Mitral Annular Disease at Cardiac MRI: What to Know and Look For.

Accurate evaluation of the mitral valve (MV) apparatus is essential for understanding the mechanisms of MV disease across various clinical scenarios. The mitral annulus (MA) is a complex and crucial structure that supports MV function; however, conventional imaging techniques have limitations in fully capturing the entirety of the MA. Moreover, recognizing annular changes might aid in identifying patients who may benefit from advanced cardiac imaging and interventions. Multimodality cardiovascular imaging plays a major role in the diagnosis, prognosis, and management of MV disease. Transthoracic echocardiography is the first-line modality for evaluation of the MA, but it has limitations. Cardiac MRI (CMR) has emerged as a robust imaging modality for assessing annular changes, with distinct advantages over other imaging techniques, including accurate flow and volumetric quantification and assessment of variations in the measurements and shape of the MA during the cardiac cycle. Mitral annular disjunction (MAD) is defined as atrial displacement of the hinge point of the MV annulus away from the ventricular myocardium, a condition that is now more frequently diagnosed and studied owing to recent technical advances in cardiac imaging. However, several unresolved issues regarding MAD, such as the functional significance of pathologic disjunction and how this disjunction advances in the clinical course, require further investigation. The authors review the role of CMR in the assessment of MA disease, with a focus on MAD and its functional implications in MV prolapse and mitral regurgitation. ©RSNA, 2024 Supplemental material is available for this article. See the invited commentary by Stojanovska and Fujikura in this issue.

Biochemical parameters, oxidative stress biomarkers, and anatomopathological changes in Wistar rats treated with 3'-demethoxy-6-O-demethylisoguaiacin and norisoguaiacin.

Artemisia cina (Ac) is a plant with anthelmintic compounds such as 3'-demethoxy-6-O-demethylisoguaiacin (D) and norisoguaiacin (N). Three major objectives were proposed: (1) To evaluate biochemical parameters in blood (2) to determine the tissue oxidative stress by biomarkers as TBARS and glutathione peroxidase activity, and (3) to evaluate anatomopathological changes in organs such as the brain, liver, kidney, and lung after oral administration of n-hexane extract of Ac and D and N. D and N were administrated following the OECD guides for acute oral toxicity evaluation (Guide 420). Fifty Wistar rats were distributed into ten groups as follows: Group 1 (G1): 4 mg/Kg; G2: 40 mg/Kg; G3: 240 mg/Kg; G4: 1600 mg/Kg of n-hexane extract of Ac. G5: 2 mg/Kg; G6: 20 mg/Kg; G7: 120 mg/Kg; G8: 800 mg/Kg of D and N, G9: water and G10: polyvinylpyrrolidone at 2000 mg/Kg. At 14 days, the rats were euthanized, and the blood, liver, brain, kidney, and lung were taken for biochemical analysis, anatomopathological changes, and TBARS and GSH evaluation. Glucose, cholesterol, and phosphorus were altered. Histopathological analysis showed multifocal neuronal degeneration in the brain (G2). The kidney and lungs had changes in G7. The GSH and TBARS increased in G6 and G7. The TBARS activity was higher in G1 and G2. In conclusion, extract and D and N of Ac did not have damage at therapeutic doses. D, N, and n-hexane extract of A. cina do not cause histopathological damage at pharmaceutical doses. Still, the brain, kidney, and liver are related to biochemical parameters at higher doses. However, compounds are proposed as antioxidant agents.

Safety and possible anti-inflammatory effect of paclitaxel associated with LDL-like nanoparticles (LDE) in patients with chronic coronary artery disease: a double-blind, placebo-controlled pilot study.

Introduction: Studies in cholesterol-fed rabbits showed that anti-proliferative chemotherapeutic agents such as paclitaxel associated with solid lipid nanoparticles (LDE) have marked anti-atherosclerotic effects. In addition, association with LDE nearly abolishes paclitaxel toxicity. We investigated whether treatment with LDE-paclitaxel changes plaque progression by coronary CT angiography and is safe in patients with chronic coronary artery disease. Methods: We conducted a prospective, randomized, double-blind, placebo-controlled pilot study in patients with multi-vessel chronic coronary artery disease. Patients were randomized to receive IV infusions of LDE-paclitaxel (paclitaxel dose: 175 mg/m2 body surface) or LDE alone (placebo group), administered every 3 weeks for 18 weeks. All participants received guideline-directed medical therapy. Clinical and laboratory safety evaluations were made at baseline and every 3 weeks until the end of the study. Analysis of inflammatory biomarkers and coronary CTA was also performed at baseline and 4 weeks after treatment. Results: Forty patients aged 65.6 ± 8 years, 20 in LDE-paclitaxel and 20 in placebo group were enrolled. Among those, 58% had diabetes, 50% had myocardial infarction, and 91% were in use of statin and aspirin. Baseline demographics, risk factors, and laboratory results were not different between groups. In all patients, no clinical or laboratory toxicities were observed. From the baseline to the end of follow-up, there was a non-significant trend toward a decrease in IL-6 levels and hsCRP in the LDE-paclitaxel group (-16% and -28%, respectively), not observed in placebo. Regarding plaque progression analysis, variation in plaque parameter values was wide, and no difference between groups was observed. Conclusion: In patients with multivessel chronic coronary artery disease and optimized medical therapy, LDE-paclitaxel was safe and showed clues of potential benefits in reducing inflammatory biomarkers. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT04148833, identifier (NCT04148833).

