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Abstract Black flounder (Paralichthys orbignyanus, Pleuronectiformes) is a commercially significant marine fish with promising aquaculture potential in Argentina. Despite extensive studies on Black flounder aquaculture, its limited genetic information available hampers the crucial role genetics plays in the development of this activity. In this study, we first employed Illumina sequencing technology to sequence the entire genome of Black flounder. Utilizing two independent libraries—one from a female and another from a male—with 150 bp paired-end reads, a mean insert length of 350 bp, and over 35 X-fold coverage, we achieved assemblies resulting in a genome size of ~ 538 Mbp. Analysis of the assemblies revealed that more than 98% of the core genes were present, with more than 78% of them having more than 50% coverage. This indicates a somehow complete and accurate genome at the coding sequence level. This genome contains 25,231 protein-coding genes, 445 tRNAs, 3 rRNAs, and more than 1,500 non-coding RNAs of other types. Black flounder, along with pufferfishes, seahorses, pipefishes, and anabantid fish, displays a smaller genome compared to most other teleost groups. In vertebrates, the number of transposable elements (TEs) is often correlated with genome size. However, it remains unclear whether the sizes of introns and exons also play a role in determining genome size. Hence, to elucidate the potential factors contributing to this reduced genome size, we conducted a comparative genomic analysis between Black flounder and other teleost orders to determine if the small genomic size could be explained by repetitive elements or gene features, including the whole genome genes and introns sizes. We show that the smaller genome size of flounders can be attributed to several factors, including changes in the number of repetitive elements, and decreased gene size, particularly due to lower amount of very large and small introns. Thus, these components appear to be involved in the genome reduction in Black flounder. Despite these insights, the full implications and potential benefits of genome reduction in Black flounder for reproduction and aquaculture remain incompletely understood, necessitating further research.

Objetivos: Describir las características de las diferentes residencias médicas de cardiología de Latinoamérica. Método: Estudio de corte transversal que tiene como objetivo evaluar las características de las residencias de cardiología en países hispanohablantes de América Latina, mediante encuestas electrónicas autoadministradas Resultados: Se encuestó a 307 residentes de 147 residencias. La mediana de edad fue 31 años y el 63% era de sexo masculino. El 98% realiza su formación en la ciudad capital. El tiempo de formación total promedio es de 4.8 años. El 44% realiza la residencia completa en medicina interna previo al inicio de cardiología, y el 10% no tiene formación previa. En cardiología la formación es de tres años en la mayoría de los países. El 54% presenta actividades académicas todos los días y el 16% solo una vez o menos, consistente en clases teóricas (93%), casos clínicos (85%), ateneos bibliográficos (69%) y redacción de trabajos científicos (68%). La supervisión es realizada por el jefe de residentes (45%), coordinador de residentes (44%), instructor de residentes (27%) o el jefe de servicio (54%), mientras que el 2.6% no presenta supervisión. Las rotaciones principales fueron ecocardiografía (99%), hemodinamia (96%), unidad coronaria (93%) y electrofisiología (92%). El 23% resaltó la necesidad de mejorar las actividades académicas y 12% la producción científica. Conclusiones: Existen importantes diferencias en la formación académica y práctica entre las residencias de los diferentes países de América.

Objetivos. Explorar la frecuencia e impacto de la violencia contra los trabajadores de salud de Argentina y compararlo con el resto de sus pares de Latinoamérica en el contexto de la pandemia por COVID-19. Materiales y métodos. Estudio de corte transversal a través de una encuesta electrónica al personal médico y no médico de Latinoamérica que desempeño tareas asistenciales desde marzo de 2020. Se utilizó una regresión de Poisson para estimar las Razones de Prevalencia crudas (RP) y ajustadas (RPa) con sus respectivos intervalos de confianza al 95%. Resultados. Un total de 3544 participantes de 19 países respondieron la encuesta; 1992 (56,0%) residían en Argentina. Entre los mismos, el 62,9% padeció al menos un hecho de violencia: 97,7% refirió violencia verbal y 11,8% violencia física. El 41,5% de los agredidos padecieron situaciones de violencia al menos una vez por semana. El personal de salud de Argentina vivenció más frecuentemente violencia que los de otros países (62,9% vs. 54,6%, p

