Aftereffects in Epigenetic Age Related to Cognitive Decline and Inflammatory Markers in Healthcare Personnel with Post-COVID-19: A Cross-Sectional Study.

Purpose: Epigenetic age and inflammatory markers have been proposed as indicators of severity and mortality in patients with COVID-19. Furthermore, they have been associated with the occurrence of neurological symptoms, psychiatric manifestations, and cognitive impairment. Therefore, we aimed to explore the possible associations between epigenetic age, neuropsychiatric manifestations and inflammatory markers (neutrophil-lymphocyte ratio [NLR], platelet-lymphocyte ratio [PLR], monocyte-lymphocyte ratio [MLR], and systemic immune-inflammation index [SII]) in healthcare personnel with post-COVID condition. Patients and Methods: We applied the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) tests to 51 Mexican healthcare workers with post-COVID-19 condition; we also estimated their epigenetic age using the PhenoAge calculator. Results: The participants had a post-COVID condition that lasted a median of 14 months (range: 1-20). High NLR (>1.73) had association with mild cognitive impairment by MMSE (p=0.013). Likewise, high MLR (>0.24) were associated with language domain in MOCA (p=0.046). Low PLR (<103.9) was also related to delayed recall in MOCA (p=0.040). Regarding comorbidities, hypertension was associated with SII (p=0.007), overweight with PLR (p=0.047) and alcoholism was associated with MLR (p=0.043). Interestingly, we observed associations of low PLR (<103.9) and low SII (<1.35) levels with increased duration of post-COVID condition (p=0.027, p=0.031). Likewise, increases in PhenoAge were associated with high levels of SII (OR=1.11, p=0.049), PLR (OR=1.12, p=0.035) and MLR (OR=1.12, p=0.030). Conclusion: We observed neurocognitive changes related to inflammatory markers and increases in epigenetic age in healthcare personnel with post-COVID-19 condition. Future research is required to assess mental and physical health in individuals with post-COVID-19 symptoms.

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Emotional Intelligence in Spanish Elite Athletes: Is There a Differential Factor between Sports?

Emotional intelligence is a determinant factor in sports performance. The present study analysed differences in total emotional intelligence and its four dimensions in 2166 Spanish athletes (25.20 ± 10.17 years) from eight sports (volleyball, track and field, shooting, football, basketball, handball, gymnastics, and judo). A total of 1200 men and 966 women answered anonymously using a Google Forms questionnaire sent via WhatsApp about demographics and psychological variables. A Pearson correlation was conducted to assess the age-emotional intelligence relationship. An independent T-test and One-Way ANOVA were carried out to check for age differences between biological sex and sport and a One-Way ANCOVA to determine differences between sports controlled by age. Age differences were observed by sex and sport (p < 0.001). An association was found between age and emotional intelligence dimensions (p < 0.001), except for other's emotional appraisal (p > 0.05). Judo was the sport with the highest levels of regulation of emotions, other's emotional appraisal, use of emotion, and total emotional intelligence (p < 0.05). Generally, emotional intelligence was found to be more developed in individual sports than in team sports, except football. Consequently, psychological skills like emotional intelligence could be critical to achieving high performance, depending on the sport.

Medidas de bioseguridad contra la COVID-19 durante la atención odontológica, en una región del Perú

Introducción: La atención odontológica, por su propia naturaleza, implica un mayor riesgo de trasmisión del SARS-CoV-2. Por tanto, es esencial que el personal del centro odontológico extreme las medidas de bioseguridad durante y después de la crisis sanitaria. Objetivo: evaluar el cumplimiento de las medidas de bioseguridad contra la COVID-19 durante la atención odontológica, en una región del Perú. Materiales y métodos: Estudio transversal realizado en la región de Ica, en Perú. Participaron 304 odontólogos de la práctica pública y privada. Se recogieron características sociolaborales y de salud. El cumplimiento de medidas de bioseguridad fue evaluado con la Escala de Bioseguridad para COVID-19, diseñada y validada por los investigadores. Se realizó un análisis descriptivo y se evaluaron diferencias con la prueba chi-cuadrado. Resultados: El 72,7 % de los participantes incumplen las medidas de bioseguridad. Se observaron mayores proporciones de incumplimiento entre los odontólogos de 41 a 50 años de edad (76 %), sin segunda especialidad (76,4 %), y en quienes recibieron la primera (100 %) y la segunda dosis (90,4 %) de la vacuna contra la COVID-19. Asimismo, entre los odontólogos que laboran en el sector privado que no tienen segunda especialidad (75,3 %); entre los que recibieron la primera dosis de la vacuna contra la COVID-19 (100 %) y la segunda dosis (92,2 %) respectivamente; en quienes tuvieron dos veces (100 %) y más de dos veces (100 %) COVID-19, y en aquellos que no tuvieron familiar fallecido por el coronavirus. Todas estas diferencias alcanzaron significancia estadística (p < 0,05). Conclusión: Durante la atención odontológica se incumplen las medidas de bioseguridad. Existen ciertos factores como la edad entre 41 y 50 años, no tener segunda especialidad, entre otros, que podrían incrementar la probabilidad de incumplir estas medidas.