Advanced Breast Cancer Guidelines in Latin America: Assessment, Adaptation, and Implementation of Fifth Advanced Breast Cancer Consensus Guidelines.

PURPOSE: As the fifth international consensus on advanced breast cancer (ABC5) established guidelines for the management of this disease, the aim of this article was to present the applicability of the consensus recommendations and to generate knowledge to improve access. METHODS: Sixty-one recommendation statements were selected and discussed by 15 breast cancer experts from Latin America (LA). After the discussion, the level of consensus was determined through a vote. In addition to this, the level of access to each of the recommendations presented, according to the country and health system, was exposed. RESULTS: Latin American experts had a high level of agreement with the ABC5 consensus recommendations (range, 83%-100%). Twelve of 61 statements are not available for all patients in LA. Among the limitations to access, the following ones are described: limited access to certain technologies (stereotactic body radiotherapy, positron emission tomography-computed tomography), the high costs of drugs that limits access to treatment with CDK4/6 inhibitors, pertuzumab, or poly(ADP-ribose) polymerase inhibitors, and the lack of molecular tests for access to therapeutic targets, as well as the difficult geography and cultural diversity of our continent. CONCLUSION: Despite the great relevance of the recommendations of the ABC5 consensus guidelines, we highlight that we still need to improve access for all patients, regardless of the country or health system they are in, for which we call to action to policy makers and patient groups to improve clinical outcomes of patients with advanced breast cancer in our region.

The Helicobacter pylori Genome Project: insights into H. pylori population structure from analysis of a worldwide collection of complete genomes.

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics.

Study of the Early Effects of Chitosan Nanoparticles with Glutathione in Rats with Osteoarthrosis.

Due to cartilage's limited capacity for regeneration, numerous studies have been conducted to find new drugs that modify osteoarthrosis's progression. Some evidence showed the capability of chitosan nanoparticles with glutathione (Np-GSH) to regulate the oxide-redox status in vitro in human chondrocytes. This work aimed to evaluate the capacity of Np-GSH in vivo, using Wistar rats with induced surgical osteoarthritis. Radiographic, biochemical (GSH and TBARS quantification), histopathological, and immunohistochemical (Col-2 and MMP-13) analyses were performed to evaluate the progress of the osteoarthritic lesions after the administration of a single dose of Np-GSH. According to the results obtained, the GSH contained in the NPs could be vectored to chondrocytes and used by the cell to modulate the oxidative state reduction, decreasing the production of ROS and free radicals induced by agents oxidizing xenobiotics, increasing GSH levels, as well as the activity of GPx, and decreasing lipid peroxidation. These results are significant since the synthesis of GSH develops exclusively in the cell cytoplasm, and its quantity under an oxidation-reduction imbalance may be defective. Therefore, the results allow us to consider these nanostructures as a helpful study tool to reduce the damage associated with oxidative stress in various diseases such as osteoarthritis.

Global Antimicrobial Resistance Gene Study of Helicobacter pylori: Comparison of Detection Tools, ARG and Efflux Pump Gene Analysis, Worldwide Epidemiological Distribution, and Information Related to the Antimicrobial-Resistant Phenotype.

