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Ignacio Cruz-Gonzalez,* Juan Carlos Rama-Merchan,* Javier Rodriguez-Collado, Javier Martin-Moreiras, Alejandro Diego-Nieto, Antonio Arribas-Jimenez, Pedro Luís SanchezDepartment of Cardiology, University Hospital of Cardiology and IBSAL, Salamanca, Spain *Ignacio Cruz-Gonzalez and Juan Carlos Rama-Merchan have contributed equally to this work and should be considered co-first authors Abstract: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. AF is associated with a 4–5-fold increased risk of stroke and systemic embolism. Oral anticoagulant is the first-line therapy for this purpose, but it has various limitations and is often contraindicated or underutilized. Autopsy and surgical data have suggested that 90% of atrial thrombi in nonvalvular AF patients originate from the left atrial appendage, leading to the development of percutaneous closure for thromboembolic prevention. This paper examines the current evidence on left atrial appendage closure devices for cardiovascular risk reduction in AF patients. Keywords: atrial fibrillation, left atrial appendage, stroke, oral anticoagulant, percutaneous closure, thromboembolic prevention

In the European project Silicon-Light we developed concepts and technologies to increase conversion efficiencies of thin film silicon solar cells on foil. Main focus was put on improved light management, using NIL for creating light scattering textures, improved TCOs using sputtering, and improved silicon absorber material made by PECVD. On foil we achieved initial cell efficiencies of 11% and on rigid substrates stable efficiencies of 11.6% were achieved. Finally, the project demonstrated the industrial scale feasibility of the developed technologies and materials. Cost of ownership calculations showed that implementation of these technologies on large scale would enable the production of these high efficiency solar modules at manufacturing cost of 0.65 €/Wp with encapsulation costs (0.20 €/Wp) being the dominant costs. Life cycle analysis showed that large scale production of modules based on the technologies developed in Silicon-Light would have an energy payback time of 0.85 years in Central European countries.

Introduction: The role of tissue remodeling in the reentrant activity during atrial fibrillation (AF) is not well understood. The aim of this study is to evaluate in an in-vitro model of AF the role of tissue remodeling in the mechanisms of perpetuation of this arrhythmia.Methods: HL-1 cultures were obtained for early stage (6.1 ± 1.3 days in culture, N=10) and late stage (11.7 ± 0.5 days in culture, N=8) AF. Bright field images together with optical calcium mapping (Rhod-2AM staining) were obtained for evaluating remodeling and electrophysiological characteristics of cell cultures.Results: The number of singularity points per square centimeter at baseline was significantly higher in the late stage group (i.e. 0.43±0.19 vs. 1.12±0.14 PS/cm2, p <0.01) and showed an inverse correlation with the degree of homogeneity in the corresponding bright field microscopy images (R2=0.78, p <0.01) (Fig.1). These results demonstrate that the electrical complexity in the dish increased with the culture time. Rotor dynamics (i.e. curvature and rotor movement) were significantly correlated with the amount of PSs in the cultures (R2=0.86 and R2=0.79 respectively, Fig. 1).Conclusion: Early and late stage HL-1 cell cultures present different degrees of electrophysiological complexity. Dynamics of functional reentries may be the main responsible for the increased complexity of remodeled cell cultures.Figure 1 [ABSTRACT FROM AUTHOR]

Adjuvants enhance, prolong, and modulate immune responses by vaccine antigens to maximize protective immunity and enable more effective immunization in the young and elderly. Most adjuvants are formulated with injectable vaccines. However, an intranasal route of vaccination may induce mucosal and systemic immune responses for enhancing protective immunity in individuals and be easier to administer compared to injectable vaccines. In this study, a next generation of broadly-reactive influenza hemagglutinin (HA) vaccines were developed using the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology. These HA vaccines were formulated with Mastoparan 7 (M7-NH 2 ) mast cell degranulating peptide adjuvant and administered intranasally to determine vaccine-induced seroconversion of antibodies against a panel of influenza viruses and protection following infection with H1N1 and H3N2 viruses in mice. Mice vaccinated intranasally with M7-NH 2 -adjuvanted COBRA HA vaccines had high HAIs against a panel of H1N1 and H3N2 influenza viruses and were protected against both morbidity and mortality, with reduced viral lung titers, following challenge with an H1N1 influenza virus. Additionally, M7-NH 2 adjuvanted COBRA HA vaccines induced Th2 skewed immune responses with robust IgG and isotype antibodies in the serum and mucosal lung lavages. Overall, this intranasally delivered M7-NH 2 -adjuvanted COBRA HA vaccine provides effective protection against drifted H1N1 and H3N2 viruses., (© 2024. The Author(s).)