Los criterios diagnósticos, los tratamientos en el momento de la admisión y los fármacos utilizados en pacientes con síndrome coronario agudo están bien definidos en innumerables guías. Sin embargo, existe incertidumbre acerca de las medidas para recomendar durante la planificación del egreso de los pacientes. Este documento reúne las evidencias más recientes y el tratamiento estandarizado y óptimo para los pacientes al momento del egreso de una hospitalización por un síndrome coronario agudo, para un cuidado integral y seguro en la transición del paciente entre la atención del evento agudo y el cuidado ambulatorio, con el objetivo de optimizar la recuperación de miocardio viable, garantizar la prevención secundaria más adecuada, reducir el riesgo de un nuevo evento coronario y la mortalidad, así como la adecuada reinserción de los pacientes en la vida cotidiana.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are enzymes that generate superoxide anion (O2•-) and hydrogen peroxide (H2O2), and that are widely distributed in mammalian tissues. Many bioactives, especially plant (poly)phenols are being studied for their capacity to regulate NOXs. The modulation of these enzymes are of central relevance to maintain redox homeostasis and regulate cell signaling.In in vitro and ex vivo assays, and in experimental animal models, different (poly)phenols are able to modulate NOX-dependent generation of O2•- and H2O2. Mechanistically, most of the known effects of (poly)phenols and of their metabolites on NOX1, NOX2, and NOX4, include the modulation of: i) the expression of the different constituent subunits, and/or ii) posttranslational modifications involved in the assembly and translocation of the protein complexes. Very limited evidence is available on a direct action of (poly)phenols on NOX active site (electron-transferring protein). Moreover, it is suggested that the regulation by (poly)phenols of systemic events, e.g. inflammation, is frequently associated with their capacity to regulate NOX activation. Although of physiological significance, more studies are needed to understand the specific targets/mechanisms of NOX regulation by (poly)phenols, and the (poly)phenol chemical structures and moieties directly involved in the observed effects. It should be kept in mind the difficulties of NOX's studies associated with the complexity of NOXs biochemistry and the methodological limitations of O2•- and H2O2 the determinations. Studies relating human ingestion of specific (poly)phenols, with NOX activity and disease conditions, are guaranteed to better understand the health importance of (poly)phenol consumption and the involvement of NOXs as biological targets.

Abstract Background The use of a Left Ventricular Assist Device (LVAD) in patients with advanced heart failure refractory to optimal medical management has progressed steadily over the past two decades. Data have demonstrated reduced LVAD efficacy, worse clinical outcome, and higher mortality for patients who experience significant ventricular tachyarrhythmia (VTA). We hypothesize that a novel prophylactic intra‐operative VTA ablation protocol at the time of LVAD implantation may reduce the recurrent VTA and adverse events postimplant. Methods We designed a prospective, multicenter, open‐label, randomized‐controlled clinical trial enrolling 100 patients who are LVAD candidates with a history of VTA in the previous 5 years. Enrolled patients will be randomized in a 1:1 fashion to intra‐operative VTA ablation (n = 50) versus conventional medical management (n = 50) with LVAD implant. Arrhythmia outcomes data will be captured by an implantable cardioverter defibrillator (ICD) to monitor VTA events, with a uniform ICD programming protocol. Patients will be followed prospectively over a mean of 18 months (with a minimum of 9 months) after LVAD implantation to evaluate recurrent VTA, adverse events, and procedural outcomes. Secondary endpoints include right heart function/hemodynamics, healthcare utilization, and quality of life. Conclusion The primary aim of this first‐ever randomized trial is to assess the efficacy of intra‐operative ablation during LVAD surgery in reducing VTA recurrence and improving clinical outcomes for patients with a history of VTA.