We conducted a global-scale study to identify H. pylori antimicrobial-resistant genes (ARG), address their global distribution, and understand their effect on the antimicrobial resistance (AMR) phenotypes of the clinical isolates. We identified ARG using several well-known tools against extensive bacterial ARG databases, then analyzed their correlation with clinical antibiogram data from dozens of patients across countries. This revealed that combining multiple tools and databases, followed by manual selection of ARG from the annotation results, produces more conclusive results than using a single tool or database alone. After curation, the results showed that H. pylori has 42 ARG against 11 different antibiotic classes (16 genes related to single antibiotic class resistance and 26 genes related to multidrug resistance). Further analysis revealed that H. pylori naturally harbors ARG in the core genome, called the 'Set of ARG commonly found in the Core Genome of H. pylori (ARG-CORE)', while ARG-ACC-the ARG in the accessory genome-are exclusive to particular strains. In addition, we detected 29 genes of potential efflux pump-related AMR that were mostly categorized as ARG-CORE. The ARG distribution appears to be almost similar either by geographical or H. pylori populations perspective; however, some ARG had a unique distribution since they tend to be found only in a particular region or population. Finally, we demonstrated that the presence of ARG may not directly correlate with the sensitive/resistance phenotype of clinical patient isolates but may influence the minimum inhibitory concentration phenotype.

Benchmarking in a beef cattle breeding program: Lessons from the best breeders.

Beef cattle breeding programs offer genetic evaluations and consulting services on animal breeding practices to help breeders improve the genetic merit of their herds. Some breeders are more willing to apply best practices and technologies than others. Consequently, the average genetic merit and genetic trends differ across herds. We benchmarked some parameters of an average herd (AVE) and the corresponding parameters of herds with higher genetic merit (TOP), both participating in a commercial Nellore breeding program. Expected progeny differences (EPD) for growth, reproductive and carcass traits and a selection index (SI) of animals born from 2005 to 2019 on 128 farms located in Brazil, Bolivia and Paraguay were used to compute the AVE parameters. The 20 herds with higher mean SI of animals born in the last five birth seasons were classified as TOP herds. The mean SI and EPD of animals born in the last five seasons in the TOP herds were, respectively, 89% and 79% to 206% higher (p ≤ 0.001) than those of animals from the AVE herd. Genetic trends over the entire period were also higher (50% for SI and 31% to 88% separately for each trait, p ≤ 0.006) in the TOP herds compared to the AVE herd. Although the difference in the numbers of cows, bulls and calves between the TOP and AVE herds did not reach statistical significance (p = 0.175, p = 0.273 and p = 0.061, respectively), the numbers of progeny per cow and per bull were 21% (p = 0.012) and 26% (p = 0.047) higher in the TOP herds, respectively. Multiple ovulation and embryo transfer and in vitro fertilization and embryo transfer (MOET/IVF) accounted for a higher percentage of births in the TOP herds compared to AVE (24.6% vs. 12.5%, p = 0.002). The generation interval was 17% shorter (p < 0.001) in the TOP herds compared to AVE. The average inbreeding coefficient of animals from the TOP herds (1.08 ± 0.52%) did not differ (p = 0.78) from that of AVE animals (1.26 ± 0.96%). In general, AVE herds are evolving in the desirable direction but differences in genetic merit between AVE and TOP herds are increasing over time. The more frequent use of MOET/IVF, a lower cow-to-bull ratio, and a larger family size (progeny per cow or per bull) can help achieve larger selection differentials and increase genetic trends and average genetic merits of TOP herds compared to AVE herds.

Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine.

PURPOSE: Predictive biomarkers for capecitabine benefit in triple-negative breast cancer (TNBC) have been recently proposed using samples from phase III clinical trials, including non-basal phenotype and biomarkers related to angiogenesis, stroma, and capecitabine activation genes. We aimed to validate these findings on the larger phase III GEICAM/CIBOMA clinical trial. EXPERIMENTAL DESIGN: Tumor tissues from patients with TNBC randomized to standard (neo)adjuvant chemotherapy followed by capecitabine versus observation were analyzed using a 164-gene NanoString custom nCounter codeset measuring mRNA expression. A prespecified statistical plan sought to verify the predictive capacity of PAM50 non-basal molecular subtype and tested the hypotheses that breast tumors with increased expression of (meta)genes for cytotoxic cells, mast cells, endothelial cells, PDL2, and 38 individual genes benefit from adjuvant capecitabine for distant recurrence-free survival (DRFS; primary endpoint) and overall survival. RESULTS: Of the 876 women enrolled in the GEICAM/CIBOMA trial, 658 (75%) were evaluable for analysis (337 with capecitabine and 321 without). Of these cases, 553 (84%) were profiled as PAM50 basal-like whereas 105 (16%) were PAM50 non-basal. Non-basal subtype was the most significant predictor for capecitabine benefit [HRcapecitabine, 0.19; 95% confidence interval (CI), 0.07-0.54; P < 0.001] when compared with PAM50 basal-like (HRcapecitabine, 0.9; 95% CI, 0.63-1.28; P = 0.55; Pinteraction<0.001, adjusted P value = 0.01). Analysis of biological processes related to PAM50 non-basal subtype revealed its enrichment for mast cells, extracellular matrix, angiogenesis, and features of mesenchymal stem-like TNBC subtype. CONCLUSIONS: In this prespecified correlative analysis of the GEICAM/CIBOMA trial, PAM50 non-basal status identified patients with early-stage TNBC most likely to benefit from capecitabine.

