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.

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.

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.

Novel insights in the relationship of gut microbiota and coronary artery diseases.

Atherosclerosis is a chronic, progressive, inflammatory disease in the vasculature and is common in both coronary and peripheral arteries. Human beings harbor a complex and dynamic population of microorganisms defined as the microbiota. Importantly, alterations in the bacterial composition (dysbiosis) and the metabolic compounds produced by these bacteria have been associated with the pathogenesis of many inflammatory diseases and infections. There is also a close relationship between intestinal microbiota and cardiovascular diseases. The aim of this review was to analyze how changes in the gut microbiota and their metabolites might affect coronary artery diseases. The most representative groups of bacteria that make up the intestinal microbiota are altered in coronary artery disease patients, resulting in a decrease in Bacteroidetes and an increase in Firmicutes. In relation to metabolites, trimethylamine-N-oxide plays an important role in atherosclerosis and may act as a cardiovascular risk predictor. In addition, the use of probiotics, prebiotics, diet modulation, and fecal transplantation, which may represent alternative treatments for these diseases, is thoroughly discussed. Finally, the role of lipid-lowering treatments is also analyzed as they may affect and alter the gut microbiota and, conversely, gut microbiota diversity could be associated with resistance or sensitivity to these treatments.

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."

Highly Similar Sequence and Structure Yet Different Biophysical Behavior: A Computational Study of Two Triosephosphate Isomerases.

Homodimeric triosephosphate isomerases (TIMs) from Trypanosoma cruzi (TcTIM) and Trypanosoma brucei (TbTIM) have markedly similar amino-acid sequences and three-dimensional structures. However, several of their biophysical parameters, such as their susceptibility to sulfhydryl agents and their reactivation speed after being denatured, have significant differences. The causes of these differences were explored with microsecond-scale molecular dynamics (MD) simulations of three different TIM proteins: TcTIM, TbTIM, and a chimeric protein, Mut1. We examined their electrostatic interactions and explored the impact of simulation length on them. The same salt bridge between catalytic residues Lys 14 and Glu 98 was observed in all three proteins, but key differences were found in other interactions that the catalytic amino acids form. In particular, a cation-π interaction between catalytic amino acids Lys 14 and His 96 and both a salt bridge and a hydrogen bond between catalytic Glu 168 and residue Arg 100 were only observed in TcTIM. Furthermore, although TcTIM forms less hydrogen bonds than TbTIM and Mut1, its hydrogen bond network spans almost the entire protein, connecting the residues in both monomers. This work provides new insight into the mechanisms that give rise to the different behavior of these proteins. The results also show the importance of long simulations.

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.

A Decreased Response to Resistin in Mononuclear Leukocytes Contributes to Oxidative Stress in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. AIMS: To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. METHODS: We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. RESULTS: Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. CONCLUSIONS: Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

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.

Antithrombotic Therapy in Patients with Peripheral Artery Disease: A Focused Review on Oral Anticoagulation.

Peripheral artery disease (PAD) is a major cause of morbidity and mortality but it is usually underdiagnosed and undertreated. Patients with PAD present dysregulated procoagulant, anticoagulant, and fibrinolytic pathways leading to arterial and venous thrombosis. The risk of several ischemic-related complications could be mitigated with appropriate antithrombotic therapy, which plays a central role in all types of PAD. For years, antiplatelets have been indicated in patients with symptomatic PAD or those who have undergone revascularization. Unfortunately, a non-negligible proportion of patients with PAD will suffer from adverse events during the follow-up, even despite proper medical therapies for the prevention of PAD complications. Thus, there is room for improving clinical outcomes in these patients. Given the implication of both, primary and secondary hemostasis in arterial thrombosis and the pathophysiology of PAD, the combination of antiplatelets and anticoagulants has emerged as a potential antithrombotic alternative to antiplatelets alone. In this narrative review article, we have highlighted the most recent evidence about antithrombotic therapy in PAD patients, with a special focus on oral anticoagulation. Certainly, COMPASS and VOYAGER PAD trials have shown promising results. Thus, rivaroxaban in combination with aspirin seem to reduce cardiovascular outcomes with a similar bleeding risk compared to aspirin alone. Nevertheless, results from real-world studies are needed to confirm these observations, and other trials will provide novel evidence about the safety and efficacy of emerging anticoagulant agents.

