Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers.

BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

Unreported ent-rosane diterpenes from Croton niveus Jacq. (Euphorbiaceae). Cytotoxic activity and docking studies.

From the bioactive extract of the euphorbiaceous Croton niveus Jacq., three previously unreported ent-rosane diterpenes have been isolated and characterized by conventional methods, in addition to the known compounds lupeol, cajucarinolide and some phytosterols. Two of the ent-rosane diterpenes displayed activity against HCT-15 and PC-3 cancer cell lines, and the results of docking calculations of these compounds with NF-κB and STAT3 receptors agreed with the proposed mode of action of diterpenes against PC-3 cells.

Drug Repurposing to Inhibit Histamine N-Methyl Transferase.

Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer's disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme-drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC50 = 72.89 µM and 45.01 µM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.

Hipoglicemia y factores asociados en recién nacidos: Un estudio observacional de centro único / Hypoglycemia and associated factors in neonates: A single-center observational study

Introducción: La hipoglicemia neonatal (HN) es una de las patologías metabólicas más frecuentes en el periodo neonatal, que aumentan la morbi-mortalidad en el recién nacido y que puede dejar secuelas de forma permanente; sin embargo, podría ser prevenida o diagnosticada y tratada tempranamente. El objetivo del presente estudio fue determinar los factores asociados a hipoglicemia neonatal, en recién nacidos del servicio de neonatología en un hospital público Vicente Corral Mosco-so en Cuenca-Ecuador. Métodos: El presente estudio de casos y controles, realizado de enero del 2018 a diciembre del 2019. Pareados por edad gestacional, sexo y residencia materna. Ingresaron al estudio pacientes con HN durante los primeros 7 días de vida. Los controles no presentaron HN. La muestra se tomó por conveniencia. Las variables fueron: Diabetes gestacional, Diabetes Mellitus tipo II no controlada, Pequeño para la edad gestacional, Macrosómico, Síndrome de dificultad respiratoria, Restricción del crecimiento intrauterino. La asociación se cuantificó mediante Odds Ratio con un Intervalo de Confianza del 95%. Resultados: Fueron 101 casos y 202 controles homogéneos en edad gestacional, sexo y, residencia materna (P>0.05). Los factores asociados a hipoglicemia neonatal estadísticamente significativos fueron: pequeños para la edad gestacional (OR 2.54; IC 1.54-4.20; P<0.001) y restricción del crecimiento intrauterino (OR 2,1; IC 1,29-3,54; P=0.003); mientras que diabetes gestacional (OR 1.2; IC 0.37-4.88; P=0.649), macrosomía (OR 1.2; IC 0.28-5.1; P=0.800) y, síndrome de dificultad respiratoria (OR 0.89; IC 0.54-1.47; P=0.672), no fueron estadísticamente significativos. Conclusión: La hipoglicemia neonatal está asociada a los factores como restricción del crecimiento intrauterino y pequeño para la edad gestacional.

Introduction: Neonatal hypoglycemia (NH) is one of the most frequent metabolic pathologies in the neonatal period. It increases morbidity and mortality in the newborn and can leave permanent sequelae; however, it can be prevented, diagnosed, and treated early. This study aimed to determine the factors associated with neonatal hypoglycemia in new-borns from the neonatology service at a Vicente Corral Moscoso public hospital in Cuenca-Ecuador. Methods: This case‒control study was conducted from January 2018 to December 2019. Matched by gestational age, sex, and maternal residence. Patients with NH entered the study during the first seven days of life, and the controls did not present NH. The sample was taken for convenience. The variables were gestational diabetes, uncontrolled type II diabetes mellitus, small for gestational age, macrosomal, respiratory distress syndrome, and intrauterine growth restriction. The association was quantified using the odds ratio with a confidence interval of 95%. Results: A total of 101 cases and 202 controls were homogeneous in gestational age, sex, and maternal residence (P>0.05). The factors associated with statistically significant neonatal hypoglycemia were small for gestational age (OR 2.54; CI 1.54-4.20; P<0.001) and intrauterine growth restriction (OR 2.1; CI 1.29-3.54; P= 0.003), while gestational diabetes (OR 1.2; IC 0.37-4.88; P=0.649), macrosomia (OR 1.2; IC 0.28-5.1; P=0.800) and respiratory distress syndrome (OR 0.89; IC 0.54-1.47; P=0.672) were not statistically significant. Conclusion: Neonatal hypoglycemia is associated with factors such as intrauterine growth restriction and small for gestational age.

Phytochemicals That Interfere With Drug Metabolism and Transport, Modifying Plasma Concentration in Humans and Animals.

Phytochemicals (Pch) present in fruits, vegetables and other foods, are known to inhibit or induce drug metabolism and transport. An exhaustive search was performed in five databases covering from 2000 to 2021. Twenty-one compounds from plants were found to modulate CYP3A and/or P-gp activities and modified the pharmacokinetics and the therapeutic effect of 27 different drugs. Flavonols, flavanones, flavones, stilbenes, diferuloylmethanes, tannins, protoalkaloids, flavans, hyperforin and terpenes, reduce plasma concentration of cyclosporine, simvastatin, celiprolol, midazolam, saquinavir, buspirone, everolimus, nadolol, tamoxifen, alprazolam, verapamil, quazepam, digoxin, fexofenadine, theophylline, indinavir, clopidogrel. Anthocyanins, flavonols, flavones, flavanones, flavonoid glycosides, stilbenes, diferuloylmethanes, catechin, hyperforin, alkaloids, terpenes, tannins and protoalkaloids increase of plasma concentration of buspirone, losartan, diltiazem, felodipine, midazolam, cyclosporine, triazolam, verapamil, carbamazepine, diltiazem, aripiprazole, tamoxifen, doxorubicin, paclitaxel, nicardipine. Interactions between Pchs and drugs affect the gene expression and enzymatic activity of CYP3A and P-gp transporter, which has an impact on their bioavailability; such that co-administration of drugs with food, beverages and food supplements can cause a subtherapeutic effect or overdose. Therefore, it is important for the clinician to consider these interactions to obtain a better therapeutic effect.