Introduction: Dental care, by its proper nature, implies a higher risk of SARS-CoV-2 transmission. It is therefore essential that the dental center staff carry to extremes biosecurity measures during and after the health crisis. Objective: To evaluate compliance with biosecurity measures against COVID-19 during dental care in a region of Peru. Materials and methods: Cross-sectional study carried out in the region of Ica, in Peru. 304 dentists from public and private practice participated. Socio-occupational and health characteristics were collected. Compliance with biosecurity measures was evaluated with the Biosecurity Scale for COVID-19, designed and validated by the researchers. A descriptive analysis was performed and differences were evaluated with the chi-square test. Results: 72.7% of the participants fail to comply with the biosecurity measures. Higher proportions of non-compliance were found among the dentists from 41 to 50 years old (76%), without a second specialization (76.4%), and in those who received the first (100%) and the second (90.4%) doses of the vaccine against COVID-19. Likewise, among dentists who work in the private sector and do not have second specialty (75.3%); among those who received the first dose (100%) and the second dose (92.2%) of the vaccine against COVID-19 respectively; in those who had COVID-19 twice (100%) and more than twice (100%), and in those dentist who did not have relatives deceased by coronavirus. All these differences reached statistical significance (p < 0, 05). Conclusions: Biosafety measures are breached during dental care. There are several factors like age between 41 and 50 years, not having a second specialty among others that could increase the probability of failing to comply with these measures.

Identification of Catechins' Binding Sites in Monomeric Aß42 through Ensemble Docking and MD Simulations.

The assembly of the amyloid-ß peptide (Aß) into toxic oligomers and fibrils is associated with Alzheimer's disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aß monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aß, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline-in the framework of the ensemble docking strategy-to identify catechins' binding sites in monomeric Aß42. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aß42. Additionally, it has been found that all the studied ligands, especially EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of Aß. Our findings are evaluated and confirmed with multi-microsecond MD simulations. Finally, it is suggested that our proposed pipeline, with low computational cost in comparison with MD simulations, is a suitable approach for the virtual screening of ligand libraries against Aß.

Impact of particulate matter on the incidence of atrial fibrillation and the risk of adverse clinical outcomes: A review.

BACKGROUND: Atrial fibrillation (AF) is common and increases the risk of stroke and mortality. Previous studies have suggested that air pollution is an important risk factor for new-onset AF. Herein, we review the evidence regarding: 1) the association between exposure to particulate matter (PM) and new-onset AF, and 2) the risk of worse clinical outcomes in patients with pre-existent AF and their relation to PM exposure. METHODS: A selection of studies between 2000 and 2023 linking PM exposure and AF was performed through searches in PubMed, Scopus, Web of Science, and Google Scholar. RESULTS: 17 studies from different geographical areas demonstrated that exposure to PM was associated with an increased risk of new-onset AF, although the results were heterogeneous regarding the temporal pattern (short- or long-term) ultimately related to AF. Most of the studies concluded that the risk of new-onset AF increased between 2 %-18 % per 10 µg/m3 increment in PM2.5 or PM10 concentrations, whereas the incidence (percentage of change of incidence) increased between 0.29 %-2.95 % per 10 µg/m3 increment in PM2.5 or PM10. Evidence about the association between PM and adverse events in patients with pre-existent AF was scarce but 4 studies showed a higher risk of mortality and stroke (between 8 %-64 % in terms of hazard ratio) in patients with pre-existent AF when PM exposure was higher. CONCLUSIONS: Exposure to PM (both PM2.5 and PM10) is a risk factor for AF, and a risk factor for mortality and stroke in patients who already suffer from AF. Since the relationship between PM and AF is independent of the region of the world, PM should be considered as a global risk factor for both AF and worse clinical outcomes in AF patients. Specific measures to prevent air pollution exposure need to be adopted.

Impact of renal function on Ticagrelor-induced antiplatelet effects in coronary artery disease patients.