Adjuvants enhance immune responses stimulated by vaccines. To date, many seasonal influenza vaccines are not formulated with an adjuvant. In the present study, the adjuvant Advax-SM™ was combined with next generation, broadly reactive influenza hemagglutinin (HA) vaccines that were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. Advax-SM™ is a novel adjuvant comprising inulin polysaccharide and CpG55.2, a TLR9 agonist. COBRA HA vaccines were combined with Advax-SM™ or a comparator squalene emulsion (SE) adjuvant and administered to mice intramuscularly. Mice vaccinated with Advax-SM™ adjuvanted COBRA HA vaccines had increased serum levels of anti-influenza IgG and IgA, high hemagglutination inhibition activity against a panel of H1N1 and H3N2 influenza viruses, and increased anti-influenza antibody secreting cells isolated from spleens. COBRA HA plus Advax-SM™ immunized mice were protected against both morbidity and mortality following viral challenge and, at postmortem, had no detectable lung viral titers or lung inflammation. Overall, the Advax-SM™-adjuvanted COBRA HA formulation provided effective protection against drifted H1N1 and H3N2 influenza viruses.

Aims: Same-day discharge (SDD) is feasible after pulmonary vein isolation (PVI). We aim to compare prospectively cryoballoon (CRYO) vs. radiofrequency (RF) ablation in a systematic SDD programme., Methods and Results: We prospectively analysed the 617 scheduled PVI performed consecutively at our institution (n = 377 CRYO, n = 240 RF) from 1 April 2019 to 31 December 2022 within a systematic programme of SDD. The feasibility of SDD, the 10-day incidence of urgent/unplanned medical care after discharge (UUC-10), and the cost per procedure due to hospital resource use were studied. The 100 procedures performed during the previous year, in which patients were systematically hospitalized, were used as a control group. Same-day discharge was achieved in 585/617 (95%) procedures, with a significant trend towards a higher monthly SDD rate from 2019 to 2022 (P = 0.03). The frequency of SDD was similar in CRYO (356/377; 94%) vs. RF (229/240; 95%). After SDD, the UUC-10 was 66/585 (11.3%), being similar for CRYO (41/356; 11.5%) and RF (25/229; 10.9%); P = 0.8 (log-rank test). Of these, 10 patients were re-hospitalized, with an identical rate in CRYO-treated (6/356; 1.7%) and RF-treated (4/229; 1.7%) patients and owing to similar causes (4 haematomas, 4 pericarditis, and 2 symptomatic sinus node dysfunction). Same-day discharge was associated with an average savings per procedure of 63% (P < 0.001), but no differences were found between the CRYO and RF (P = 0.8)., Conclusion: In a systematic SDD programme, feasibility (95%, increasing over time), safety (11% UUC-10, 1.7% re-hospitalizations), and savings (63% per procedure) were similar for CRYO and RF ablation procedures., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Disease progression in patients with mild-to-moderate aortic stenosis is heterogenous and requires periodic echocardiographic examinations to evaluate severity., Objectives: This study sought to explore the use of machine learning to optimize aortic stenosis echocardiographic surveillance automatically., Methods: The study investigators trained, validated, and externally applied a machine learning model to predict whether a patient with mild-to-moderate aortic stenosis will develop severe valvular disease at 1, 2, or 3 years. Demographic and echocardiographic patient data to develop the model were obtained from a tertiary hospital consisting of 4,633 echocardiograms from 1,638 consecutive patients. The external cohort was obtained from an independent tertiary hospital, consisting of 4,531 echocardiograms from 1,533 patients. Echocardiographic surveillance timing results were compared with the European and American guidelines echocardiographic follow-up recommendations., Results: In internal validation, the model discriminated severe from nonsevere aortic stenosis development with an area under the receiver-operating characteristic curve (AUC-ROC) of 0.90, 0.92, and 0.92 for the 1-, 2-, or 3-year interval, respectively. In external application, the model showed an AUC-ROC of 0.85, 0.85, and 0.85, for the 1-, 2-, or 3-year interval. A simulated application of the model in the external validation cohort resulted in savings of 49% and 13% of unnecessary echocardiographic examinations per year compared with European and American guideline recommendations, respectively., Conclusions: Machine learning provides real-time, automated, personalized timing of next echocardiographic follow-up examination for patients with mild-to-moderate aortic stenosis. Compared with European and American guidelines, the model reduces the number of patient examinations., Competing Interests: Funding Support and Author Disclosures This study was supported by the Spanish Cardiovascular Network (CIBERCV) and the Technological Development Projects in Health (DTS19/00098) and by a Research Project in Healthcare (PI21/00369); and was supported by national, public, and competitive resources from the Carlos III Health Institute (Ministry of Science and Innovation, Spain) founded by the European Union European Regional Development Fund. Drs Dorado-Díaz, Sampedro-Gómez, Sánchez-González, Vicente-Palacios, and Sanchez are the inventors of a patent on the method (Aortic Stenosis Echocardiographic Follow-Up Expert System; International Publication No. WO 2020/157212 A1) described in this paper. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15) 1-3 . However, the molecular signals that underlie the development of LRRC15 + cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin + universal fibroblasts is essential for the development of cancer-associated LRRC15 + myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15-diphtheria toxin receptor knock-in mice to selectively deplete LRRC15 + CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8 + T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15 + CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8 + T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15 + myofibroblasts may improve patient survival and response to immunotherapy., (© 2022. The Author(s).)

