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Abstract The development of biocompatible hybrid nanosystems for advanced functional applications presents significant challenges to the research community. Key obstacles include the poor solubility of these nanosystems in water and the difficulty of precisely controlling their nanostructure dimensions and composition. A promising approach to overcoming these challenges is the self-assembly of surfactant-based building blocks into well-ordered hybrid nanostructures. In this study, we explore the relationship between structure and self-assembly in novel low molecular weight amphiphilic molecules to produce stable and biocompatible hybrid nanostructures. We investigated the self-assembly behavior of two families of amphiphiles derived from alkenyl lipids with one or two double bonds, leading to distinct hybrid supramolecular structures facilitated by the incorporation of hydrophobic iron oxide nanoparticles (IONPs) as templates. The presence of double bonds in the lipid tail and the morphology of the amphiphile influence the arrangement on the hydrophobic NPs. Amphiphiles with a single double bond in the lipid tail form highly water-soluble, well-ordered micellar-like structures on the IONP surfaces, while those with two double bonds create disordered lipid nanoparticles. Furthermore, these amphiphilic molecules can self-organize into higher-order hybrid supramolecular structures, such as vesicles, with potential applications in magnetic resonance imaging (MRI).

Abstract Cardioneuroablation (CNA) represents a promising therapy for recurrent vasovagal syncope (VVS), extrinsically driven atrioventricular block (AVB) and sinus node dysfunction (SND). However, effectiveness in patients aged 50 and above is not well-established. In this prospective study of patients referred for CNA, we compared syncope and pacemaker implantation free survival, heart rate (HR) variability (HRV) and quality of life between two age groups: group A (

Introduction: Diabetes mellitus (DM) is a common endocrinopathy in felines. Treatment is based on glycemic control and management of clinical signs by insulin administration coupled with a low-carbohydrate and high-protein content diet. However, achieving adequate remission or glycemia control is not always possible. Effects of cannabinoids on the regulation of glucose uptake and the incidence of diabetes have been observed in experimental models. Nevertheless, little is known about their possible relevance in controlling this condition in veterinary and human medicine. Case presentation: This is a case study of an 18-year-old, neutered, mixed-breed female domestic longhair cat diagnosed with type 2 diabetes mellitus. She was treated with long-acting glargine (3 to 5 IU/12 hs), and her diet changed to ultra-processed commercial food for diabetic cats. Three months after the start of the treatment with insulin, Cannabidiol (CBD)-enriched extract in handmade olive oil, THC: CBD ratio = 1:24, was incorporated. The route of administration was oromucosal. After three months, the glycemia was reduced. The patient decreased the polyuria/polydipsia, recovered sleep cycles, remained attentive to all movements, and increased her physical activity. Conclusion: This report provides evidence that using a CBD-rich extract was effective as a co-adjuvant in alleviating clinical signs of DM and concurrent disorders, allowing for the reduction of insulin intake.

Abstract Background Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. Methods A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. Results In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. Conclusions MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3–5 years to evaluate the research advancements and update this guidance as needed.

Abstract In the frontline high-dose phase 3 FIL-MCL0208 trial (NCT02354313), 8% of enrolled mantle cell lymphoma (MCL) patients could not be randomised to receive lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) due to inadequate hematological recovery and 52% of those who started LEN, needed a dose reduction due to toxicity. We therefore focused on the role played by CD34 + hematopoietic stem cells (PBSC) harvesting and reinfusion on toxicity and outcome. Overall, 90% (n = 245) of enrolled patients who underwent the first leukapheresis collected ≥ 4 × 106 PBSC/kg, 2.6% (n = 7) mobilized 10 days) was associated with a worse outcome, both in terms of PFS and OS. In conclusion, although the harvesting procedures proved feasible for younger MCL patients, long-lasting cytopenia following ASCT remains a significant issue: this can hinder the administration of effective maintenance therapies, potentially increasing the relapse rate and negatively affecting survival outcomes.

Objective Lynch syndrome (LS) is a hereditary condition associated with an increased risk of colorectal and endometrial cancer. This study aimed to assess the knowledge, attitudes, and beliefs of women with LS regarding combined hormonal contraceptive (CHC) use compared to a control group of healthy women.Methods Pre-menopausal women with LS (n = 43) and an age-matched control group of healthy women (n = 128) participated in this prospective, cross-sectional study (NCT05909410). Participants completed an electronic questionnaire evaluating perceptions of CHC use and its impact on various cancers, medical conditions, and symptoms. Statistical analysis compared responses between the two groups, with reported p-values.Results Women with LS were less likely to use CHCs compared to the control group (p = 0.03) and had a more negative perception of CHCs’ impact on colorectal cancer (p = 0.023) and endometrial cancer (p = 0.028). Limited knowledge was observed in both groups regarding the protective effects of CHCs against colorectal and ovarian cancer. Perceptions of CHC use and its impact on symptoms and chronic diseases did not significantly differ between the groups (p > 0.05). CHC use was not associated with greater awareness of the protective effect against colorectal (p = 0.89) and endometrial cancer (p = 0.47), but it was associated with a desire for contraception (OR 21.25; 95% CI 1.16 to 388.21; p = 0.039).Conclusion This study highlights contrasting perceptions of CHCs and their implications in oncology between women with LS and healthy women. Tailored counselling and support strategies are crucial for empowering women with LS to make informed decisions about their gynaecologic health.

Case description: We report here the case of a 64-year-old male presenting pathological fractures of T6 and T7 due to pseudomyxoma peritonei extension to the pleural cavity and thoracic spine. He presented interscapular pain with mild spinal cord compression symptoms. He was treated by achieving T5-T8 laminectomy, T2-T10 pedicle fixation, and T6-T7 vertebrectomy. The postoperative course was uneventful apart from a pulmonary embolism with favorable evolution under anticoagulants. Conclusion: Pseudomyxoma peritonei is a rare condition, with no previously described location in the spine. Here is described the case of a PMP extension to the thorax then the spine, treated with two-level vertebrectomy, laminectomy, and posterior fusion.

Abstract Background KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. Methods Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. Results Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. Conclusions We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

Abstract Genome interpretation (GI) encompasses the computational attempts to model the relationship between genotype and phenotype with the goal of understanding how the first leads to the second. While traditional approaches have focused on sub-problems such as predicting the effect of single nucleotide variants or finding genetic associations, recent advances in neural networks (NNs) have made it possible to develop end-to-end GI models that take genomic data as input and predict phenotypes as output. However, technical and modeling issues still need to be fixed for these models to be effective, including the widespread underdetermination of genomic datasets, making them unsuitable for training large, overfitting-prone, NNs. Here we propose novel GI models to address this issue, exploring the use of two types of transfer learning approaches and proposing a novel Biologically Meaningful Sparse NN layer specifically designed for end-to-end GI. Our models predict the leaf and seed ionome in A.thaliana, obtaining comparable results to our previous over-parameterized model while reducing the number of parameters by 8.8 folds. We also investigate how the effect of population stratification influences the evaluation of the performances, highlighting how it leads to (1) an instance of the Simpson’s Paradox, and (2) model generalization limitations.