Introduction:Trypanosoma cruzi, Trypanosoma brucei, and Leishmania spp., commonly referred to as TriTryps, are a group of protozoan parasites that cause important human diseases affecting millions of people belonging to the most vulnerable populations worldwide. Current treatments have limited efficiencies and can cause serious side effects, so there is an urgent need to develop new control strategies. Presently, the identification and prioritization of appropriate targets can be aided by integrative genomic and computational approaches.Methods: In this work, we conducted a genome-wide multidimensional data integration strategy to prioritize drug targets. We included genomic, transcriptomic, metabolic, and protein structural data sources, to delineate candidate proteins with relevant features for target selection in drug development.Results and Discussion: Our final ranked list includes proteins shared by TriTryps and covers a range of biological functions including essential proteins for parasite survival or growth, oxidative stress-related enzymes, virulence factors, and proteins that are exclusive to these parasites. Our strategy found previously described candidates, which validates our approach as well as new proteins that can be attractive targets to consider during the initial steps of drug discovery.

Infiltrative cardiomyopathies are an increasingly recognized cause of heart failure warranting systematic evaluation. Given overlap of clinical and imaging findings among etiologies of infiltrative cardiomyopathies, comprehensive evaluation, including a history and physical examination, advanced cardiac imaging, and sometimes endomyocardial biopsy, is required for diagnosis. We report a case of infiltrative cardiomyopathy in which endomyocardial biopsy confirmed diagnosis of cobalt-induced cardiomyopathy. The novel teaching points highlighted by this case report include identification of heavy-metal toxicity as a cause of infiltrative cardiomyopathy, and the outline of a diagnostic approach and management for cobalt-induced cardiomyopathy. Résumé: Le fait que les cardiomyopathies infiltrantes sont de plus en plus reconnues comme la cause de l’insuffisance cardiaque justifie une évaluation systématique. Puisque les résultats cliniques et d’imagerie se recoupent entre les étiologies des cardiomyopathies infiltrantes, l’évaluation exhaustive, y compris les antécédents et l’examen physique, les techniques avancées en imagerie cardiaque et parfois la biopsie endomyocardique, est nécessaire au diagnostic. Nous présentons un cas de cardiomyopathie infiltrante pour lequel la biopsie endomyocardique a permis de confirmer le diagnostic d’une cardiomyopathie induite par le cobalt. Parmi les points à enseigner illustrés dans cette observation, on cite la reconnaissance de la toxicité des métaux lourds comme une cause de cardiomyopathie infiltrante, et la vue d’ensemble de l’approche diagnostique et de la prise en charge de la cardiomyopathie induite par le cobalt.

BACKGROUND A patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO’s ability to predict clinical response to gastrointestinal (GI) cancers.METHODS We generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments.RESULTS We report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures.CONCLUSION While we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.TRIAL REGISTRATION Not applicable.FUNDING The Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research, GI Cancer program of the Mayo Clinic Cancer Center, Mayo Clinic SPORE in Pancreatic Cancer, Center of Individualized Medicine (Mayo Clinic), Department of Laboratory Medicine and Pathology (Mayo Clinic), Incyte Pharmaceuticals and Mayo Clinic Hepatobiliary SPORE, University of Minnesota-Mayo Clinic Partnership, and the Early Therapeutic program (Department of Oncology, Mayo Clinic).

