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Abstract Cell cycle checkpoints, activated by stressful events, halt the cell cycle progression, and prevent the transmission of damaged DNA. These checkpoints prompt cell repair but also trigger cell death if damage persists. Decision-making between these responses is multifactorial and context-dependent, with the tumor suppressor p53 playing a central role. In many tumor cells, p53 alterations lead to G1/S checkpoint loss and the weakening of the G2 checkpoint, rendering cell viability dependent on the strength of the latter through mechanisms not fully characterized. Cells with a strong pro-survival drive can evade cell death despite substantial DNA lesions. Deciphering the integration of survival pathways with p53-dependent and -independent mechanisms governing the G2/M transition is crucial for understanding G2 arrest functionality and predicting tumor cell response to chemotherapy. The serine/threonine kinase GRK2 emerges as a signaling node in cell cycle modulation. In cycling cells, but not in G2 checkpoint-arrested cells, GRK2 protein levels decline during G2/M transition through a process triggered by CDK2-dependent phosphorylation of GRK2 at the S670 residue and Mdm2 ubiquitination. We report now that this downmodulation in G2 prevents the unscheduled activation of the PI3K/AKT pathway, allowing cells to progress into mitosis. Conversely, higher GRK2 levels lead to tyrosine phosphorylation by the kinase c-Abl, promoting the direct association of GRK2 with the p85 regulatory subunit of PI3K and AKT activation in a GRK2 catalytic-independent manner. Hyperactivation of AKT is conditioned by p53’s scaffolding function, triggering FOXO3a phosphorylation, impaired Cyclin B1 accumulation, and CDK1 activation, causing a G2/M transition delay. Upon G2 checkpoint activation, GRK2 potentiates early arrest independently of p53 through AKT activation. However, its ability to overcome the G2 checkpoint in viable conditions depends on p53. Our results suggest that integrating the GRK2/PI3K/AKT axis with non-canonical functions of p53 might confer a survival advantage to tumor cells.

Abstract Introduction Atrial fibrillation (AF) represents the most common arrhythmia in the postoperative setting. We aimed to investigate the incidence of postoperative AF (POAF) and determine its predictors, with a specific focus on inflammation markers. Methods We performed a retrospective single tertiary center cohort study including consecutive adult patients who underwent a major surgical procedure between January 2016 and January 2020. Patients were divided into four subgroups according to the type of surgery. Results Among 53,387 included patients (79.4% male, age 64.5 ± 9.5 years), POAF occurred in 570 (1.1%) with a mean latency after surgery of 3.4 ± 2.6 days. Ninety patients died (0.17%) after a mean of 13.7 ± 8.4 days. The 28‐day arrhythmia‐free survival was lower in patients undergoing lung and cardiovascular surgery (p

Background: Low-voltage area (LVA) ablation, in addition to pulmonary vein isolation (PVI), has been proposed as a new strategy in patients with atrial fibrillation (AF), but clinical trials have shown conflicting results. We performed a systematic review and meta-analysis to assess the impact of LVA ablation in patient undergoing AF ablation (PROSPERO-registered CRD42024537696). Methods: Randomized clinical trials investigating the role of LVA ablation in addition to PVI in patients with AF were searched on PubMed, Embase, and the Cochrane Library from inception to 22 April 2024. Primary outcome was atrial arrhythmia recurrence after the first AF ablation procedure. Secondary endpoints included procedure time, fluoroscopy time, and procedure-related complication rate. Sensitivity analysis including only patients with LVA demonstration at mapping and multiple subgroups analyses were also performed. Results: 1547 patients from 7 studies were included. LVA ablation in addition to PVI reduced atrial arrhythmia recurrence (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.52–0.81, p < 0.001) with a number needed to treat to prevent recurrence of 10. No difference in procedure time (mean difference [MD] −5.32 min, 95% CI −19.01–8.46 min, p = 0.45), fluoroscopy time (MD −1.10 min, 95% CI −2.48–0.28 min, p = 0.12) and complication rate (OR 0.81, 95% CI 0.40–1.61, p = 0.54) was observed. Consistent results were demonstrated when considering only patients with LVA during mapping and in prespecified subgroups for AF type (paroxysmal vs. persistent), multicentric vs. monocentric trial, and ablation strategy in control group. Conclusions: In patients with AF, ablation of LVAs in addition to PVI reduces atrial arrhythmia recurrence without a significant increase in procedure time, fluoroscopy time, or complication rate.

