosologies, in terms of the composite endpoint of all-cause death and rehospitalization due to HF, at 12-month follow-up. Key words: heart failure; HLM score; prognosis; mortality; rehospitalization. Figure 1.

Mini-drones can be used for a variety of tasks, such as weather monitoring, package delivery, search and rescue, and recreation. Their uses are mostly restricted to outside locations with access to the Global Positioning System (GPS) and/or similar systems since their usefulness, safety, and performance substantially rely on ubiquitously accurate positioning and navigation. Indoor localization is getting better, thanks to technologies like Visual Simultaneous Localization and Mapping (V-SLAM). However, more advancements are still required for mini-drone navigation applications with greater safety standards. In this research, a novel method for enhancing indoor mini-drone localization performance is proposed. By merging Oriented Rotated Brief SLAM (ORB-SLAM2), Semi-Direct Monocular Visual Odometry (SVO), and an Adaptive Complementary Filter, the suggested strategy improves V-SLAM approaches (ACF). The findings demonstrate that, when compared to other widely-used indoor localization algorithms, the suggested methodology performs better at estimating location under various situations (low light, low texture, and dynamic environments).

Background. Atrial fibrillation surgical radiofrequency ablation (AFSA) during mitral valve surgery (MVS) has almost completely superseded the Cox-Maze procedure for the treatment of atrial fibrillation. Methods. We retrospectively analyzed 100 patients who underwent MVS + AFSA in our institution from January 2008 to June 2017. We compared the effectiveness of AFSA in patients who underwent LAA exclusion to those who did not. Moreover, we analyzed the role of preoperative AF duration (≤ or >1 year) and medial-lateral left atrial dimensions (ML-LAD) (≤ or >6 cm). The efficacy endpoint was freedom from AF at discharge and at 2-year follow-up. The safety endpoints were need of a permanent pacemaker (PMK), surgical re-exploration, occurrence of stroke, and left circumflex artery or esophageal lesions. Results. Overall, the rate of AF freedom was 69% at discharge and 80% at 2-year follow-up. LAA exclusion did not influence AF freedom at 2-year follow-up, and 84.6% of patients who underwent LAA exclusion were in the sinus rythm (SR) at 2 year compared to 75% of those who did not receive LAA exclusion free from AF as well ( p = 0.230 ). AF duration ≤1 or >1 year did not influence sinus rhythm (SR) maintenance (85.7% vs. 75.8%; p = 0.224 ), and in these two groups, LAA exclusion did not change the efficacy of AFSA. ML-LAD ≤ 6 cm was associated with better results in terms of SR maintenance. A statistically significant association between LAA exclusion and SR maintenance at 2-year follow-up ( p = 0.017 ) was found among patients with ML-LAD ≤ 6 cm. Complications included 7 cases of PMK implantation, 2 cases of surgical re-exploration, and 1 case of stroke. No circumflex artery or esophageal lesions occurred after surgical procedures. Conclusions. In our experience, AFSA during isolated MVS resulted in good outcomes in terms of SR maintenance and incidence of complications. AF duration ≤ 1 year did not influence results, while patients with ML-LAD ≤ 6 cm had significantly better results regarding SR at follow-up. In patients with ML-LAD ≤ 6 cm, LAA exclusion significantly increased the success rate of SR maintenance at 2-year follow-up.

Background: Direct oral anticoagulants (DOACs) are the preferred anticoagulant drugs for the prevention of atrial fibrillation (AF)-related thromboembolic complications and for the treatment and the prevention of recurrences of venous thromboembolism (VTE). The evaluation of self-reported adverse drug reactions (ADRs) available from databases of drug-regulatory agencies such as the Italian Medicines Agency (AIFA) pharmacovigilance database represents a novel aid to guide decision making. Objective: To assess the safety profile of DOACs by analyzing ADR rates in the real-world Italian scenario. Methods: Post-marketing surveillance data recorded by the National Pharmacovigilance Network were retrieved for the time period 2017–2021 from the AIFA online site. The following data were collected for each DOAC: total ADR number, serious ADR number, gastrointestinal (GI) ADR, intracranial hemorrhage events (ICH ADR), and more frequently reported ADR for the study year. The safety profile was expressed by the risk index (RI). Results: Rivaroxaban use was associated with consistent and stable low rates of serious ADR, GI ADR, and ICH ADR across the 5-year study period. Rivaroxaban and apixaban showed the lowest RI for serious ADR and GI ADR, while rivaroxaban use was associated with significantly lower ICH events as compared to apixaban. Dabigatran was related to the highest RIs for every ADR class, in particular GI ADRs. Conclusions: DOACs presented an acceptable safety profile in the current post-market analysis. However, rivaroxaban and apixaban were associated with more favorable safety profiles as compared to dabigatran, while rivaroxaban provoked statistically significantly fewer ICH events as compared to apixaban.

Background During the COVID‐19 pandemic in‐person visits for patients with cardiac implantable electronic devices should be replaced by remote monitoring (RM), in order to prevent viral transmission. A direct home‐delivery service of the RM communicator has been implemented at 49 Italian arrhythmia centers. Methods According to individual patient preference or the organizational decision of the center, patients were assigned to the home‐delivery group or the standard in‐clinic delivery group. In the former case, patients received telephone training on the activation process and use of the communicator. In June 2020, the centers were asked to reply to an ad hoc questionnaire to describe and evaluate their experience in the previous 3 months. Results RM was activated in 1324 patients: 821 (62%) received the communicator at home and the communicator was activated remotely. Activation required one additional call in 49% of cases, and the median time needed to complete the activation process was 15 min [25th‐75th percentile: 10–20]. 753 (92%) patients were able to complete the correct activation of the system. At the time when the questionnaire was completed, 743 (90%) communicators were regularly transmitting data. The service was generally deemed useful (96% of respondents) in facilitating the activation of RM during the COVID‐19 pandemic and possibly beyond. Conclusions Home delivery of the communicator proved to be a successful approach to system activation, and received positive feedback from clinicians. The increased use of a RM protocol will reduce risks for both providers and patients, while maintaining high‐quality care.

Ventricular tachycardia in patients with structural heart disease is a significant cause of morbidity and mortality. According to current guidelines, cardioverter defibrillator implantation, antiarrhythmic drugs, and catheter ablation are established therapies in the management of ventricular arrhythmias but their efficacy is limited in some cases. Sustained ventricular tachycardia can be terminated by cardioverter-defibrillator therapies although shocks in particular have been demonstrated to increase mortality and worsen patients’ quality of life. Antiarrhythmic drugs have important side effects and relatively low efficacy, while catheter ablation, even if it is actually an established treatment, is an invasive procedure with intrinsic procedural risks and is frequently affected by patients’ hemodynamic instability. Stereotactic arrhythmia radioablation for ventricular arrhythmias was developed as bail-out therapy in patients unresponsive to traditional treatments. Radiotherapy has been mainly applied in the oncological field, but new current perspectives have developed in the field of ventricular arrhythmias. Stereotactic arrhythmia radioablation provides an alternative non-invasive and painless therapeutic strategy for the treatment of previously detected cardiac arrhythmic substrate by three-dimensional intracardiac mapping or different tools. Since preliminary experiences have been reported, several retrospective studies, registries, and case reports have been published in the literature. Although, for now, stereotactic arrhythmia radioablation is considered an alternative palliative treatment for patients with refractory ventricular tachycardia and no other therapeutic options, this research field is currently extremely promising.