Introducción: En la última década los anticoagulantes orales directos (ACOD) se incorporaron como herramienta para la anticoagulación en pacientes con tromboembolia pulmonar (TEP) aguda. Aunque tienen un mejor perfil farmacológico que los antagonistas de la vitamina K (AVK), el uso de estos fármacos no es masivo. El objetivo del presente trabajo fue evaluar el uso de ACOD en pacientes con TEP aguda y detectar determinantes de su indicación. Metodología: Análisis preespecificado del registro CONAREC XX que incorporó pacientes con TEP aguda en 64 centros de Argentina. Se realizó un análisis para detectar predictores de prescripción de ACOD al alta. Resultados: Se analizaron 579 pacientes que recibieron anticoagulación al alta hospitalaria: el 60% recibió AVK, el 21% heparinas y el 19% ACOD (de ellos, un 49% rivaroxabán, un 34% apixabán y un 17% dabigatrán). Los pacientes que recibieron ACOD tenían TEP de menor gravedad, menor riesgo de hemorragia y menos complicaciones intrahospitalarias. En el seguimiento a 30 días no hubo diferencias en mortalidad por todas las causas o sangrados. La cobertura de salud por un seguro social (odds ratio [OR]: 7.45; intervalo de confianza del 95% [IC 95%]: 1.74-31.9; p < 0.01) o por cobertura privada (OR: 10.5; IC 95%: 2.4-45.9; p < 0.01) fueron predictores independientes de la prescripción de ACOD al alta, y el antecedente de insuficiencia cardiaca (OR: 0.19; IC 95%: 0.04-0.84; p = 0.028) y de enfermedad oncológica (OR: 0.49; IC 95%: 0.27-0.89; p = 0.02) fueron predictores de no prescribirlos. Conclusiones: Uno de cada cinco supervivientes de TEP aguda recibió ACOD al egreso hospitalario en Argentina, y esto fue determinado por variables clínicas y económicas

Objetivos: Determinar si los pacientes con cardiopatía chagásica (CCh) presentaron choques apropiados del desfibrilador automático implantable (DAI) de manera más precoz que los pacientes con cardiopatía isquémica (CI). Métodos: Estudio de cohorte retrospectivo que incluyó los pacientes con CCh y CI en quienes se implantó un DAI entre los años 2009 y 2018 en un hospital de alta complejidad. El seguimiento se realizó hasta los 36 meses, evaluándose el momento del primer choque apropiado del dispositivo. Resultados: Se incluyeron 64 pacientes, 20 con CCh y 44 con CI. Se observó que una mayor proporción de pacientes con CCh presentaron choques apropiados durante el primer año (hazard ratio [HR]: 8.4; intervalo de confianza del 95% [IC95%]: 2.09-34.02; p = 0.0027) y a 3 años (HR: 4.61; IC95%: 1.51-14.07; p = 0.0072). El 100% de la población con CCh e implante del DAI como prevención secundaria de muerte súbita presentaron choques apropiados durante los primeros 26 meses de seguimiento. Conclusiones: Los pacientes con CCh presentaron choques apropiados del DAI de manera más precoz que los pacientes con CI. Todos los pacientes con CCh y DAI como prevención secundaria presentaron choques apropiados, representando una población de mayor riesgo. Esta información apoya la indicación del DAI en estos pacientes a pesar de la escasa evidencia en ensayos aleatorizados.

Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target.

Abstract Background Whole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution —the genetic variability of M. tuberculosis at short time scales— of a parental strain into clonal variants with a patient is a relevant issue that has not been yet completely addressed. To our knowledge, a whole genome sequence microevolution analysis in a single patient with inadequate adherence to treatment has not been previously reported. Case presentation In this work, we applied whole genome sequencing analysis for a more in-depth analysis of the microevolution of a parental Mycobacterium tuberculosis strain into clonal variants within a patient with poor treatment compliance in Argentina. We analyzed the whole-genome sequence of 8 consecutive Mycobacterium tuberculosis isolates obtained from a patient within 57-months of intermittent therapy. Nineteen mutations (9 short-term, 10 fixed variants) emerged, most of them associated with drug resistance. The first isolate was already resistant to isoniazid, rifampicin, and streptomycin, thereafter the strain developed resistance to fluoroquinolones and pyrazinamide. Surprisingly, isolates remained susceptible to the pro-drug ethionamide after acquiring a frameshift mutation in ethA, a gene required for its activation. We also found a novel variant, (T-54G), in the 5′ untranslated region of whiB7 (T-54G), a region allegedly related to kanamycin resistance. Notably, discrepancies between canonical and phage-based susceptibility testing to kanamycin were previously found for the isolate harboring this mutation. In our patient, microevolution was mainly driven by drug selective pressure. Rare short-term mutations fixed together with resistance-conferring mutations during therapy. Conclusions This report highlights the relevance of whole-genome sequencing analysis in the clinic for characterization of pre-XDR and MDR resistance profile, particularly in patients with incomplete and/or intermittent treatment.