The treatment of outflow tract ventricular arrhythmias (OTVA) through radiofrequency ablation requires the precise identification of the site of origin (SOO). Pinpointing the SOO enhances the likelihood of a successful procedure, reducing intervention times and recurrence rates. Current clinical methods to identify the SOO are based on qualitative analysis of pre-operative electrocardiograms (ECG), heavily relying on physician’s expertise. Although computational models and machine learning (ML) approaches have been proposed to assist OTVA procedures, they either consume substantial time, lack interpretability or do not use clinical information. Here, we propose an alternative strategy for automatically predicting the ventricular origin of OTVA patients using ML. Our objective was to classify ventricular (left/right) origin in the outflow tracts (LVOT and RVOT, respectively), integrating ECG and clinical data from each patient. Extending beyond differentiating ventricle origin, we explored specific SOO characterization. Utilizing four databases, we also trained supervised learning models on the QRS complexes of the ECGs, clinical data, and their combinations. The best model achieved an accuracy of 89%, highlighting the significance of precordial leads V1-V4, especially in the R/S transition and initiation of the QRS complex in V2. Unsupervised analysis revealed that some origins tended to group closer than others, e.g., right coronary cusp (RCC) with a less sparse group than the aortic cusp origins, suggesting identifiable patterns for specific SOOs.

We examined the longitudinal relation between behavioral inhibition (BI) and social anxiety symptoms and behavior and the mediating role of emotion regulation (ER). Moreover, we investigated the influence of parenting behavior on the development of ER strategies. Participants were 291 children (135 male) followed longitudinally from 2 to 13 years. Mothers were predominantly well educated and non-Hispanic Caucasian. Children were screened for BI using maternal report and observational measures (ages 2 and 3), parenting behavior was observed while children and their mothers participated in a fear-eliciting task (age 3), ER strategies were observed while children completed a disappointment task (age 5), and socially anxious behavior was measured via multimethod assessment at 10 and 13 years. Children who exhibited high BI in early childhood exhibited more socially anxious behavior across ages 10 and 13, and there was a significant indirect effect of BI on socially anxious behavior through ER strategies. Children who were high in BI demonstrated less engaged ER strategies during the disappointment task, which in turn predicted more socially anxious behavior. Furthermore, parenting behavior moderated the pathway linking early BI and ER strategies to social anxiety outcomes such that children who exhibited high BI and who received more affectionate/oversolicitous behavior from their mother displayed less engaged ER strategies and more socially anxious behavior than children low in BI or low in oversolicitous parenting behaviors. These findings expand on our understanding of the role that ER strategies and parenting play in the developmental pathway linking early BI to future social anxiety outcomes.

Abstract Background Frequent and highly prevalent as comorbidities in Chronic Obstructive Pulmonary Disease (COPD) patients, both depression and anxiety seem to have an impact on COPD prognosis. However, they are underdiagnosed and rarely treated properly. Aim To establish the prevalence of depression and anxiety in patients admitted for Acute Exacerbation of COPD (AECOPD) and determine their influence on COPD prognosis. Methods Prospective observational study conducted from October 1, 2016 to October 1, 2018 at the following centers in Galicia, Spain: Salnés County Hospital, Arquitecto Marcide, and Clinic Hospital Complex of Santiago de Compostela. Patients admitted for AECOPD who agreed to participate and completed the anxiety and depression scale (HADS) were included in the study. Results 288 patients (46.8%) were included, mean age was 73.7 years (SD 10.9), 84.7% were male. 67.7% patients were diagnosed with probable depression, and depression was established in 41.7%; anxiety was probable in 68.2% and established in 35.4%. 60.4% of all patients showed symptoms of both anxiety and depression. Multivariate analysis relates established depression with a higher risk of late readmission (OR 2.06, 95% CI 1.28; 3.31) and a lower risk of mortality at 18 months (OR 0.57, 95% CI 0.37; 0.90). Conclusion The prevalence of anxiety and depression in COPD patients is high. Depression seems to be an independent factor for AECOPD, so early detection and a multidisciplinary approach could improve the prognosis of both entities. The study was approved by the Ethical Committee of Galicia (code 2016/460).