Background: Weaning from venoarterial extracorporeal membrane oxygenation (VA-ECMO) support fails in 30% to 70% of patients., Objective: To explore the utility of echocardiographic parameters in predicting successful disconnection from VA-ECMO., Methods: Patients receiving VA-ECMO in a referral hospital were included. The relationships between echocardiographic parameters during the weaning trial and weaning success (survival > 24 hours after VA-ECMO explant and no death from cardiogenic shock, heart failure, or cardiac arrest during the hospital stay) and survival were evaluated., Results: Of 85 patients included, 61% had successful weaning. Parameters significantly related to weaning success were higher left ventricular ejection fraction (LVEF; 40% in patients with weaning success vs 30% in patients with weaning failure, P = .01), left ventricular outflow tract velocity time integral (15 cm vs 11 cm, P = .01), aortic valve opening in every cycle (98% vs 91% of patients, P = .01), and normal qualitative right ventricular function (60% vs 42% of patients, P = .02). The LVEF remained as an independent predictor of weaning success (hazard ratio, 0.938; 95% CI, 0.888-0.991; P = .02). An LVEF >33.4% was the optimal cutoff value to discriminate patients with successful weaning (area under the curve, 0.808; sensitivity, 93%; specificity, 72%) and was related to higher survival at discharge (60% vs 20%, P < .001)., Conclusion: Among weaning trial echocardiographic parameters, LVEF was the only independent predictor of successful VA-ECMO weaning. An LVEF >33.4% was the optimal cutoff value to discriminate patients with successful weaning and was related to final survival., (©2022 American Association of Critical-Care Nurses.)

Background: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction., Methods: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke., Results: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups., Conclusions: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.)., (Copyright © 2022 Massachusetts Medical Society.)

Competing Interests: Funding Support and Author Disclosures Drs Barreiro-Perez and Cruz-Gonzalez are proctors for Abbott Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Age over 70 years seems to confer poor prognosis for patients under mechanical circulatory support (MCS). Advanced age is usually a relative contraindication. Our objective was to assess the impact of age on survival of patients with short-term MCS., Methods: Retrospective analysis of ≥70-year-old patients supported with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or Impella CP® due to cardiogenic shock and other situations of hemodynamic instability in a referral hospital (elderly group), compared with younger patients (<70 years). We analyze factors associated with survival in elderly group., Results: Out of 164 short-term MCS implants from 2013 to October 2020, 45 (27.4%) correspond to ≥70-year-old patients (73.3% VA-ECMO; 26.7% Impella CP®), 80% as bridge to recovery and 15.6% for high-risk percutaneous coronary intervention (PCI). We found no significant differences in complications developed between both groups. Survivals at discharge (40% vs. 43.7%, p = 0.403) and at follow-up (median 13.6 [30] months) were similar in elderly and young patients (35.6% vs. 37.8%, log-rank p = 0.061). Predictive factors of mortality in elderly patients were peripheral artery disease (p = 0.037), higher lactate (p = 0.003) and creatinine (p = 0.035) at implant, longer cardiac arrest (p = 0.003), and worse post-implantation left ventricular ejection fraction (p = 0.003). Patients with indication of MCS for high-risk PCI had higher survival compared to other indications (p = 0.013)., Conclusion: Short-term MCS with VA-ECMO or Impella CP® in elderly patients may be a reasonable option in hemodynamic compromise situations as bridge to recovery or elective high-risk PCI, without a significant increase in complications or mortality. Age should not be an absolute contraindication, but careful selection of candidate patients is necessary., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Paravalvular leak incidence after mitral surgical replacement ranges from 7% to 17%. Between 1% and 5% of these are clinically significant. Large PVLs can cause important clinical manifestations such as heart failure or haemolysis. Current guidelines consider that surgical reparation is the gold-standard therapy in symptomatic patients with paravalvular leak. However, these recommendations are based in non-randomized observational registries. On the other hand, transcatheter paravalvular leak closure has shown excellent results with a low rate of complications, and nowadays it is considered the first option in selected patients in some experienced centres. In this review, we summarize the clinical manifestations, diagnosis, procedural details, and results of transcatheter mitral PVL closure.