BackgroundEffects of Sacubitril/Valsartan (S/V) on left ventricular (LV) mechanics and ventricular-arterial coupling in patients with heart failure with reduced ejection fraction (HFrEF) are not completely understood. The aim of this study was to evaluate both cardiac and vascular remodeling in a group of HFrEF patients undergoing S/V therapy.MethodsFifty HFrEF patients eligible to start a therapy with S/V were enrolled. Echocardiographic evaluation was performed at baseline and after 6 months of follow-up (FU). Beside standard evaluation, including global longitudinal strain (GLS), estimated hemodynamic forces (HDFs) and non-invasive pressure-volume curves (PV loop) were assessed using dedicated softwares. HDFs were evaluated over the entire cardiac cycle, in systole and diastole, both in apex to base (A-B) and latero-septal (L-S) directions. The distribution of LV HDFs was evaluated by L-S over A-B HDFs ratio (L-S/A-B HDFs ratio). Parameters derived from estimated PV loop curves were left ventricular end-systolic elastance (Ees), arterial elastance (Ea), and ventricular-arterial coupling (VAC).ResultsAt 6 months of FU indexed left ventricular end-diastolic and end-systolic volumes decreased (EDVi: 101 ± 28 mL vs. 86 ± 30 mL, p < 0.001; ESVi: 72 ± 23 mL vs. 55 ± 24 mL, p < 0.001), ejection fraction and GLS significantly improved (EF: 29 ± 6% vs. 37 ± 7%, p < 0.001; GLS: −9 ± 3% vs. −13 ± 4%, p < 0.001). A reduction of Ea (2.11 ± 0.91 mmHg/mL vs. 1.72 ± 0.44 mmHg/mL, p = 0.008) and an improvement of Ees (1.01 ± 0.37 mmHg/mL vs. 1.35 ± 0.6 mmHg/mL, p < 0.001) and VAC (2.3 ± 1.1 vs. 1.5 ± 0.7, p < 0.001) were observed. Re-alignment of HDFs occurred, with a reduction of diastolic L-S/A-B HDFs ratio [23 (20–35)% vs. 20 (11–28) %, p < 0.001].ConclusionS/V therapy leads to a complex phenomenon of reverse remodeling involving increased myocardial contractility, HDFs distribution improvement, and afterload reduction.

The frequent coexistence in daily clinical practice of chronic kidney disease (CKD) and atrial fibrillation (AF), especially in the elderly, represents a conundrum for physicians, mainly related to the management of anticoagulant therapy. The reduction of estimated glomerular filtration rate (eGFR) impairs anticoagulant clearance, increasing bleeding propensity. Moreover, dysfunctional responses of endothelial cells and inflammatory systems both trigger thromboembolic status. Those mechanisms pose an increased risk of adverse events for AF patients with CKD. While several data suggested the use of direct oral anticoagulants (DOACs) over warfarin as preferred anticoagulant strategy in patients with Stage 3A to Stage 4 CKD (eGFR range of 15–49 mL/min/1.73 m2), less is known about the optimal anticoagulation management in patients with end-stage renal disease (ESRD) or on renal replacement therapy (RRT). Furthermore, a pivotal feature to be considered when choosing the anticoagulant drug in CKD patients is represented by nephroprotective capability. Indeed, anticoagulant therapy with warfarin showed detrimental effects on kidney function, whereas DOACs demonstrated a beneficial effect on renal function preservation. Mounting data showed that, when pharmacological treatment cannot be pursued due to contraindication to anticoagulation, left atrial appendage occlusion (LAAO) may represent a valid alternative. This brief review outlines the current knowledge regarding anticoagulation therapy in ESRD/RRT patients, reporting new lines of evidence on the nephroprotective effect of oral anticoagulants and on the use of LAAO as a non-pharmacological alternative to oral anticoagulation.

INTRODUCTION: Remote monitoring (RM) has significantly transformed the standard of care for patients with cardiac electronic implantable devices It provides easy access to valuable information, such as arrhythmic events, acute decompensation manifestations and device-related issues, without the need of in-person visits METHODS: Starting March 1st, 332 patients were introduced to a RM program during the Italian lockdown in order to limit the risk of in-hospital exposure to Severe Acute Respiratory Syndrome-Coronavirus-2 Patients were categorized into two groups based on the modality of RM delivery [home (n=229) vs office (n= 103) delivered] The study aimed at assessing the efficacy of the new follow-up protocol, assessed as mean RM Activation Time (AT) and need for technical support Additionally, patients' acceptance and anxiety status were quantified via the Home Monitoring Acceptance and Satisfaction Questionnaire and the Generalized Anxiety Disorder 7-item scale RESULTS: AT time was

Aims The aim of the study was to describe ECG modifications and arrhythmic events in COVID-19 patients undergoing hydroxychloroquine (HCQ) therapy in different clinical settings. Methods and results COVID-19 patients at seven institutions receiving HCQ therapy from whom a baseline and at least one ECG at 48+ h were available were enrolled in the study. QT/QTc prolongation, QT-associated and QT-independent arrhythmic events, arrhythmic mortality, and overall mortality during HCQ therapy were assessed. A total of 649 COVID-19 patients (61.9 ± 18.7 years, 46.1% males) were enrolled. HCQ therapy was administrated as a home therapy regimen in 126 (19.4%) patients, and as an in-hospital-treatment to 495 (76.3%) hospitalized and 28 (4.3%) intensive care unit (ICU) patients. At 36–72 and at 96+ h after the first HCQ dose, 358 and 404 ECGs were obtained, respectively. A significant QT/QTc interval prolongation was observed (P < 0.001), but the magnitude of the increase was modest [+13 (9–16) ms]. Baseline QT/QTc length and presence of fever (P = 0.001) at admission represented the most important determinants of QT/QTc prolongation. No arrhythmic-related deaths were reported. The overall major ventricular arrhythmia rate was low (1.1%), with all events found not to be related to QT or HCQ therapy at a centralized event evaluation. No differences in QT/QTc prolongation and QT-related arrhythmias were observed across different clinical settings, with non-QT-related arrhythmias being more common in the intensive care setting. Conclusion HCQ administration is safe for a short-term treatment for patients with COVID-19 infection regardless of the clinical setting of delivery, causing only modest QTc prolongation and no directly attributable arrhythmic deaths.