Introduction: Atrial fibrillation (AF) represents the most common arrhythmia in the postoperative setting. We aimed to investigate the incidence of postoperative AF (POAF) and determine its predictors, with a specific focus on inflammation markers. Methods: We performed a retrospective single tertiary center cohort study including consecutive adult patients who underwent a major surgical procedure between January 2016 and January 2020. Patients were divided into four subgroups according to the type of surgery. Results: Among 53,387 included patients (79.4% male, age 64.5 ± 9.5 years), POAF occurred in 570 (1.1%) with a mean latency after surgery of 3.4 ± 2.6 days. Ninety patients died (0.17%) after a mean of 13.7 ± 8.4 days. The 28‐day arrhythmia‐free survival was lower in patients undergoing lung and cardiovascular surgery (p <.001). Patients who developed POAF had higher levels of C‐reactive protein (CRP) (0.70 ± 0.03 vs. 0.40 ± 0.01 log10 mg/dl; p <.001). In the multivariable Cox regression analysis, adjusting for confounding factors, CRP was an independent predictor of POAF [HR per 1 mg/dL increase in log‐scale = 1.81 (95% CI 1.18–2.79); p =.007]. Moreover, independent predictors of POAF were also age (HR/1 year increase = 1.06 (95% CI 1.04–1.08); I <.001), lung and cardiovascular surgery (HR 23.62; (95% CI 5.65–98.73); p <.001), and abdominal and esophageal surgery (HR 6.26; 95% CI 1.48–26.49; p =.013). Conclusions: Lung and cardiovascular surgery had the highest risk of POAF in the presented cohort. CRP was an independent predictor of POAF and postsurgery inflammation may represent a major driver in the pathophysiology of the arrhythmia. [ABSTRACT FROM AUTHOR]

Resumen: Introducción: En las últimas décadas se ha incrementado el número de pacientes crónicos complejos (PCC). Existen pocos datos referentes a la prevalencia de PCC en población pediátrica y su impacto en los ingresos hospitalarios. Los objetivos principales de este trabajo son determinar en nuestro medio la proporción de PCC en hospitalización pediátrica y compararla con la de otros grupos de pacientes ingresados (agudos y crónicos). Pacientes y métodos: Estudio descriptivo retrospectivo realizado en un hospital materno-infantil terciario (de diciembre de 2016 a noviembre de 2017). Se incluyó a todos los pacientes ingresados en el Servicio de Pediatría con una periodicidad quincenal. Se recogieron una serie de variables demográficas, clínicas y de gestión. Para identificar el grado de complejidad de los pacientes se utilizó el sistema de clasificación Clinical Risk Group (CRG) y se crearon 3 grupos: agudos, crónicos y PCC. Para el análisis estadístico se usó SPSS v24. Resultados: Se incluyó a 1.433 pacientes. La proporción de PCC en la planta de Pediatría fue del 14,4%. Los PCC tenían mayor edad, ingresaron principalmente por descompensación o progresión de su enfermedad de base, estuvieron ingresados más tiempo y precisaron soporte en la Unidad de Cuidados Intensivos Pediátricos con mayor frecuencia que los otros subgupos. Un 44,7% de los PCC era portador de dispositivos tecnológicos. Del total de largas estancias (>1 mes), el 71,3% fue de PCC. Conclusiones: Los PCC requieren de estancias hospitalarias largas, tienen mayor necesidad de cuidados intensivos y uso de tecnología. Es necesario plantear nuevos enfoques de tratamiento y seguimiento que sean costo-eficientes y que, a la vez, disminuyan el impacto de la enfermedad en el niño y su familia. Abstract: Introduction: The number of patients with complex chronic conditions (CCC) has increased in the last 20 years or so. There is limited data as regards the prevalence of CCC in the paediatric population and its impact on hospital admissions. The main objectives of this study are to determine the proportion of CCC in the paediatric hospital population and compare them with other groups of patients admitted (acute and chronic). Patients and methods: A descriptive, retrospective study was carried out in a tertiary maternity-paediatric hospital (from December 2016 to November 2017). All patients admitted into the Paediatric Department were recruited with a fortnightly frequency. A series of demographic, clinical, and pregnancy data were collected. In order to identify the level of complexity of the patients, the Clinical Risk Group (CRG) was used, with 3 groups being created: acute, chronic, and CCC. Statistics analysis was performed using SPSS v24. Results: A total of 1,433 patients were included. The proportion of CCC on the Paediatric Ward was 14.4%. The CCC were older patients, mainly admitted due to decompensation or progression of their underlying disease, had a longer admission time, and required support in the Paediatric Intensive Care Unit more often than that of the other sub-groups. Just under half (44.7%) of the CCC were carriers of a technological device. Of the total of long stays (>1 month), 71.3% had CCC. Conclusions: Patients with CCC require long hospital stays, a greater need of intensive care, and use of technology. New approaches to treatment and follow-up need to be established. They should be cost-effective, and at the same time decrease the impact of the disease on the children and their family.