Abstract Background Lung regions excluded from mechanical insufflation are traditionally assumed to be spared from ventilation-associated lung injury. However, preliminary data showed activation of potential mechanisms of injury within these non-ventilated regions (e.g., hypoperfusion, inflammation). Methods In the present study, we hypothesized that non-ventilated lung injury (NVLI) may develop within 24 h of unilateral mechanical ventilation in previously healthy pigs, and we performed extended pathophysiological measures to profile NVLI. We included two experimental groups undergoing exclusion of the left lung from the ventilation with two different tidal volumes (15 vs 7.5 ml/kg) and a control group on bilateral ventilation. Pathophysiological alteration including lung collapse, changes in lung perfusion, lung stress and inflammation were measured. Lung injury was quantified by histological score. Results Histological injury score of the non-ventilated lung is significantly higher than normally expanded lung from control animals. The histological score showed lower intermediate values (but still higher than controls) when the tidal volume distending the ventilated lung was reduced by 50%. Main pathophysiological alterations associated with NVLI were: extensive lung collapse; very low pulmonary perfusion; high inspiratory airways pressure; and higher concentrations of acute-phase inflammatory cytokines IL-6, IL-1β and TNF-α and of Angiopoietin-2 (a marker of endothelial activation) in the broncho-alveolar lavage. Only the last two alterations were mitigated by reducing tidal volume, potentially explaining partial protection. Conclusions Non-ventilated lung injury develops within 24 h of controlled mechanical ventilation due to multiple pathophysiological alterations, which are only partially prevented by low tidal volume.

Background: Hydroxyurea (HU), also known as hydroxycarbamide, is an oral ribonucleotide reductase inhibitor. In 1999, the United States Food and Drug Administration (FDA) approved HU for the treatment of sickle cell disease (SCD). Since then, it has become the cornerstone in the management of SCD patients, helping to reduce vaso-occlusive crises, acute chest syndrome, the need for blood transfusions, hospitalizations and mortality. There is considerable variability among individuals in HU pharmacokinetic (Pk) parameters that can influence treatment efficacy and toxicity. The objective of this work is part of a clinical study aimed at investigating HU Pk and determining the optimal sampling time to estimate the Area Under the Curve (AUC) in SCD patients. Methods: HU plasma concentration in 80 patients at various time points (2, 4, 6, 24 h) following a 48-h drug washout was quantified using High-Pressure Liquid Chromatography (HPLC) coupled with an ultraviolet (UV) detection method previously described in the literature and adapted to new conditions with partial modifications. Results: The mean HU administered dose was 19.5 ± 5.1 mg/kg (range: 7.7–37.5 mg/kg). The median AUC quantified in plasma patients was 101.3 mg/L/h (Interquartile Range (IQR): 72.5–355.9) and it was not influenced by the weight-based dose. However, there was a strong positive correlation between AUC and Body Mass Index (BMI) as well as dose per Body Surface Area (BSA). Along with a three-point approach for AUC determination present in the literature, we show results obtained from a four-point sampling strategy, which is more useful and effective for better optimizing dose escalation to the maximum tolerated dose (MTD). Moreover, we observed that most patients achieved the maximum HU plasma concentration two hours after drug administration, regardless of age differences. Conclusions: HU treatment, which represents a milestone in the treatment of SCD due to its ability to reduce disease complications and improve patients’ quality of life, requires careful monitoring to optimize the individual dose for saving potential side effects and/or adverse events.

ABSTRACT Objective: To identify, synthesize, and analyze the scientific knowledge produced regarding the implications of using clinical simulation for undergraduate nursing or medical students' motivation for learning. Methods: The search for articles was conducted between July 28 and August 3, 2022, on the PubMed/MEDLINE, Scopus, Web of Science, and SciELO databases. The following was used for the search: P - undergraduate students attending Nursing or Medicine courses; C - motivation for learning, and C - skills and clinical simulation laboratory. The following research question guided the study: “What are the implications of clinical simulation on the motivation for learning of undergraduate students of nursing and medicine?” Of the 1,783 articles found, 13 were included in the sample for analysis. All stages of the selection process were carried out by two independent evaluators. The results were presented as charts and a discursive report. Results: The studies analyzed indicated the beneficial effects of clinical simulation on students' motivation, in addition to other gains such as competencies, technical and non-technical skills, knowledge, belonging, autonomy, clinical judgment, critical and reflective thinking, self-efficacy and decreased anxiety, self-management, and improvements in learning and learning climate. Conclusion: Clinical simulation provides a positive learning environment favorable to the development of technical and interpersonal skills and competencies, and raising the level of motivational qualities.

La enfermedad de Meniere así como la pérdida progresiva de la audición son consideradas como idiopáticas. Las mismas se deben a un hidrops endolinfático y posterior disrupción de diversas estructuras del oído interno, que conducen al vértigo o a la sordera progresiva. Desde hace algún tiempo estas enfermedades han sido consideradas como autoinmunes. La respuesta inmunológica ataca a variadas estructuras, en el oído interno está presente el colágeno tipo II. El propósito de este trabajo en correlacic r la presencia de IgG anti colágeno tipo II ei pacientes afectados de Meniere, pérdida progresiva de la audición y compararlos con pérdida súbita de la audición, vértigo de origen vascular y controles normales. Para este trabajo hemos estudiado a 71 pacientes con manifestaciones compatibles con diferentes enfermedades relacionadas con el oído interno. Las mismas se dividieron en: Enfermedad de Meniere (n:27), Pérdida progresiva de la audición (n: 20), Pérdida súbita de la audición (n: 15), Vértigo vascular (n:9) y 30 controles normales de similar edad y proporciones de sexo. A todos los pacientes y controles se les practicó dosaje de IgG específica para colágeno tipo II por ELISA. Se consideró determinación positiva cuando era más de 2 DS de la media de los normales. Resultados:1° El grupo Meniere presentó IgG específica para colágeno II (+) en 22 de 27 casos, p

Abstract Background Media fills are used to demonstrate the adequacy of the aseptic conditions of a pharmaceutical production process, according to good manufacturing practice (GMP), using a growth medium in place of the product solution. For advanced therapy medicinal product (ATMP), where the final product consists of viable cells, the media fill is still a challenge, but represents the starting point for process validation. Methods The aim of this paper is to describe the media fill test procedure in the context of ATMP manufacturing, in particular of Cytokine-Induced Killer (CIK) cell expansion process under GMP conditions, including quality control tests and environmental monitoring. The media fill test has been designed to cover all the critical steps of the process, including worst cases and deviations. Results From July 2019 to August 2022, we performed 16 media fill tests. During these years, the media fill protocol has been gradually improved and the worst cases were designed to be closer to reality and occurring cases. Although some deviations occurred, all the media fills performed were compliant. Conclusions A good media fill design combined with a robust environmental monitoring program provides a high degree of assurance of the microbial safety of ATMPs.