A nurse-led atrial fibrillation clinic: Impact on anticoagulation therapy and clinical outcomes.

BACKGROUND: Nurses play a central role in the management of atrial fibrillation (AF) patients. An unresolved question is whether a nurse-led clinic would improve clinical outcomes. Herein, we investigated the impact of a nurse-led clinic on anticoagulation therapy and clinical outcomes in a cohort of naïve AF patients. METHODS: Prospective study including AF patients starting vitamin K antagonists (VKAs) into a nurse-led AF clinic. These patients were followed in this specific AF clinic. Additionally, AF patients already taking VKAs for 6 months followed according to the routine clinical practice were included as comparison group. The quality of anticoagulation was assessed at 6 months. Efficacy and safety endpoints were recorded during follow-up. RESULTS: We included 223 patients (Nurse-led clinic: 107; Usual care: 116). The mean time in therapeutic range and the proportion of INRs within the therapeutic range were similar in both groups. During 2.06 (IQR 1.01-2.94) years of follow-up, 64 (28.7%) patients changed to direct-acting oral anticoagulants. The proportion of switchers was higher in the nurse-led clinic (37.4%) than in the usual care group (20.7%) (P = .006) and these patients spent less time to switch (2.0 [IQR 0.7-2.9] vs 6.0 [IQR 3.7-11.2] years; P < .001). Importantly, the annual rate of ischaemic stroke/TIA was significantly lower in the nurse-led clinic (0.47%/year vs 3.88%/year, P = .016), without differences in safety endpoints. CONCLUSION: A nurse-led AF clinic may offer a "patient-centered" review and holistic follow-up, and it would be associated with a reduction of ischaemic stroke/TIA, without increasing bleeding complications. Further studies should confirm these results.

Higher socioeconomic status is related to healthier levels of fatness and fitness already at 3 to 5 years of age: The PREFIT project.

This study aimed to analyse the association between socioeconomic status (SES) and fatness and fitness in preschoolers. 2,638 preschoolers (3-5 years old; 47.2% girls) participated. SES was estimated from the parental educational and occupational levels, and the marital status. Fatness was assessed by body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR). Physical fitness components were assessed using the PREFIT battery. Preschoolers whose parents had higher educational levels had lower fatness (P < 0.05). BMI significantly differed across occupational levels of each parent (P < 0.05) and WHtR across paternal levels (P = 0.004). Musculoskeletal fitness was different across any SES factor (P < 0.05), except handgrip across paternal occupational levels (P ≥ 0.05). Preschoolers with high paternal occupation had higher speed/agility (P = 0.005), and those with high or low maternal education had higher VO2max (P = 0.046). Odds of being obese and having low musculoskeletal fitness was lower as SES was higher (P < 0.05). Those with married parents had higher cardiorespiratory fitness than single-parent ones (P = 0.010). School-based interventions should be aware of that children with low SES are at a higher risk of obesity and low fitness already in the first years of life.

Weissella paramesenteroides encapsulation and its application in the use of fish waste.

The goal of the present study was to evaluate the encapsulation of Weissella paramesenteroides, isolated from bee bread, as a technological tool for its use in biological fish silage. The pH decrease in fish silages using the bacteria encapsulated and in a non-encapsulated form was compared. W. paramesenteroides showed a good performance in the development of biological fish silage. The alginate encapsulation method showed an encapsulation efficacy of 85% and provides a reliable technological application.

Association between Breast Feeding and Paediatric Sleep Disordered Breathing: a Systematic Review.

BACKGROUND: Breast feeding has been suggested as a potential protective factor against childhood snoring and sleep disordered breathing (SDB). SDB can have major health consequences. The objective of this systematic review is to synthesise the available literature concerning any potential association between infant feeding methods and SDB in young children. METHODS: Five electronic databases were searched. All searches were inclusive until August 5, 2016. Two authors independently reviewed potentially relevant articles for eligibility. Any prospective or retrospective study, case-control study, cohort study, clinical trial, and cross-sectional study that evaluated the association between infant feeding methods and SDB were included. Data on study design, aim of study, sample size, study population, assessment tool, infant feeding methods, and outcome measures were extracted. RESULTS: Nine studies fulfilled the criteria to be finally included in this review, only cohorts and cross-sectional studies were identified. While seven of the selected studies reported a statistically significant association between breast feeding and reduced risk of SDB, the remaining two studies did not report any association. The main methodological limitation was high heterogeneity in the diagnostic criteria and assessment tools to identify SDB and limited data collection on infant feeding methods. CONCLUSIONS: The current evidence may point to a protective association, however, as uncertainty is moderate, any suggestion that breast feeding may or may not decrease the risk of SDB is currently unwarranted. More research on the topic is required to resolve some of the contradictions between included studies.