Background: Chronic renal failure (CKD) is associated with the presence of increased platelet reactivity and lower clinical benefit of clopidogrel. Ticagrelor has a more favorable pharmacodynamic and pharmacokinetic profile compared to clopidogrel, which has translated into better clinical outcomes in patients with acute coronary syndrome (ACS). We conducted a prospective mechanistic cohort study in order to investigate the impact of renal failure on the pharmacokinetics and pharmacodynamics of ticagrelor in patients with acute ACS. Methods: Patients were divided into two groups based on their estimated renal clearances (eGFR ≥ 60 mL/min and eGFR < 60 mL/min). Platelet function was determined using the VerifyNow system at baseline, after the ticagrelor loading dose and at discharge. In addition, levels of ticagrelor and its active metabolite (AR-C124910XX) were determined in the first hour after loading dose. Results: 48 patients were recruited (eGFR ≥ 60 mL/min: 35 and eGFR < 60 mL/min: 13). There were no significant differences between the groups in terms of platelet inhibition after the loading or after 7 days of treatment (p = 0.219). However, the levels of ticagrelor and its active metabolite were lower in subjects with normal renal function than in CKD, especially at 4 (p = 0.02 and 0.04 respectively) and 6 h of loading (p = 0.042 and 0.08 respectively). Conclusion: No differences in platelet inhibition were observed after treatment with ticagrelor in patients with different renal function, although patients with renal impairment showed higher levels of ticagrelor and AR-C124910XX after 4 h of the loading dose.

Extrarenal rhabdoid tumor of anterior mediastinal location.

BACKGROUND: Rhabdoid tumors are malignant neoplasms of low prevalence, aggressive behavior, and high mortality. They were initially described as renal tumors, although tumors with the same histopathological and immunohistochemical characteristics have been discovered in other locations, mainly in the central nervous system. Few cases of mediastinal location have been reported internationally. This work aimed to describe the case of a mediastinal rhabdoid tumor. CASE REPORT: We describe the case of an 8-month-old male patient admitted to the pediatric department with dysphonia and laryngeal stridor progressing to severe respiratory distress. Contrast-enhanced computed tomography of the thorax showed a large mass with homogeneous soft tissue density, and smooth and well-defined borders, with suspicion of malignant neoplasm. Due to the oncological emergency compressing the airway, empirical chemotherapy was initiated. Subsequently, the patient underwent incomplete tumor resection due to its invasive nature. The pathology report showed morphology compatible with a rhabdoid tumor, which immunohistochemical and genetic studies corroborated. Chemotherapy and radiotherapy to the mediastinum were administered. However, the patient died three months after the initial treatment due to the aggressive behavior of the tumor. CONCLUSIONS: Rhabdoid tumors are aggressive and malignant entities difficult to control and have poor survival. Early diagnosis and aggressive treatment are required, although the 5-year survival does not exceed 40%. It is necessary to analyze and report more similar cases to establish specific treatment guidelines.

INTRODUCCIÓN: Los tumores rabdoides son neoplasias malignas de baja prevalencia, con comportamiento agresivo y alta mortalidad. Inicialmente fueron descritos como renales, aunque posteriormente se han descrito tumores con las mismas características histopatológicas e inmunohistoquímicas en otros sitios, principalmente en el sistema nervioso central. Internacionalmente se han descrito pocos casos de localización mediastinal. El objetivo del presente trabajo fue describir el caso de un tumor rabdoide de localización mediastinal. CASO CLÍNICO: Se presenta el caso de un paciente de sexo masculino de 8 meses de edad que ingresó al servicio de pediatría con disfonía y estridor laríngeo que progresó a dificultad respiratoria severa. En la tomografía computarizada contrastada de tórax se observó una gran masa homogénea con densidad de tejidos blandos, de bordes lisos y bien definidos, por lo que se sospechó una neoplasia maligna. Debido a la urgencia oncológica compresiva de la vía aérea se inició con un esquema empírico de quimioterapia. Posteriormente se sometió a resección tumoral incompleta por carácter invasor. El reporte de patología mostró morfología compatible con un tumor rabdoide, el cual se corroboró con estudios de inmunohistoquímica y genética. Se administró un esquema de quimioterapia y radioterapia al mediastino. Sin embargo, el paciente falleció a los 3 meses del inicio de tratamiento debido al comportamiento agresivo del tumor. CONCLUSIONES: Los tumores rabdoides son entidades agresivas y malignas de difícil control y con pobre supervivencia. A pesar de que se requiere un diagnóstico precoz y un tratamiento agresivo, no se ha logrado la supervivencia a 5 años mayor al 40%. Es necesario analizar una mayor cantidad de casos para establecer guías específicas de tratamiento.