Journal of applied crystallography 53(4), 927 - 936 (2020). doi:10.1107/S1600576720006925, The ever-increasing brightness of synchrotron radiation sources demands improved X-ray optics to utilize their capability for imaging and probing biological cells, nano-devices and functional matter on the nanometre scale with chemical sensitivity. Hard X-rays are ideal for high-resolution imaging and spectroscopic applications owing to their short wavelength, high penetrating power and chemical sensitivity. The penetrating power that makes X-rays useful for imaging also makes focusing them technologically challenging. Recent developments in layer deposition techniques have enabled the fabrication of a series of highly focusing X-ray lenses, known as wedged multi-layer Laue lenses. Improvements to the lens design and fabrication technique demand an accurate, robust, in situ and at-wavelength characterization method. To this end, a modified form of the speckle tracking wavefront metrology method has been developed. The ptychographic X-ray speckle tracking method is capable of operating with highly divergent wavefields. A useful by-product of this method is that it also provides high-resolution and aberration-free projection images of extended specimens. Three separate experiments using this method are reported, where the ray path angles have been resolved to within 4 nrad with an imaging resolution of 45 nm (full period). This method does not require a high degree of coherence, making it suitable for laboratory-based X-ray sources. Likewise, it is robust to errors in the registered sample positions, making it suitable for X-ray free-electron laser facilities, where beam-pointing fluctuations can be problematic for wavefront metrology., Published by Wiley-Blackwell, [S.l.]

Nowadays, progressive improvements of engine performance must be performed to reduce fuel consumption, which directly affects the amount of CO2 released in the atmosphere. For this purpose, considering modern technologies in the automotive scenario, Gasoline Compression Ignition (GCI) combustion might represent one promising solution, since it experiences high thermal efficiency of Compression Ignited (CI) engines and pollutant emission mitigation. This paper shows the first step of a project aimed at reproducing the combustion behavior of a Diesel engine running with GCI combustion by means of CFD simulations. In particular, this work presents a methodology used to reconstruct the mixing process inside the cylinder before the combustion event, since those engines are dramatically sensitive to the global and local mixture quality. Firstly, a reverse-engineering procedure aimed at generating the CAD model of the engine was performed. Afterwards, the discharge coefficients of the intake and exhaust valves through specifically designed 3D CFD simulations were determined, which was necessary due to the customized intake/exhaust line. Eventually, to reasonably reconstruct the in-cylinder state, the Rate of Heat Release (RoHR) curve, calculated from the analysis of the in-cylinder pressure signal running the engine in GCI mode, was imposed in GT-Power by means of a combination of Wiebe functions with the purpose of generating representative trends of pressure, temperature, and mass flow to properly define the domains of the CFD model.

Atrial fibrillation (AF) is the most frequent chronic arrhythmia worldwide, and it is associated with significant morbidity and mortality, making it a considerable burden both to patients and the healthcare system. Nowadays, an early attempt to restore sinus rhythm in acute symptomatic AF through electrical or pharmacological cardioversion is the most common approach in the Emergency Department (ED). However, considering the high percentage of spontaneous cardioversion of paroxysmal AF reported by many studies, this approach may not be the ideal choice for all patients. In this manuscript we performed a review of the most relevant studies found in literature with the aim of identifying the main determinants of spontaneous cardioversion, focusing on those easy to detect in the ED. We have found that the most relevant predictors of spontaneous cardioversion are the absence of Heart Failure (HF), a small atrial size, recent-onset AF, rapid Atrial Fibrillatory Rate and the relationship between a previous AF episode and Heart Rate/Blood Pressure. A number of those are utilized, along with other easily determined parameters, in the recently developed “ReSinus” score which predicts the likelihood of AF spontaneous cardioversion. Such identification may help the physician decide whether immediate cardioversion is necessary, or whether to adopt a “watch-and-wait” strategy in the presence of spontaneous cardioversion determinants.

Background The remote device management (RM) is recommended for patients with cardiac implantable electronic devices (CIEDs). RM underutilization is frequently driven by the lack of correct system activation. The MyLATITUDE Patient App (Boston Scientific) has been developed to encourage patient compliance with RM by providing information on communicator setup, troubleshooting, and connection status of the communicator. Methods At 14 centers, patients with CIEDs were invited to download and install the App on a mobile device. After 3 months, patients were asked to complete an ad hoc questionnaire to evaluate their experience. Results The App was proposed to 242 consecutive patients: 81 before RM activation, and 161 during follow-up. The App was successfully installed by 177 (73%) patients. The time required for activation of the communicator and the need for additional support were similar between patients who followed the indications provided by the App and those who underwent standard in-clinic training. During follow-up, notifications of lack of connection were received by 20 (11%) patients and missed transmission by 22 (12%). The median time from notification to resolution was 2 days. After 3 months, 175 (99%) communicators of the 177 patients who installed the App were in “Monitored” status versus 113 (94%) of 120 patients without the App installed (p=0.033). The use of the app made 84% of patients feel reassured. Conclusions The App was well accepted by CIED patients and offered support for communicator management and installation. Its use enabled patients to remain connected with greater continuity during follow-up.

Regenerative braking is an established technique that can improve the driving range of vehicles with full-electric or hybrid/hybridized powertrain, thus promoting their large-scale adoption. In this paper, the design of an MPC strategy for maximizing regenerative braking in a real vehicle that has been hybridized by means of a kit is presented. The kit is entirely built by the partners of the European Horizon2020 LIFE-SAVE (Solar Aided Vehicle Electrification – LIFE16 ENV/IT/000442) funded project, and features two in-wheel-motors placed on the rear axle, PV panels installed on the roof and the bonnet and a battery pack placed in the trunk. The proposed MPC strategy will serve as a baseline for the implementation of an additional algorithm to the actual version of the hybridized powertrain control such that the new kit will endow the vehicle also with regenerative braking. Since the kit cannot access the vehicle's ECU in order to avoid code infringements, the MPC relies only on information that can be retrieved via the vehicle's CAN. In addition to the maximization of the energy recovery during braking, the proposed strategy considers aspects such as the in-wheel-motors non-ideal efficiency and rated specifications, the constraints given by the brake operating region and possible comfort requirements that have a positive impact on the driver's experience. Furthermore, it also includes a penalty term to force the controller to trade-off with possible high-efficiency operations. The simulation outcomes show the effectiveness of the proposed MPC strategy, enabling the recovery up to approximately 18% of the vehicle's kinetic energy, and suggest that it can be fruitfully used as a baseline for an additional regenerative braking algorithm to be implemented onto the real vehicle.

NendoU from SARS-CoV-2 is responsible for the virus's ability to evade the innate immune system by cleaving the polyuridine leader sequence of antisense viral RNA. Here we report the room-temperature structure of NendoU, solved by serial femtosecond crystallography at an X-ray free-electron laser to 2.6Å resolution. The room-temperature structure provides insight into the flexibility, dynamics, and other intrinsic properties of NendoU, with indications that the enzyme functions as an allosteric switch. Functional studies examining cleavage specificity in solution and in crystals support the uridine-purine cleavage preference, and we demonstrate that enzyme activity is fully maintained in crystal form. Optimizing the purification of NendoU and identifying suitable crystallization conditions set the benchmark for future time-resolved serial femtosecond crystallography studies. This could advance the design of antivirals with higher efficacy in treating coronaviral infections, since drugs that block allosteric conformational changes are less prone to drug resistance.