Sinus Node Artery Occlusion During Cardiac Denervation Procedures.

Cardioneural ablation is a novel treatment for functional bradycardia. However, the risk of acute complications is still unknown. The aim of this case report is to describe acute occlusion of the sinus node artery after cardiac denervation procedures in 2 patients and to encourage measures to prevent it, such as evaluating the aortic angulation in older patients before the procedure and by monitoring signs of sinus failure during ablation in patients with electroanatomical maps showing a constricted aspect of the right atrium. (Level of Difficulty: Advanced.).

Factores de riesgo asociados con el bajo peso al nacer en un policlínico de Santiago de Cuba / Risk factors associated with low birth weight in a polyclinic of Santiago de Cuba

Introducción: El bajo peso al nacer se considera un indicador de morbilidad y mortalidad perinatales. Objetivo: Identificar los factores de riesgo asociados con el bajo peso al nacer en el área de salud del Policlínico Docente Ramón López Peña, de Santiago de Cuba. Métodos: Se realizó un estudio analítico observacional de tipo caso-control, que incluyó a 20 neonatos con bajo peso al nacer (casos), y otro grupo integrado por 80 bebés, los cuales no presentaron dicha condición (controles), pertenecientes al área de salud señalada, desde enero hasta diciembre del 2021. Se determinó la razón de productos cruzados, el intervalo de confianza, la prueba de Ji al cuadrado y el riesgo atribuible en expuesto porcentual. Resultados: El parto pretérmino, el embarazo múltiple y el bajo peso materno presentaron una razón de productos cruzados de 13,7; 7 y 3,2, respectivamente. De igual manera, esta resultó elevada en las enfermedades relacionadas con la gestación, tales como anemia, hipertensión arterial e infecciones vaginal y urinaria. Conclusiones: El peso deficiente a la captación, el parto pretérmino, el embarazo múltiple y la presencia de enfermedades relacionadas con la gestación fueron los factores de riesgo asociados con el bajo peso al nacer.

Introduction: The low birth weight is considered an indicator of perinatal morbidity and mortality. Objective: To identify the risk factors associated with low birth weight in a health area of Ramón Lopez Peña Teaching Polyclinic, in Santiago de Cuba. Methods: An observational analytic case-control study was carried out, that included 20 newborns with low birth weight (cases), and another group integrated by 80 infants, who didn't present this condition (controls), belonging to the health area abovementioned, from January to December, 2021. The ratio of crossed products, the confidence interval, chi-square test and the attributable risk in exposed percentage were determined. Results: The preterm birth, multiple pregnancy and low maternal weight presented a ratio of crossed products of 13.7; 7 and 3.2, respectively. In a same way, it was elevated in the diseases related to pregnancy, such as anemia, hypertension and vaginal and urinary infections. Conclusions: The inadequate weight at the first prenatal visit, preterm childbirth, multiple pregnancy and the presence of diseases related to pregnancy were the risk factors associated with low birth weight.

Excessive Consumption Hibiscus sabdariffa L. Increases Inflammation and Blood Pressure in Male Wistar Rats via High Antioxidant Capacity: The Preliminary Findings.

Hibiscus sabdariffa L. (HSL) has high amounts of antioxidants and many beneficial effects in several pathologies. However, few studies describe the possible harmful effects of high concentrations of HSL. Here we evaluate the effect of excessive and chronic consumption of infusions with different percentages of HSL on some oxidative stress markers in serum, and the possible association with inflammation and increased systolic blood pressure (SBP), in healthy rats. A total of 32 male Wistar rats were used to form 4 groups with 8 animals each. Group 1 control (drinking tap water), group 2, 3 and 4, drinking water supplemented with 15, 30 and 60 g/L of HSL calyxes respectively. SBP was evaluated and determinations in serum of the NO3-/NO2- ratio, glutathione (GSH), total antioxidant capacity (TAC), selenium (Se), TNF-α, IL-1α/IL-1F1, IL-1ß, IL-10, extracellular superoxide dismutase (EcSOD), thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) activities, were evaluated. The SBP (p = 0.01), GPx activity, GSH, TAC, Se, TNF-α and EcSOD activities (p ≤ 0.001) and IL-1α/IL-1F1, IL-1ß, TrxR and NO3-/NO2- (p ≤ 0.05), were increased but IL-10 (p < 0.001) was decreased in rats that consumed the 3 and 6% HSL infusions. The excessive and chronic consumption of HSL may increase the TAC that could lead to a proinflammatory state which is associated with hypertension.