Background: Post-traumatic stress disorder (PTSD) is a common long-term outcome after intensive care of critical illness., Objectives: Assess the prevalence and factors associated to PTSD after veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support., Methods: Retrospective analysis of admission data and cross-sectional assessment of PTSD symptoms in adult survivors from admission requiring VA-ECMO support in a referral hospital. People were screened through abbreviated Impact of Event Scale-6 (IES-6)., Results: Out of 135 VA-ECMO implants performed from 2013 to 2020, 48 (35.6%) patients survived the admission. After a median follow-up of 31.4 [36] months, 34 survivors responded the questionnaire. All patients required sedation and invasive mechanical ventilation. Up to 29.4% of patients had PTSD symptoms. Patients with altered IES-6 items had passed a longer time since admission in ICCU (44±15 vs 30±20 months, p = 0.034). No baseline characteristic or admission-related variables were correlated with IES-6 except the lower time under mechanical ventilation (6.5 [8.5] vs. 8.5 [21] days, p = 0.044)., Conclusions: Survivors from admission requiring VA-ECMO support show high prevalence of PTSD symptoms, appearing more frequently when more time has elapsed since admission. Special attention should be paid to psychological symptoms after VA-ECMO support., (Published by Elsevier Inc.)

Cardiovascular disease (CVD) involves the second cause of death in low-risk myelodysplastic syndrome (MDS) population. Prospective study to characterise the CVD and to identify predictors for the combined event (CE) cardiovascular event and/or all-cause mortality in transfusion dependent low-risk MDS patients. Thirty-one patients underwent a cardiac assessment including biomarkers and cardiac magnetic resonance (cMR) with parametric sequences (T1, T2 and T2* mapping) and myocardial deformation by feature tracking (FT) and were analysed for clonal hematopoiesis of indeterminate potential mutations. Cardiac assessment revealed high prevalence of unknown structural heart disease (51% cMR pathological findings). After 2·2 [0·44] years follow-up, 35·5% of patients suffered the CE: 16% death, 29% cardiovascular event. At multivariate analysis elevated NT-proBNP ≥ 486pg/ml (HR 96·7; 95%-CI 1·135-8243; P = 0·044), reduced native T1 time < 983ms (HR 44·8; 95%-CI 1·235-1623; P = 0·038) and higher left ventricular global longitudinal strain (LV-GLS) (HR 0·4; 95%-CI 0·196-0·973; P = 0·043) showed an independent prognostic value. These variables, together with the myocardial T2* time < 20ms, showed an additive prognostic value (Log Rank: 12·4; P = 0·001). In conclusion, low-risk MDS patients frequently suffer CVD. NT-proBNP value, native T1 relaxation time and longitudinal strain by FT are independent predictors of poor cardiovascular prognosis, thus, their determination would identify high-risk patients who could benefit from a cardiac treatment and follow-up., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Myocardial deformation with echocardiography allows early detection of systolic dysfunction and is related to myocardial iron overload (MIO) determined by T2* in hereditary anemias under transfusion support. Our aim was to analyze the diagnostic and prognostic usefulness of magnetic resonance feature tracking (MR-FT) myocardial strain in low-risk myelodysplastic syndromes (LR-MDS) patients., Methods: Prospective study in transfusion-dependent LR-MDS patients and healthy controls who underwent a cardiac MR-FT. We analyzed the relationships between strain MR-FT and iron overload parameters and its prognostic impact in cardiovascular events and/or death., Results: Thirty-one patients and thirteen controls were included. MIO (T2* < 20 ms) was detected in 9.7% of patients. Left ventricular global longitudinal strain (LV-GLS) by MR-FT was pathological (> -19.3%) in 32.3% of patients. Less negative strain values correlated with lower T2* (R = -0.37, p = 0.033) and native myocardial T1 (R = -0.39, p = 0.031) times. LV-GLS by MR-FT was significantly associated with higher incidence of the combined cardiovascular events and/or all-cause death (p = 0.047), with a cut-off value of -17.7% for predicting them (63% sensitivity and 81% specificity, area under the curve = 0.69). After adjusting analysis including demographic, biomarkers and imaging variables, a higher LV-GLS value by MR-FT remained as predictor of combined event in transfusion-dependent LR-MDS patients (hazard ratio, 0.4; confidence interval, 0.15-0.98; p = 0.045)., Conclusions: Longitudinal myocardial strain by MR-FT in LR-MDS patients is associated to MIO and correlates with adverse events in the follow-up, what could serve as a prognostic tool., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2021 Korean Society of Echocardiography.)