The feasibility and effectiveness of virtual visits (VVs) for cardiac electrophysiology patients are still unknown. We aimed to assess the feasibility and effectiveness of VVs as compared to in-person visits, and to describe patient experience with virtual care in clinical electrophysiology. We prospectively enrolled patients scheduled to receive a clinical electrophysiology evaluation, dividing them in two groups: a VV group and an in-person visit group. Outcomes of interest were: (1) improvement in symptoms after the index visit, (2) disappearance of remote monitoring (RM) alerts at follow-up, (3) necessity of urgent hospitalization and (4) patient satisfaction measured by the Patient Satisfaction Questionnaire-18 (PSQ-18). This study included 162 patients in the VV group and 185 in the in-office visit group. As compared to in-person visits, VVs resulted in a similar reduction in RM alerts (51.5% vs. 43.2%, p-value 0.527) and in symptomatic patient rates (73.6% vs. 56.9%, p-value 0.073) at follow-up, without differences in urgent hospitalization rates (p-value 0.849). Patient satisfaction with VVs was higher than with in-person evaluation (p-value < 0.012). VVs proved to be as feasible and as effective as in-person visits, with high patient satisfaction. A hybrid model of care including VVs and in-person visits may become the new standard of care after the COVID-19 pandemic is over.

Aims Remote monitoring (RM) has significantly transformed the standard of care for patients with cardiac electronic implantable devices. It provides easy access to valuable information, such as arrhythmic events, acute decompensation manifestations, and device-related issues, without the need of in-person visits. Methods and results Starting 1 March, 332 patients were introduced to an RM programme during the Italian lockdown to limit the risk of in-hospital exposure to severe acute respiratory syndrome-coronavirus-2. Patients were categorized into two groups based on the modality of RM delivery [home (n = 229) vs. office (n = 103) delivered]. The study aimed at assessing the efficacy of the new follow-up protocol, assessed as mean RM activation time (AT), and the need for technical support. In addition, patients’ acceptance and anxiety status were quantified via the Home Monitoring Acceptance and Satisfaction Questionnaire and the Generalized Anxiety Disorder 7-item scale. AT time was less than 48 h in 93% of patients and 7% of them required further technical support. Despite a higher number of trans-telephonic technical support in the home-delivered RM group, mean AT was similar between groups (1.33 ± 0.83 days in home-delivered vs. 1.28 ± 0.81 days in office-delivered patients; P = 0.60). A total of 28 (2.5%) urgent/emergent in-person examinations were required. A high degree of patient satisfaction was reached in both groups whereas anxiety status was higher in the office-delivered group. Conclusions The adoption of RM resulted in high patient satisfaction, regardless of the modality of modem delivery; nonetheless, in-office modem delivery was associated with a higher prevalence of anxiety symptoms.

Aims Significant concern has been raised about the effect of pre-existing cardiovascular diseases (CVD), cardiovascular (CV) risk factors and CV therapies on COVID-19 course. On the other hand, COVID-19 could worse pre-existing CVD or trigger the development of new-onset CVD. The aim of this study was to evaluate the relationship between pre-existing CVD, CV risk factors, and CV therapy with the clinical course of hospitalized COVID-19 patients. Methods and results Consecutive hospitalized COVID-19 patients admitted to the Cardiovascular COVID-19 Unit at Policlinico Umberto I of Rome between December 2020 and April 2021 were enrolled. All patients underwent a cardiovascular evaluation including troponin, electrocardiogram (ECG), and echocardiogram. Data on medical history, pre-existing CVD, CV risk factors, and therapy were collected. Admission to the Intensive Care Unit (ICU) or Cardiac Intensive Care Unit (CICU), as well as the development of new-onset CVD, were considered as endpoint of the study. Among n = 229 patients enrolled, 22 (10%) died. Nearly half of patients (112, 49%) were admitted to the ICU/CICU. The presence of prior ischaemic heart disease nearly doubled the probability of hospitalization in the ICU/CICU (HR: 2.09, 95% CI: 1.132–3.866, P 0.018). In regards of therapy, beta blockers reduced the likelihood of admission in the ICU/CICU (HR: −1016, 95% CI: 0.192–10.682, P 0.002). However, neither the use of RAAS blockers, heparin or dexamethasone influenced the risk of ICU/CICU admission (respectively, HR: 0.85, 95% CI: 0.498–1.450, P 0.551; HR: 0.768, 95% CI: 0.435–1.356, P 0.363; HR: 0.861, 95% CI: 0.453–1.635, P 0.647). N = 89 patients (39%) experienced a new onset CVD including arrythmias (18.3%) with nearly half experiencing atrial fibrillation, acute coronary syndrome (10.9%), acute pulmonary embolism (5.3%), heart failure (HF) (3%), and myocarditis and pericarditis (1.3%). A pre-existing diagnosis of HF substantially increased the likelihood of new onset CVD (HR: 2.380, 95% CI: 1.004–5.638, P 0.049). However, treatment with heparin or dexamethasone reduced the risk of new onset CVD (HR: 0.482 95% CI: 0.268–0.867, P 0.015; HR: 0.487, 95% CI: 0.253–0.937, P 0.031, respectively). Conclusions Our study found that hospitalized COVID-19 patients who have at least one CV risk factor or pre-existing CVD had a greater likelihood of being admitted to the ICU/CICU and experiencing new onset CVD.

Aims The outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic forced a reorganization of the healthcare system. In order to prevent potential risk of exposure, virtual visit (VV) has been implemented in the treatment and follow-up of COVID-19 patients with cardiovascular diseases. The aim of this study is to evaluate the feasibility and efficacy of VV in the management of post COVID-19 cardiovascular patients. Methods and results We enrolled all patients with cardiovascular comorbidities tested negative for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) and discharged from our Cardiology Department from January 2021 to June 2021. We scheduled a VV after 30 days from discharge to check the clinical status of the patients, optimize therapy, and establish a Follow-up protocol. Blood pressure, arterial oxygen saturation, heart rate and body weight were registered. To evaluate the patients’ satisfaction of VV, a questionnaire was administered. We performed 25 VVs in the study period; the mean age of patients was 67.5 ± 15.6 and male were 15 (65.2%). The mean duration of VV was 25.9 ± 4.6 min. The caregiver had an active role in nine (36%) cases. No urgent/emergent in-person examinations were performed. A high degree of patient satisfaction was reached and VV was preferred to in-person evaluation. Conclusions VV visit was useful to Follow-up post COVID-19 cardiovascular patients. A high degree of patient satisfaction was reached without jeopardizing quality of care.