Introduction: The number of patients with complex chronic conditions (CCC) has increased in the last 20 years or so. There is limited data as regards the prevalence of CCC in the paediatric population and its impact on hospital admissions. The main objectives of this study are to determine the proportion of CCC in the paediatric hospital population and compare them with other groups of patients admitted (acute and chronic). Patients and methods: A descriptive, retrospective study was carried out in a tertiary maternity-paediatric hospital (from December 2016 to November 2017). All patients admitted into the Paediatric Department were recruited with a fortnightly frequency. A series of demographic, clinical, and pregnancy data were collected. In order to identify the level of complexity of the patients, the Clinical Risk Group (CRG) was used, with 3 groups being created: acute, chronic, and CCC. Statistics analysis was performed using SPSS v24. Results: A total of 1433 patients were included. The proportion of CCC on the Paediatric Ward was 14.4%. The CCC were older patients, mainly admitted due to decompensation or progression of their underlying disease, had a longer admission time, and required support in the Paediatric Intensive Care Unit (PICU) more often than that of the other sub-groups. Just under half (44.7%) of the CCC were carriers of a technological device. Of the total of long stays (>1 month), 71.3% had CCC. Conclusions: Patients with CCC require long hospital stays, a greater need of intensive care, and use of technology. New approaches to treatment and follow-up need to be established. They should be cost-effective, and at the same time decrease the impact of the disease on the children and their family. Resumen: Introducción: En las últimas décadas se ha incrementado el número de pacientes crónicos complejos (PCC). Existen pocos datos referentes a la prevalencia de PCC en población pediátrica y su impacto en los ingresos hospitalarios. Los objetivos principales de este trabajo son determinar en nuestro medio la proporción de PCC en hospitalización pediátrica y compararlos con otros grupos de pacientes ingresados (agudos y crónicos). Pacientes y métodos: Estudio descriptivo retrospectivo realizado en un hospital materno-infantil terciario (de diciembre 2016 a noviembre 2017). Se reclutaron a todos los pacientes ingresados en el servicio de Pediatría con una periodicidad quincenal. Se recogieron una serie de variables demográficas, clínicas y de gestión. Para identificar el grado de complejidad de los pacientes se utilizó el sistema de clasificación Clinical Risk Group (CRG) y se crearon 3 grupos: agudos, crónicos y PCC. Para el análisis estadístico se usó SPSS v24. Resultados: Se incluyeron 1.433 pacientes. La proporción de PCC en planta de Pediatría fue del 14,4%. Los PCC fueron pacientes de mayor edad, ingresaron principalmente por descompensación o progresión de su enfermedad de base, estuvieron ingresados más tiempo y precisaron soporte en la Unidad de Cuidados Intensivos Pediátricos (UCIP) con mayor frecuencia que los otros subgupos. Un 44,7% de los PCC era portador de dispositivos tecnológicos. Del total de largas estancias (>1 mes), el 71,3% fue de PCC. Conclusiones: Los PCC requieren de estancias hospitalarias largas, mayor necesidad de cuidados intensivos y uso de tecnología. Es necesario plantear nuevos enfoques de tratamiento y seguimiento que sean costo-eficientes a la vez que disminuyan el impacto de la enfermedad en el niño y su familia.