Weaning failure and mortality rates in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) supported patients are significant. Small studies suggest the possible usefulness of levosimendan in this environment, especially in postcardiotomy shock. We performed a retrospective analysis of VA-ECMO implants in a referral hospital comparing weaning failure and survival of patients treated with levosimendan with a control group. From 2013 to May 2020, 123 VA-ECMO for several indications were implanted. Levosimendan was administered in 23 patients (18.7%) with good tolerance. Levosimendan was used more frequently in cardiogenic shock due to acute coronary syndrome indication, and in patients with lower left ventricular ejection fraction (LVEF) at the implant. No significant differences were found in success of ECMO weaning (60.9% levosimendan group vs. 44% non-levosimendan group, P = .169) despite worse LVEF in levosimendan group. Survival at follow-up (20.6 [58] months) was higher in the group that received levosimendan, although without finding statistically significant differences (47.8% vs. 32.0%, log rank P = .124). Levosimendan can be safely administered during VA-ECMO support. Patients receiving levosimendan were weaned similarly from circulatory support despite worse LVEF. Its use did not influence in short- and medium-term survival. Randomized studies are needed to evaluate the levosimendan impact in this indication., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Background: Efficient and early triage of hospitalized Covid-19 patients to detect those with higher risk of severe disease is essential for appropriate case management., Methods: We trained, validated, and externally tested a machine-learning model to early identify patients who will die or require mechanical ventilation during hospitalization from clinical and laboratory features obtained at admission. A development cohort with 918 Covid-19 patients was used for training and internal validation, and 352 patients from another hospital were used for external testing. Performance of the model was evaluated by calculating the area under the receiver-operating-characteristic curve (AUC), sensitivity and specificity., Results: A total of 363 of 918 (39.5%) and 128 of 352 (36.4%) Covid-19 patients from the development and external testing cohort, respectively, required mechanical ventilation or died during hospitalization. In the development cohort, the model obtained an AUC of 0.85 (95% confidence interval [CI], 0.82 to 0.87) for predicting severity of disease progression. Variables ranked according to their contribution to the model were the peripheral blood oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) ratio, age, estimated glomerular filtration rate, procalcitonin, C-reactive protein, updated Charlson comorbidity index and lymphocytes. In the external testing cohort, the model performed an AUC of 0.83 (95% CI, 0.81 to 0.85). This model is deployed in an open source calculator, in which Covid-19 patients at admission are individually stratified as being at high or non-high risk for severe disease progression., Conclusions: This machine-learning model, applied at hospital admission, predicts risk of severe disease progression in Covid-19 patients., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The aims of this study were to quantify the pain and distress associated with the administration of intranasal (IN) midazolam in young children using 4 observational measures and to evaluate the degree of validity of these measures., Methods: We conducted a prospective observational pilot study. Children aged 1 to 7 years requiring IN midazolam were enrolled. Children were videotaped, and scores were assigned to baseline and administration phases using the Observational Scale of Behavioral Distress-Revised (OSBD-R), Children's Hospital of Eastern Ontario Pain Scale (CHEOPS), and the Faces-Legs-Activity-Cry-Consolability (FLACC) scale. The cry duration following administration was assessed. Interrater reliability and convergent validity were determined for all 4 measures. Internal consistency and responsivity for the OSBD-R, CHEOPS, and FLACC scales were determined., Results: We enrolled 20 children. The mean OSBD-R, CHEOPS, and FLACC scores associated with administration of IN midazolam were 27.1 (SD, 13.5), 11.5 (SD, 1.2), and 8.9 (SD, 2.7), respectively. The mean cry duration was 105.5 (SD, 68.8) seconds. The intraclass correlation coefficients for all measures ranged from 0.82 to 0.99. The Cronbach α's for the OSBD-R, CHEOPS, and FLACC were between 0.71 and 0.97. Pearson correlation coefficients for comparisons between OSBD-R, CHEOPS, and FLACC were between 0.82 and 0.96 but were between 0.32 and 0.51 for comparisons involving cry duration., Conclusions: We have identified estimates of pain and distress associated with administration of IN midazolam in young children that can be used to determine desired effect sizes for trials that study interventions to treat this pain and distress. The OSBD-R, CHEOPS, and FLACC scales are suitable choices for outcome measures., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Machine learning (ML) has arrived in medicine to deliver individually adapted medical care. This study sought to use ML to discriminate stent restenosis (SR) compared with existing predictive scores of SR. To develop an easily applicable model, we performed our predictions without any additional variables other than those obtained in daily practice., Methods: The dataset, obtained from the Grupo de Análisis de la Cardiopatía Isquémica Aguda (GRACIA)-3 trial, consisted of 263 patients with