Simplified Geleijnse score for identifying chest pain features associated with coronary ischemia.

BACKGROUND: The Geleijnse score, which was proposed to assess for coronary ischemia, has practical limitations. OBJECTIVES: Our aim was to design and evaluate a simplified version of the Geleijnse score. METHODS: We enrolled patients with suspected coronary heart disease but negative troponin T or absence of enzymatic curve, and a non-diagnostic 12-lead ECG. The initial study was performed in a retrospective derivation cohort and the results were subsequently validated in a prospective cohort. RESULTS: From 109 patients included in the derivation cohort, 33 (30.3%) received a diagnosis of coronary heart disease. Chest pain with both arms radiation (OR 3.54), severe intensity (OR 2.41), improvement by nitroglycerin (OR 1.61), associated dyspnea (OR 1.97) and prior exertional angina history (OR 2.91) were independently associated with an ischemic origin on multivariate logistic regression analysis. ROC curves comparison demonstrated both the original and simplified scores presented modest predictive ability with significant difference when analyzed using dichotomous cut-offs (0.647 [simplified] vs. 0.544 [original], p = 0.042) but not as a continuous variable (0.670 [simplified] vs. 0.621 [original], p = 0.396). In 305 patients from the validation cohort, the simplified score presented extensively increased predictive accuracy than the Geleijnse, in the continuous (c-indexes = 0.735 vs. 0.685, p = 0.040) and the dichotomic (c-indexes = 0.682 vs. 0.514, p<0.001) forms. CONCLUSIONS: A simplified version of the Geleijnse score, including some routine clinical manifestations associated with coronary heart disease, presented significantly better predictive ability compared to the original score.

Extrarenal rhabdoid tumor of anterior mediastinal location / Tumor rabdoide extrarrenal de localización mediastinal anterior

Abstract Background: Rhabdoid tumors are malignant neoplasms of low prevalence, aggressive behavior, and high mortality. They were initially described as renal tumors, although tumors with the same histopathological and immunohistochemical characteristics have been discovered in other locations, mainly in the central nervous system. Few cases of mediastinal location have been reported internationally. This work aimed to describe the case of a mediastinal rhabdoid tumor. Case report: We describe the case of an 8-month-old male patient admitted to the pediatric department with dysphonia and laryngeal stridor progressing to severe respiratory distress. Contrast-enhanced computed tomography of the thorax showed a large mass with homogeneous soft tissue density, and smooth and well-defined borders, with suspicion of malignant neoplasm. Due to the oncological emergency compressing the airway, empirical chemotherapy was initiated. Subsequently, the patient underwent incomplete tumor resection due to its invasive nature. The pathology report showed morphology compatible with a rhabdoid tumor, which immunohistochemical and genetic studies corroborated. Chemotherapy and radiotherapy to the mediastinum were administered. However, the patient died three months after the initial treatment due to the aggressive behavior of the tumor. Conclusions: Rhabdoid tumors are aggressive and malignant entities difficult to control and have poor survival. Early diagnosis and aggressive treatment are required, although the 5-year survival does not exceed 40%. It is necessary to analyze and report more similar cases to establish specific treatment guidelines.

Resumen Introducción: Los tumores rabdoides son neoplasias malignas de baja prevalencia, con comportamiento agresivo y alta mortalidad. Inicialmente fueron descritos como renales, aunque posteriormente se han descrito tumores con las mismas características histopatológicas e inmunohistoquímicas en otros sitios, principalmente en el sistema nervioso central. Internacionalmente se han descrito pocos casos de localización mediastinal. El objetivo del presente trabajo fue describir el caso de un tumor rabdoide de localización mediastinal. Caso clínico: Se presenta el caso de un paciente de sexo masculino de 8 meses de edad que ingresó al servicio de pediatría con disfonía y estridor laríngeo que progresó a dificultad respiratoria severa. En la tomografía computarizada contrastada de tórax se observó una gran masa homogénea con densidad de tejidos blandos, de bordes lisos y bien definidos, por lo que se sospechó una neoplasia maligna. Debido a la urgencia oncológica compresiva de la vía aérea se inició con un esquema empírico de quimioterapia. Posteriormente se sometió a resección tumoral incompleta por carácter invasor. El reporte de patología mostró morfología compatible con un tumor rabdoide, el cual se corroboró con estudios de inmunohistoquímica y genética. Se administró un esquema de quimioterapia y radioterapia al mediastino. Sin embargo, el paciente falleció a los 3 meses del inicio de tratamiento debido al comportamiento agresivo del tumor. Conclusiones: Los tumores rabdoides son entidades agresivas y malignas de difícil control y con pobre supervivencia. A pesar de que se requiere un diagnóstico precoz y un tratamiento agresivo, no se ha logrado la supervivencia a 5 años mayor al 40%. Es necesario analizar una mayor cantidad de casos para establecer guías específicas de tratamiento.