Demographic and clinical characterization of pediatric group patients with inborn errors of the immune system in a Colombian tertiary hospital.

INTRODUCTION: In recent decades, there has been a growing increase in the diagnosis of patients with inborn errors of the immune system, formerly known as primary immunodeficiency disorders (PIDs). Timely diagnosis remains a challenge due to low clinical suspicion and poor education on the subject. It is estimated that between 70% and 90% of these pathologies remain underdiagnosed in our environment. OBJECTIVE: The objective of this study is to characterize the demographic and clinical presentation of pediatric group patients with inborn errors of the immune system in a Colombian tertiary hospital. METHODS: Retrospective descriptive study of 306 patients with a diagnosis of innate errors of the immune system who consulted the PID clinic between 2011 and 2018 in a high-complexity institution in Cali, Colombia. RESULTS: Three-hundred and six patients were included. The median age was 4 years (IQR 2.3-7.7 years), and 59.5% of the patients were male. According to the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency classification for inborn errors of the immune system, the most common group was antibody deficiency in 74.8% (n˂229), especially in the age group between 1 and 5 years. The least frequent in our population was complement deficiency. Of the warning signs stipulated for these pathologies, the most frequent were the (1) need for intravenous antibiotics (32%), (2) difficulty growing (15.7%), (3) four or more episodes of ear infection (10.8%), and (4) abscesses in organs or cutaneous abscesses (12.7%). No patient reported two or more episodes of pneumonia or sinusitis, and only 5.8% of the patients received a bone marrow transplant. CONCLUSIONS: Innate errors of the immune system require an early diagnosis with follow-up from an early age to ensure adequate management and follow-up in order to reduce morbidity and mortality. It is imperative to sensitize the medical population about the existence of these pathologies so that early intervention can be carried out, which improves the quality of life of patients and their families.

[Deliberative dialogue with Ibero-American universities on interventions in student mental health during the COVID-19 pandemicDiálogo deliberativo com universidades ibero-americanas sobre intervenções em saúde mental dos estudantes na pandemia de COVID-19]. / Diálogo deliberativo con universidades iberoamericanas sobre intervenciones en salud mental estudiantil durante la pandemia de COVID-19.

Objective: To contextualize a synthesis of evidence on interventions in student mental health during the COVID-19 pandemic through a deliberative dialogue with Ibero-American universities. Methods: An evidence synthesis and synchronous dialogues were previously conducted, consisting of subgroup discussions about the design and implementation of mental health interventions. An analysis of dialogic data was conducted, then organized by topic. Results: Fifty-seven representatives of 17 public and private Ibero-American universities participated in the meeting. In terms of the design of interventions, mental health is perceived as neglected, although its profile was raised by the pandemic. Interventions are guided by detection of needs; scientific evidence is rarely used to design them. Importance was given to forming an interdisciplinary team with continuous training in order to design a specific program that also covers families and teaching/administrative staff. In terms of implementation, problems include saturation of services due to high demand and lack of basic resources among students. Regarding the provision of resources, the influence of the broader context, including the institutional context, is undeniable. The dialogues were perceived as an opportunity to build a new set of interventions. Conclusions: These dialogues enriched the description of interventions already described in the literature on student mental health during the COVID-19 pandemic. However, implementing such interventions in the region means addressing previous neglect and a high level of unmet basic needs.

Objetivo: Contextualizar uma síntese de evidências sobre intervenções em saúde mental de estudantes universitários na pandemia de COVID-19, por meio do diálogo deliberativo com universidades ibero-americanas. Métodos: A partir de uma síntese de evidências previamente elaborada, o diálogo síncrono foi conduzido por meio de discussões em subgrupos sobre o planejamento e a implementação de intervenções em saúde mental. Os dados obtidos foram analisados e resumidos por área temática. Resultados: Cinquenta e sete integrantes de 17 universidades ibero-americanas públicas e privadas participaram do encontro. Os participantes indicaram que a saúde mental é negligenciada no planejamento das intervenções, mas ganhou visibilidade na pandemia. As intervenções são direcionadas às necessidades identificadas e raramente planejadas com base em evidências científicas. Disseram considerar importante formar uma equipe interdisciplinar com capacitação contínua para planejar um programa específico que englobe também familiares e o corpo docente e administrativo. Implementar intervenções é complicado porque os serviços estão sobrecarregados devido à grande demanda e à falta de recursos básicos para os estudantes. O contexto macro e institucional claramente influencia a disponibilização de recursos. O diálogo foi visto como uma oportunidade para consolidar um novo conjunto de intervenções. Conclusões: O presente diálogo contribuiu para enriquecer a literatura de intervenções de saúde mental para estudantes universitários na pandemia de COVID-19. Implementar intervenções no nosso contexto requer sanar as falhas por negligência passada e as enormes necessidades básicas não atendidas.

Risk factors and incidence of cytomegalovirus viremia and disease in pediatric patients with allogeneic hematopoietic stem cell transplantation: An 8-year single-center experience in Latin America.