Aims IHD is determined by inadequate coronary blood supply to myocardium and endothelial dysfunction may represent one of the main pathophysiological mechanisms involved. Genetic predisposition to endothelial dysfunction has been associated with IHD and its clinical manifestation. However, studies are often confounding and inconclusive for several reasons, such as interethnic differences. Results validation on larger cohorts and new population is needed. The aim of the study is to evaluate the association among the allelic variants of eNOS rs1799983 single-nucleotide polymorphism, IHD susceptibility, and its clinical presentation. Methods A total of 362 consecutive patients with suspected myocardial ischemia were enrolled. Patients were divided into three groups: G1, coronary artery disease (CAD); G2, coronary microvascular dysfunction (CMD); G3, control group with anatomically and functionally normal coronary arteries. Analysis of three allelic variants, GT, GG, and TT of rs1799983 for NOS3 gene, encoding for eNOS has been performed. Results rs1799983_GT is significantly more expressed by ischaemic groups (G1 and G2) compared with G3. The TT variant is significantly more expressed by G1 group, compared with G2 group. Among ischaemic patients, GT is significantly more expressed in patients with acute coronary syndrome (ACS) presentation, compared to other clinical presentation. At multivariate analysis, the allelic variant GT may represent an independent predictor of IHD and ACS presentation. Conclusions The SNP rs1799983_GT, encoding for eNOS, is an independent risk factor for IHD and, remarkably, for ACS presentation, independently from cardiovascular risk factors. These results may be useful for the prediction of IHD development, in particular with acute clinical manifestation. It may allow the early identification of patients at high risk to develop IHD with an ACS, promoting a genetic-based prevention strategy against IHD.

Aims During the COVID-19 pandemic in-person visits for patients with cardiac implantable electronic devices should be replaced by remote monitoring (RM), in order to prevent viral transmission. A direct home-delivery service of the RM communicator has been implemented at 49 Italian arrhythmia centres. Methods and results According to individual patient preference or the organizational decision of the centre, patients were assigned to the home-delivery group or the standard in-clinic delivery group. In the former case, patients received telephone training on the activation process and use of the communicator. In June 2020, the centres were asked to reply to an ad hoc questionnaire to describe and evaluate their experience in the previous 3 months. RM was activated in 1324 patients: 821 (62%) received the communicator at home and the communicator was activated remotely. Activation required one additional call in 49% of cases, and the median time needed to complete the activation process was 15 min (25th–75th percentile: 10–20). 753 (92%) patients were able to complete the correct activation of the system. At the time when the questionnaire was completed, 743 (90%) communicators were regularly transmitting data. The service was generally deemed useful (96% of respondents) in facilitating the activation of RM during the COVID-19 pandemic and possibly beyond. Conclusions Home delivery of the communicator proved to be a successful approach to system activation, and received positive feedback from clinicians. The increased use of a RM protocol will reduce risks for both providers and patients, while maintaining high-quality care.

Precision medicine, providing the right therapeutic strategy for the right patient, could revolutionize management and prognosis of patients affected by cardiovascular diseases. Big data and artificial intelligence are pivotal for the realization of this ambitious design. In the setting of pulmonary arterial hypertension (PAH), the use of computational models and data derived from ambulatory implantable hemodynamic monitors could provide useful information for tailored treatment, as requested by precision medicine.

Aims Following the COVID-19 pandemic-related lockdown period in Italy, people have experienced psycho-physical distress. Many hospitals were converted in COVID-19 healthcare places and many specialist outpatient’s services were drastically reduced. Virtual visits may represent a strategy to overcome the lack of HF outpatient’s services, during this period. Our own experience underlines the importance of virtual visits to face the clinical and health status deterioration, associated with COVID-19, in HF outpatients. Methods and results We conducted an observational study, enrolling consecutive HF outpatients, previously hospitalized at the Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences of Sapienza University of Rome, who were discharged within 31 March 2019, and 30 April 2019. Two follow-up periods were scheduled: (i) within 20–30 days after the beginning of lockdown (ii) at 3 months after lockdown’s end. Virtual visits were conducted through telephone, assessing changes in clinical and health status; the latter was assessed through the short version of the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). According to the presence of at least one sign of HF deterioration, patients were divided into two groups: Group 1: patients who experienced a modification in at least one clinical parameter suggestive of HF deterioration. Group 2: patients who do not experienced any modification of HF deterioration clinical parameter. KCCQ-12 mean scores were compared between the two groups, at both scheduled virtual visits, in order to evaluate any change in HF outpatients’ health status, during and after the COVID-19-related-lockdown. 160 HF outpatients have been included in the study: 63 in the group 1, 97 in the group 2. At the first virtual visit, group 1 reported significantly lower mean KCCQ-12 score, compared to group 2 [46.2 (±14.6) vs. 53.8 (±11); CI: 95% 11.6 to − 3.6; P = 0.0003]. At the second virtual visit, group 1 patients reported a slightly, but not statistically significant, lower mean KCCQ-12 score, compared to group 2 [52.2 (± 13.3) vs. 53.1(±14.4); 95% CI: −5.4 to 3.6; P = 0.69]. Comparing the KCCQ-12 mean scores of each group between the two scheduled virtual visits, group 1 reported a statistically significant increase at the second visit, compared to the first [52.2 (±13.3) vs. 46.2 (±14.6); CI: 95% 1.1–11; P = 0.017]. Group 2 showed no statistically significant variation of mean KCCQ-12 score between the two follow-up periods [53.1 (±14.4) vs. 53.8 (±11); CI: 95% −4.3 to 3; P = 0.704]. Conclusions we observed a significant worsening of health status in HF outpatients who have experienced clinical deterioration. Therefore, patients were either hospitalized or received the optimization of diuretic and anti-hypertensive therapies. A significant health status improvement was observed at three months after the end of the lockdown, suggesting the importance of virtual visit as an adequate method to follow-up HF outpatients, reporting particular benefits in those with worsening of HF clinical signs and health status.

Premature ventricular contractions in the absence of structural heart disease are among the most common arrhythmias in clinical practice, with well-defined sites of origin in the right and left ventricle. In this review, starting from the electrocardiographic localization of premature ventricular contractions, we investigated the mechanisms, prevalence in the general population, diagnostic work-up, prognosis and treatment of premature ventricular contractions, according to current scientific evidence.

Multimeric protein assemblies are abundant in nature. Streptavidin is an attractive protein that provides a paradigm system to investigate the intra- and intermolecular interactions of multimeric protein complexes. Also, it offers a versatile tool for biotechnological applications. Here, we present two apo-streptavidin structures, the first one is an ambient temperature Serial Femtosecond X-ray crystal (Apo-SFX) structure at 1.7 Å resolution and the second one is a cryogenic crystal structure (Apo-Cryo) at 1.1 Å resolution. These structures are mostly in agreement with previous structural data. Combined with computational analysis, these structures provide invaluable information about structural dynamics of apo streptavidin. Collectively, these data further reveal a novel cooperative allostery of streptavidin which binds to substrate via water molecules that provide a polar interaction network and mimics the substrate biotin which displays one of the strongest affinities found in nature.