Effectiveness of Nurse-Led Preoperative Assessment for Anesthesia: A Prospective Cohort Study.

PURPOSE: This study aimed to evaluate, in low-complexity surgical patients, the effectiveness of preoperative assessment carried out by nurses with formal postgraduate anesthetic training compared to that carried out by anesthesiologists in terms of cancellations and inadequate surgical preparation. DESIGN: This experimental research was conducted using a prospective cohort study. METHODS: One hundred and eighty-three patients were recruited who had undergone low-complexity surgery between May and September 2020. Sixty-nine patients were preoperatively assessed by a nurse with specific 1-year postgraduate university training in anesthesia and 114 by an anesthesiologist. Data collection included a questionnaire to assess patient satisfaction and knowledge acquired from the preoperative assessment. FINDINGS: Cancellations of surgery were the same in both cohorts (3.8%, 2.6%). The incidence of poor preparation attributable to the patient was also similar in both cohorts (17.0% vs 18.4%). Patients seen by nurses valued the satisfaction with the preoperative assessment more highly than patients seen by anesthesiologists (median 91.67 vs 84.62). In terms of Knowledge obtained from the preoperative assessment, both professionals did not show statistically significant differences in knowledge levels. CONCLUSIONS: Preoperative patient assessment performed by a nurse, with formal anesthesia training, in low-complexity surgical patients can be as effective as that performed by an anesthesiologist, without having an impact on surgical cancellations or patient preparation. On the day of surgery, patients who had been assessed by a nurse were more satisfied with their care during the visit and acquired similar knowledge about preoperative preparation as patients assessed by anesthesiologists.

Impact of Embryo Cryopreservation on Large for Gestational Age Babies Born by Embryo Transfer: Cohort Retrospective Study.

The transfer of frozen-thawed embryos has been associated with an increased risk of large for gestational age at birth. Our objective is to assess its impact on the risk of large for gestational age (LGA) in order to improve the bias control in relation with the available studies. Retrospective cohort study on cumulative sample of 801 single live births of 32 weeks or longer of gestation, resulting from pregnancies obtained by cryopreserved or fresh embryo transfer which are not affected by disorders that could impair fetal growth and carried out at Hospital General Universitario Gregorio Marañón, in Madrid, during the period 2005-2017. The relative risk (RR) of LGA has been estimated with its confidence interval (CI) at 95%. Multivariate analysis using logistic regression was applied to adjust the crude effect. LGA was more frequent in babies born after cryotransfer in comparison with the reference group (20.9% vs. 6.0%; p < 0.001), as well as macrosomia (8.2% vs. 0.9%; p < 0.001). Frequencies of weight > 4500 g were similar (0.7% vs. 0.1%; p > 0.05). Nulliparity was associated to a higher risk of LGA (RR: 3.8; CI95%: 2.0-7.0; p < 0.005), as well as cleaving embryo transfer (RR: 2; CI95%: 1.07-3.8; p < 0.05). According to the multivariate analysis, the exposure variable was the only one independently associated with LGA (OR: 3.5; CI95%: 2.0-6.1; p < 0.001). Frozen-thawed embryo transfer significantly increases the risk of LGA, regardless of the influence of factors relating to the patient's condition, the embryos transferred, or the fetal sex.

Imaging in atrial fibrillation: A way to assess atrial fibrosis and remodeling to assist decision-making.

The 2020 ESC atrial fibrillation (AF) guidelines suggest the novel 4S-AF scheme for the characterization of AF. Imaging techniques could be helpful for this objective in everyday clinical practice, and information derived from these techniques reflects basic aspects of the pathophysiology of AF, which may facilitate treatment decision-making, and optimal management of AF patients. The aim of this review is to provide an overview of the mechanisms associated with atrial fibrosis and to describe imaging techniques that may help the management of AF patients in clinical practice. Transthoracic echocardiography is the most common procedure given its versatility, safety, and simplicity. Transesophageal echocardiography provides higher resolution exploration, and speckle tracking echocardiography can provide incremental functional and prognostic information over conventional echocardiographic parameters. In addition, LA deformation imaging, including LA strain and strain rate, are related to the extent of fibrosis. On the other hand, multidetector-row computed tomography and cardiac magnetic resonance provide higher resolution data and more accurate assessment of the dimensions, structure, and spatial relationships of the LA. Imaging is central when deciding on catheter ablation or cardioversion, and helps in selecting those patients who will really benefit from these procedures. Moreover, imaging enhances the understanding of the underlying mechanisms of atrial remodeling and might assists in refining the risk of stroke, which help to select the best medical therapies/interventions. In summary, evaluation of LA enlargement, LA remodeling and fibrosis with imaging techniques adds clinical and prognostic information and should be assessed as a part of routine comprehensive AF evaluation.