demographic, clinical, and angiographic characteristics; 23 (9%) of them presented with SR at 12 months after stent implantation. A methodology to work with small imbalanced datasets, based in cross-validation and the precision/recall (PR) plots, was used, and state-of-the-art ML classifiers were trained., Results: Our best performing model (0.46, area under the PR curve [AUC-PR]) was developed with an extremely randomized trees classifier, which showed better performance than chance alone (0.09 AUC-PR, corresponding to the 9% of patients presenting SR in our dataset) and 3 existing scores; Prevention of Restenosis With Tranilast and its Outcomes (PRESTO)-1 (0.31 AUC-PR), PRESTO-2 (0.27 AUC-PR), and Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) (0.18 AUC-PR). The most important variables ranked according to their contribution to the predictions were diabetes, ≥2 vessel-coronary disease, post-percutaneous coronary intervention thrombolysis in myocardial infarction (PCI TIMI)-flow, abnormal platelets, post-PCI thrombus, and abnormal cholesterol. To counteract the lack of external validation for our study, we deployed our ML algorithm in an open source calculator, in which the model would stratify patients of high and low risk as an example tool to determine generalizability of prediction models from small imbalanced sample size., Conclusions: Applied immediately after stent implantation, a ML model better differentiates those patients who will present with SR over current discriminators., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: A more complete assessment of coronary artery disease (CAD) can be performed by coronary computed tomography angiography (CCTA). The aim was to assess the prevalence, distribution and characteristics of coronary artery disease (CAD) and the reclassification of cardiovascular risk by CCTA in an asymptomatic Spanish population., Design: We included, in a cross-sectional study, 501 random subjects from asymptomatic population, aged 35 and 75. Risk factors, target organ damage and cardiovascular risk were assessed. CCTA was offered to measure the coronary artery calcium score(CACS), segment involvement score(SIS) and segment stenosis score(SSS). The offer was accepted by 220 subjects (44%), with a mean age of 58 ± 14 years, 56% of them male., Results: The mean CACS was 119.6 ± 381.7 (median (IQR) (0 (0-61.55))), with higher scores in males (191.9 ± 493.1) than females (26.1 ± 73.3; P < .01). CCTA revealed coronary atherosclerosis in 89 cases, 40% (CI95%:34%-46%) in global, 51% in male and 25% in female, of which 13 had obstructive lesions (5.9%). Mean SIS was 1.5 ± 2.5 and SSS 1.2 ± 3.1. When the CACS was included in the CAD risk scale, there was a reclassification of 24%, and when using the SIS percentile, it was 38%, with a 9% increase in risk in both cases., Conclusions: The prevalence of CAD in asymptomatic Spanish population was 40%, with greater proportion among males. The incorporation of CACS and SIS in the assessment of cardiovascular risk allows reclassifying subjects who are at low or moderate risk and thus identify those with high cardiovascular risk and also the other way., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Objective: Pain and distress associated with intranasal midazolam administration can be decreased by administering lidocaine before intranasal midazolam (preadministered lidocaine) or combining lidocaine with midazolam in a single solution (coadministered lidocaine). We hypothesized coadministered lidocaine is non-inferior to preadministered lidocaine for decreasing pain and distress associated with intranasal midazolam administration., Methods: Randomized, outcome assessor-blinded, noninferiority trial. Children aged 6 months to 7 years undergoing laceration repair received intranasal midazolam with preadministered or coadministered lidocaine. Pain and distress were evaluated with the Observational Scale of Behavioral Distress-Revised (OSBD-R) (primary outcome; non-inferiority margin 1.8 units) and the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Faces, Legs, Activity, Cry, Consolability (FLACC) scales and cry duration (secondary outcomes). Secondary outcomes also included adverse events, clinician and caregiver satisfaction, and pain and distress associated with intranasal lidocaine administration., Results: Fifty-one patients were analyzed. Mean OSBD-R scores associated with intranasal midazolam administration were 6.4 (95% confidence interval [CI] 5, 7.8) and 7 (95% CI 5.2, 8.9) units for preadministered and coadministered lidocaine, respectively. The difference of 0.6 (95% CI -1.7, 2.8) units represented an inconclusive non-inferiority determination. CHEOPS and FLACC scores and cry duration were similar between groups. OSBD-R, CHEOPS, and FLACC scores and cry duration associated with intranasal lidocaine administration were 3.8, 9.9, and 6 units, and 56 seconds, respectively. Clinicians considered coadministered lidocaine easier to administer., Conclusion: Pain and distress associated with intranasal midazolam administration were similar when using coadministered or preadministered lidocaine, but our non-inferiority determination was inconclusive. Administration of intranasal lidocaine by itself was associated with a measurable degree of pain and distress.Keywords: intranasal, midazolam, anxiolysis, sedation, emergency department, emergency medicine, pain, distress, pediatric, lidocaine, laceration., Competing Interests: None of the authors have any conflicts of interest to disclose., (© 2020 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of the American College of Emergency Physicians.)