Recombination events drives the emergence of Colombian Helicobacter pylori subpopulations with self-identity ancestry.

Helicobacter pylori have coevolved with mankind since its origins, adapting to different human groups. In America, H. pylori has evolved into several subpopulations. We analysed the genome of 154 Colombian strains along with 1,091 strains from worldwide populations to discern the ancestry and adaption to Colombian people. Population structure and ancestry was inferred with FineStructure and ChromoPainter. Phylogenetic relationship and the relative effect of recombination were analysing the core SNPs. Also, a Fst index was calculated to identify the gene variants with the strongest fixation in the Colombian subpopulations compared to their parent population hspSWEurope. FineStructure allowed the identification of two Colombian subpopulations, the previously described hspSWEuropeColombia and a novel subpopulation named hspColombia, that included three subgroups following their geographic origin. Colombian subpopulations represent an admixture of European, African and Indigenous ancestry; although some genomes showed a high proportion of self identity, suggesting an advanced adaption to these mestizo Colombian groups. We found that recombination is more important that punctual mutations in H. pylori genome diversity, 13.9 more important in hspSWEurope, 12.5 in hspSWEColombia and 10.5 in hspColombia, reflecting the divergence of these subpopulations. Fst analysis identified 82 SNPs fixed in 26 genes of the hspColombia subpopulation that encode for outer membrane and central metabolism proteins. Strongest fixation indexes were identified in genes encoding HofC, HopE, FrpB-4 and Sialidase A. These findings demonstrate that H. pylori has evolved in Colombia to give rise to subpopulations with a self identity ancestry, reflected in allele changes on genes encoding for outer membrane proteins.

Hematologic evaluation of peripheral blood in Sprague Dawley rats by chronic exposure to aluminum chloride (AlCl3).

This study aimed to evaluate whether aluminum chloride (AlCl3) causes hematological changes in the peripheral blood of Sprague-Dawley (SD) rats. Five groups of female SD rats were intragastrically administered with 4 different concentrations of AlCl3 for 5 days a week for a total of 90 days. The aluminum concentration was determined via graphite furnace atomic absorption spectroscopy. Analysis of serum iron-kinetic profiles, blood cytometry outcomes, and blood smears of the blood samples. Scanning electron microscopy (SEM) and Raman spectroscopy were used to search for structural and ultrastructural changes, respectively. Blood aluminum concentration ranged 12.38-16.24 µg/L with no significant difference between experimental treatments. At the AlCl3 concentration of 40 mg Al/kg bw of rats/day, the mean ferritin value in the serum iron kinetic profile was 29.81±6.1 ng/mL, and this value showed a significant difference between experimental treatments. Blood cytometry revealed that there were 6.45-7.11×106 cells/µL erythrocytes, 8.91-9.32×103 cells/µL leukocytes, and 477.2-736.3×103 cells/µL platelets along with a hemoglobin of 37.38-41.93 g/dL and hematocrit level of 37.38-41.93%; the experimental treatments showed no significant differences. Erythrocyte structural analysis using SEM showed no differences between experimental treatments, whereas ultrastructural evaluation using Raman spectroscopy made it possible to identify the following bands: 741, 1123, 1350, 1578, and 1618 cm-1, which were respectively associated with the following vibrational modes and compounds: vibration of the tryptophan ring, asymmetric C-O-C stretching of glucose, C-H curve of tryptophan, C=C stretching of the heme group, and C-N stretching of the heme group, with no significant differences between experimental treatments. Therefore, AlCl3 administration does not induce ultrastructural changes in the erythrocyte membrane. This study revealed that serum ferritin concentration was the only parameter affected by AlCl3 exposure at 40 mg of Al/kg bw of rats/day.

Precision-cut liver slices as a model for assess hepatic cellular response of chitosan-glutathione nanoparticles on cultures treated with zilpaterol and clenbuterol.