Abstract Mathematical models based on partial differential equations (PDEs) can be exploited to handle clinical data with space/time dimensions, e.g. tumor growth challenged by neoadjuvant therapy. A model based on simplified assessment of tumor malignancy and pharmacodynamics efficiency was exercised to discover new metrics of patient prognosis in the OLTRE trial. We tested in a 17-patients cohort affected by early-stage triple negative breast cancer (TNBC) treated with 3 weeks of olaparib, the capability of a PDEs-based reactive–diffusive model of tumor growth to efficiently predict the response to olaparib in terms of SUVmax detected at 18FDG-PET/CT scan, by using specific terms to characterize tumor diffusion and proliferation. Computations were performed with COMSOL Multiphysics. Driving parameters governing the mathematical model were selected with Pearson's correlations. Discrepancies between actual and computed SUVmax values were assessed with Student’s t test and Wilcoxon rank sum test. The correlation between post-olaparib true and computed SUVmax was assessed with Pearson’s r and Spearman’s rho. After defining the proper mathematical assumptions, the nominal drug efficiency (εPD) and tumor malignancy (r c) were computationally evaluated. The former parameter reflected the activity of olaparib on the tumor, while the latter represented the growth rate of metabolic activity as detected by SUVmax. εPD was found to be directly dependent on basal tumor-infiltrating lymphocytes (TILs) and Ki67% and was detectable through proper linear regression functions according to TILs values, while r c was represented by the baseline Ki67-to-TILs ratio. Predicted post-olaparib SUV*max did not significantly differ from original post-olaparib SUVmax in the overall, gBRCA-mutant and gBRCA-wild-type subpopulations (p > 0.05 in all cases), showing strong positive correlation (r = 0.9 and rho = 0.9, p

Background Adolescent malnutrition is a significant public health challenge in low-income and middle-income countries (LMICs), with long-term consequences for health and development. Community-based interventions have the potential to address multiple forms of malnutrition and improve the health outcomes of adolescents. However, there is a limited understanding of the content, implementation and effectiveness of these interventions. This scoping review aims to synthesise evidence on community-based interventions targeting multiple forms of malnutrition among adolescents in LMICs and describe their effects on nutrition and health.Methods and analysis A comprehensive search strategy will be implemented in multiple databases including MEDLINE (through PubMed), Embase, CENTRAL (through Cochrane Library) and grey literature, covering the period from 1 January 2000 to 14 July 2023. We will follow the Participants, Concept and Context model to design the search strategy. The inclusion criteria encompass randomised controlled trials and quasi-experimental studies focusing on adolescents aged 10–19 years. Various types of interventions, such as micronutrient supplementation, nutrition education, feeding interventions, physical activity and community environment interventions, will be considered. Two reviewers will perform data extraction independently, and, where relevant, risk of bias assessment will be conducted using standard Cochrane risk-of-bias tools. We will follow the PRISMA Extension for Scoping Reviews checklist while reporting results.Ethics and dissemination The scope of this scoping review is restricted to publicly accessible databases that do not require prior ethical approval for access. The findings of this review will be shared through publications in peer-reviewed journals, and presentations at international and regional conferences and stakeholder meetings in LMICs.Scoping review registration The final protocol was registered prospectively with the Open Science Framework on 19 July 2023 (https://osf.io/t2d78).

Summary: Small nucleolar RNAs (snoRNAs) have been identified dysregulated in several pathologies, and these alterations can be detected in tissues and in circulation. The main aim of this study was to analyze the whole snoRNome in advanced colorectal neoplasms and to identify new potential non-invasive snoRNA-based biomarkers in fecal samples by different analytical approaches. SNORA51, SNORD15B, SNORA54, SNORD12B, SNORD12C, SNORD72, SNORD89, and several members of SNORD115 and SNORD116 clusters were consistently deregulated in both tissue sets. After technical validation, SNORA51 and SNORD15B were detected in FIT+ samples. SNORA51 was significantly upregulated in FIT+ samples from CRC patients compared to healthy controls. This upregulation, together with the fecal hemoglobin concentration, was sufficient to identify, among FIT+ individuals, patients with CRC (AUC = 0.86) and individuals with advanced adenomas (AUC = 0.68). These findings portray snoRNAs as an alternative source of candidates for further studies and SNORA51 appears as a potential non-invasive biomarker for CRC detection.

Background and objectivesThe scarcity of data for training deep learning models in pediatrics has prompted questions about the feasibility of employing CNNs trained with adult images for pediatric populations. In this work, a pneumonia classification CNN was used as an exploratory example to showcase the adaptability and efficacy of such models in pediatric healthcare settings despite the inherent data constraints.MethodsTo develop a curated training dataset with reduced biases, 46,947 chest X-ray images from various adult datasets were meticulously selected. Two preprocessing approaches were tried to assess the impact of thoracic segmentation on model attention outside the thoracic area. Evaluation of our approach was carried out on a dataset containing 5,856 chest X-rays of children from 1 to 5 years old.ResultsAn analysis of attention maps indicated that networks trained with thorax segmentation placed less attention on regions outside the thorax, thus eliminating potential bias. The ensuing network exhibited impressive performance when evaluated on an adult dataset, achieving a pneumonia discrimination AUC of 0.95. When tested on a pediatric dataset, the pneumonia discrimination AUC reached 0.82.ConclusionsThe results of this study show that adult-trained CNNs can be effectively applied to pediatric populations. This could potentially shift focus towards validating adult models over pediatric population instead of training new CNNs with limited pediatric data. To ensure the generalizability of deep learning models, it is important to implement techniques aimed at minimizing biases, such as image segmentation or low-quality image exclusion.

