Variables predictoras del compromiso laboral y académico en trabajadores y estudiantes de una universidad peruana / Predictive Variables of Work and Academic Engagement in Workers and Students of a Peruvian University / Variáveis preditoras do compromisso laboral e académico em trabalhadores e estudantes de uma universidade peruana

Resumen Objetivo. Analizar las variables personales, psicológicas y laborales o académicas que predicen el compromiso en trabajadores (docentes y administrativos) y estudiantes de una universidad peruana. El estudio 1 analiza el compromiso laboral, y el estudio 2, el compromiso académico. Método. En el estudio participaron 512 trabajadores y 1078 estudiantes de una universidad privada de Lima, Perú. A todos se les administró el SF-36, las escalas de Afectividad y Florecimiento que evalúan bienestar, la UWES-9 laboral o académica y la Escala de Eficacia Profesional del MBI para trabajadores y la de Autoeficacia Académica para los estudiantes. Resultados. Las variables predictoras más significativas del compromiso laboral fueron satisfacción con el trabajo (β = 0.34, p< 0.001), eficacia profesional (β = 0.21, p< 0.001) y florecimiento (β = 0.21, p< 0.001), y las del compromiso académico, satisfacción con la carrera (β = 0.35, p< 0.001), florecimiento (β = 0.33, p< 0.001) y autoeficacia académica (β = 0.19, p< 0.001). Conclusiones. Las variables predictoras del compromiso fueron similares en ambos estudios. Destacan la satisfacción con el trabajo o la carrera, la autoeficacia y el florecimiento, que es la dimensión del bienestar que supone una vida con sentido, caracterizada por la presencia de vínculos positivos y gratificantes.

Abstract Objectives. To analyze the personal, psychological and labor or academic variables that predict engagement in workers (professors and administrative workers) and students of a Peruvian university. Study 1 analyzes work engagement; Study 2, academic engagement. Method. The participants were 512 workers and 1078 students from a private university in Lima, Peru. All were administered the SF-36, the Affectivity and Flourishing scales that assess well-being, the Work or Academic UWES-9 and the scales of Professional Self-efficacy of the MBI for the workers, and the Academic Self-efficacy for students. Results. The predictive variables most significant for work engagement were job satisfaction (β = 0.34, p < 0.001), professional self-efficacy (β = 0.021, p < 0.001) and flourishing (β=0.21, p<0.001); for academic engagement: satisfaction with the career (β = 0.35, p < 0.001), flourishing (β = 0.33, p < 0.001) and academic self-efficacy (β = 0.19, p < 0.001). Conclusions. The predictive variables of engagement were similar in both studies. The most important ones were satisfaction with work or career, self-efficacy and flourishing, which is the dimension of well-being that entails a purposeful life, characterized by positive and gratifying social relationships.

Resumo Escopo. Analisar as variáveis pessoais, psicológicas e laborais ou académicas que predizem o compromisso em trabalhadores (docentes ou administrativos) e estudantes de uma universidade peruana. O estudo 1 analisa o compromisso laboral, e o estudo 2, o compromisso académico. Metodologia. No estudo participaram 512 trabalhadores e 1078 estudantes de uma universidade privada de Lima, Perú. A todos foi administrado o SF-36, as escadas de Afetividade e Floração que avaliam o bem-estar, a UWES-9 laboral ou académica e a Escada de Eficácia Profissional do MBI para trabalhadores e a de Autoeficácia Académica para os estudantes. Resultados. As variáveis preditoras mais significativas do compromisso laboral foram satisfação com o trabalho (β = 0.34, p< 0.001), eficácia profissional (β = 0.34, p< 0.001) e floração (β = 0.21, p< 0.001), e as de compromisso académico, satisfação com a carreira (β = 0.35, p< 0.001), floração (β = 0.33, p< 0.001) e a autoeficácia académica (β = 0.19, p< 0.001). Conclusão. As variáveis preditoras do compromisso foram similares nos dois estudos. Destacam a satisfação com o trabalho ou carreira, a autoeficácia e a floração, que é uma dimensão do bem-estar que supõe uma vida com sentido, caracterizada pela presença de vínculos positivos e gratificantes.