Zilpaterol and clenbuterol are two ß-adrenergic agonist drugs used in animal production. Both drugs have anabolic effects with advantages on carcass yield. Meanwhile, zilpaterol is approved for animal feed in authorized countries. Clenbuterol is a banned substance due to the risk of toxicity; however, it is still being used in unknown dose levels in many farm species. Therefore, the use and abuse of these substances should be closely monitored, considering the clenbuterol ability and the not proved yet of zilpaterol to produce reactive oxygen and nitrogen species. Regarding glutathione which is the main intracellular antioxidant plays detoxification functions on liver metabolism; in this work, it is our interest to know the capacity of chitosan-glutathione nanoparticles (CS/GSH-NP) as a complementary source of exogenous GSH to modify the oxide-reduction status on bovine precision-cut liver slice cultures (PCLS) exposed to clenbuterol and zilpaterol. A single drug assay was performed in first instance by adding clenbuterol, zilpaterol, chitosan nanoparticles (CS-NP), and CS/GSH-NP. Then combinate drug assay was carried out by testing clenbuterol and zilpaterol combined with CS-NP or CS/GSH-NP. The results showed that both ß-adrenergic agonists modify in a dose-dependent manner in oxide-reduction response through ROS generation. The activity or content of glutathione peroxidase activity, intracellular GSH, gamma glutamyl-transpeptidase, aspartate aminotrasnferase and alanine aminotrasnferase were modified. The exogenous GSH delivered by nanoparticles could be used to modulate these markers.

Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients.

Tamoxifen (TAM), a selective oestrogen receptor modulator, is one of the most used treatments in oestrogen receptor-positive (ER+) early and metastatic breast cancer (BC) patients. The response to TAM has a high degree of inter-individual variability. This is mainly due to genetic variants in CYP2D6 gene, as well as other genes encoding proteins involved in the TAM pharmacokinetic and/or pharmacodynamic. Therefore, prediction of the TAM response using these genetic factors together with other non-genetic variables may be relevant to improve breast cancer treatment. Thus, in this work, we used genetic polymorphisms and clinical variables for TAM response modelling. One hundred sixty-two ER + BC patients with 2 years of TAM treatment were retrospectively recruited, and the genetic polymorphisms CYP2D6*4, CYP3A4*1B (CYP3A4*1.001), CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2, and ESRA V364E were analyzed by PCR-RFLP. Concomitantly, the therapeutic response was obtained from clinical records for association with genotypes using univariate and multivariate biostatistical models. Our results show that UGT2B15*1/*2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A5*3/*3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A1*1/*2 genotype avoids vaginal bleeding (OR = 0.09; p = 0.03) and ESRA 364E/364E genotype increases the probability of vaginal bleeding (OR = 5.68; p = 0.02). Logistic regression models, including genomic and non-genomic variables, allowed us to obtain preliminary predictive models to explain relapse (p = 0.010), endometrial hyperplasia (p = 0.002) and vaginal bleeding (p = 0.014). Our results suggest that the response to TAM treatment in ER + BC patients might be associated with the presence of the studied genetic variants in UGT2B15, CYP3A5, SULT1A1 and ESRA genes. After clinical validation protocols, these models might be used to help to predict a percentage of BC relapse and adverse reactions, improving the individual response to TAM-based treatment.

Uso sostenible de recursos en los procesos del Hospital Pediátrico Provincial de Holguín, Cuba, 2014-2019 / The sustainable use of resources in the processes of the Provincial Pediatric Hospital of Holguín, Cuba, 2014-2019

Introducción: El cambio climático se atribuye directa o indirectamente a la actividad humana, pues esta altera la composición de la atmósfera, de conjunto con la variabilidad natural del clima. De ahí que las instituciones hospitalarias, requieran de control y manejo de residuos y sustancias peligrosas durante la prestación de sus servicios. Objetivo: Valorar la implementación de buenas prácticas en el uso sostenible de los recursos hídrico, la energía eléctrica, la administración segura de sustancias peligrosas y el manejo razonable de los residuos que producen los servicios en el Hospital Pediátrico Provincial de Holguín para la gestión ambiental y de enfrentamiento al cambio climático. Métodos: Se realizó un estudio longitudinal a todos los procesos hospitalarios, mediante técnica de la investigación cualitativa y explicativa. Se empleó el estudio de caso como estrategia de investigación para desarrollar las fases de preparación y diagnóstico, seguido de una etapa de proyección de la implementación. Por último, se realizó la evaluación y mejora del problema identificado, con criterios de sostenibilidad desde la gestión organizacional según niveles de actividad hospitalarios. Resultados: Se obtuvo un considerable ahorro de agua (64 877 m3) y una disminución significativa en gastos al presupuesto (348 miles de pesos), así como un factor de potencia entre 0,92 y 1,0 que muestra la conversión de energía consumida en trabajo. Se obtuvo una reducción significativa de líquido fijador en estudios radiográficos y se mejoró el manejo de las sustancias peligrosas (líquido fijador de Rx). Conclusiones: Para dar respuesta a las necesidades de cambio en la forma de gestión de los procesos hospitalarios se precisa recurrir a herramientas de control de consumo, análisis, normas y procedimientos que permitan alcanzar su mejora, según los niveles de actividad en los servicios(AU)