Abstract In this study we examined the combined association of physical activity and sitting time with cardiometabolic risk factors in adults in Chile. This is a cross-sectional study based on 3201 adults aged from 18 to 98 years from the Chilean National Health Survey (2016–2017) who responded to the GPAQ questionnaire. Participants were considered inactive if spent

Background Population distribution of reduced diffusing capacity of the lungs for carbon monoxide (DLCO) in smokers and main consequences are not properly recognised. The objectives of this study were to describe the prevalence of reduced DLCO in a population-based sample of current and former smoker subjects without airflow limitation and to describe its morphological, functional and clinical implications.Methods A sample of 405 subjects aged 40 years or older with postbronchodilator forced expiratory volume in 1 s/forced vital capacity (FVC) >0.70 was obtained from a random population-based sample of 9092 subjects evaluated in the EPISCAN II study. Baseline evaluation included clinical questionnaires, exhaled carbon monoxide (CO) measurement, spirometry, DLCO determination, 6 min walk test, routine blood analysis and low-dose CT scan with evaluation of lung density and airway wall thickness.Results In never, former and current smokers, prevalence of reduced DLCO was 6.7%, 14.4% and 26.7%, respectively. Current and former smokers with reduced DLCO without airflow limitation were younger than the subjects with normal DLCO, and they had greater levels of dyspnoea and exhaled CO, greater pulmonary artery diameter and lower spirometric parameters, 6 min walk distance, daily physical activity and plasma albumin levels (all p

Abstract Cedrela species occur within the Tropical montane cloud forest (TMCF) and rainforest in North America (Mexico), Central and South America. We assessed the hypothesis that functional xylem hydraulic architecture might be influenced by specific climatic variations. We investigated the effect of climate on tree-ring width and vessel traits (diameter, vessel density, vulnerability index and hydraulic diameter) of three relict-endemic and threatened Cedrela species (Cedrela fissilis, C. nebulosa and C. angustifolia) inhabiting Peruvian Tropical Andean cloud forests. All Cedrela species showed a significant reduction in radial growth and adjusted vessel trait linked with temperature, precipitation, and evapotranspiration. Ring-width and vessel traits showed adaptation within Cedrela species, crucial to understanding a rough indication of the plant’s ability to withstand drought-induced embolism or cavitation. Our results provide evidence for hydraulic mechanisms that determine specific wood anatomical functionality to climatic variation and drought responses. Therefore, changing the frequency or intensity of future drought events might exceed the adaptive limits of TMCF tree species, resulting in a substantial reduction of hydraulic functionality in Peruvian Cedrela species.

Abstract Understanding the responses of insect herbivores to plant chemical defences is pivotal for the management of crops and pests. However, the mechanisms of interaction are not entirely understood. In this study, we compared the whole transcriptome gene expression of the aphid Macrosiphum euphorbiae grown on two different varieties of tomato that differ in their inducible chemical defences. We used two isogenic lines of tomato with a shared genetic background that only differ in the presence of type IV glandular trichomes and their associated acylsucrose excretions. This works also reports a de novo transcriptome of the aphid M. euphorbiae. Subsequently, we identified a unique and distinct gene expression profile for the first time corresponding to aphid´s exposure to type IV glandular trichomes and acylsugars. The analysis of the aphid transcriptome shows that tomato glandular trichomes and their associated secretions are highly efficient in triggering stress-related responses in the aphid, and demonstrating that their role in plant defence goes beyond the physical impediment of herbivore activity. Some of the differentially expressed genes were associated with carbohydrate, lipid and xenobiotic metabolisms, immune system, oxidative stress response and hormone biosynthesis pathways. Also, the observed responses are compatible with a starvation syndrome. The transcriptome analysis puts forward a wide range of genes involved in the synthesis and regulation of detoxification enzymes that reveal important underlying mechanisms in the interaction of the aphid with its host plant and provides a valuable genomic resource for future study of biological processes at the molecular level using this aphid.

Abstract This study aims to establish cut-off points for the number of minutes of physical activity intensity and the number of daily steps that identify overweight/obesity in adolescents, adults, and older adults. This study examined data from 2737 participants. Physical activity intensity and the number of daily steps were assessed using GT3X+ ActiGraph model accelerometers. Body mass index, waist-to-height ratio, and waist-to-hip ratio were used as indicators of overweight/obesity. The cut-off points for moderate-to-vigorous physical activity for the prevention of overweight/obesity according to body mass index in women ranged from 15.1 to 30.2 min/day; in men, the values were from 15.4 to 33.8 min/day. The lowest cut-off point for daily steps was established in the adolescent group for women and men (7304 and 5162). The highest value in women was 11,412 (51–65 years) and 13,234 in men (18–30 years). Results from measurements different from BMI, show average cut-off points for moderate-to-vigorous physical activity and daily steps of 29.1/8348 and 43.5/10,456 according to waist-to-height ratio; and results of 29.3/11,900 and 44.3/11,056 according to the waist-to-hip ratio; in women and men respectively. A more specific recommendation of physical activity and daily steps adjusted by sex and age range is suggested to prevent overweight/obesity.

Histological transformation (HT) to a more aggressive disease–mostly diffuse large B-cell lymphoma–is considered one of the most dismal events in the clinical course of follicular lymphoma (FL). Current knowledge has not found a single biological event specific for HT, although different studies have highlighted common genetic alterations, such as TP53 and CDKN2A/B loss, and MYC translocations, among others. Together, they increase genomic complexity and mutational burden at HT. A better knowledge of HT pathogenesis would presumably help to find diagnostic biomarkers allowing the identification of patients at high-risk of transformation, as well as the discrimination from patients with FL recurrence, and those who remain in remission. This would also help to identify new drug targets and the design of clinical trials for the treatment of transformation. In the present review we provide a comprehensive overview of the genetic events frequently identified in transformed FL contributing to the switch towards aggressive behaviour, and we will discuss current open questions in the field of HT.

Abstract Coronavirus disease-19 (COVID-19) patients with severe complications present comorbidities like cardiovascular-disease, hypertension and type-2 diabetes mellitus (DM), sharing metabolic alterations like insulin resistance (IR) and dyslipidemia. Our objective was to evaluate the association among different components of the lipid-lipoprotein profile, such as remnant lipoprotein (RLP)-cholesterol, in patients with COVID-19, and to analyze their associations with the severity of the disease and death. We studied 193 patients (68 (29–96) years; 49.7% male) hospitalized for COVID-19 and 200 controls (46 (18–79) years; 52.5% male). Lipoprotein profile, glucose and procalcitonin were assessed. Patients presented higher glucose, TG, TG/HDL-cholesterol and RLP-cholesterol levels, but lower total, LDL, HDL and no-HDL-cholesterol levels (p

Introducción: El cambio climático global podría alterar la circulación del virus sincicial respiratorio (VSR). Objetivo: Evaluar modificaciones en la circulación de VSR en los últimos 25 años y su correlación con la temperatura ambiente. Métodos: Estudio transversal, utilizando registros de VSR y temperatura de la Ciudad de Buenos Aires (1995-2019). Para cada año, describimos inicio, fin y duración de la temporada de VSR y evaluamos su correlación con la temperatura media anual. Resultados: Se identificaron 10183 infecciones por VSR. La duración de la temporada disminuyó significativamente (1995: 29 semanas vs. 2019: 18 semanas; R: 0.6 (p< 0,001)), debido a una finalización más precoz (1995: semana 45 vs. 2019: semana 34; 0,6 (p