BACKGROUND: Cytomegalovirus infection represents a significant cause of morbidity and mortality after hematopoietic stem cell transplantation. This study aimed to evaluate the incidence of viremia and disease due to cytomegalovirus and the risk factors in pediatric patients with hematopoietic stem cell transplantation in our institution. METHODS: This was a retrospective cohort of patients under 19 years of age who underwent allogeneic hematopoietic stem cell transplantation due to any indication between 2012 and 2019. The analysis included the diagnosis of cytomegalovirus viremia or disease during post-transplant follow-up, evaluation of risk factors, and outcomes. The statistical analysis included univariate and multivariate analyses, and the cumulative incidence of cytomegalovirus viremia was determined by the Kaplan-Meier method using STATA 14 statistical software. RESULTS: A total of 182 transplants were included. At 100 days, the cumulative incidence of cytomegalovirus viremia was 70.5%, and that of cytomegalovirus disease was 4.7%. Overall survival at 2 years was 74%, and event-free survival was 64%. The remaining demographic characteristics were not predictors of infection. There was no association between viremia and relapse or survival of the patients. Higher mortality was noted in cytomegalovirus disease. CONCLUSIONS: During the study period, the incidence of cytomegalovirus disease was similar to that of other pediatric reports, but the incidence of viremia was higher. Pre-emptive therapy has diminished disease rates and death due to infection. Viral load cutoff points should be standardized to guide treatment and avoid myelotoxicity.

Diálogo deliberativo con universidades iberoamericanas sobre intervenciones en salud mental estudiantil durante la pandemia de COVID-19

[RESUMEN]. Objetivo. Contextualizar una síntesis de evidencia sobre intervenciones en salud mental estudiantil durante la pandemia de la enfermedad por el coronavirus 2019 (COVID-19, por su sigla en inglés) por medio de un diálogo deliberativo con universidades iberoamericanas. Métodos. Se realizó previamente una síntesis de evidencia y un diálogo sincrónico, que consistió en la discusión en subgrupos acerca del diseño y aplicación de las intervenciones en salud mental. Se realizó un análisis de datos dialógicos y se sintetizó por temas. Resultados. Cincuenta y siete miembros de 17 universidades iberoamericanas públicas y privadas participaron en el encuentro. En el diseño de las intervenciones, se percibe la salud mental como desatendida, y visibilizada con la pandemia. La detección de necesidades es la que orienta las intervenciones y rara vez se utiliza evidencia científica para diseñarlas. Se considera importante conformar un equipo interdisciplinario con capacitación continua para diseñar un programa específico, que cubra también familias y personal docente y administrativo. En la aplicación, existen problemas como la saturación de los servicios por la alta demanda y la falta de recursos básicos de los estudiantes. Es innegable la influencia del contexto macro e institucional por la disposición de recursos. El diálogo fue percibido como oportunidad para construir un consolidado nuevo de intervenciones. Conclusiones. Este diálogo permitió enriquecer la descripción de intervenciones en salud mental estudiantil durante la pandemia de COVID-19 ya descritas en la literatura, aunque llevarlas a la práctica en nuestro contexto supone hacer frente a la deuda por la desatención previa y las altas necesidades básicas insatisfechas.

[ABSTRACT]. Objective. To contextualize a synthesis of evidence on interventions in student mental health during the COVID-19 pandemic through a deliberative dialogue with Ibero-American universities. Methods. An evidence synthesis and synchronous dialogues were previously conducted, consisting of subgroup discussions about the design and implementation of mental health interventions. An analysis of dialogic data was conducted, then organized by topic. Results. Fifty-seven representatives of 17 public and private Ibero-American universities participated in the meeting. In terms of the design of interventions, mental health is perceived as neglected, although its profile was raised by the pandemic. Interventions are guided by detection of needs; scientific evidence is rarely used to design them. Importance was given to forming an interdisciplinary team with continuous training in order to design a specific program that also covers families and teaching/administrative staff. In terms of implementation, problems include saturation of services due to high demand and lack of basic resources among students. Regarding the provision of resources, the influence of the broader context, including the institutional context, is undeniable. The dialogues were perceived as an opportunity to build a new set of interventions. Conclusions. These dialogues enriched the description of interventions already described in the literature on student mental health during the COVID-19 pandemic. However, implementing such interventions in the region means addressing previous neglect and a high level of unmet basic needs.

[RESUMO]. Objetivo. Contextualizar uma síntese de evidências sobre intervenções em saúde mental de estudantes universitários na pandemia de COVID-19, por meio do diálogo deliberativo com universidades ibero-americanas. Métodos. A partir de uma síntese de evidências previamente elaborada, o diálogo síncrono foi conduzido por meio de discussões em subgrupos sobre o planejamento e a implementação de intervenções em saúde mental. Os dados obtidos foram analisados e resumidos por área temática. Resultados. Cinquenta e sete integrantes de 17 universidades ibero-americanas públicas e privadas participaram do encontro. Os participantes indicaram que a saúde mental é negligenciada no planejamento das intervenções, mas ganhou visibilidade na pandemia. As intervenções são direcionadas às necessidades identificadas e raramente planejadas com base em evidências científicas. Disseram considerar importante formar uma equipe interdisciplinar com capacitação contínua para planejar um programa específico que englobe também familiares e o corpo docente e administrativo. Implementar intervenções é complicado porque os serviços estão sobrecarregados devido à grande demanda e à falta de recursos básicos para os estudantes. O contexto macro e institucional claramente influencia a disponibilização de recursos. O diálogo foi visto como uma oportunidade para consolidar um novo conjunto de intervenções. Conclusões. O presente diálogo contribuiu para enriquecer a literatura de intervenções de saúde mental para estudantes universitários na pandemia de COVID-19. Implementar intervenções no nosso contexto requer sanar as falhas por negligência passada e as enormes necessidades básicas não atendidas.

Factors Associated With Hospitalization or Intensive Care Admission in Children With COVID-19 in Latin America.