Background The dismal clinical outcome of relapsed/refractory (R/R) T cell acute lymphoblastic leukemia (T-ALL) highlights the need for innovative targeted therapies. Although chimeric antigen receptor (CAR)-engineered T cells have revolutionized the treatment of B cell malignancies, their clinical implementation in T-ALL is in its infancy. CD1a represents a safe target for cortical T-ALL (coT-ALL) patients, and fratricide-resistant CD1a-directed CAR T cells have been preclinically validated as an immunotherapeutic strategy for R/R coT-ALL. Nonetheless, T-ALL relapses are commonly very aggressive and hyperleukocytic, posing a challenge to recover sufficient non-leukemic effector T cells from leukapheresis in R/R T-ALL patients.Methods We carried out a comprehensive study using robust in vitro and in vivo assays comparing the efficacy of engineered T cells either expressing a second-generation CD1a-CAR or secreting CD1a x CD3 T cell-engaging Antibodies (CD1a-STAb).Results We show that CD1a-T cell engagers bind to cell surface expressed CD1a and CD3 and induce specific T cell activation. Recruitment of bystander T cells endows CD1a-STAbs with an enhanced in vitro cytotoxicity than CD1a-CAR T cells at lower effector:target ratios. CD1a-STAb T cells are as effective as CD1a-CAR T cells in cutting-edge in vivo T-ALL patient-derived xenograft models.Conclusions Our data suggest that CD1a-STAb T cells could be an alternative to CD1a-CAR T cells in coT-ALL patients with aggressive and hyperleukocytic relapses with limited numbers of non-leukemic effector T cells.

In order to determine the site of origin (SOO) in outflow tract ventricular arrhythmias (OTVAs) before an ablation procedure, several algorithms based on manual identification of electrocardiogram (ECG) features, have been developed. However, the reported accuracy decreases when tested with different datasets. Machine learning algorithms can automatize the process and improve generalization, but their performance is hampered by the lack of large enough OTVA databases. We propose the use of detailed electrophysiological simulations of OTVAs to train a machine learning classification model to predict the ventricular origin of the SOO of ectopic beats. We generated a synthetic database of 12-lead ECGs (2,496 signals) by running multiple simulations from the most typical OTVA SOO in 16 patient-specific geometries. Two types of input data were considered in the classification, raw and feature ECG signals. From the simulated raw 12-lead ECG, we analyzed the contribution of each lead in the predictions, keeping the best ones for the training process. For feature-based analysis, we used entropy-based methods to rank the obtained features. A cross-validation process was included to evaluate the machine learning model. Following, two clinical OTVA databases from different hospitals, including ECGs from 365 patients, were used as test-sets to assess the generalization of the proposed approach. The results show that V2 was the best lead for classification. Prediction of the SOO in OTVA, using both raw signals or features for classification, presented high accuracy values (>0.96). Generalization of the network trained on simulated data was good for both patient datasets (accuracy of 0.86 and 0.84, respectively) and presented better values than using exclusively real ECGs for classification (accuracy of 0.84 and 0.76 for each dataset). The use of simulated ECG data for training machine learning-based classification algorithms is critical to obtain good SOO predictions in OTVA compared to real data alone. The fast implementation and generalization of the proposed methodology may contribute towards its application to a clinical routine.

Periodontitis is commonly diagnosed based on clinical parameters. However, the analysis of a few unique biomarkers of the disease process present in the saliva and blood can further assist the estimation of the rate of disease progression. Aim: The present study attempted to correlate the alkaline phosphatase (ALP) and acid phosphatase (ACP) levels in saliva and serum between patients with healthy periodontium, gingivitis, and chronic periodontitis. Materials and methods: The present study was conducted in 135 subjects between 20 and 55 years of age. The subjects were divided into three groups, namely healthy (Group A), gingivitis (Group B), and chronic periodontitis (Group C). The clinical parameters were recorded using the plaque index (PI), gingival index (GI), and probing depth (PD). Saliva and serum were analyzed for ALP and ACP levels using an auto analyzer. All patients underwent scaling and root planning (SRP) along with oral hygiene instructions. Patients were then recalled after four weeks, and blood and saliva samples were collected to estimate ALP and ACP levels prior to clinical examination. Results: The clinical parameters exhibited a statistically significant decrease in the PI and GI in both group B and group C after SRP. A significant change in the PD and attachment levels (AL) was observed in the periodontitis group after SRP. The mean salivary & serum ALP levels exhibited a statistically significant decrease in group B & C after SRP. The mean serum ACP levels exhibited a statistically significant decrease in group B & C after SRP However, the salivary ACP levels decrease after SRP was only statistically significant in group C. Conclusion: Serum and salivary ALP and ACP levels were markedly decreased in the gingivitis and periodontitis groups after SRP and were positively correlated with the clinical parameters.