Summary: Background: While a low CD4/CD8 ratio during HIV treatment correlates with immunosenescence, its value in identifying patients at an increased risk for clinical events remains unclear. Methods: We analyzed data from the CoRIS cohort to determine whether CD4 count, CD8 count, and CD4/CD8 ratio at year two of antiretroviral therapy (ART) could predict the risk of serious non-AIDS events (SNAEs) during the next five years. These included major adverse cardiovascular events, non-AIDS-defining malignancies, and non-accidental deaths. We used pooled logistic regression with inverse probability weighting to estimate the survival curves and cumulative risk of clinical events. Findings: The study included 4625 participants, 83% male, of whom 200 (4.3%) experienced an SNAE during the follow-up period. A CD4/CD8 ratio

El examen clínico objetivo estructurado (ECOE) es una herramienta válida para medir competencias clínicas. En el contexto de la pandemia por COVID-19 se debieron adaptar las evaluaciones, habitualmente presenciales, a un formato virtual. El objetivo de este artículo es comunicar la experiencia de utilizar una modalidad virtual del ECOE para residentes de primer año de pediatría durante la pandemia por COVID-19. El ECOE comprendió 12 estaciones utilizando casos simulados en línea y consultas virtuales a distancia. Participaron del ECOE 115 residentes, aprobaron 110 (95,7%) y solo 17 participantes aprobaron el 100% de las estaciones. Las estaciones con mejor rendimiento fueron las referidas a alimentación complementaria, abordaje del traumatismo encéfalo craneano, interpretación de resultados de laboratorio y de imágenes radiológicas. El menor rendimiento se observó en uso de equipo de protección personal y vacunas. La encuesta de satisfacción fue respondida por 80/115 participantes (69,5%). El 91% de los participantes encontró fácil de utilizar la plataforma virtual. La mayoría (73/80) consideró que los temas fueron acordes al nivel de formación. La estación de pautas madurativas fue identificada como la más difícil. El 57% refirió que el ECOE les resultó útil para identificar puntos débiles en su formación. La implementación de una modalidad virtual del ECOE fue posible y presentó buena aceptación de los participantes.

Abstract Osteosarcoma is still associated with limited response to standard-of-care therapy and alarmingly elevated mortality rates, especially in low- and middle-income countries. Despite multiple efforts to repurpose β-blocker propranolol in oncology, its potential application in osteosarcoma management remains largely unexplored. Considering the unsatisfied clinical needs of this aggressive disease, we evaluated the antitumoral activity of propranolol using different in vitro and in vivo osteosarcoma preclinical models, alone or in addition to chemotherapy. Propranolol significantly impaired cellular growth in β2-adrenergic receptor-expressing MG-63 and U-2OS cells, and was capable of blocking growth-stimulating effects triggered by catecholamines. siRNA-mediated ADRB2 knockdown in MG-63 cells was associated with decreased cell survival and a significant attenuation of PPN anti-osteosarcoma activity. Direct cytostatic effects of propranolol were independent of apoptosis induction and were associated with reduced mitosis, G0/G1 cell cycle arrest and a significant down-regulation of cell cycle regulator Cyclin D1. Moreover, colony formation, 3D spheroid growth, cell chemotaxis and capillary-like tube formation were drastically impaired after propranolol treatment. Interestingly, anti-migratory activity of β-blocker was associated with altered actin cytoskeleton dynamics. In vivo, propranolol treatment (10 mg/kg/day i.p.) reduced the early angiogenic response triggered by MG-63 cells in nude mice. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agent cisplatin. Sustained administration of propranolol (10 mg/kg/day i.p., five days a week), alone and especially in addition to low-dose metronomic cisplatin (2 mg/kg/day i.p., three times a week), markedly reduced xenograft progression. After histological analysis, propranolol and cisplatin combination resulted in low tumor mitotic index and increased tumor necrosis. β-blockade using propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness. Further translational studies of propranolol repurposing in osteosarcoma are warranted.

Abstract Surveillance of malaria vector species and the monitoring of insecticide resistance are essential to inform malaria control strategies and support the reduction of infections and disease. Genetic barcoding of mosquitoes is a useful tool to assist the high-throughput surveillance of insecticide resistance, discriminate between sibling species and to detect the presence of Plasmodium infections. In this study, we combined multiplex PCR, custom designed dual indexing, and Illumina next generation sequencing for high throughput single nucleotide polymorphism (SNP)-profiling of four species from the Anopheles (An.) gambiae complex (An. gambiae sensu stricto, An. coluzzii, An. arabiensis and An. melas). By amplifying and sequencing only 14 genetic fragments (500 bp each), we were able to simultaneously detect Plasmodium infection; insecticide resistance-conferring SNPs in ace1, gste2, vgsc and rdl genes; the partial sequences of nuclear ribosomal internal transcribed spacers (ITS1 and ITS2) and intergenic spacers (IGS), Short INterspersed Elements (SINE), as well as mitochondrial genes (cox1 and nd4) for species identification and genetic diversity. Using this amplicon sequencing approach with the four selected An. gambiae complex species, we identified a total of 15 non-synonymous mutations in the insecticide target genes, including previously described mutations associated with resistance and two new mutations (F1525L in vgsc and D148E in gste2). Overall, we present a reliable and cost-effective high-throughput panel for surveillance of An. gambiae complex mosquitoes in malaria endemic regions.

Abstract Background The “HER2-low” nomenclature identifies breast carcinomas (BCs) displaying a HER2 score of 1+/2+ in immunohistochemistry and lacking ERBB2 amplification. Whether HER2-low BCs (HLBCs) constitute a distinct entity is debated. Methods We performed DNA and RNA high-throughput analysis on 99 HLBC samples (n = 34 cases with HER2 score 1+/HLBC-1, n = 15 cases with HER2 score 2+ and ERBB2 not amplified/HLBC-2N, and n = 50 cases with score 2+ and ERBB2 copy number in the equivocal range/HLBC-2E). We compared the mutation rates with data from 1317 samples in the Memorial Sloan-Kettering Cancer Center (MSKCC) BC cohort and gene expression data with those from an internal cohort of HER2-negative and HER2-positive BCs. Results The most represented mutations affected PIK3CA (31/99, 31%), GATA3 (18/99, 18%), TP53 (17/99, 17%), and ERBB2 (8/99, 8%, private to HLBC-2E). Tumor mutational burden was significantly higher in HLBC-1 compared to HLBC-2E/N (P = 0.04). Comparison of mutation spectra revealed that HLBCs were different from both HER2-negative and HER2-positive BCs, with HLBC-1 resembling more HER2-negative tumors and HLBC-2 mutationally related to HER2-addicted tumors. Potentially actionable alterations (annotated by using OncoKB/ESCAT classes) affected 52 patients. Intra-group gene expression revealed overlapping features between HLBC-1 and control HER2-negative BCs, whereas the HLBC-2E tumors showed the highest diversity overall. The RNA-based class discovery analysis unveiled four subsets of tumors with (i) lymphocyte activation, (ii) unique enrichment in HER2-related features, (iii) stromal remodeling alterations, and (iv) actionability of PIK3CA mutations (LAURA classification). Conclusions HLBCs harbor distinct genomic features when compared with HER2-positive and HER2-negative BCs; however, differences across IHC classes were also unveiled thus dissecting the full picture of heterogeneity across HER2-low disease. The HLBC-2E category harbors most distinctive features, whereas HLBC-1 seems superimposable to HER2-negative disease. Further studies are needed to ascertain whether the four genomic-driver classes of the LAURA classification hold prognostic and/or predictive implications.