Contact pathway in surgical and transcatheter aortic valve replacement.

Background: Aortic valve replacement is the gold standard treatment for severe symptomatic aortic stenosis, but thrombosis of bioprosthetic valves (PVT) remains a concern. Objective: To analyze the factors involved in the contact pathway during aortic valve replacement and to assess their impact on the development of thromboembolic complications. Methods: The study was conducted in 232 consecutive patients who underwent: transcatheter aortic valve replacement (TAVR, N = 155), and surgical valve replacement (SAVR, N = 77) (MUVITAVI project). Demographic and clinical data, outcomes including a combined end point (CEP) of thrombotic events, and imaging controls were recruited. Samples were collected 24 h before and 48 h after valve replacement. FXII, FXI and (pre)kallikrein were evaluated by Western Blot and specific ELISA with nanobodies. Results: The CEP of thrombotic events was reached by 19 patients: 13 patients presented systemic embolic events and 6 patients subclinical PVT. Valve replacement did not cause FXII activation or generation of kallikrein. There was a significant reduction of FXI levels associated with the procedure, which was statistically more pronounced in SAVR than in TAVR. Cases with reductions of FXI below 80% of basal values had a lower incidence of embolic events during the procedure than patients in whom FXI increased above 150%: 2.7 vs. 16.7%; p: 0.04. Conclusion: TAVR or SAVR did not significantly activate the contact pathway. A significant reduction of FXI, was observed, particularly in SAVR, associated with lower incidence of thrombotic events. These results encourage evaluating the usefulness and safety of FXI-directed antithrombotic treatments in these patients.

Competitividad de los gobiernos subnacionales y su relación con la mortalidad por COVID-19 en Perú / Competitiveness of subnational governments and their relationship with COVID-19 mortality in Peru

Introducción: La pandemia por COVID-19 ha puesto de manifiesto las grandes desigualdades en la población mundial. Objetivo: Describir la correlación entre la competitividad y la mortalidad por COVID-19 en el Perú, teniendo como elemento de estudio a los gobiernos subnacionales. Material y Métodos: Estudio observacional basado en el análisis secundario de las muertes por COVID-19 en el 2020 y el índice de competitividad regional de los gobiernos subnacionales 2019. Se calcularon: tasas bruta y estandarizada, índice de efecto y de desigualdad de la pendiente, diferencia y razón de tasas brutas y estandarizadas, riesgo atribuible poblacional, gradiente social, así como brechas relativas y absolutas de mortalidad por COVID-19. Resultados: En el año 2020, la tasa estandarizada de mortalidad por COVID-19 (TEM-COVID-19) fue 267,61 muertes x 105 habitantes. El 21,53 por ciento de la varianza de la TEM-COVID-19 es explicada por el índice de competitividad regional del año 2019 (p= 0,019); el índice de desigualdad de la pendiente fue 29,68 y, por cada punto en el INCORE 2019, la TEM-COVID-19 aumentó 100,78 puntos (R2a= 0,181). En el quintil 1 de competitividad regional, esta fue 151,83, mientras que en el quintil 5 llegó a 449,15. La brecha de desigualdad absoluta entre ambos quintiles fue 297,32 y alcanzó 2,95 en la brecha de desigualdad relativa. La curva de concentración evidenció la desigualdad socio geográfica de las muertes por COVID-19 en el año 2020. Conclusiones: La mortalidad por COVID-19 se incrementó a medida que aumentaba la competitividad de los gobiernos subnacionales evidenciando la desigualdad socio-geográfica del impacto de la pandemia(AU)