This study examines how airlines in the United States report risk at a difficult and uncertain time as a result of the COVID-19 pandemic. The fundamental differences between the years 2019 and 2020 are identified using Leximancer, which is used to locate the key ideas and themes addressed in the risk reporting sections. Following the pandemic, the themes that addressed generic and recurring hazards were afforded less weight than themes that highlighted risks particular to day-to-day business and the stock market. The findings also point to the need for corporations to disclose future-oriented risks more fully in post-COVID-19 reporting, with an emphasis on unpredictability, stock volatility, and operational disruption. This study adds to the body of knowledge on risk profiling, particularly as it relates to the airline business, and it offers stakeholders and investors a glimpse into the general concerns of airlines. The inherent information imbalance between management and investors is lessened and transparency is increased because of this improved understanding of the market.

BackgroundFamily clusters offer a good opportunity to study viral transmission in a stable setting. We aimed to analyze the specific role of children in transmission of SARS-CoV-2 within households.MethodsA prospective, longitudinal, observational study, including children with documented acute SARS-CoV-2 infection attending 22 summer-schools in Barcelona, Spain, was performed. Moreover, other patients and families coming from other school-like environments that voluntarily accessed the study were also studied. A longitudinal follow-up (5 weeks) of the family clusters was conducted to determine whether the children considered to be primary cases were able to transmit the virus to other family members. The household reproduction number (Re*) and the secondary attack rate (SAR) were calculated.Results1905 children from the summer schools were screened for SARS-CoV-2 infection and 22 (1.15%) tested positive. Moreover, 32 additional children accessed the study voluntarily. Of these, 37 children and their 26 households were studied completely. In half of the cases (13/26), the primary case was considered to be a child and secondary transmission to other members of the household was observed in 3/13, with a SAR of 14.2% and a Re* of 0.46. Conversely, the SAR of adult primary cases was 72.2% including the kids that gave rise to the contact tracing study, and 61.5% without them, and the estimated Re* was 2.6. In 4/13 of the paediatric primary cases (30.0%), nasopharyngeal PCR was persistently positive > 1 week after diagnosis, and 3/4 of these children infected another family member (pConclusionsChildren may not be the main drivers of the infection in household transmission clusters in the study population. A prolonged positive PCR could be associated with higher transmissibility.

Nowadays, employees’ readiness for change plays a key role to implement many organizational change initiatives.Using a sample of 510 bank employees in Jordan, this study seeks to analyze how high-performance human resource management practices and affective commitment impact employees’ readiness for change. We also seek to study the role of readiness for change in improving employee performance.The results obtained through statistical analysis demonstrate a positive association between some high-performance human resource management practices with both affective commitment and readiness for change. Results also show a positive relationship between affective commitment and readiness for change.We have also found that readiness for change is positively related to employees’ individual performance. Finally, our findings show that hierarchy culture positively moderates the relation of high-performance human resource management practices with affective commitment.

Background: Identification of signaling pathways altered at early stages after cardiac ischemia/reperfusion (I/R) is crucial to develop timely therapies aimed at reducing I/R injury. The expression of G protein-coupled receptor kinase 2 (GRK2), a key signaling hub, is up-regulated in the long-term in patients and in experimental models of heart failure. However, whether GRK2 levels change at early time points following myocardial I/R and its functional impact during this period remain to be established. Methods: We have investigated the temporal changes of GRK2 expression and their potential relationships with the cardioprotective AKT pathway in isolated rat hearts and porcine preclinical models of I/R. Findings: Contrary to the maladaptive up-regulation of GRK2 reported at later times after myocardial infarction, successive GRK2 phosphorylation at specific sites during ischemia and early reperfusion elicits GRK2 degradation by the proteasome and calpains, respectively, thus keeping GRK2 levels low during early I/R in rat hearts. Concurrently, I/R promotes decay of the prolyl-isomerase Pin1, a positive regulator of AKT stability, and a marked loss of total AKT protein, resulting in an overall decreased activity of this pro-survival pathway. A similar pattern of concomitant down-modulation of GRK2/AKT/Pin1 protein levels in early I/R was observed in pig hearts. Calpain and proteasome inhibition prevents GRK2/Pin1/AKT degradation, restores bulk AKT pathway activity and attenuates myocardial I/R injury in isolated rat hearts. Interpretation: Preventing transient degradation of GRK2 and AKT during early I/R might improve the potential of endogenous cardioprotection mechanisms and of conditioning strategies. Keywords: GRK2, AKT, Ischemia-reperfusion, Cardioprotection, Pin1, Proteasome, Calpains