Abstract Preterm infants have a low level of bone mineralization compared to those born at term. The purpose of the present study was to investigate the effect of reflex locomotion therapy (RLT) on bone mineralization and growth in preterm infants and compare its effect to other physiotherapy procedures. Forty-six preterm infants born at 29–34 weeks were randomized into three groups: one group received RLT (n = 17); the other group received passive movements with gentle joint compression (n = 14); and the control group received massages (n = 15). All the treatments were performed at the neonatal unit for one month. The main outcome measure was bone mineralization, which was measured using the tibial speed of sound (Tibial-SOS). All the groups were similar in terms of gestational age (31.8 ± 1.18), birth weight (1,583.41 ± 311.9), and Tibia-SOS (1,604.7 ± 27.9) at the beginning of the intervention. At the end of the study, significant differences were found among the groups in the Tibial-SOS [F(4,86) = 2.77, p = 0.049, ηp 2 = 0.114] in terms of the benefit to the RLT group. In conclusion, RLT has been effective at improving Tibial-SOS levels and has been more effective than other physical therapy modalities; therefore, it could be considered an effective physiotherapeutic modality for the prevention and treatment of osteopenia from prematurity.

Abstract In November 2015, cases of Zika virus infection were recorded in Cabo Verde (Africa), originating from Brazil. The outbreak subsided after seven months with 7580 suspected cases. We performed a serological survey (n = 431) in Praia, the capital city, 3 months after transmission ceased. Serum samples were screened for arbovirus antibodies using ELISA techniques and revealed seroconverted individuals with Zika (10.9%), dengue (1–4) (12.5%), yellow fever (0.2%) and chikungunya (2.6%) infections. Zika seropositivity was predominantly observed amongst females (70%). Using a logistic model, risk factors for increased odds of Zika seropositivity included age, self-reported Zika infection, and dengue seropositivity. Serological data from Zika and dengue virus assays were strongly correlated (Spearman’s rs = 0.80), which reduced when using a double antigen binding ELISA (Spearman’s rs = 0.54). Overall, our work improves an understanding of how Zika and other arboviruses have spread throughout the Cabo Verde population. It also demonstrates the utility of serological assay formats for outbreak investigations.

Abstract This study aimed to compare compliance with 24-h movement guidelines across countries and examine the associations with markers of adiposity in adults from eight Latin American countries. The sample consisted of 2338 adults aged 18–65 years. Moderate-to-vigorous physical activity (MVPA) and sedentary behavior (SB) data were objectively measured using accelerometers. Sleep duration was self-reported using a daily log. Body mass index and waist circumference were assessed as markers of adiposity. Meeting the 24-h movement guidelines was defined as ≥ 150 min/week of MVPA; ≤ 8 h/day of SB; and between 7 and 9 h/day of sleep. The number of guidelines being met was 0.90 (95% CI 0.86, 0.93) with higher value in men than women. We found differences between countries. Meeting two and three movement guidelines was associated with overweight/obesity (OR: 0.75, 95% CI 0.58, 0.97 and OR: 0.69, 95% CI 0.51, 0.85, respectively) and high waist circumference (OR: 0.74, 95% CI 0.56, 0.97 and OR: 0.77, 95% CI 0.62, 0.96). Meeting MVPA and SB recommendations were related to reduced adiposity markers but only in men. Future research is needed to gain insights into the directionality of the associations between 24-h movement guidelines compliance and markers of adiposity but also the mechanisms underlying explaining differences between men and women.

Objectives Despite several effective targeted therapies, biomarkers that predict whether a patient with psoriatic arthritis (PsA) will respond to a particular treatment are currently lacking.Methods We analysed proteomics data from serum samples of nearly 2000 patients with PsA in placebo-controlled phase-III clinical trials of the interleukin-17 inhibitor secukinumab. To discover predictive biomarkers of clinical response, we used statistical learning with controlled feature selection. The top candidate was validated using an ELISA and was separately assessed in a trial of almost 800 patients with PsA treated with secukinumab or the tumour necrosis factor inhibitor adalimumab.Results Serum levels of beta-defensin 2 (BD-2) at baseline were found to be robustly associated with subsequent clinical response (eg, American College of Rheumatology definition of 20%, 50% and 70% improvement) to secukinumab, but not to placebo. This finding was validated in two independent clinical studies not used for discovery. Although BD-2 is known to be associated with psoriasis severity, the predictivity of BD-2 was independent of baseline Psoriasis Area and Severity Index. The association between BD-2 and response to secukinumab was observed as early as 4 weeks and maintained up to 52 weeks. BD-2 was also found to predict response to treatment with adalimumab. Unlike in PsA, BD-2 was not predictive of response to secukinumab in rheumatoid arthritis.Conclusions In PsA, BD-2 at baseline is quantitatively associated with clinical response to secukinumab. Patients with high levels of BD-2 at baseline reach and sustain higher rates of clinical response after treatment with secukinumab.

Infection by Brucella species in pregnant animals and humans is associated with an increased risk of abortion, preterm birth, and transmission of the infection to the offspring. The pathogen has a marked tropism for the placenta and the pregnant uterus and has the ability to invade and replicate within cells of the maternal–fetal unit, including trophoblasts and decidual cells. Placentitis is a common finding in infected pregnant animals. Several proinflammatory factors have been found to be increased in both the placenta of Brucella-infected animals and in trophoblasts or decidual cells infected in vitro. As normal pregnancies require an anti-inflammatory placental environment during most of the gestational period, Brucella-induced placentitis is thought to be associated with the obstetric complications of brucellosis. A few studies suggest that the blockade of proinflammatory factors may prevent abortion in these cases.