We report on the use of multilayer Laue lenses to focus the intense X-ray Free Electron Laser (XFEL) beam at the European XFEL to a spot size of a few tens of nanometers. We present the procedure to align and characterize these lenses and discuss challenges working with the pulse trains from this unique x-ray source.

Deregulation of the power network, along with integration of renewable energy resources and energy storage systems, anticipates an increased decision making autonomy to the end-users. Curtailing the peak, also known as peak shaving, is one such aspect where the end-users could play a significant role in making the grid more resilient and robust. In this regard, we consider a grid-connected community microgrid comprising of a number of residential households, each equipped with a PV panel and a battery. We formulate the peak shaving of the community microgrid as a non-cooperative aggregative game, where the allowable peak acts as the global constraint which has to be satisfied by the community. Further, we propose a decentralized control algorithm to achieve the equilibrium strategy of the aggregative game, known as the generalized Nash equilibrium. To validate the usefulness of the proposed approach, we carry out different case studies using real dataset and highlight the key findings of the study.

Demand side management strategies are used in many application scenarios in order to mitigate high peak demands and reduce them to comply with the availability of electricity, which has many implications such as, e.g., costs minimization and efficiency increase, among the others. In this paper, we present a game-theoretic approach for the demand side management of a neighbourhood of smart homes with real and virtual energy storage, where the neighborhood interacts with the energy retailer by means of a local coordinator. We model the strategic interaction among the smart homes as a non-cooperative aggregative game, so as to save communication bandwidth, computational burden and preserve data privacy. The key highlights of the study are: non-simultaneous charging and discharging of the battery using relaxed convex formulation and reduction in the peak-to-average ratio using game-theoretic DSM modelling.

A novel prize-winner algorithm designed for a path following problem within the Unmanned Aerial Vehicle (UAV) field is presented in this paper. The proposed approach exploits the advantages offered by the pure pursuing algorithm to set up an intuitive and simple control framework. A path fora quad-rotor UAV is obtained by using downward facing camera images implementing an Image-Based Visual Servoing (IBVS) approach. Numerical simulations in MATLAB together with the MathWorks Virtual Reality (VR) toolbox demonstrate the validity and the effectiveness of the proposed solution. The code is released as open-source making it possible to go through any part of the system and to replicate the obtained results., 6 pages, 11 figures, conference

Nature methods 2020(17), 73–78 (2019). doi:10.1038/s41592-019-0628-z, The European XFEL (EuXFEL) is a 3.4-km long X-ray source, which produces femtosecond, ultrabrilliant and spatially coherent X-ray pulses at megahertz (MHz) repetition rates. This X-ray source has been designed to enable the observation of ultrafast processes with near-atomic spatial resolution. Time-resolved crystallographic investigations on biological macromolecules belong to an important class of experiments that explore fundamental and functional structural displacements in these molecules. Due to the unusual MHz X-ray pulse structure at the EuXFEL, these experiments are challenging. Here, we demonstrate how a biological reaction can be followed on ultrafast timescales at the EuXFEL. We investigate the picosecond time range in the photocycle of photoactive yellow protein (PYP) with MHz X-ray pulse rates. We show that difference electron density maps of excellent quality can be obtained. The results connect the previously explored femtosecond PYP dynamics to timescales accessible at synchrotrons. This opens the door to a wide range of time-resolved studies at the EuXFEL., Published by Nature Publishing Group, London [u.a.]

Heart failure is a multifaceted syndrome addressing for a high rate of death among the general population. The common approach to this disease has been always based on the evaluation of the left ventricular ejection fraction by two-dimensional echocardiography with Simpson’s method. Mounting evidences have demonstrated the pitfalls of this method and have suggested that the management of heart failure requires a deep knowledge of the pathophysiological insights of the disease and cannot rely only on the evaluation of the left ventricular ejection fraction. Several advanced imaging technologies overwhelm the evaluation of ejection fraction and could provide a better understanding of the myocardial abnormalities underlying heart failure. Considering the limitation of left ventricular ejection fraction and the systemic involvement of heart failure, classifications of heart failure based on ejection fraction should be substituted with a comprehensive “staging” of multiorgan damage, not only considering the heart but also the lungs, kidneys, and liver, such as the HLM staging system. Such a holistic approach based on the HLM staging system and multimodality imaging can provide a global assessment of patient features allowing for targeted therapies and better heart failure management.

Currently, atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with a prevalence of about 2-3% in the general population, representing a powerful risk factor for stroke and systemic thromboembolism and increased mortality and morbidity. Restoration of sinus rhythm is an important treatment option in AF and has a high success rate, but there is the need for an effective anticoagulation strategy to reduce the risk of embolic events. Anticoagulation with vitamin K antagonists is often associated with failure to achieving effective international normalized ratio. In this setting, recent data have led to extended approval for rivaroxaban in clinical practice, because it is effective and safe in patients with AF undergoing cardioversion, avoiding additional health costs and related time loss, while improving patient satisfaction. The present report provides an overview of the main randomized controlled trial and the main real-life studies, documenting the use of rivaroxaban in patients with non-valvular AF who underwent the cardioversion procedure. Considering that novel non-vitamin K antagonist oral anticoagulants in left atrial appendage thrombi resolution is still unknown in the real-world practice, the main findings on the use of rivaroxaban in this setting are also discussed.

The last decade has witnessed a tremendous technological advance in the field of cardiac electrophysiology, which has transformed our understanding of the mechanisms underlying the development of the majority of cardiac ventricular arrhythmias (VAs).

Key Clinical Message Delayed efficacy of radiofrequency energy can suppress ventricular arrhythmias after a failed ablation procedure. The implant of cardiac defibrillator for arrhythmia‐induced cardiomyopathy should be procrastinated after a period of follow‐up. Waiting for delayed efficacy is a reasonable choice to reduce the risk of complications associated with aggressive ablative approaches.

COVID-19 pandemic severely affected national health systems, altering the modality and the type of care of patients with acute and chronic diseases. To minimize the risk of exposure to SARS-CoV2 for patients and health professionals, face-to-face visits were cancelled or postponed and the use of telemedicine was strongly encouraged. This reorganization involved especially patients with rare diseases needing periodic comprehensive assessment, such as pulmonary arterial hypertension (PAH).The paper reports a proposal of strategy adopted for patients followed at our PAH center in Rome, where patients management was diversified based on clinical risk according to the European Society of Cardiology/European Respiratory Society PH guidelines-derived score and the REVEAL 2.0 score. A close monitoring and support of these patients were made possible by policy changes reducing barriers to telehealth access and promoting the use of telemedicine. Synchronous/asynchronous modalities and remote monitoring were used to collect and transfer medical data in order to guide physicians in therapeutic-decision making. Conversely, the use of implantable monitors providing hemodynamic information and echocardiography-mobile devices wirelessly connecting was limited by the poor experience existing in this setting. Large surveys and clinical trials are welcome to test the potential benefit of the optimal balance between traditional PAH management and telemedicine opportunities.Italy was found unprepared to manage the dramatic effects caused by COVID-19 on healthcare systems. In this emergency situation telemedicine represented a promising tool especially in rare diseases as PAH, but was limited by its scattered availability and legal and ethical issues. Cohesive partnership of health care providers with regional public health officials is needed to prioritize PAH patients for telemedicine by dedicated tools.