Objective: Primary percutaneous coronary intervention (P-PCI) has demonstrated its efficacy in patients with ST segment elevation myocardial infarction (STEMI). However, patients with STEMI ≥75 years receive less P-PCI than younger patients despite their higher in-hospital morbimortality. The objective of this analysis was to determine the effectiveness of P-PCI in patients with STEMI ≥75 years., Methods: We included 979 patients with STEMI ≥75 years, from the ATención HOspitalaria del Síndrome coronario study, a registry of 8142 consecutive patients with acute coronary syndrome admitted at 31 Spanish hospitals in 2014-2016. We calculated a propensity score (PS) for the indication of P-PCI. Patients that received or not P-PCI were matched by PS. Using logistic regression, we compared the effectiveness of performing P-PCI versus non-performance for the composite primary event, which included death, reinfarction, acute pulmonary oedema or cardiogenic shock during hospitalisation., Results: Of the included patients, 81.5 % received P-PCI. The matching provided two groups of 169 patients with and without P-PCI. Compared with its non-performance, P-PCI presented a composite event OR adjusted by PS of 0.55 (95% CI 0.34 to 0.89)., Conclusions: Receiving a P-PCI was significantly associated with a reduced risk of major intrahospital complications in patients with STEMI aged 75 years or older., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Aims: Current guidelines recommend sacubitril/valsartan for patients with heart failure and reduced left ventricular ejection fraction (LVEF), but there is lack of evidence of its efficacy and safety in cancer therapy-related cardiac dysfunction (CTRCD). Our aim was to analyse the potential benefit of sacubitril/valsartan in patients with CTRCD., Methods and Results: We performed a retrospective multicentre registry (HF-COH) in six Spanish hospitals with cardio-oncology clinics including all patients treated with sacubitril/valsartan. Demographic and clinical characteristics and laboratory and echocardiographic data were collected. Median follow-up was 4.6 [1; 11] months. Sixty-seven patients were included (median age was 63 ± 14 years; 64% were female, 87% had at least one cardiovascular risk factor). Median time from anti-cancer therapy to CTRD was 41 [10; 141] months. Breast cancer (45%) and lymphoma (39%) were the most frequent neoplasm, 31% had metastatic disease, and all patients were treated with combination antitumor therapy (70% with anthracyclines). Thirty-nine per cent of patients had received thoracic radiotherapy. Baseline median LVEF was 33 [27; 37], and 21% had atrial fibrillation. Eighty-five per cent were on beta-blocker therapy and 76% on mineralocorticoid receptor antagonists; 90% of the patients were symptomatic NYHA functional class ≥II. Maximal sacubitril/valsartan titration dose was achieved in 8% of patients (50 mg b.i.d.: 60%; 100 mg b.i.d.: 32%). Sacubitril/valsartan was discontinued in four patients (6%). Baseline N-terminal pro-B-type natriuretic peptide levels (1552 pg/mL [692; 3624] vs. 776 [339; 1458]), functional class (2.2 ± 0.6 vs. 1.6 ± 0.6), and LVEF (33% [27; 37] vs. 42 [35; 50]) improved at the end of follow-up (all P values ≤0.01). No significant statistical differences were found in creatinine (0.9 mg/dL [0.7; 1.1] vs. 0.9 [0.7; 1.1]; P = 0.055) or potassium serum levels (4.5 mg/dL [4.1; 4.8] vs. 4.5 [4.2; 4.8]; P = 0.5). Clinical, echocardiographic, and biochemical improvements were found regardless of the achieved sacubitril-valsartan dose (low or medium/high doses)., Conclusions: Our experience suggests that sacubitril/valsartan is well tolerated and improves echocardiographic functional and structural parameters, N-terminal pro-B-type natriuretic peptide levels, and symptomatic status in patients with CTRCD., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objectives: Cardiac surgery or catheter interventions are nowadays commonly performed to reduce volume loading of the right ventricle in adults with congenital heart disease. However, little is known, on the effect of such procedures on pre-existing tricuspid regurgitation (TR). We assessed the potential reduction in the severity of TR after atrial septal defect (ASD) closure and pulmonic valve replacement (PVR)., Methods: Demographics, clinical and echocardiographic characteristics of consecutive patients undergoing ASD closure or PVR between 2005 and 2014 at a single centre who had at least mild preoperative TR were collected and analysed., Results: Overall, 162 patients (mean age at intervention 41.6±16.1 years, 38.3% male) were included: 101 after ASD closure (61 transcatheter vs 40 surgical) and 61 after PVR (3 transcatheter vs 58 surgical). Only 11.1% received concomitant tricuspid valve surgery (repair). There was significant reduction in the severity of TR in the overall population, from 38 (23.5%) patients having moderate or severe TR preoperatively to only 11 (6.8%) and 20 (12.3%) at 6 months and 12 months of follow-up, respectively (McNemar p<0.0001). There was a significant reduction in tricuspid valve annular diameter (p<0.0001), coaptation distance (p<0.0001) and systolic tenting area (p<0.0001). The reduction in TR was also observed in patients who did not have concomitant tricuspid valve (TV) repair (from 15.3% to 6.9% and 11.8% at 6 and 12 months, respectively, p<0.0001). On multivariable logistic regression including all univariable predictors of residual TR at 12 months, only RA area remained in the model (OR 1.2, 95% CI 1.04 to 1.37, p=0.01)., Conclusions: ASD closure and PVR are associated with a significant reduction in tricuspid regurgitation, even among patients who do not undergo concomitant tricuspid valve surgery., Competing Interests: Competing interests: ACM-G has received support from the Instituto de Investigacion Biomedica de Salamanca (IBSAL). KD, AK and AM-G from the Royal Brompton Hospital have received unrestricted educational and research grants and acted as consultants for Bayer, Pfizer, Actelion and GSK. SVB-N was supported by the British Heart Foundation (FS/11/38/28864)., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This study aims to obtain data on the prevalence and incidence of structural heart disease in a population setting and, to analyse and present those data on the application of spatial and machine learning methods that, although known to geography and statistics, need to become used for healthcare research and for political commitment to obtain resources and support effective public health programme implementation., Methods and Analysis: We will perform a cross-sectional survey of randomly selected residents of Salamanca (Spain). 