Introducción: La contaminación del aire incrementaría el riesgo de infección respiratoria aguda (IRA) en pediatría. Objetivo: evaluar el impacto de la contaminación del aire en las consultas por IRA realizadas en efectores del Gobierno de la Ciudad de Buenos Aires. Método: estudio ecológico, de series temporales. Fuentes de información: Agencia de Protección Ambiental, Servicio Meteorológico Nacional e Historia de Salud Integral del Sistema de Gestión Hospitalaria. Población: Pacientes menores de 2 años que consultaron por IRA a un efector del GCBA y que residían en una comuna con monitoreo ambiental continuo, durante el 2018. Variables de predicción: Niveles diarios de CO, NO2, PM10 de las estaciones de monitoreo ambiental continuo de la Ciudad Autónoma de Buenos Aires. Variables de resultado: número de consultas totales y por IRA. Variables a controlar: efector, sexo y temperatura media. Se construyó una definición operativa para seleccionar en la base de datos a las consultas objeto de estudio. Resultados: Se registraron 80.287 consultas, 24.847 por IRA (30%). Las consultas por IRA tuvieron correlación positiva en la estación “Córdoba” con el N2O (RR: 1,13 [1,00-1,28]). El número de consultas por IRA en los meses fríos fue mayor que en los cálidos (19,9% vs 11,9%; RR:1,67 [1,61-1,72]). Conclusión: Los valores promedios de PM10 y N2O muestran correlación con el número de las consultas totales y por infección respiratoria aguda, respectivamente. Las consultas se incrementaron durante el invierno.

Normal development of the immune system is essential for overall health and disease resistance. Bony fish, such as the zebrafish (Danio rerio), possess all the major immune cell lineages as mammals and can be employed to model human host response to immune challenge. Zebrafish neutrophils, for example, are present in the transparent larvae as early as 48 hours post fertilization and have been examined in numerous infection and immunotoxicology reports. One significant advantage of the zebrafish model is the ability to affordably generate high numbers of individual larvae that can be arrayed in multi-well plates for high throughput genetic and chemical exposure screens. However, traditional workflows for imaging individual larvae have been limited to low-throughput studies using traditional microscopes and manual analyses. Using a newly developed, parallelized microscope, the Multi-Camera Array Microscope (MCAM™), we have optimized a rapid, high-resolution algorithmic method to count fluorescently labeled cells in zebrafish larvae in vivo. Using transgenic zebrafish larvae, in which neutrophils express EGFP, we captured 18 gigapixels of images across a full 96-well plate, in 75 seconds, and processed the resulting datastream, counting individual fluorescent neutrophils in all individual larvae in 5 minutes. This automation is facilitated by a machine learning segmentation algorithm that defines the most in-focus view of each larva in each well after which pixel intensity thresholding and blob detection are employed to locate and count fluorescent cells. We validated this method by comparing algorithmic neutrophil counts to manual counts in larvae subjected to changes in neutrophil numbers, demonstrating the utility of this approach for high-throughput genetic and chemical screens where a change in neutrophil number is an endpoint metric. Using the MCAM™ we have been able to, within minutes, acquire both enough data to create an automated algorithm and execute a biological experiment with statistical significance. Finally, we present this open-source software package which allows the user to train and evaluate a custom machine learning segmentation model and use it to localize zebrafish and analyze cell counts within the segmented region of interest. This software can be modified as needed for studies involving other zebrafish cell lineages using different transgenic reporter lines and can also be adapted for studies using other amenable model species.

Systemic AA-amyloidosis is a protein-misfolding disease characterized by fibril deposition of serum amyloid-A protein (SAA) in several organs in humans and many animal species. Fibril deposits originate from abnormally high serum levels of SAA during chronic inflammation. A high prevalence of AA-amyloidosis has been reported in captive cheetahs and a horizontal transmission has been proposed. In domestic cats, AA-amyloidosis has been mainly described in predisposed breeds but only rarely reported in domestic short-hair cats. Aims of the study were to determine AA-amyloidosis prevalence in dead shelter cats. Liver, kidney, spleen and bile were collected at death in cats from 3 shelters. AA-amyloidosis was scored. Shedding of amyloid fibrils was investigated with western blot in bile and scored. Descriptive statistics were calculated. In the three shelters investigated, prevalence of AA-amyloidosis was 57.1% (16/28 cats), 73.0% (19/26) and 52.0% (13/25), respectively. In 72.9% of cats (35 in total) three organs were affected concurrently. Histopathology and immunofluorescence of post-mortem extracted deposits identified SAA as the major protein source. The duration of stay in the shelters was positively associated with a histological score of AA-amyloidosis (B = 0.026, CI95% = 0.007-0.046; p = 0.010). AA-amyloidosis was very frequent in shelter cats. Presence of SAA fragments in bile secretions raises the possibility of fecal-oral transmission of the disease. In conclusion, AA-amyloidosis was very frequent in shelter cats and those staying longer had more deposits. The cat may represent a natural model of AA-amyloidosis.

External causes continue to be one of the main causes of mortality in the world and Cabo Verde is no exception. Economic evaluations can be used to demonstrate the disease burden of public health problems such as injuries and external causes and support prioritization of interventions aimed at improving the health of the population. The objective of this study was to estimate the indirect costs of premature mortality in 2018 due to injuries and other consequences of external causes in Cabo Verde. Years of potential life lost, years of potential productive life lost and human capital approach were used to estimate the burden and indirect costs of premature mortality. In 2018, 244 deaths were registered due to injury and other consequences of external causes. Males were responsible for 85.4% and 87.73% of years of potential life lost and years of potential productive life lost, respectively. The cost of productivity lost due to premature death caused by injury was 4,580,225.91 USD. The social and economic burden due to trauma was substantial. There is a need for more evidence on the burden of disease due to injuries and their consequences, to support the implementation of targeted multi-sectoral strategies and policies for the prevention, management, and reduction of costs due to injuries in Cabo Verde.

Abstract The unstructured nature of Real-World (RW) data from onco-hematological patients and the scarce accessibility to integrated systems restrain the use of RW information for research purposes. Natural Language Processing (NLP) might help in transposing unstructured reports into standardized electronic health records. We exploited NLP to develop an automated tool, named ARGO (Automatic Record Generator for Onco-hematology) to recognize information from pathology reports and populate electronic case report forms (eCRFs) pre-implemented by REDCap. ARGO was applied to hemo-lymphopathology reports of diffuse large B-cell, follicular, and mantle cell lymphomas, and assessed for accuracy (A), precision (P), recall (R) and F1-score (F) on internal (n = 239) and external (n = 93) report series. 326 (98.2%) reports were converted into corresponding eCRFs. Overall, ARGO showed high performance in capturing (1) identification report number (all metrics > 90%), (2) biopsy date (all metrics > 90% in both series), (3) specimen type (86.6% and 91.4% of A, 98.5% and 100.0% of P, 92.5% and 95.5% of F, and 87.2% and 91.4% of R for internal and external series, respectively), (4) diagnosis (100% of P with A, R and F of 90% in both series). We developed and validated a generalizable tool that generates structured eCRFs from real-life pathology reports.