Encoding the sodium iodide symporter (NIS) by an adenovirus (Ad) is a promising strategy to facilitate non-invasive imaging and radiotherapy of pancreatic cancer. However, insufficient levels of NIS expression in tumor cells have limited its clinical translation. To optimize Ad-based radiotherapy and imaging, we investigated the effect of Ad death protein (ADP) deletion on NIS expression. We cloned two sets of oncolytic NIS-expressing Ads that differed only in the presence or absence of ADP. We found that ADP expression negatively affected NIS membrane localization and inhibited radiotracer uptake. ADP deletion significantly improved NIS-based imaging in pancreatic cancer models including patient-derived xenografts, where effective imaging was possible for up to 6 weeks after a single virus injection. This study demonstrates that improved oncolysis may hinder the therapeutic effect of oncolytic viruses designed to express NIS. In vivo studies in combination with 131I showed potential for effective radiotherapy. This also highlights the need for further investigation into optimal timing of 131I administration and suggests that repeated doses of 131I should be considered to improve efficacy in clinical trials. We conclude that ADP deletion is essential for effective NIS-based theranostics in cancer.

Left ventricular assist devices (LVAD) are increasingly being used as destination therapy in patients with Stage D heart failure. It has been reported that a majority of patients who receive a durable LVAD (dLVAD) present in cardiogenic shock due to decompensated heart failure (ADHF‐CS). As it stands, there is no consensus on the optimal management strategy for patients presenting with ADHF. Bridging with intra‐aortic balloon pumps (IABPs) continues to be a therapeutic option in patients with hemodynamic instability due to cardiogenic shock. The majority of data regarding the use of IABP in cardiogenic shock come from studies in patients presenting with acute myocardial infarction with cardiogenic shock and demonstrates that there is no benefit of routine IABP use in this patient population. However, the role of IABPs as a bridge to dLVAD in ADHF‐CS has yet to be determined. The hemodynamic changes seen in acute myocardial infarction with cardiogenic shock are known to be different and more acutely impaired than those presenting with ADHF‐CS as evidenced by differences in pressure/volume loops. Thus, data should not be extrapolated across these 2 very different disease processes. The aim of this review is to describe results from contemporary studies examining the use of IABPs as a bridge to dLVAD in patients with ADHF‐CS. Retrospective evidence from large registries suggests that the use of IABP as a bridge to dLVAD is feasible and safe when compared with other platforms of temporary mechanical circulatory support. However, there is currently a paucity of high‐quality evidence examining this increasingly important clinical question.

Decades of successful use of antibiotics is currently challenged by the emergence of increasingly resistant bacterial strains. Novel drugs are urgently required but, in a scenario where private investment in the development of new antimicrobials is declining, efforts to combat drug-resistant infections become a worldwide public health problem. Reasons behind unsuccessful new antimicrobial development projects range from inadequate selection of the molecular targets to a lack of innovation. In this context, increasingly available omics data for multiple pathogens has created new drug discovery and development opportunities to fight infectious diseases. Identification of an appropriate molecular target is currently accepted as a critical step of the drug discovery process. Here, we review how diverse layers of multi-omics data in conjunction with structural/functional analysis and systems biology can be used to prioritize the best candidate proteins. Once the target is selected, virtual screening can be used as a robust methodology to explore molecular scaffolds that could act as inhibitors, guiding the development of new drug lead compounds. This review focuses on how the advent of omics and the development and application of bioinformatics strategies conduct a “big-data era” that improves target selection and lead compound identification in a cost-effective and shortened timeline.