Carga anticolinérgica en pacientes mayores de 65 años con tratamiento farmacológico ambulatorio en una población colombiana / Anticholinergic load in patients older 65 years with ambulatory pharmacological treatment in a Colombian population

RESUMEN Introducción: los fármacos con potencial efecto anticolinérgico son prescritos frecuentemente en la población mayor de 65 años. Existen varias escalas para calcular la carga anticolinérgica: Anticholinergic Drug Scale, Anticholinergic Risk Scale y Anticholinergic Cognitive Burden. Objetivo: caracterizar la carga anticolinérgica en pacientes mayores de 65 años con polifarmacia que son formulados ambulatoriamente. Métodos: estudio de corte transversal, retrospectivo con información de prescripción registrada desde abril hasta septiembre de 2016. Se utilizó la base de datos transaccional de prescripción de una EPS nacional registrada en la plataforma tecnológica de un PBM (Pharmacy Benefit Management). Se analizaron los medicamentos con propiedades anticolinérgicas y carga anticolinérgica. Resultados: fueron 115.713 los pacientes formulados, con una edad media de 74 años. Los grupos terapéuticos más asociados con carga anticolinérgica moderada fueron, en un 6,5 %, dimenhidrinato, amantadina, biperideno y quetiapina. Un 13,1 % con carga anticolinérgica alta donde se encuentran el butil bromuro de hioscina y la amitriptilina. Discusión: el manejo de las patologías en los pacientes adultos mayores es compleja y se llega hasta el punto de requerir prescripción de múltiples medicamentos; por lo cual, se hace fundamental evaluar la necesidad del uso de estos, además de verificar su pertinencia y las posibles interacciones farmacológicas de alta significancia clínica, para evitar la presencia de eventos adversos. Por esto se han desarrollado escalas que permiten mejorar el resultado terapéutico especialmente en fármacos con carga anticolinérgica.

SUMMARY Background: Drugs with potential anticholinergic effect are usually prescribed to the population over 65 years. There are several scales created to calculate anticholinergic burden: Anticholinergic Drug Scale, Anticholinergic Risk Scale, and Anticholinergic Cognitive Burden. Objective: To characterize the anticholinergic burden in patients older than 65 years with polypharmacy who are prescribed in ambulatory settings. Methods: Retrospective cross-sectional study with information registered from April to September 2016. The database of prescription records of a health management organization (HMO), with national registries in the Pharmacy Benefit Management (PBM) technology platform, was used. Medicines were analyzed by its anticholinergic properties and anticholinergic burden. Results: There were 115,713 patients with a median age of 74 years. The medicines with moderate anticholinergic burden were dimenhydrinate, amantadine, biperidene and quetiapine in 6.5 %, and with high anticholinergic burden hyoscine butylbromide and amitryptiline in 13.1 %. Discussion: The medical attention of diseases of the elderly is complex and requires the prescription of multiple medications. It is important to evaluate the medicines and verify their relevance and possible pharmacological interactions, to avoid the presence of adverse events. For this reason, scales have been developed, they allow improving therapeutic results, and especially in medicines with anticholinergic burden and systems of clinical alerts that promotes correct formulation.

Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma.

Targeting RAS is one of the greatest challenges in cancer therapy. Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis. Thus far, there are no clinical agents available to effectively target NRAS or any other RAS oncogene. An alternative approach is to identify and target critical tumor vulnerabilities or non-oncogene addictions that are essential for tumor survival. We investigated the consequences of NRAS blockade in NRAS-mutant melanoma and show that decreased expression of the telomerase catalytic subunit, TERT, is a major consequence. TERT silencing or treatment of NRAS-mutant melanoma with the telomerase-dependent telomere uncapping agent, 6-thio-2'-deoxyguanosine (6-thio-dG), led to rapid cell death, along with evidence of both telomeric and non-telomeric DNA damage, increased ROS levels, and upregulation of a mitochondrial antioxidant adaptive response. Combining 6-thio-dG with the mitochondrial inhibitor Gamitrinib attenuated this adaptive response and more effectively suppressed NRAS-mutant melanoma. Our study uncovers a robust dependency of NRAS-mutant melanoma on TERT, and provides proof-of-principle for a new combination strategy to combat this class of tumors, which could be expanded to other tumor types.

Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma.

Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS-mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.

Psychometric properties of the Resilience Scale for Adults (RSA) and its relationship with life-stress, anxiety and depression in a Hispanic Latin-American community sample.

Resilience is a multi-dimensional construct associated with health and well-being. At present, we do not yet have a valid, scientific instrument that is designed to evaluate adult resilience in Spanish-speaking countries and that accounts for family, social and individual components. This study aimed at investigating the construct and cross-cultural validity of the Resilience Scale for Adults (RSA) by combining Confirmatory Factor Analysis (CFA), Multidimensional Scaling (MDS) and Hierarchical Regression models in a Hispanic Latin-American group. A community sample of 805 adults answered the RSA, Spanish Language Stressful Life-Events checklist (SL-SLE), and the Hopkins Symptom Checklist-25 (HSCL-25). First-order CFA verified the six factors structure for the RSA (RMSEA = .037, SRMR = .047, CFI = .91, TLI = .90). Five RSA scales and total score have good internal consistency (scales α > .70; total score α = .90). Two second-order CFA verified the intrapersonal and interpersonal dimensions of the protector factors of resilience, as well as their commonality and uniqueness with affective symptoms (anxiety and depression). An exploratory MDS reproduced the relations of RSA items and factors at first and second-order levels against random simulated data, thereby providing initial evidence of its cross-cultural validity in a Spanish-speaking group. The Four-steps hierarchical model showed that the RSA scales are the strongest predictors of anxiety and depression-greater than gender, age, education and stressful life-events. Three RSA scales are significant unique predictors of affective symptoms. In addition, similar to findings in diverse cultural settings, resilience is positively associated with age but not with education. Women report higher scores of Social Resources and Social Competence and lower scores of Perception of the Self. In conclusion, this study demonstrates the construct and criterion-related validity of the RSA in broad, diverse and Spanish speaking sample.

Resilience or hope? Incremental and convergent validity of the resilience scale for adults (RSA) and the Herth hope scale (HHS) in the prediction of anxiety and depression.

BACKGROUND: Hope and resilience protect against inner vulnerabilities or harsh life circumstances; they explain individual differences in physical or mental health outcomes under high stress. They have been studied in complementary or competing theoretical frameworks; therefore, the study of measures of hope and resilience should be undertaken prior to explore if they are truly value-added for research. This study investigates the convergent and incremental validity of the Resilience Scale for Adults (RSA) and the Herth Hope Scale (HHS), in the prediction of anxiety and depression (HSCL-25). METHODS: Participants in this community-based sample are 762 adults from 18 to 74 years old. They answered the RSA, HHS, Spanish Language Stressful Life-Events Checklist (SL-SLE), and the Hopkins Symptom Checklist-25 (HSCL-25). Incremental validity analyses combined hierarchical regression and structural equation models (SEM). First, hierarchical regression models were compared based on three criteria (R 2Diff., ΔF, and semi-partial r), then the direct effect of resilience on affective symptoms was compared with the mediated effect of resilience on affective symptoms through hope. RESULTS: The hierarchical models showed that (1) hope and resilience account significantly for the variance of affective symptoms above age, sex, and life-stress; (2) Resilience Total score has greater incremental validity than positive scales of HHS Hope; and (3) RSA Total score, HHS Optimism/Spiritual support, Stressful life-events and sex are unique predictors of affective symptoms. The SEM analyses verified a stronger direct effect of resilience in the prediction of affective symptoms above the significant partial mediated effect of resilience through hope. Additionally, results show that age and better educational opportunities were associated with protection (i.e. resilience and hope) and emotional well-being (i.e. affective symptoms and hopelessness). Women showed higher scores in social competences and resources (RSA), interconnectedness and initiative to take action (HHS). However, they have poorer evaluations of own abilities and efficacy (RSA), and higher scores in all the affective symptoms assessed. CONCLUSION: The RSA has incremental validity above the HHS, however, both the RSA and the HHS are effective, differentiated and complementary measures of protection that are of high relevance for research on psychosocial and emotional well-being.