Idiopathic ventricular arrhythmias are ventricular tachycardias or premature ventricular contractions presumably not related to myocardial scar or disorders of ion channels. Of the ventricular arrhythmias (VAs) without underlying structural heart disease, those arising from the ventricular outflow tracts (OTs) are the most common. The right ventricular outflow tract (RVOT) is the most common site of origin for OT-VAs, but these arrhythmias can, less frequently, originate from the left ventricular outflow tract (LVOT). OT-VAs are focal and have characteristic ECG features based on their anatomical origin. Radiofrequency catheter ablation (RFCA) is an effective and safe treatment strategy for OT-VAs. Prediction of the OT-VA origin according to ECG features is an essential part of the preprocedural planning for RFCA procedures. Several ECG criteria have been proposed for differentiating OT site of origin. Unfortunately, the ECG features of RVOT-VAs and LVOT-VAs are similar and could possibly lead to misdiagnosis. The authors review the ECG criteria used in clinical practice to differentiate RVOT-VAs from LVOT-VAs.

This paper presents a computationally efficient novel heuristic approach for solving the combined heat and power economic dispatch (CHP-ED) problem in residential buildings considering component interconnections. The proposed solution is meant as a substitute for the cutting-edge approaches, such as model predictive control, where the problem is a mixed-integer nonlinear program (MINLP), known to be computationally-intensive, and therefore requiring specialized hardware and sophisticated solvers, not suited for residential use. The proposed heuristic algorithm targets simple embedded hardware with limited computation and memory and, taking as inputs the hourly thermal and electrical demand estimated from daily load profiles, computes a dispatch of the energy vectors including the CHP. The main idea of the heuristic is to have a procedure that initially decomposes the three energy vectors’ requests: electrical, thermal, and hot water. Then, the latter are later combined and dispatched considering interconnection and operational constraints. The proposed algorithm is illustrated using series of simulations on a residential pilot with a nano-cogenerator unit and shows around 25–30% energy savings when compared with a meta-heuristic genetic algorithm approach.

Efficient energy production and consumption are fundamental points for reducing carbon emissions that influence climate change. Alternative resources, such as renewable energy sources (RESs), used in electricity grids, could reduce the environmental impact. Since RESs are inherently unreliable, during the last decades the scientific community addressed research efforts to their integration with the main grid by means of properly designedenergy storage systems(ESSs). In order to highlight the best performance from these hybrid systems, proper design and operations are essential. The purpose of this paper is to present a so-called model predictive controller (MPC) for the optimal operations of grid-connected wind farms with hydrogen-based ESSs and local loads. Such MPC has been designed to take into account the operating and economical costs of the ESS, the local load demand and the participation to the electricity market, and further it enforces the fulfillment of the physical and the system's dynamics constraints. The dynamics of the hydrogen-based ESS have been modeled by means of the mixed-logic dynamic (MLD) framework in order to capture different behaviors according to the possible operating modes. The purpose is to provide a controller able to cope both with all the main physical and operating constraints of a hydrogen-based storage system, including the switching among different modes such as ON, OFF, STAND-BY and, at the same time, reduce the management costs and increase theequipment lifesaving. The case study for this paper is a plant under development in the north Norway. Numerical analysis on the related plant data shows the effectiveness of the proposed strategy, which manages the plant and commits the equipment so as to preserve the given constraints and save them from unnecessary commutation cycles.

A mono-dimensional code for the simulation of the effects of High Frequency Ignition systems (HFI) on the production of chemical radicals was developed and here presented. The simulations were carried out by considering the typical environmental thermodynamic conditions of a nowadays engine at full load. An electron transport model is linked with a Boltzmann solver coupled with a chemistry solver, affecting the Electron Energy Distribution Function (EEDF) in order to obtain the physical conditions leading to the production of radical components for a given fuel mixture. The transport equations for the electrons, the positive and the negative ions, and the Gauss’ law in a steady-state plasma region. Then the Boltzmann equation for the electrons, in a spatially homogeneous steady-state case, is solved in order to obtain the EEDF. Finally the chemical kinetics model is employed assuming a fuel-air mixture neglecting the fuel carbon atoms due to the assumption that electron-impact dissociation reactions, which initiate the combustion, exhibit a greater reaction rate compared to those based on hydrocarbon thermal dissociation and therefore can be neglected in this work. Results show the production of the hydrogen (H), nitrogen (N), and oxygen (O) radicals and the radius of the initial discharge under different simulated engine operating conditions characterizing the role of a plasma corona effect for the induced chemical ignition in gasoline-powered engines.

Background Rivaroxaban is a direct inhibitor of activated Factor X (FXa), an anti-inflammatory protein exerting a protective effect on the cardiac valve and vascular endothelium. We compare the effect of Warfarin and Rivaroxaban on inflammation biomarkers and their contribution to heart valve calcification progression and renal preservation in a population of atrial fibrillation (AF) patients with chronic kidney disease (CKD) stage 3b – 4. Methods This was an observational, multicenter, prospective study enrolling 347 consecutive CKD stage 3b – 4 patients newly diagnosed with AF: 247 were treated with Rivaroxaban and 100 with Warfarin. Every 12 months, we measured creatinine levels and cardiac valve calcification via standard trans-thoracic echocardiogram, while plasma levels of inflammatory mediators were quantified by ELISA at baseline and after 24 months. Results Over a follow-up of 24 months, long-term treatment with Rivaroxaban was associated with a significative reduction of cytokines. Patients treated with Rivaroxaban experienced a more frequent stabilization/regression of valve calcifications comparing with patients treated with Warfarin. Rivaroxaban use was related with an improvement in kidney function in 87.4% of patients, while in those treated with Warfarin was reported a worsening of renal clearance in 98% of cases. Patients taking Rivaroxaban experienced lower adverse events (3.2% vs 49%, p-value Conclusions Our findings suggest that Rivaroxaban compared to Warfarin is associated with lower levels of serum markers of inflammation. The inhibition of FXa may exert an anti-inflammatory effect contributing to reduce the risk of cardiac valve calcification progression and worsening of renal function.

The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2., Graphical abstract, Durdağı et al. represent radiation damage-free high-resolution SARS-CoV-2 main protease SFX structures obtained at near-physiological temperature and performed MD simulation of apo-form proteins and three known main protease inhibitors. The structures reveal alternate conformation, while MD simulation indicates asymmetric behavior of the protein, which is invaluable information for immediate drug-repurposing studies.