Introduction: The COVID-19 pandemic has revealed high disparities in the world population. Objective: To describe the correlation between competitiveness and mortality from COVID-19 in Peru, with subnational governments as an element of study. Material and Methods: Observational study based on the secondary analysis of deaths from COVID-19 that occurred in 2020 and the regional competitiveness index of subnational governments in 2019. The crude and standardized rates, the effect index, the difference and ratio of crude and standardized rates, the population attributable risk, the inequality gradient, and the relative and absolute gaps in mortality from COVID-19 were calculated. Results: In 2020, the standardized mortality rate for COVID-19 (COVID-19-SMR) was 267,61 deaths per 105 inhabitants. Additionally, 21,53 percent of the variance from the COVID-19-SMR is explained by the regional competitiveness index 2019 (p= 0,019); the slope inequality index was 29,68 and, for each point in the INCORE 2019, the COVID-19-SMR increased 100,78 points (R2a= 0,181). In quintile 1 of regional competitiveness, it was 151,83, while in quintile 5 it reached 449,15. The absolute inequality gap between both quintiles was 297,32 and it reached 2,95 in the relative inequality gap. The concentration curve evidenced the socio-geographic inequality of deaths from COVID-19 in 2020. Conclusions: Mortality increased as subnational governments became more competitive, evidencing the socio-geographical inequality of the impact of the COVID-19 pandemic(AU)

MiR-146a Contributes to Thromboinflammation and Recurrence in Young Patients with Acute Myocardial Infarction.

Studies on older patients have established notable conceptual changes in the etiopathogenesis of acute coronary syndrome (ACS), but little is known about this disease in young patients (<45 years). Of special interest is thromboinflammation, key at onset, evolution and therapy of cardiovascular pathology. Therefore, we explored whether ACS at an early age is a thromboinflammatory disease by analyzing NETs and rs2431697 of miR-146a (a miRNA considered as a brake of TLR/NF-kB pathway), elements previously related to higher rates of recurrence in atrial fibrillation and sepsis. We included 359 ACS patients (<45 years) and classified them for specific analysis into G1 (collected during the hospitalization of the first event), G2 and G3 (retrospectively collected from patients with or without ACS recurrence, respectively). cfDNA and citH3−DNA were quantified, and rs2431697 was genotyped. Analysis in the overall cohort showed a moderate but significant correlation between cfDNA and citH3−DNA and Killip−Kimball score. In addition, patients with citH3−DNA > Q4 more frequently had a history of previous stroke (6.1% vs. 1.6%). In turn, rs2431697 did not confer increased risk for the onset of ACS, but T carriers had significantly higher levels of NET markers. By groups, we found that cfDNA levels were similarly higher in all patients, but citH3−DNA was especially higher in G1, suggesting that in plasma, this marker may be attenuated over time. Finally, patients from G2 with the worst markers (cfDNA and citH3−DNA > Q2 and T allele) had a two-fold increased risk of a new ischemic event at 2-year follow-up. In conclusion, our data confirm that ACS is younger onset with thromboinflammatory disease. In addition, these data consolidate rs2431697 as a silent proinflammatory factor predisposing to NETosis, and to a higher rate of adverse events in different cardiovascular diseases.

HLA-DQB1*05:02, *05:03, and *03:01 alleles as risk factors for myasthenia gravis in a Spanish cohort.

BACKGROUND: Myasthenia gravis (MG) is a very heterogenic chronic autoimmune disease caused by the failure of neuromuscular transmission. The HLA gene complex has conventionally been recognized as its main genetic risk and phenotype modifying factor. Our aim was to investigate the prevalence of HLA class I and II alleles and to identify possible risk factors for sporadic MG in a Spanish cohort. METHODS: We designed a clinical case-control study comparing HLA alleles and haplotype frequencies in a cohort of 234 patients with sporadic autoimmune MG with data from a group of 492 randomly selected healthy subjects. Using a high-resolution next-generation sequencing (NGS)-based HLA genotyping assay, we investigated the contribution of HLA genotypes and haplotypes in the resulting phenotype, especially, the age at onset, sex, onset MGFA class, thymic histopathology, and serological status. RESULTS: We found that the DQB1*05:02 and DQB1*05:03 alleles could be novel risk factors for Spanish MG cases. The HLA alleles A*01:01, B*08:01, DRB1*03:01, DRB1*14:54, and DQB1*02:01 were also risk factors for the disease. DQB1*03:01 acted as a risk factor for EOMG in women with AChR-positive antibodies and thymus hyperplasia. Additionally, several alleles were identified as potential phenotype-modifying factors that could exert a protective effect: HLA-B*35:08, DRB1*13:01, and DQB1*06:03 in MG; HLA-A*24:02 in women and DRB1*07:01 and DQB1*02:02 for early onset. HLA-C*07:01 and haplotype A1-B8-C7-DR3-DQ2 were associated with an early-onset phenotype.

Dosing for Personalized Prophylaxis in Hemophilia A Highly Varies on the Underlying Population Pharmacokinetic Models.