Introduction: Climate change is attributed directly or indirectly to human activity, as this alters the composition of the atmosphere, in conjunction with the natural variability of the climate. Hence, hospital institutions require control and management of wastes and hazardous substances during the provision of their services. Objective: Assess the implementation of good practices in the sustainable use of water resources, electrical energy, the safe administration of hazardous substances and the reasonable management of waste produced by the services at the Provincial Pediatric Hospital of Holguín for environmental management and the fight against climate change. Methods: A longitudinal study was carried out on all hospital processes, using qualitative and explanatory research technique. The case study was used as a research strategy to develop the preparation and diagnosis phases, followed by a projection stage of implementation. Finally, the evaluation and improvement of the identified problem was carried out, with sustainability criteria from the organizational management according to hospital activity levels. Results: Considerable water savings were obtained (64 877 m3) and a significant decrease in budget expenses (348 000 pesos), as well as a power factor between 0.92 and 1.0 that shows the conversion into work of they energy consumed. A significant reduction in fixer fluid was obtained in radiographic studies and the handling of hazardous substances (Rx fixer liquid) was improved. Conclusions: To respond to the needs of change in the way hospital processes are managed, it is necessary to resort to consumption control tools, analysis, standards and procedures that allow them to be improved, according to the levels of activity in the services(AU)

Modification of Proliferation and Apoptosis in Breast Cancer Cells by Exposure of Antioxidant Nanoparticles Due to Modulation of the Cellular Redox State Induced by Doxorubicin Exposure.

In this report, we investigated whether the use of chitosan-carrying-glutathione nanoparticles (CH-GSH NPs) can modify proliferation and apoptosis, and reduce cell damage induced by doxorubicin on breast cancer cells. Doxorubicin is a widely used antineoplasic agent for the treatment of various types of cancer. However, it is also a highly toxic drug because it induces oxidative stress. Thus, the use of antioxidant molecules has been considered to reduce the toxicity of doxorubicin. CH-GSH NPs were characterized in size, zeta potential, concentration, and shape. When breast cancer cells were treated with CH-GSH nanoparticles, they were localized in the cellular cytoplasm. Combined doxorubicin exposure with nanoparticles increased intracellular GSH levels. At the same time, decreasing levels of reactive oxygen species and malondialdehyde were observed and modified antioxidant enzyme activity. Levels of the Ki67 protein were evaluated as a marker of cell proliferation and the activity of the Casp-3 protein related to cell apoptosis was measured. Our data suggests that CH-GSH NPs can modify cell proliferation by decreasing Ki67 levels, induce apoptosis by increasing caspase-3 activity, and reduce the oxidative stress induced by doxorubicin in breast cancer cells by modulating molecules associated with the cellular redox state. CH-GSH NPs could be used to reduce the toxic effects of this antineoplastic. Considering these results, CH-GSH NPs represent a novel delivery system offering new opportunities in pharmacy, material science, and biomedicine.

Au@Ag Core@Shell Nanoparticles Synthesized with Rumex hymenosepalus as Antimicrobial Agent.

In this work, we used a sequential method of synthesis for gold-silver bimetallic nanoparticles with core@shell structure (Au@AgNPs). Rumex hymenosepalus root extract (Rh), which presents high content in catechins and stilbenes, was used as reductor agent in nanoparticles synthesis. Size distribution obtained by Transmission Electron Microscopy (TEM) gives a mean diameter of 36 ± 11 nm for Au@AgNPs, 24 ± 4 nm for gold nanoparticles (AuNPs), and 13 ± 3 nm for silver nanoparticles (AgNPs). The geometrical shapes of NPs were principally quasi-spherical. The thickness of the silver shell over AuNPs is around 6 nm and covered by active biomolecules onto the surface. Nanoparticles characterization included high angle annular dark field images (HAADF) recorded with a scanning transmission electron microscope (STEM), Energy-Dispersive X-ray Spectroscopy (EDS), X-Ray Diffraction (XRD), UV-Vis Spectroscopy, Zeta Potential, and Dynamic Light Scattering (DLS). Fourier Transform Infrared Spectrometer (FTIR), and X-ray Photoelectron Spectroscopy (XPS) show that nanoparticles are stabilized by extract molecules. A growth kinetics study was performed using the Gompertz model for microorganisms exposed to nanomaterials. The results indicate that AgNPs and Au@AgNPs affect the lag phase and growth rate of Escherichia coli and Candida albicans in a dose-dependent manner, with a better response for Au@AgNPs.