Autophagy has been shown to be a key cellular event controlling tumor growth in different neoplasms including hepatocellular carcinoma (HCC). Although this biological role of autophagy has been clearly established, the mechanism underlying its regulation remains elusive. Here, we demonstrate a role of sulfatase 2 (SULF2), a 6‐O‐endosulfatase modulating various growth factors and cytokine‐related signaling pathways controlling tumor cell proliferation and survival, in the regulation of autophagy in HCC cells. SULF2 increased autophagosome formation, shown by increased LC3B‐II protein and green fluorescent protein–LC3 puncta. Increased fusion between autophagosomes and lysosomes/lysosomal enzymes, higher expression of lysosomal membrane protein, and an increase in autolysosomes were also shown by western blot, immunofluorescence, and electron microscopy of SULF2‐expressing cells, indicating enhanced autophagic flux. In contrast, RNA‐interference silencing of SULF2 in Huh7 cells induced lysosomal membrane permeabilization with diffuse cytosolic staining of cathepsin D and punctate staining of galectin‐3. Analysis of the mechanism showed that inhibition of lysosome‐associated protein transmembrane 4 beta (LAPTM4B), a gene induced by SULF2, resulted in decreased autophagosome formation, decreased fusion between autophagosomes and lysosomes, and increased lysosomal membrane permeabilization. Interestingly, down‐regulation of LAPTM4B also phenocopies the knockdown of SULF2, significantly reducing cell viability and colony formation. Conclusion: Our results demonstrate a role for SULF2 in the regulation of autophagic flux that is mediated through LAPTM4B induction in HCC cells, and provide a foundation for future translational efforts targeting autophagy in liver malignancies.

Gestational trophoblastic disease (GTD) is a heterogeneous group of lesions arising from placental tissue. Epithelioid trophoblastic tumor (ETT), derived from chorionic-type trophoblast, is the rarest form of GTD with only approximately 130 cases described in the literature. Due to its morphologic mimicry of epithelioid smooth muscle tumors and carcinoma, ETT can be misdiagnosed. To date, molecular characterization of ETTs is lacking. Furthermore, ETT is difficult to treat when disease spreads beyond the uterus. Here using RNA-Seq analysis in a cohort of ETTs and other gestational trophoblastic lesions we describe the discovery of LPCAT1-TERT fusion transcripts that occur in ETTs and coincide with underlying genomic deletions. Through cell-growth assays we demonstrate that LPCAT1-TERT fusion proteins can positively modulate cell proliferation and therefore may represent future treatment targets. Furthermore, we demonstrate that TERT upregulation appears to be a characteristic of ETTs, even in the absence of LPCAT1-TERT fusions, and that it appears linked to copy number gains of chromosome 5. No evidence of TERT upregulation was identified in other trophoblastic lesions tested, including placental site trophoblastic tumors and placental site nodules, which are thought to be the benign chorionic-type trophoblast counterpart to ETT. These findings indicate that LPCAT1-TERT fusions and copy-number driven TERT activation may represent novel markers for ETT, with the potential to improve the diagnosis, treatment, and outcome for women with this rare form of GTD.

The introduction of non-vitamin K antagonists oral anticoagulants, a class of medicines which includes dabigatran, apixaban, edoxaban and rivaroxaban, has resulted in improvements in the safety and efficacy of non valvular atrial fibrillation treatment for stroke prevention, with significant reductions in stroke, intracranial haemorrhage, and mortality. For these reasons, a team of World Heart Federation Emerging Leaders led efforts to add non-vitamin K antagonists oral anticoagulants to the World Health Organization’s Model List of Essential Medicines in 2019. Following the inclusion of this class of medicines in the Essential Medicines List, this editorial proposes several recommendations to improve the accessibility, affordability and acceptability of non-vitamin K oral anticoagulants, especially in low- and middle-income settings, in order to successfully manage non-valvular atrial fibrillation and to lower the risk of stroke.

Non-vitamin K antagonist oral anticoagulants (NOACs) represent a paradigm shift in the treatment of non-valvular atrial fibrillation (AF) with major practice guidelines around the world recommending NOACs over vitamin K antagonist oral anticoagulants for initial treatment of AF for stroke prevention. Here we describe the evidence collated and the process followed for the successful inclusion of NOACs into the 21st WHO Model List of Essential Medicines (EML). Individual NOACs have been reported to be non-inferior or superior to warfarin in preventing stroke and systemic embolism in eligible AF patients with a reduction in the risk of stroke and systemic embolism and a lower risk of major bleeding in patients with non-valvular AF compared with warfarin in both RCTs and real-world data. The successful inclusion of NOACs in the WHO EML is an important step forward in the global fight against cardiovascular morbidity and mortality, especially in low- and middle-income countries, where the burden of disease is high and limited access to diagnosis and treatment translates into a higher burden of morbidity, mortality, and economic costs.