Background: Limited data is available from low-middle and upper-middle income countries of the factors associated with hospitalization or admission to pediatric intensive care unit (PICU) for children with COVID-19. Objective: To describe the factors associated with hospitalization or PICU admission of children with COVID-19 in Latin America. Method: Multicenter, analytical, retrospective study of children reported from 10 different Latin American countries to the Latin-American Society of Pediatric Infectious Diseases (SLIPE-COVID) research network from June 1, 2020, and February 28, 2021. Outpatient or hospitalized children <18 years of age with COVID-19 confirmed by polymerase chain reaction or antigen detection from the nasopharynx were included. Children with multisystem inflammatory syndrome in children (MIS-C) were excluded. Associations were assessed using univariate and multivariable logistic regression models. Results: A total of 1063 children with COVID-19 were included; 500 (47%) hospitalized, with 419 (84%) to the pediatric wards and 81 (16%) to the ICU. In multivariable analyses, age <1 year (Odds Ratio [OR] 1.78; 95% CI 1.08-2.94), native race (OR 5.40; 95% CI 2.13-13.69) and having a co-morbid condition (OR 5.3; 95% CI 3.10-9.15), were associated with hospitalization. Children with metabolic or endocrine disorders (OR 4.22; 95% CI 1.76-10.11), immune deficiency (1.91; 95% CI 1.05-3.49), preterm birth (OR 2.52; 95% CI 1.41-4.49), anemia at presentation (OR 2.34; 95% CI 1.28-4.27), radiological peribronchial wall thickening (OR 2.59; 95% CI 1.15-5.84) and hypoxia, altered mental status, seizures, or shock were more likely to require PICU admission. The presence of pharyngitis (OR 0.34; 95% CI 0.25-0.48); myalgia (OR 0.47; 95% CI 0.28-0.79) or diarrhea (OR 0.38; 95% CI 0.21-0.67) were inversely associated with hospital admission. Conclusions: In this data analysis reported to the SLIPE research network in Latin America, infants, social inequalities, comorbidities, anemia, bronchial wall thickening and specific clinical findings on presentation were associated with higher rates of hospitalization or PICU admission. This evidence provides data for prioritization prevention and treatment strategies for children suffering from COVID-19.

Prophylaxis for invasive fungal infection in pediatric patients with allogeneic hematopoietic stem cell transplantation.

Background: Antifungal prophylaxis is recommended for hematopoietic stem cell transplantation (HSCT) to decrease the incidence of invasive fungal infections (IFI). This study aimed to compare the two groups of antifungal prophylaxis in pediatric patients undergoing allogeneic HSCT. Methods: This observational, analytic, retrospective cohort study compared the incidence of IFI with antifungal prophylaxis with voriconazole vs. other antifungals in the first 100 days after allogeneic HSCT in patients aged <18 years between 2012 and 2018. The statistical analysis included univariate and multivariate analyses and determination of the cumulative incidence of invasive fungal infection by the Kaplan‒Meier method using STATA 14 statistical software. Results: A total of 139 allogeneic HSCT were performed. The principal diagnosis was acute leukemia (63%). The 75% had haploidentical donors, and 50% used an antifungal in the month before transplantation. Voriconazole (69%) was the most frequently administered antifungal prophylaxis. The cumulative incidence of IFI was 5% (7 cases). Of the patients with IFIs, four began prophylaxis with voriconazole, one with caspofungin, and one with fluconazole. Additionally, six were possible cases, one was proven (Candida parapsilosis), and 1/7 died. Conclusion: There were no differences in the incidence of IFI between patients who received prophylaxis with voriconazole and other antifungal agents.

Increase in ADAR1p110 activates the canonical Wnt signaling pathway associated with aggressive phenotype in triple negative breast cancer cells.

Triple-negative breast cancer (TNBC) represents a challenge in the search for new therapeutic targets. TNBCs are aggressive and generate resistance to chemotherapy. Tumors of TNBC patients with poor prognosis present a high level of adenosine deaminase acting on RNA1 (ADAR1). We explore the connection of ADAR1 with the canonical Wnt signaling pathway and the effect of modulation of its expression in TNBC. Expression data from cell line sequencing (DepMap) and TCGA samples were downloaded and analyzed. We lentivirally generated an MDA-MB-231 breast cancer cell line that overexpress (OE) ADAR1p110 or an ADAR knockdown. Abundance of different proteins related to Wnt/ß-catenin pathway and activity of nuclear ß-catenin were analyzed by Western blot and luciferase TOP/FOP reporter assay, respectively. Cell invasion was analyzed by matrigel assay. In mice, we study the behavior of tumors generated from ADAR1p110 (OE) cells and tumor vascularization immunostaining were analyzed. ADAR1 connects to the canonical Wnt pathway in TNBC. ADAR1p110 overexpression decreased GSK-3ß, while increasing active ß-catenin. It also increased the activity of nuclear ß-catenin and increased its target levels. ADAR1 knockdown has the opposite effect. MDA-MB-231 ADAR1 (OE) cells showed increased capacity of invasion. Subsequently, we observed that tumors derived from ADAR1p110 (OE) cells showed increased invasion towards the epithelium, and increased levels of Survivin and CD-31 expressed in vascular endothelial cells. These results indicate that ADAR1 overexpression alters the expression of some key components of the canonical Wnt pathway, favoring invasion and neovascularization, possibly through activation of the ß-catenin, which suggests an unknown role of ADAR1p110 in aggressiveness of TNBC tumors.