2400 individuals stratified by age and sex and by place of residence (rural and urban) will be studied. The variables to analyse will be obtained from the clinical history, different surveys including social status, Mediterranean diet, functional capacity, ECG, echocardiogram, VASERA and biochemical as well as genetic analysis., Ethics and Dissemination: The study has been approved by the ethical committee of the healthcare community. All study participants will sign an informed consent for participation in the study. The results of this study will allow the understanding of the relationship between the different influencing factors and their relative importance weights in the development of structural heart disease. For the first time, a detailed cardiovascular map showing the spatial distribution and a predictive machine learning system of different structural heart diseases and associated risk factors will be created and will be used as a regional policy to establish effective public health programmes to fight heart disease. At least 10 publications in the first-quartile scientific journals are planned., Trial Registration Number: NCT03429452., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To obtain initial data on the effect of different levels of targeted temperature management (TTM) in out-of-hospital cardiac arrest (OHCA)., Methods: We designed a multicentre pilot trial with 1:1:1 randomization to either 32 °C (n = 52), 33 °C (n = 49) or 34 °C (n = 49), via endovascular cooling devices during a 24-h period in comatose survivors of witnessed OHCA and initial shockable rhythm. The primary endpoint was the percentage of subjects surviving with good neurologic outcome defined by a modified Rankin Scale (mRS) score of ≤ 3, blindly assessed at 90 days., Results: At baseline, different proportions of patients who had received defibrillation administered by a bystander were assigned to groups of 32 °C (13.5%), 33 °C (34.7%) and 34 °C (28.6%; p = 0.03). The percentage of patients with an mRS ≤ 3 at 90 days (primary endpoint) was 65.3, 65.9 and 65.9% in patients assigned to 32, 33 and 34 °C, respectively, non-significant (NS). The multivariate Cox proportional hazards model identified two variables significantly related to the primary outcome: male gender and defibrillation by a bystander. Among the 43 patients who died before 90 days, 28 died following withdrawal of life-sustaining therapy, as follows: 7/16 (43.8%), 10/13 (76.9%) and 11/14 (78.6%) of patients assigned to 32, 33 and 34 °C, respectively (trend test p = 0.04). All levels of cooling were well tolerated., Conclusions: There were no statistically significant differences in neurological outcomes among the different levels of TTM. However, future research should explore the efficacy of TTM at 32 °C., Clinical Trial Registration: ClinicalTrials.gov unique identifier: NCT02035839 ( http://clinicaltrials.gov ).

Background Ticagrelor use during acute coronary syndromes demonstrated a decrease in all-cause mortality in the PLATO (Platelet Inhibition and Patient Outcomes) trial. This effect has been attributed to a non-platelet-derived improvement in endothelial function. The aim of this study was to determine differences in the number of endothelial progenitor cells and/or circulating endothelial cells found in peripheral blood in patients treated with either ticagrelor or clopidogrel during non-ST-segment-elevation myocardial infarction. Methods and Results In this multicenter, randomized study ( NCT 02244710), patients were considered for inclusion after non-ST-segment-elevation myocardial infarction whenever they were P2Y 12 -inhibitor naïve. Ticagrelor and clopidogrel were allocated at a 1:1 ratio. Blood samples for determining endothelial progenitor cells and circulating endothelial cells were extracted before the antiplatelet loading dose, 48 hours after presentation of index symptoms, and 1 month after the event. A multichannel cytometer was used for optimal cell characterization. A total of 96 patients fulfilled the inclusion criteria. Circulating endothelial cell levels corrected by white blood cells were as follows at baseline, 48 hours, and 1 month: 44 (28-64), 50 (33-63), and 38 (23-62) cells/mL, respectively, for clopidogrel and 38 (29-60), 45 (32-85), and 35 (24-71) cells/mL, respectively, for ticagrelor ( P=0.6). Endothelial progenitor cell levels were 29 (15-47), 27 (15-33), and 18 (10-25) cells/mL, respectively, for clopidogrel and 20 (11-33), 22 (12-32), and 18 (11-29) cells/mL, respectively, for ticagrelor ( P=0.9). No differences in intraindividual changes were found. Conclusions Patients treated with ticagrelor during non-ST-segment-elevation myocardial infarction, in comparison to clopidogrel, showed similar levels of endothelial progenitor cells and circulating endothelial cells. These data suggest that the endothelial protective effect mediated by ticagrelor is not related to bone marrow physiology modulation. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 02244710.