Changes in nuclear shape have been extensively associated with the dynamics and functionality of cancer cells. In most normal cells, nuclei have a regular ellipsoid shape and minimal variation in nuclear size; however, an irregular nuclear contour and abnormal nuclear size is often observed in cancer, including pancreatic cancer. Furthermore, alterations in nuclear morphology have become the ‘gold standard’ for tumor staging and grading. Beyond the utility of altered nuclear morphology as a diagnostic tool in cancer, the implications of altered nuclear structure for the biology and behavior of cancer cells are profound as changes in nuclear morphology could impact cellular responses to physical strain, adaptation during migration, chromatin organization, and gene expression. Here, we aim to highlight and discuss the factors that regulate nuclear dynamics and their implications for pancreatic cancer biology.

The World Health Organization (WHO) estimates that 40% of tuberculosis (TB) cases are not diagnosed and treated correctly. Even though there are several diagnostic tests available in the market, rapid, easy, inexpensive detection, and drug susceptibility testing (DST) of Mycobacterium tuberculosis is still of critical importance specially in low and middle-income countries with high incidence of the disease. In this work, we have developed a microscopy-based methodology using the reporter mycobacteriophage mCherrybombϕ for detection of Mycobacterium spp. and phenotypic determination of rifampicin resistance within just days from sputum sample collection. Fluoromycobacteriophage methodology is compatible with regularly used protocols in clinical laboratories for TB diagnosis and paraformaldehyde fixation after infection reduces biohazard risks with sample analysis by fluorescence microscopy. We have also set up conditions for discrimination between M. tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM) strains by addition of p-nitrobenzoic acid (PNB) during the assay. Using clinical isolates of pre-XDR and XDR-TB strains from this study, we tested mCherrybombΦ for extended DST and we compared the antibiotic resistance profile with those predicted by whole genome sequencing. Our results emphasize the utility of a phenotypic test for M. tuberculosis extended DST. The many attributes of mCherrybombΦ suggests this could be a useful component of clinical microbiological laboratories for TB diagnosis and since only viable cells are detected this could be a useful tool for monitoring patient response to treatment.

La dronedarona es un nuevo antiarrítmico derivado de la amiodarona. Es útil en el tratamiento de la fibrilación auricular. Es menos lipofílica que la amiodarona y no posee yodo en su molécula. Posee menor vida media, menor acumulación pero similares efectos electrofisiológicos. El riesgo de hipertiroidismo o hipotiroidismo es menor. Faltan estudios comparativos y a largo plazo para demostrar los beneficios y seguridad de la Dronedarona.

Drosophila is a well-established model to study the molecular basis of neurodegenerative diseases. We carried out a misexpression screen to identify genes involved in neurodegeneration examining locomotor behavior in young and aged flies. We hypothesized that a progressive loss of rhythmic activity could reveal novel genes involved in neurodegenerative mechanisms. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain. Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant. Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor. Thus, this mutant recapitulates two important features of human neurodegenerative diseases, i.e., vulnerability of certain neuronal populations and progressive degeneration, offering a unique scenario in which to unravel the specific mechanisms in an easily tractable organism.

New lines of geological evidence strongly suggest that the main period of hydrocarbon maturation within Assistência Formation should be Permian-Triassic, stimulated by a high geothermal gradient that also sustained various manifestations of hydrothermal activity. Three main stages of fluid/hydrocarbon migration can also be inferred on the basis of multiscale observations: confined flow in late Permian to Triassic times, depending on the local build-up of fluid pressures; heterogeneous flow in Lower Cretaceous, triggered by a rejuvenated temperature gradient assisted by the early developed permeability conditions; and a late flow possibly driven by local pressure gradients, after complete cooling of dolerite dykes/sills. The early maturation and multistage migration of hydrocarbons have significant consequences in the design of exploration models to be applied in Paraná Basin.