Diálogo deliberativo con universidades iberoamericanas sobre intervenciones en salud mental estudiantil durante la pandemia de COVID-19 / Deliberative dialogue with Ibero-American universities on interventions in student mental health during the COVID-19 pandemic / Diálogo deliberativo com universidades ibero-americanas sobre intervenções em saúde mental dos estudantes na pandemia de COVID-19

RESUMEN Objetivo. Contextualizar una síntesis de evidencia sobre intervenciones en salud mental estudiantil durante la pandemia de la enfermedad por el coronavirus 2019 (COVID-19, por su sigla en inglés) por medio de un diálogo deliberativo con universidades iberoamericanas. Métodos. Se realizó previamente una síntesis de evidencia y un diálogo sincrónico, que consistió en la discusión en subgrupos acerca del diseño y aplicación de las intervenciones en salud mental. Se realizó un análisis de datos dialógicos y se sintetizó por temas. Resultados. Cincuenta y siete miembros de 17 universidades iberoamericanas públicas y privadas participaron en el encuentro. En el diseño de las intervenciones, se percibe la salud mental como desatendida, y visibilizada con la pandemia. La detección de necesidades es la que orienta las intervenciones y rara vez se utiliza evidencia científica para diseñarlas. Se considera importante conformar un equipo interdisciplinario con capacitación continua para diseñar un programa específico, que cubra también familias y personal docente y administrativo. En la aplicación, existen problemas como la saturación de los servicios por la alta demanda y la falta de recursos básicos de los estudiantes. Es innegable la influencia del contexto macro e institucional por la disposición de recursos. El diálogo fue percibido como oportunidad para construir un consolidado nuevo de intervenciones. Conclusiones. Este diálogo permitió enriquecer la descripción de intervenciones en salud mental estudiantil durante la pandemia de COVID-19 ya descritas en la literatura, aunque llevarlas a la práctica en nuestro contexto supone hacer frente a la deuda por la desatención previa y las altas necesidades básicas insatisfechas.

ABSTRACT Objective. To contextualize a synthesis of evidence on interventions in student mental health during the COVID-19 pandemic through a deliberative dialogue with Ibero-American universities. Methods. An evidence synthesis and synchronous dialogues were previously conducted, consisting of subgroup discussions about the design and implementation of mental health interventions. An analysis of dialogic data was conducted, then organized by topic. Results. Fifty-seven representatives of 17 public and private Ibero-American universities participated in the meeting. In terms of the design of interventions, mental health is perceived as neglected, although its profile was raised by the pandemic. Interventions are guided by detection of needs; scientific evidence is rarely used to design them. Importance was given to forming an interdisciplinary team with continuous training in order to design a specific program that also covers families and teaching/administrative staff. In terms of implementation, problems include saturation of services due to high demand and lack of basic resources among students. Regarding the provision of resources, the influence of the broader context, including the institutional context, is undeniable. The dialogues were perceived as an opportunity to build a new set of interventions. Conclusions. These dialogues enriched the description of interventions already described in the literature on student mental health during the COVID-19 pandemic. However, implementing such interventions in the region means addressing previous neglect and a high level of unmet basic needs.

RESUMO Objetivo. Contextualizar uma síntese de evidências sobre intervenções em saúde mental de estudantes universitários na pandemia de COVID-19, por meio do diálogo deliberativo com universidades ibero-americanas. Métodos. A partir de uma síntese de evidências previamente elaborada, o diálogo síncrono foi conduzido por meio de discussões em subgrupos sobre o planejamento e a implementação de intervenções em saúde mental. Os dados obtidos foram analisados e resumidos por área temática. Resultados. Cinquenta e sete integrantes de 17 universidades ibero-americanas públicas e privadas participaram do encontro. Os participantes indicaram que a saúde mental é negligenciada no planejamento das intervenções, mas ganhou visibilidade na pandemia. As intervenções são direcionadas às necessidades identificadas e raramente planejadas com base em evidências científicas. Disseram considerar importante formar uma equipe interdisciplinar com capacitação contínua para planejar um programa específico que englobe também familiares e o corpo docente e administrativo. Implementar intervenções é complicado porque os serviços estão sobrecarregados devido à grande demanda e à falta de recursos básicos para os estudantes. O contexto macro e institucional claramente influencia a disponibilização de recursos. O diálogo foi visto como uma oportunidade para consolidar um novo conjunto de intervenções. Conclusões. O presente diálogo contribuiu para enriquecer a literatura de intervenções de saúde mental para estudantes universitários na pandemia de COVID-19. Implementar intervenções no nosso contexto requer sanar as falhas por negligência passada e as enormes necessidades básicas não atendidas.

Comparative Bioavailability and Pharmacokinetics Between the Solid Form of Metformin vs a Novel Liquid Extemporaneous Formulation in Children.

Metformin pharmacokinetics in a liquid extemporaneous formulation from commercial tablets was determined in paediatric patients. A randomized, transversal clinical trial was conducted in 34 children and adolescents between 7 and 17 years of age. 17 children were randomized to take metformin in the liquid formulation and, after a 1-week wash period, a 500 mg metformin tablet was administered to them. Blood samples were obtained in Whatman 903® cards at 0, 1, 2, 4, 8, 12 and 24 hours. Extraction was made by direct precipitation with acetonitrile (ACN) and methanol, detection by UPLC and tandem mass spectrometry. The method was accurate, precise, selective and linear from 50 to 1000 ng/mL (r = .9982). Comparative pharmacokinetics, tablet vs formulation, were as follows: Cmax 1503.2 ng/mL vs 1521.4, Tmax 1.5 h vs 2.3, and half-life 8.2 vs 7.5 h. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, and the ratios (90% CI) of geometric mean for metformin were 100.63% (89.13-113.6), 98.08% (88.04-109.2), and 97.52% (84.9-112.01), for Cmax, AUC0-t, and AUC 0-∞, respectively. Pharmacokinetics was determined using WinNonlin Pro 3.1 software. The liquid formulation of metformin showed similar pharmacokinetics to the tablet, allowing a more precise dose adjustment and ease of administration.