Prenatal Diagnosis of an Aortopulmonary Window With an Interrupted Aortic Arch.

A prenatal aortopulmonary window with an interrupted aortic arch was detected in a 22-week-old fetus. The 3-vessel and trachea view showed a communication between the ascending aorta and the pulmonary artery. Early postnatal surgery was successful. A PubMed-based search identified all cases of prenatal aortopulmonary windows between 2002 and 2015. Nine articles were identified. The average gestational age at diagnosis was 28 weeks (range, 22-33 weeks). The most frequent aortopulmonary window was type I (40%). All cases were associated with congenital heart defects, mainly an interrupted aortic arch (50%). No chromosomal or extracardiac abnormalities were seen. Prenatal echocardiography is useful for early diagnosis of an aortopulmonary window. The prognosis depends on the time of surgery and the nature of the associated anomalies.

Roothaan's approach to solve the Hartree-Fock equations for atoms confined by soft walls: Basis set with correct asymptotic behavior.

In this report, we use a new basis set for Hartree-Fock calculations related to many-electron atoms confined by soft walls. One- and two-electron integrals were programmed in a code based in parallel programming techniques. The results obtained with this proposal for hydrogen and helium atoms were contrasted with other proposals to study just one and two electron confined atoms, where we have reproduced or improved the results previously reported. Usually, an atom enclosed by hard walls has been used as a model to study confinement effects on orbital energies, the main conclusion reached by this model is that orbital energies always go up when the confinement radius is reduced. However, such an observation is not necessarily valid for atoms confined by penetrable walls. The main reason behind this result is that for atoms with large polarizability, like beryllium or potassium, external orbitals are delocalized when the confinement is imposed and consequently, the internal orbitals behave as if they were in an ionized atom. Naturally, the shell structure of these atoms is modified drastically when they are confined. The delocalization was an argument proposed for atoms confined by hard walls, but it was never verified. In this work, the confinement imposed by soft walls allows to analyze the delocalization concept in many-electron atoms.

Evaluation of adequacy of protein and energy.

Growth assessment is the most common measure of nutritional adequacy in pediatrics, especially when evaluating nutrition of preterm neonates. The American Academy of Pediatrics defines postnatal nutrient intake to promote growth as one that "approximates the rate of growth...for a normal fetus of the same post-menstrual age." It is known that in the fetus, fat and lean body mass are accreted progressively as gestation progresses, whereas postnatal growth and observed accretion of fat and lean body mass differ. This review discusses anthropometric measures used to assess growth, biochemical markers used to monitor nutritional sufficiency, and the effect of growth trajectory in preterm infants on health outcomes later in life.

Genome-wide in silico identification of GPI proteins in Mycosphaerella fijiensis and transcriptional analysis of two GPI-anchored ß-1,3-glucanosyltransferases.

The hemibiotrophic fungus Mycosphaerella fijiensis is the causal agent of black Sigatoka (BS), the most devastating foliar disease in banana (Musa spp.) worldwide. Little is known about genes that are important during M. fijiensis-Musa sp. interaction. The fungal cell wall is an attractive area of study because it is essential for maintenance of cellular homeostasis and it is the most external structure in the fungal cell and therefore mediates the interaction of the pathogen with the host. In this manuscript we describe the in silico identification of glycosyl phosphatidylinositol-protein (GPI) family in M. fijiensis, and the analysis of two ß-1,3-glucanosyltrans-ferases (Gas), selected by homology with fungal pathogenicity factors. Potential roles in pathogenesis were evaluated through analyzing expression during different stages of black Sigatoka disease, comparing expression data with BS symptoms and fungal biomass inside leaves. Real-time quantitative RT-PCR showed nearly constant expression of MfGAS1 with slightly increases (about threefold) in conidia and at speck-necrotrophic stage during banana-pathogen interaction. Conversely, MfGAS2 expression was increased during biotrophy (about seven times) and reached a maximum at speck (about 23 times) followed by a progressive decrease in next stages, suggesting an active role in M. fijiensis pathogenesis.