A better understanding of the complex crosstalk among key receptors and signaling pathways involved in cancer progression is needed to improve current therapies. We have investigated in cell models representative of the major subtypes of breast cancer (BC) the interplay between the chemokine CXCL12/CXCR4/ACKR3 and EGF receptor (EGFR) family signaling cascades. These cell lines display a high heterogeneity in expression profiles of CXCR4/ACKR3 chemokine receptors, with a predominant intracellular localization and different proportions of cell surface CXCR4+, ACKR3+ or double-positive cell subpopulations, and display an overall modest activation of oncogenic pathways in response to exogenous CXCL12 alone. Interestingly, we find that in MDA-MB-361 (luminal B subtype, Her2-overexpressing), but not in MCF7 (luminal A) or MDA-MB-231 (triple negative) cells, CXCR4/ACKR3 and EGFR receptor families share signaling components and crosstalk mechanisms to concurrently promote ERK1/2 activation, with a key involvement of the G protein-coupled receptor kinase 2 (GRK2) signaling hub and the cytosolic tyrosine kinase Src. Our findings suggest that in certain BC subtypes, a relevant cooperation between CXCR4/ACKR3 and growth factor receptors takes place to integrate concurrent signals emanating from the tumor microenvironment and foster cancer progression.

The use of recruitment maneuvers (RMs) is suggested to improve severe oxygenation failure in patients with acute respiratory distress syndrome (ARDS). Lung ultrasound (LUS) is a non-invasive, safe, and easily repeatable tool. It could be used to monitor the lung recruitment process in real-time. This paper aims to evaluate bedside LUS for assessing PEEP-induced pulmonary reaeration during RMs in pediatric patients. A case of a child with severe ARDS due to Haemophilus influenzae infection is presented. Due to his poor clinical, laboratory, and radiological evolution, he was placed on venovenous extracorporeal membrane oxygenation (ECMO). Despite all measures, severe pulmonary collapse prevented proper improvement. Thus, RMs were indicated, and bedside LUS was successfully used for monitoring and assessing lung recruitment. The initial lung evaluation before the maneuver showed a tissue pattern characterized by a severe loss of lung aeration with dynamic air bronchograms and multiple coalescent B-lines. While raising a PEEP of 30 mmH2O, LUS showed the presence of A-lines, which was considered a predictor of reaeration in response to the recruitment maneuver. The LUS pattern could be used to assess modifications in the lung aeration, evaluate the effectiveness of RMs, and prevent lung overdistension.

Background. Voltage mapping allows identifying the arrhythmogenic substrate during scar-related ventricular arrhythmia (VA) ablation procedures. Slow conducting channels (SCCs), defined by the presence of electrogram (EGM) signals with delayed components (EGM-DC), are responsible for sustaining VAs and constitute potential ablation targets. However, voltage mapping, as it is currently performed, is time-consuming, requiring a manual analysis of all EGMs to detect SCCs, and its accuracy is limited by electric far-field. We sought to evaluate an algorithm that automatically identifies EGM-DC, classifies mapping points, and creates new voltage maps, named “Slow Conducting Channel Maps” (SCC-Maps). Methods. Retrospective analysis of electroanatomic maps (EAM) from 20 patients (10 ischemic, 10 with arrhythmogenic right ventricular dysplasia/cardiomyopathy) was performed. EAM voltage maps were acquired during sinus rhythm and used for ablation. Preprocedural contrast-enhanced cardiac magnetic resonance (Ce-CMR) imaging was available for the ischemic population. Three mapping modalities were analysed: (i) EAM voltage maps using standard (EAM standard) or manual (EAM screening) thresholds for defining core and border zones; (ii) SCC-Maps derived from the use of the novel SCC-Mapping algorithm that automatically identify EGM-DCs measuring the voltage of the local component; and (iii) Ce-CMR maps (when available). The ability of each mapping modality in identifying SCCs and their agreement was evaluated. Results. SCC-Maps and EAM screening identified a greater number of SCC entrances than EAM standard (3.45 ± 1.61 and 2.95 ± 2.31, resp., vs. 1.05 ± 1.10; p