Pediatric hemophagocytic lymphohistiocytosis: A rarely diagnosed entity in a developing country.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an exaggerated inflammatory reaction secondary to a host's inadequate immune response causing a self-perpetuating loop of altered regulation. Signs and symptoms of HLH are compatible with other common diseases and are nonspecific. Underdiagnosis makes it difficult to estimate the real incidence of HLH, especially in developing countries. METHODS: Retrospective, descriptive study of pediatric patients admitted to a high-complexity institution in Cali, Colombia between 2012 and 2019 with HLH diagnosis. Medical history review to complete an electronic database and a secondary, descriptive analysis was carried out. The study was approved by the Institutional Ethics Committee. RESULTS: Twenty-one patients were included. 52.4 % of the population was male with a median age of 9.3 years [IQR (3.0-13.7 years)]. More than half of patients (66.6 %) had viral disease at diagnosis, the most frequent being Epstein-Barr Virus (EBV) (52.3 %) and dengue (14.3 %). Three patients had confirmed gene mutations (G6PC3, XIAP, and UNC13D). 95 % of the patients were treated with the HLH 2004 protocol, half of them received incomplete protocol with intravenous immunoglobulin (IVIG) and/or systemic steroids, while the other half received the complete protocol including etoposide and cyclosporine. More than three-fourths (76.2 %) required admission to an ICU with a median stay of 14 days [IQR (11-37 days)] and a median hospital stay of 30 days [IQR (18-93 days)]. 14.3 % (n = 3) of patients died. CONCLUSIONS: HLH is a complex disease that requires multidisciplinary management with secondary HLH due to EBV infection being a common cause. There is increasing awareness of HLH diagnosis in developing countries such as Colombia which can offer earlier treatment options and better outcomes.

Intervenciones para la salud mental de estudiantes universitarios durante la pandemia por COVID-19: una síntesis crítica de la literatura / Mental health interventions for college and university students during the COVID-19 pandemic: a critical synthesis of the literature

RESUMEN Introducción: Los estudiantes de educación superior son una población vulnerable a los trastornos mentales, más aún durante la pandemia por COVID-19. Su salud mental se ha visto afectada por el confinamiento, las dificultades en el desarrollo de las actividades académicas y las exigencias de las nuevas modalidades pedagógicas. Se planteó entonces la pregunta: en las instituciones de educación superior, ¿cuáles acciones en torno a a) promoción y prevención, b) atención a síntomas mentales y c) adaptaciones pedagógicas pueden desarrollarse con el fin de mejorar la salud mental de sus estudiantes? Métodos: Síntesis crítica a partir de la revisión sistemática de la literatura. Se realizó la búsqueda de artículos científicos de alcance descriptivo, analítico, experimental o evaluativo, así como recursos web de organizaciones relacionadas con el tema. Se realizó una síntesis en función de los 3 focos de la pregunta mediante comparación constante, hasta realizar la agrupación de acciones por similitud en los actores que las ejecutarían y recibirían. Se anticipó una baja calidad de la evidencia, por lo que no se realizó evaluación estandarizada. Resultados: Se exploraron 68 artículos y 99 recursos web. Después de la revisión del texto completo se incluyeron 12 artículos científicos y 11 recursos web. Como lineamentos generales, se encontró que la propuesta más frecuente es el diseño de un programa estructurado específico para el tema de salud mental en las instituciones educativas, que sea multidisciplinario, incluyente, dinámico y sensible a la cultura. Las acciones deben ser divulgadas periódicamente para que los estudiantes y demás miembros de la comunidad educativa las tengan claras, e idealmente se propone mantenerlas hasta el periodo pospandémico e incluir a los egresados. Para a) la promoción y prevención, se encontró la psicoeducación por vía electrónica, donde se expliquen estilos de vida saludable, reacciones emocionales en pandemia, estrategias de afrontamiento y signos de alarma. Se propone la participación de los pares como estrategia de apoyo y espacios de interacción social que no se enfoquen únicamente en aspectos académicos. Se reporta la necesidad de cribar síntomas mentales por medio de envío frecuente de formularios en línea o aplicaciones móviles, donde también se indague por la satisfacción de las necesidades básicas y tecnológicas. En cuanto a b) atención de síntomas mentales, una de las acciones que se encontró con mayor frecuencia es disponer de un centro de consultoría que sea capaz de realizar atención en salud mental por vía telefónica, por tecnologías e incluso presencial, con atención permanente las 24 h o equipos de respuesta rápida ante una situación de crisis, como la conducta suicida y la violencia doméstica. Para c) las adaptaciones pedagógicas, se señala como requisito indispensable la comunicación fluida para tener instrucciones claras sobre el desarrollo de las actividades académicas para disminuir la incertidumbre y, por ende, la ansiedad y favorecer la gestión del tiempo por el estudiante. Los profesores y pedagogos de la institución pueden ofrecer asesorías directas (por videollamadas o reuniones de grupos en línea) para proveer apoyo en hábitos de estudios, materias propias de cada carrera y salud mental. Conclusiones: Los recursos incluidos proponen que la institución educativa cree un programa que aborde específicamente la salud mental de los estudiantes. Esta síntesis puede proveer lineamientos que faciliten la toma de decisiones, sin perder de vista que la institución y el estudiante están inmersos en un contexto complejo, con circunstancias y otros actores en varios niveles que también intervienen en la salud mental. Se requieren investigaciones sobre la evolución de la situación de salud mental y el efecto de las acciones que se vayan tomando.