Validación de las escalas de bienestar, de florecimiento y afectividad / Validation of the Scales of Well-being of Flourishing and Feelings / Validação das escalas de bem-estar de florescimento e afetividade

Objetivo. El presente estudio analiza las propiedades psicométricas de las escalas de florecimiento y afecto positivo y negativo, propuestas por Diener et al. (2010), para la evaluación del bienestar. Método. Se realizaron dos estudios. El primero empleó 656 estudiantes universitarios para analizar la contabilidad y la estructura factorial de las escalas. En el segundo, con 201 estudiantes universitarios, se calculó la validez convergente y divergente de las escalas con otras medidas de bienestar y se efectuó un análisis factorial confirmatorio. Resultados. Ambos estudios mostraron adecuadas propiedades psicométricas en las escalas. Los coeficientes de confiabilidad fueron de 0.89 para la escala de florecimiento y 0.91 y 0.87 para las escalas de afecto positivo y negativo, respectivamente. La varianza explicada en el análisis factorial exploratorio para cada una de las escalas mencionadas fue, en su orden, de 52.82%, 69.49% y 61.56%. Las correlaciones de las escalas de florecimiento y afecto positivo fueron positivas y significativas con la Escala de Optimismo (LOT-R), la Escala de Afecto Positivo PANAS, la Escala de Satisfacción con la Vida (SWLS) y la Escala de Bienestar (Bieps-A), y negativas y significativas con la Escala de Afecto Negativo. Conclusión. El análisis factorial confirmatorio mostró índices de ajuste adecuados tanto para la escala de florecimiento como para la de afectividad. Estos resultados permiten confirmar la validez y utilidad de las escalas para la evaluación del bienestar en población hispana.

Objective. The present study analyzes, the psychometric properties of the Flourishing and Positive and Negative Feelings scales proposed by Diener et al. (2010) to evaluate wellbeing. Two Studies were carried out with this purpose. Method. The first study, of 656 university, students analyzed the reliability and factorial structure of the scales. The second, of 201 university students, calculated the convergent and divergent validity of the scales with other measures of wellbeing, and carried out a confirmatory factorial analysis. Results. The results of both studies showed adequate psychometric properties in the three scales. The reliability was 0.89 for flourishing and 0.91 and 0.87 for positive and negative experience coefficients respectively. The variance in the exploratory factorial analysis was 52.82% 69.49% and 61.56% for the three scales. The correlation between the Flourishing and Positive Affections scales was positive and significant with Optimism (LOT-R), Positive Affection of the PAPAS, Satisfaction With Life (SWLS) and Wellbeing (Bieps-A), and negative and significant with Negative Affection. Conclusion. The confirmatory factorial analyses showed adequate indexes for Flourishing and for Affectivity. These results confirm the validity and usefulness of these scales in the wellbeing assessment for a Hispanic population.

Escopo. O presente estudo analisa as propriedades psicométricas das escalas de florescimento e afeto positivo e negativo, propostas por Diener et. al. (2010), para a avaliação do bem-estar. Metodologia. Foram feitos dois estudos. O primeiro empregou 656 estudantes universitários para analisar a confiabilidade e a estrutura fatorial das escalas. No segundo, com 201 estudantes universitários, foi calculada a validez convergente e divergente das escalas com outras medidas de bem-estar e foi efetuada uma análise fatorial confirmatória. Resultados. Os dois estudos mostraram adequadas propriedades psicométricas nas escalas. Os coeficientes de confiabilidade foram de 0.89 para a escala de florescimento, e 0.91 e 0.87 para as escalas de afeto positivo e negativo, respetivamente. A variação explicada na análise fatorial exploratória para cada uma das escalas mencionadas foi, nesta ordem, de 52.82%, 69.49% e 61.56%. As escalas de florescimento e afeto positivo correlacionaram com a escala de otimismo (LOT-R), as escalas de afeto positivo PANAS, Satisfação com a Vida (SWLS) e Bem-estar (Bieps-A). As duas primeiras escalas correlacionaram negativamente com a escala de Afeto negativo. Conclusão. A análise fatorial confirmatória mostrou índices de ajuste adequados tanto para a escala de florescimento como para a de afetividade. Estes resultados permitem confirmar a validez e utilidade das escalas para a avaliação do bem-estar em população hispana.