Diagnostic Performance of a Machine Learning-Based CT-Derived FFR in Detecting Flow-Limiting Stenosis. / Performance Diagnóstica da FFR por Angiotomografia de Coronárias através de Software Baseado em Inteligência Artificial.

BACKGROUND: The non-invasive quantification of the fractional flow reserve (FFRCT) using a more recent version of an artificial intelligence-based software and latest generation CT scanner (384 slices) may show high performance to detect coronary ischemia. OBJECTIVES: To evaluate the diagnostic performance of FFRCT for the detection of significant coronary artery disease (CAD) in contrast to invasive FFR (iFFR) using previous generation CT scanners (128 and 256- detector rows). METHODS: Retrospective study with patients referred to coronary artery CT angiography (CTA) and catheterization (iFFR) procedures. Siemens Somatom Definition Flash (256-detector rows) and AS+ (128-detector rows) CT scanners were used to acquire the images. The FFRCT and the minimal lumen area (MLA) were evaluated using a dedicated software (cFFR version 3.0.0, Siemens Healthineers, Forchheim, Germany). Obstructive CAD was defined as CTA lumen reduction ≥ 50%, and flow-limiting stenosis as iFFR ≤0.8. All reported P values are two-tailed, and when <0.05, they were considered statistically significant. RESULTS: Ninety-three consecutive patients (152 vessels) were included. There was good agreement between FFRCT and iFFR, with minimal FFRCT overestimation (bias: -0.02; limits of agreement:0.14-0.09). Different CT scanners did not modify the association between FFRCT and FFRi (p for interaction=0.73). The performance of FFRCT was significantly superior compared to the visual classification of coronary stenosis (AUC 0.93vs.0.61, p<0.001) and to MLA (AUC 0.93vs.0.75, p<0.001), reducing the number of false-positive cases. The optimal cut-off point for FFRCT using a Youden index was 0.85 (87% Sensitivity, 86% Specificity, 73% PPV, 94% NPV), with a reduction of false-positives. CONCLUSION: Machine learning-based FFRCT using previous generation CT scanners (128 and 256-detector rows) shows good diagnostic performance for the detection of CAD, and can be used to reduce the number of invasive procedures.

FUNDAMENTO: A quantificação não invasiva da reserva fracionada de fluxo miocárdico (FFR TC ) através de software baseado em inteligência artificial em versão mais atualizada e tomógrafo de última geração (384 cortes) apresenta elevada performance na detecção de isquemia coronariana. OBJETIVOS: Avaliar o desempenho diagnóstico da FFR TC na detecção de doença arterial coronariana (DAC) significativa em relação ao FFRi, em tomógrafos de gerações anteriores (128 e 256 cortes). MÉTODOS: Estudo retrospectivo com pacientes encaminhados à angiotomografia de artérias coronárias (TCC) e cateterismo (FFRi). Foram utilizados os tomógrafos Siemens Somatom Definition Flash (256 cortes) e AS+ (128 cortes). A FFR TC e a área luminal mínima (ALM) foram avaliadas em software (cFFR versão 3.0.0, Siemens Healthineers, Forchheim, Alemanha). DAC obstrutiva foi definida como TCC com redução luminal ≥50% e DAC funcionalmente obstrutiva como FFRi ≤0,8. Todos os valores de p reportados são bicaudais; e quando <0,05, foram considerados estatisticamente significativos. RESULTADOS: Noventa e três pacientes consecutivos (152 vasos) foram incluídos. Houve boa concordância entre FFR TC e FFRi, com mínima superestimação da FFR TC (viés: ­0,02; limites de concordância: 0,14 a 0,09). Diferentes tomógrafos não modificaram a relação entre FFR TC e FFRi (p para interação = 0,73). A FFR TC demonstrou performance significativamente superior à classificação visual de estenose coronariana (AUC 0,93 vs. 0,61, p <0,001) e à ALM (AUC 0,93 vs. 0,75, p <0,001) reduzindo o número de casos falso-positivos. O melhor ponto de corte para a FFR TC utilizando um índice de Youden foi de 0,85 (sensiblidade, 87%; especificidade, 86%; VPP, 73%; NPV, 94%), com redução de falso-positivos. CONCLUSÃO: FFR TC baseada em inteligência artificial, em tomógrafos de gerações anteriores (128 e 256 cortes), apresenta boa performance diagnóstica na detecção de DAC, podendo ser utilizada para reduzir procedimentos invasivos.