Infection by rhinovirus (RV) and enterovirus (EV) in children ranges from asymptomatic infection to severe lower respiratory tract infection (LRTI). This cohort study evaluates the clinical impact of RV/EV species, alone or in codetection with other viruses, in young children with severe LRTI. Seventy-one patients aged less than 5 years and admitted to the Paediatric Intensive Care Unit (PICU) of a reference children’s hospital with RV or EV (RV/EV) LRTI were prospectively included from 1/2018 to 3/2020. A commercial PCR assay for multiple respiratory pathogens was performed in respiratory specimens. In 22/71, RV/EV + respiratory syncytial virus (RSV) was found, and 18/71 had RV/EV + multiple viral detections. Patients with single RV/EV detection required invasive mechanical ventilation (IMV) as frequently as those with RSV codetection, whereas none of those with multiple viral codetections required IMV. Species were determined in 60 samples, 58 being RV. No EV-A, EV-C, or EV-D68 were detected. RV-B and EV-B were only found in patients with other respiratory virus codetections. There were not any associations between RV/EV species and severity outcomes. To conclude, RV/EV detection alone was observed in young children with severe disease, while multiple viral codetections may result in reduced clinical severity. Differences in pathogenicity between RV and EV species could not be drawn.

Atrial fibrillation (AF) and hypertrophic cardiomyopathy (HCM) are two very common clinical entities, which often occur simultaneously, giving a hard time to both patients and cardiologists. Myocyte hypertrophy, myocyte disarray and interstitial fibrosis in the left atrium (LA) predisposes to atrial arrhythmias due to modifications of the substrate that promote re-entry. AF is usually poorly tolerated due to the shortening of the diastolic time with rapid heart rates and the lack of the atrial contribution to the diastolic filling in patients who often have a previous diastolic dysfunction. AF onset frequently results in exercise intolerance and recurrent heart failure admissions and also has prognostic implications. Early maintenance of sinus rhythm appears as a worthy approach in these patients, especially when started early in the course of the disease. However, treatment with antiarrhythmic (AA) agents in HCM patients is less effective than in patients without the disease, and concerns regarding safety frequently limit the long-term adherence. Catheter ablation has limited efficacy in patients with persistent AF but can play an important role in patients with paroxysmal AF, emphasizing the importance of an accurate patient selection. The aim of this review is to provide an overview of the pathophysiology of combined HCM and AF and the principal pharmacological and non-pharmacological treatments recommended in this complex clinical scenario.

Atrial fibrillation (AF) is the most prevalent form of cardiac arrhythmia. It is often related to diverse pathological conditions affecting the atria and leading to remodeling processes including collagen accumulation, fatty infiltration, and amyloid deposition. All these events generate atrial fibrosis, which contribute to beget AF. In this scenario, cardiac imaging appears as a promising noninvasive tool for monitoring the presence and degree of LA fibrosis and remodeling. The aim of this review is to comprehensively examine the bench mechanisms of atrial fibrosis moving, then to describe the principal imaging techniques that characterize it, such as cardiac magnetic resonance (CMR) and multidetector cardiac computed tomography (MDCT), in order to tailor atrial fibrillation ablation to each individual.

In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators. Interestingly, a correlation between GRK2 expression and Pin1 levels and de-acetylation status is detected in breast cancer patients. Activation of the HDAC6-Pin1 axis underlies the positive effects of GRK2 on promoting growth factor signaling, cellular proliferation and anchorage-independent growth in both luminal and basal breast cancer cells. Enhanced GRK2 levels promote tumor growth in mice, whereas GRK2 down-modulation sensitizes cells to therapeutic drugs and abrogates tumor formation. Our data suggest that GRK2 acts as an important onco-modulator by strengthening the functionality of key players in breast tumorigenesis such as HDAC6 and Pin1.