ABSTRACT Background: College and university students are a population vulnerable to mental disorders, especially during the COVID-19 pandemic. Their mental health has been affected by confinement, difficulties in the development of academic activities, and the demands of new pedagogical modalities. We aimed to respond to the question: what are the actions around a) promotion and prevention, b) mental symptoms care, and c) pedagogical adaptations that can be developed in order to improve the mental health of college and university students? Methods: We conducted a critical synthesis from a systematic review of the literature. A search was made for scientific articles with descriptive, analytical, empirical or evaluative designs, as well as web resources of organizations related to the topic. A synthesis was carried out based on the three aspects of the question by means of a constant comparative method, until the aggregation of actions by similarity in the actors. We anticipated low evidence quality; therefore, a standardized evaluation was not performed. Results: We explored 68 articles and 99 web resources. After reviewing the full text, 12 scientific articles and 11 web resources were included. As general guidelines, we found that the most frequent suggestion is the design of a specific structured mental health program within universities, one that should be multidisciplinary, inclusive, dynamic and culturally sensitive. All actions taken by the university should be reported and published periodically so that students and other members of the university community are clear about them. Ideally, it is suggested to keep them until the post-pandemic period and include alumni. Regarding a) promotion and prevention, digital psychoeducation was recommended, with information about healthy lifestyles, common emotional reactions to epidemics, coping strategies and warning signs. Peer participation is suggested as a support strategy, as well as spaces for social interaction that focus not only on academic aspects but also on leisure. Screening for mental symptoms is suggested through frequent submission of online forms or mobile applications. In addition to mental health, it is important to inquire about the degree of satisfaction of basic and technology-related needs. For b) the care of mental symptoms, one of the actions commonly identified was a consulting centre that can provide mental health care by telephone, by technology, and even in person -if required -, with permanent availability with rapid response teams for crisis situations, such as suicidal behavior and domestic violence. For c) pedagogical adaptations, fluent communication is an indispensable requirement; having clear instructions on academic activities can reduce uncertainty and therefore anxiety. The teaching and pedagogical staff at the institution can offer direct advice (via video calls or online group meetings) to provide support in study habits, degree-specific material and mental health. Conclusions: Included resources suggest the creation of a program that specifically addresses the mental health of students. This synthesis can provide guidelines that facilitate decision-making by the university, without losing sight of the fact that the institution and the student are immersed in a complex context, with circumstances and other actors at various levels that also intervene in mental health. Research is required on the evolution of the mental health situation and the effect of the actions that are being taken.

Diagnósticos frecuentes de consulta externa de medicina general de la Universidad Santo Tomás (USTA), Bucaramanga, 2015-2017 / Frequent diagnosis in primary care physician services of the Santo Tomás University (USTA), Bucaramanga, 2015-2017

RESUMEN Objetivo Determinar los diagnósticos más frecuentes de los pacientes atendidos en el servicio de consulta externa de medicina general de la Universidad Santo Tomás (USTA), seccional Bucaramanga, entre 2015 y 2017. Método Estudio descriptivo retrospectivo de los registros diarios de pacientes atendidos en el servicio médico con un N=13 892 pacientes -estudiantes, administrativos, docentes, egresados y División de Educación Abierta y a Distancia (DUAD)-. Se excluyeron 5 907 registros para un n=7 985 datos de exploración, correspondientes a pacientes que hicieron uso exclusivamente del servicio de consulta médica. Resultados 5 808 (73%) de las consultas fueron realizadas por mujeres y 2 177 (27%) hombres; jóvenes entre 19 y 26 años (60,9%), estudiantes de pregrado (71,8%), de odontología (29,6%) y derecho (26,5%), atendidos por enfermedades del aparato respiratorio (16,4%), con afectaciones más frecuentes a adolescentes (15,4%) y jóvenes (17,2%). La rinofaringitis aguda fue el principal diagnóstico CIE-10. Los jóvenes consultaron por diarrea y gastroenteritis de presunto origen infeccioso (6,7%); los adultos (5,7%) y docentes (6,1%), por cervicalgia, y el personal administrativo, por infección viral no especificada (5,7%). Conclusiones La población atendida en consulta médica de la USTA entre 2015 y 2017 fueron principalmente mujeres y jóvenes entre 19 a 26 años. Las enfermedades transmisibles como las enfermedades del aparato respiratorio fueron más frecuentes que las enfermedades crónicas no transmisibles, principalmente la rinofaringitis aguda, enfermedad de alta transmisibilidad en comunidad. Las mujeres, adolescentes y estudiantes de pregrado, fueron atendidos en consulta por consejo y asesoramiento sobre la anticoncepción, lo que coincide con la Encuesta Nacional De Demografía y Salud.

ABSTRACT Objective To determine the most frequent diagnoses of the patients treated in primary medical care services of the Santo Tomás University (USTA, by its initials in Spanish), Bucaramanga section, between 2015 and 2017. Method A retrospective descriptive study of the daily records of patients treated in primary medical care services with an N=13 892 patients -students, administrative workers, professors, graduates, and Open and at Distance Education Division (DUAD, by its initials in Spanish)-. 5 907 records were excluded for a n=7 985 scan data corresponding to patients who used the medical consultation service exclusively. Results 5 808 (73%) of the consultations were conducted by women and 2 177 (27%) by men; young people between 19 and 26 years (60.9%), undergraduate students (71.8%), in dentistry (29.6%) and law (26.5%), people treated for respiratory diseases (16.4%), affected adolescents (15.4%) and young people (17.2%) more frequently. Acute rhinopharyngitis was the main diagnosis ICD-10. Young people consulted for diarrhea and gastroenteritis of suspected infectious origin (6.7%); adults (5.7%) and professors (6.1%), for neck pain, and administrative workers, for unspecified viral infection (5.7%). Conclusions The population who attended medical consultation of the Santo Tomás University in Bucaramanga throughout 2015-2017 were mainly women and young people between 19 and 26 years. Communicable diseases such as respiratory diseases were more frequent than chronic noncommunicable diseases, mainly acute rhinopharyngitis, a disease of high transmissibility in the community. Women, adolescents, and undergraduate students were treated in consultation for contraceptive counseling, which coincides with the National Demography and Health Survey.