Abstract The phase angle is a versatile measurement to assess body composition, frailty and prognosis in patients with chronic diseases. In cirrhosis, patients often present alterations in body composition that are related to adverse outcomes. The phase angle could be useful to evaluate prognosis in these patients, but data are scarce. The aim was to analyse the prognostic value of the phase angle to predict clinically relevant events such as hospitalisation, falls, and mortality in patients with cirrhosis. Outpatients with cirrhosis were consecutively included and the phase angle was determined by electrical bioimpedance. Patients were prospectively followed to determine the incidence of hospitalisations, falls, and mortality. One hundred patients were included. Patients with phase angle ≤ 4.6° (n = 31) showed a higher probability of hospitalisation (35% vs 11%, p = 0.003), falls (41% vs 11%, p = 0.001) and mortality (26% vs 3%, p = 0.001) at 2-year follow-up than patients with PA > 4.6° (n = 69). In the multivariable analysis, the phase angle and MELD-Na were independent predictive factors of hospitalisation and mortality. Phase angle was the only predictive factor for falls. In conclusion, the phase angle showed to be a predictive marker for hospitalisation, falls, and mortality in outpatients with cirrhosis.

Abstract For their stability and detectability faecal microRNAs represent promising molecules with potential clinical interest as non-invasive diagnostic and prognostic biomarkers. However, there is no evidence on how stool miRNA profiles change according to an individual’s age, sex, and body mass index (BMI) or how lifestyle habits influence the expression levels of these molecules. We explored the relationship between the stool miRNA levels and common traits (sex, age, BMI, and menopausal status) or lifestyle habits (physical activity, smoking status, coffee, and alcohol consumption) as derived by a self-reported questionnaire, using small RNA-sequencing data of samples from 335 healthy subjects. We detected 151 differentially expressed miRNAs associated with one variable and 52 associated with at least two. Differences in miR-638 levels were associated with age, sex, BMI, and smoking status. The highest number of differentially expressed miRNAs was associated with BMI (n = 92) and smoking status (n = 84), with several miRNAs shared between them. Functional enrichment analyses revealed the involvement of the miRNA target genes in pathways coherent with the analysed variables. Our findings suggest that miRNA profiles in stool may reflect common traits and lifestyle habits and should be considered in relation to disease and association studies based on faecal miRNA expression.

Abstract CD157/BST-1 (a member of the ADP-ribosyl cyclase family) is expressed at variable levels in 97% of patients with acute myeloid leukemia (AML), and is currently under investigation as a target for antibody-based immunotherapy. We used peripheral blood and bone marrow samples from patients with AML to analyse the impact of CD157-directed antibodies in AML survival and in response to cytarabine (AraC) ex vivo. The study was extended to the U937, THP1 and OCI-AML3 AML cell lines of which we engineered CD157-low versions by shRNA knockdown. CD157-targeting antibodies enhanced survival, decreased apoptosis and reduced AraC toxicity in AML blasts and cell lines. CD157 signaling activated the PI3K/AKT/mTOR and MAPK/ERK pathways and increased expression of Mcl-1 and Bcl-XL anti-apoptotic proteins, while decreasing expression of Bax pro-apoptotic protein, thus preventing Caspase-3 activation. The primary CD157-mediated anti-apoptotic mechanism was Bak sequestration by Mcl-1. Indeed, the Mcl-1-specific inhibitor S63845 restored apoptosis by disrupting the interaction of Mcl-1 with Bim and Bak and significantly increased AraC toxicity in CD157-high but not in CD157-low AML cells. This study provides a new role for CD157 in AML cell survival, and indicates a potential role of CD157 as a predictive marker of response to therapies exploiting Mcl-1 pharmacological inhibition.

Abstract Cryoablation is safe and effective for the treatment of atrial fibrillation (AF) in controlled clinical trials, but contemporary real-world usage and outcomes are limited. The Report of the Spanish Cryoballoon Ablation Registry (RECABA) was designed to evaluate acute and 12-month outcomes of cryoballoon ablation for the treatment of AF in Spain. Patients from 27 Spanish centers were prospectively enrolled. Patients were treated with cryoballoon ablation and managed according to standard of care protocols at each center. The primary endpoint was ≥ 30 s freedom from AF at 12-month after a 3-month blanking period. Secondary endpoints included a description of patient characteristics, cryoablation procedural strategy and safety, and predictors of efficacy. In total, 1742 patients (71.4% PAF, 68.8% male, mean age 58.02 ± 10.40 years, 76.1% overweight or obese, CHA2DS2-VASc index 1.40 ± 1.28) were enrolled. Patients received 7.2 ± 2.67 cryo-applications. PV potentials could be detected in 61% of the PVs during ablation, with a mean time to block of 52.9 ± 37.02 s. Acute PVI was observed in 97% of PVs with 75.8% isolated with the first cryo-application. Mean procedural time was 113 ± 41 min. Acute complications occurred in 4.4% of the cases. With follow-up in 1628 patients, AF-free survival was 78.5% (PAF: 80.6% vs PersAF 73.3%; p

Patients with congenital heart disease (CHD) seem to have a higher risk for specific malignancies. We hypothesize a pathogenetic link between particular congenital heart defects and cancer originating from specific cellular lineages. We report a series of patients, followed in two high-volume referral centers, with CHD involving neural crest-derived structures who developed cancer later in life. Fourteen patients (five female) developed neoplasia with a cellular origin embryologically linked to the neural crest between 2010 and 2020. If confirmed on larger datasets, this observation might support the hypothesis of common embryogenetic pathway suggesting tailored surveillance of a specific subset of patients.

Summary: Background: Despite that pediatric COVID-19 is usually asymptomatic or mild, SARS-CoV-2 infection typically results in the development of an antibody response. Contradictory observations have been reported when the antibody response of children and adults were compared in terms of strength, specificity and perdurability. Methods: This observational study includes three cohorts infected with SARS-CoV-2 between March 2020-July 2021: unvaccinated infected children (n=115), unvaccinated infected adults (n=62), and vaccinated infected children (n=76). Plasma anti-spike IgG antibodies and neutralising activity against Wuhan, Delta and Omicron variants after 7-17 months post-infection were analysed. Findings: More than 95% of unvaccinated infected children and adults remained seropositive when evaluated at 382-491 and 386-420 days after infection, respectively. Anti-spike IgG titers and plasma neutralising activity against Wuhan, Delta and Omicron variants were higher in children compared to adults. No differences were found when unvaccinated infected children were stratified by age, gender or presence/absence of symptoms in the acute phase of SARS-CoV-2 infection, but a slight decrease in the antibody response was observed in those with comorbidities. Vaccination of previously infected children with two doses of the inactivated BBIBP-CorV or the mRNA vaccines, BNT162b2 and/or mRNA-1273, further increased anti-spike IgG titers and neutralising activity against Wuhan, Delta and Omicron variants. Interpretation: Unvaccinated infected children mount a more potent and sustained antibody response compared with adults, which is significantly increased after vaccination. Further studies including not only the analysis of the immune response but also the effectiveness to prevent reinfections by the different Omicron lineages are required to optimise vaccination strategy in children. Funding: National Agency for Scientific and Technological Promotion from Argentina (PICTO-COVID-SECUELAS-00007 and PMO-BID-PICT2018-2548).