BACKGROUND: Model-informed personalized prophylaxis with factor VIII (FVIII) replacement therapy aimed at higher trough levels is becoming indispensable for patients with severe hemophilia A. This study aimed to identify the most suitable population pharmacokinetic (PK) models for personalized prophylaxis using various FVIII products and 2 clinical assays and to implement the most suitable one in open-access software. METHODS: Twelve published population PK models were systematically compared to predict the time above target (TaT) for a reference dosing occasion. External validation was performed using a 5-point PK data from 39 adult patients with hemophilia A with FVIII measured by chromogenic substrate (CSA) and 1-stage assays (OSAs) using NONMEM under 3 different conditions: a priori (with all FVIII samples blinded), a posteriori (with 1 trough sample), and general model fit (with all FVIII samples including the reference dosing occasion provided). RESULTS: On average, the baseline covariate models overpredicted TaT (a priori; bias -3.8 hours to 49.6 hours). When additionally including 1 previous trough FVIII sample before the reference dosing occasion (a posteriori), only 50% of the models improved in bias (-1.0 hours to 36.5 hours) and imprecision (22.4 hours and 60.7 hours). Using all the time points (general model fit), the models accurately predicted (individual TaT less than ±12 hours compared with the reference) 62%-90% and 33%-74% of the patients using CSA and OSA data, respectively. Across all scenarios, predictions using CSA data were more accurate than those using the OSA data. CONCLUSIONS: One model performed best across the population (bias: -3.8 hours a priori, -1.0 hours a posteriori , and 0.6 hours general model fit ) and acceptably predicted 44% (a priori) to 90% ( general model fit ) of the patients. To allow the community-based evaluation of patient-individual FVIII dosing, this model was implemented in the open-access model-informed precision dosing software "TDMx."

Multiscale Computational Study of the Conformation of the Full-Length Intrinsically Disordered Protein MeCP2.

The malfunction of the methyl-CpG binding protein 2 (MeCP2) is associated with the Rett syndrome, one of the most common causes of cognitive impairment in females. MeCP2 is an intrinsically disordered protein (IDP), making its experimental characterization a challenge. There is currently no structure available for the full-length MeCP2 in any of the databases, and only the structure of its MBD domain has been solved. We used this structure to build a full-length model of MeCP2 by completing the rest of the protein via ab initio modeling. Using a combination of all-atom and coarse-grained simulations, we characterized its structure and dynamics as well as the conformational space sampled by the ID and transcriptional repression domain (TRD) domains in the absence of the rest of the protein. The present work is the first computational study of the full-length protein. Two main conformations were sampled in the coarse-grained simulations: a globular structure similar to the one observed in the all-atom force field and a two-globule conformation. Our all-atom model is in good agreement with the available experimental data, predicting amino acid W104 to be buried, amino acids R111 and R133 to be solvent-accessible, and having a 4.1% α-helix content, compared to the 4% found experimentally. Finally, we compared the model predicted by AlphaFold to our Modeller model. The model was not stable in water and underwent further folding. Together, these simulations provide a detailed (if perhaps incomplete) conformational ensemble of the full-length MeCP2, which is compatible with experimental data and can be the basis of further studies, e.g., on mutants of the protein or its interactions with its biological partners.

Clinical implications of diabetes mellitus in patients with acute coronary syndrome: Prognostic role and use of new P2Y12 receptor inhibitors.

AIMS: We investigated the impact of diabetes mellitus (DM) in acute coronary syndrome (ACS) patients, and the 2-year prognosis based on antiplatelet therapy. METHODS: This is a prospective and multicenter registry including hospitalized ACS patients. Clinical management and antiplatelet therapy at discharge were recorded. Bleeding events, all-cause mortality and major adverse cardiovascular events (MACEs) were recorded during 2-years and compared according to DM and the P2Y12 receptor inhibitor. RESULTS: From 1717 ACS patients, 653 (38%) had DM. Diabetic patients were older, more commonly females, with higher prevalence of comorbidities and more conservative management. After excluding antiplatelet monotherapy or oral anticoagulation, clopidogrel was prescribed in 59.6% of DM patients. Cox regression analysis showed that DM was an independent risk factor for MACE (aHR 1.39, 95% CI 1.05-1.83). The use of clopidogrel instead of ticagrelor/prasugrel was also independently associated with MACE (aHR 1.71, 95% CI 1.11-2.63), and all-cause mortality (aHR 2.47, 95% CI 1.23-4.96) in diabetic patients (log-rank p-values < 0.001). CONCLUSIONS: In ACS patients, DM was associated with higher risk of MACE. In such patients, the use of ticagrelor/prasugrel reduced MACE and mortality compared to clopidogrel. Novel P2Y12 receptor inhibitors might be used as the first therapeutic choice in these high-risk patients.