Concordance Analysis of ALK Gene Fusion Detection Methods in Patients with Non-Small-Cell Lung Cancer from Chile, Brazil, and Peru.

About 4% to 7% of the non-small-cell lung cancer patients have anaplastic lymphoma kinase (ALK) rearrangements, and specific targeted therapies improve patients' outcomes significantly. ALK gene fusions are detected by immunohistochemistry or fluorescent in situ hybridization as gold standards in South America. Next-generation sequencing-based assays are a reliable alternative, able to perform simultaneous detection of multiple events from a single sample. We analyzed 4240 non-small-cell lung cancer samples collected in 37 hospitals from Chile, Brazil, and Peru, where ALK rearrangements were determined as part of their standard of care (SofC) using either immunohistochemistry or fluorescent in situ hybridization. A subset of 1450 samples was sequenced with the Oncomine Focus Assay (OFA), and the concordance with the SofC tests was measured. An orthogonal analysis was performed using a real-time quantitative PCR echinoderm microtubule-associated protein-like 4-ALK fusion detection kit. ALK fusion prevalence is similar for Chile (3.67%; N = 2142), Brazil (4.05%; N = 1013), and Peru (4.59%; N = 675). Although a comparison between OFA and SofC assays showed similar sensitivity, OFA had significantly higher specificity and higher positive predictive value, which opens new opportunities for a more specific determination of ALK gene rearrangements.

[Mental health interventions for college and university students during the COVID-19 pandemic: a critical synthesis of the literature]. / Intervenciones para la salud mental de estudiantes universitarios durante la pandemia por COVID-19: una síntesis crítica de la literatura.

BACKGROUND: College and university students are a population vulnerable to mental disorders, especially during the COVID-19 pandemic. Their mental health has been affected by confinement, difficulties in the development of academic activities, and the demands of new pedagogical modalities. We aimed to respond to the question: what are the actions around a) promotion and prevention, b) mental symptoms care, and c) pedagogical adaptations that can be developed in order to improve the mental health of college and university students? METHODS: We conducted a critical synthesis from a systematic review of the literature. A search was made for scientific articles with descriptive, analytical, empirical or evaluative designs, as well as web resources of organisations related to the topic. A synthesis was carried out based on the three aspects of the question by means of a constant comparative method, until the aggregation of actions by similarity in the actors. We anticipated low evidence quality; therefore, a standardised evaluation was not performed. RESULTS: We explored 68 articles and 99 web resources. After reviewing the full text, 12 scientific articles and 11 web resources were included. As general guidelines, we found that the most frequent suggestion is the design of a specific structured mental health programme within universities, one that should be multidisciplinary, inclusive, dynamic and culturally sensitive. All actions taken by the university should be reported and published periodically so that students and other members of the university community are clear about them. Ideally, it is suggested to keep them until the post-pandemic period and include alumni. Regarding a) promotion and prevention, digital psychoeducation was recommended, with information about healthy lifestyles, common emotional reactions to epidemics, coping strategies and warning signs. Peer participation is suggested as a support strategy, as well as spaces for social interaction that focus not only on academic aspects but also on leisure. Screening for mental symptoms is suggested through frequent submission of online forms or mobile applications. In addition to mental health, it is important to inquire about the degree of satisfaction of basic and technology-related needs. For b) the care of mental symptoms, one of the actions commonly identified was a consulting centre that can provide mental health care by telephone, by technology, and even in person --if required --, with permanent availability with rapid response teams for crisis situations, such as suicidal behaviour and domestic violence. For c) pedagogical adaptations, fluent communication is an indispensable requirement; having clear instructions on academic activities can reduce uncertainty and therefore anxiety. The teaching and pedagogical staff at the institution can offer direct advice (via video calls or online group meetings) to provide support in study habits, degree-specific material and mental health. CONCLUSIONS: Included resources suggest the creation of a programme that specifically addresses the mental health of students. This synthesis can provide guidelines that facilitate decision-making by the university, without losing sight of the fact that the institution and the student are immersed in a complex context, with circumstances and other actors at various levels that also intervene in mental health. Research is required on the evolution of the mental health situation and the effect of the actions that are being taken.

[Sucecesfull bone marrow transplantation in a case of familial hemophagocytic lymphohistiocytosis type 3]. / Trasplante de médula ósea exitoso en un caso de linfohistiocitosis hemofagocítica familiar tipo 3.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an exaggerated activation of the immune system which can be either primary (familial) or secondary. Familial hemophagocytic lymphohistiocytosis type 3 (FHL-3) is a severe immune disorder, caused by mutations in the UNC13D gene, which codes for a protein crucial to the cytotoxic function of lymphocytes. OBJECTIVE: To describe the diagnostic relevance of next-generation sequencing in the approach of a patient with suspected FHL and to demonstrate the effectiveness of bone marrow transplantation as the only curative measure. CLINICAL CASE: 4-year-old preschool male, previously healthy, who presented with mononucleosis syndrome and positive IgM for Epstein Barr virus, developing hepatosplenomegaly and progressive clinical de terioration. A lymphoproliferative syndrome was suspected, which was ruled out by bone marrow aspiration, finding evidence of active hemophagocytosis. The patient met the criteria for hemophago cytic syndrome (bone marrow aspiration, pancytopenia, elevated ferritin, and hypertriglyceridemia) and, given the lack of response to first-line management, including antiviral treatment, a possible primary etiology was considered. A molecular study was completed with NGS that was positive for FHL-3. Due to the progressive clinical deterioration, a bone marrow transplantation was performed, presenting successful results after the first year had elapsed. CONCLUSION: NGS is an indispensable tool in the diagnosis of FHL, mainly when the response to standard treatment is not adequate and facilitates the timely implementation of the necessary therapeutic measures.