Background Direct oral anticoagulants (DOACs) are recommended as first-line anticoagulants in patients with atrial fibrillation (AF). However, in patients with cancer and AF the efficacy and safety of DOACs are not well established. Objective We performed a meta-analysis comparing available data regarding the efficacy and safety of DOACs vs vitamin K antagonists (VKAs) in cancer patients with non-valvular AF. Methods An online search of Pubmed and EMBASE libraries (from inception to May, 1 2020) was performed, in addition to manual screening. Nine studies were considered eligible for the meta-analysis involving 46,424 DOACs users and 182,797 VKA users. Results The use of DOACs was associated with reduced risks of systemic embolism or any stroke (RR 0.65; 95% CI 0.52–0.81; p 0.001), ischemic stroke (RR 0.84; 95% CI 0.74–0.95; p 0.007) and hemorrhagic stroke (RR 0.61; 95% CI 0.52–0.71; p 0.00001) as compared to VKA group. DOAC use was associated with significantly reduced risks of major bleeding (RR 0.68; 95% CI 0.50–0.92; p 0.01) and intracranial or gastrointestinal bleeding (RR 0.64; 95% CI 0.47–0.88; p 0.006). Compared to VKA, DOACs provided a non-statistically significant risk reduction of the outcomes major bleeding or non-major clinically relevant bleeding (RR 0.94; 95% CI 0.78–1.13; p 0.50) and any bleeding (RR 0.91; 95% CI 0.78–1.06; p 0.24). Conclusions In comparison to VKA, DOACs were associated with a significant reduction of the rates of thromboembolic events and major bleeding complications in patients with AF and cancer. Further studies are needed to confirm our results.

18 pags, 11 figs, 5 tabs, Here, we illustrate what happens inside the catalytic cleft of an enzyme when substrate or ligand binds on single-millisecond timescales. The initial phase of the enzymatic cycle is observed with near-atomic resolution using the most advanced X-ray source currently available: the European XFEL (EuXFEL). The high repetition rate of the EuXFEL combined with our mix-and-inject technology enables the initial phase of ceftriaxone binding to the Mycobacterium tuberculosis β-lactamase to be followed using time-resolved crystallography in real time. It is shown how a diffusion coefficient in enzyme crystals can be derived directly from the X-ray data, enabling the determination of ligand and enzyme-ligand concentrations at any position in the crystal volume as a function of time. In addition, the structure of the irreversible inhibitor sulbactam bound to the enzyme at a 66 ms time delay after mixing is described. This demonstrates that the EuXFEL can be used as an important tool for biomedically relevant research., This work was supported by the National Science Foundation Science and Technology Center 'BioXFEL' through award STC-1231306, and in part by the US Department of Energy, Office of Science, Basic Energy Sciences under contract DESC0002164 (AO, algorithm design and development) and by the National Science Foundation under contract Nos. 1551489 (AO, underlying analytical models) and DBI-2029533 (AO, functional conformations). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. 1450681 to JLO. The work was also supported by funds from the National Institutes of Health grant R01 GM117342-0404. Funding and support are also acknowledged from the National Institutes of Health grant R01 GM095583, from the Biodesign Center for Applied Structural Discovery at ASU, from National Science Foundation award No. 1565180 and the US Department of Energy through Lawrence Livermore National Laboratory under contract DE-AC52-07NA27344. KAZ was supported by the Cornell Molecular Biophysics Training Program (NIH T32-GM008267). This work was also supported by the Cluster of Excellence 'CUI: Advanced Imaging of Matter' of the Deutsche Forschungsgemeinschaft (DFG), EXC 2056, project ID 390715994. CFEL is supported by the Gottfried Wilhelm Leibniz Program of the DFG, the 'X-probe' project funded by the European Union 2020 Research and Innovation Program under Marie Sklodowska-Curie grant agreement 637295, the European Research Council, 'Frontiers in Attosecond X-ray Science: Imaging and Spectroscopy (AXSIS)', ERC-2013-SyG 609920, and the Human Frontiers Science Program grant RGP0010 2017. This work is also supported by the AXSIS project funded by the European Research Council under the European Union Seventh Framework Program (FP/2007-2013)/ERC Grant Agreement No. 609920.

Funding Acknowledgements Type of funding sources: None. Background Sacubitril/valsartan is a well-established therapeutic option for patients with heart failure with reduced ejection fraction (HFrEF). While it was clearly demonstrated to improve patients’ clinical conditions, its potential role in inducing left ventricle (LV) reverse remodeling is still under investigation. Purpose to evaluate clinical and echocardiographic effect of sacubitril/valsartan on a cohort of patients with HFrEF after six months of therapy. Methods 36 patients with HFrEF eligible to start a therapy with sacubitril/valsartan were enrolled. A standard and advanced echocardiographic evaluation was performed before starting the therapy and after six months of follow up (FU). Off-line analysis of left ventricle global longitudinal strain (GLS), longitudinal strain of the free wall of the right ventricle (RVFWSL) and left atrial strain (LAS) was conducted. Clinical and biochemical parameters were evaluated as well. Results At six months of FU NYHA class improved in the vast majority of patients (NYHA class III at baseline vs FU: 56% vs 5%, p 0.001). We observed a significant reduction in LV end-diastolic (99.62 ± 33.24 vs 91.54 ± 33.36, p 0.043) and end-systolic (69.99 ± 26.01 vs 58.68 ± 25.7, p 0.001) volumes and an improvement of LV ejection fraction (30.4 ± 5.02 vs 37.3 ± 6.4, p < 0.001). After six months of therapy, GLS significantly improved (-9.71 ± 2.87 vs -13.04 ± 3.14, p < 0.001). No differences in left and right atrial volumes (respectively 56.6 ± 29 vs 54 ± 30, p 0.349; 54.7 ± 23.7 vs 48.3 ± 19, p 0.157), RVFWSL (-16,5 ± 5,4 vs -16,8 ± 1,5) and LAS (14 ± 6 vs 19 ± 8, p 0.197) were found at FU. Conclusion Left ventricular function evaluated with standard and advanced echocardiographic parameters improved after six months of therapy with sacubitril/valsartan in HFrEF patients. Reduction in LV volumes was found as well. Echo Analysis Baseline Echo Analysis (n= 36) 6 Months FU Echo Analysis (n= 36) p LVEDVi, mL/m2 99, 62 ± 33,24 91,54 ± 33,36 0,043 LVESVi, mL/m2 69,99 ± 26,01 58,68 ± 25,7 0,001 LVEF, % 30,4 ± 5, 02 37,3 ± 6,4 < 0,001 E/E’ average 12,16 ± 3,74 9,71 ± 1,33 0,023 LS Endo Average ,% -9,71 ± 2,87 -13,04 ± 3,14 < 0,001 LVEF left ventricular ejection fraction, LVEDVi: left ventricular end diastolic volume indexed, LVESVi: left ventricular end systolic volume indexed; LS: longitudinal strain