[Comprehensive sexual education in Mexico: an analysis of coverage, comprehensiveness and continuity of contents in Mexican public and private schools]. / Educación sexual integral: cobertura, homogeneidad, integralidad y continuidad en escuelas de México.

OBJECTIVE:: To analyze coverage of comprehensive sex education (CSE) in high schools in Mexico and describe whether it is comprehensive, homogeneous and has continuity based on student reports of exposure to topics in three dimensions: reproductive and sexual health, self-efficacy and rights and relations. MATERIALS AND METHODS:: Within a probabilistic, cross-sectional survey with stratified, cluster sampling, a nationally representative sample of 3 824 adolescents attending 45 public and private high-schools in urban and rural areas completed questionnaires on CSE. RESULTS:: The proportion of adolescents reporting having received sex education from school personnel varies depending on topics and grade level. Topics most frequently covered are those related to sexual and reproductive health while rights and relations are least frequently dealt with. Most sex education topics are covered during junior high school and much less frequently in elementary or high school. CONCLUSIONS:: CSE needs to be comprehensive and homogenous in terms of content, ensure inclusion of priority topics, meet national and international recommendations, ensure continuity and adapt contents to student age through all education levels.

Educación sexual integral: cobertura, homogeneidad, integralidad y continuidad en escuelas de México / Comprehensive sexual education in Mexico: an analysis of coverage, comprehensiveness and continuity of contents in Mexican public and private schools

Resumen: Objetivo: Analizar la cobertura de la educación sexual integral (ESI) en México y describir su integralidad, homogeneidad y continuidad en cuanto a contenidos sobre salud sexual y reproductiva, autoeficacia, derechos y relaciones. Material y métodos: En una encuesta probabilística transversal con muestreo estratificado y por conglomerados, se aplicó un cuestionario sobre ESI a una muestra representativa a nivel nacional de 3 824 adolescentes de 45 escuelas de educación media superior públicas y privadas, en localidades urbanas y rurales. Resultados: El porcentaje de adolescentes que reportan recibir educación sexual integral varía dependiendo de los temas y nivel escolar. Los temas más frecuentes están relacionados con salud sexual y reproductiva; los menos tratados con derechos y relaciones. Los contenidos de educación sexual se trasmiten mayoritariamente durante la escuela secundaria. Conclusiones: Se requiere garantizar la integralidad, homogeneidad y continuidad de los contenidos de la ESI, asegurando que se imparta la totalidad de los temas planteados en recomendaciones nacionales e internacionales.

Abstract Objective: To analyze coverage of comprehensive sex education (CSE) in high schools in Mexico and describe whether it is comprehensive, homogeneous and has continuity based on student reports of exposure to topics in three dimensions: reproductive and sexual health, self-efficacy and rights and relations. Materials and methods: Within a probabilistic, cross-sectional survey with stratified, cluster sampling, a nationally representative sample of 3 824 adolescents attending 45 public and private high-schools in urban and rural areas completed questionnaires on CSE. Results: The proportion of adolescents reporting having received sex education from school personnel varies depending on topics and grade level. Topics most frequently covered are those related to sexual and reproductive health while rights and relations are least frequently dealt with. Most sex education topics are covered during junior high school and much less frequently in elementary or high school. Conclusions: CSE needs to be comprehensive and homogenous in terms of content, ensure inclusion of priority topics, meet national and international recommendations, ensure continuity and adapt contents to student age through all education levels.

Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma.

The discovery of activating BRAF mutations in approximately 50% of melanomas has led to the development of MAPK pathway inhibitors, which have transformed melanoma therapy. However, not all BRAF-V600E melanomas respond to MAPK inhibition. Therefore, it is important to understand why tumors with the same oncogenic driver have variable responses to MAPK inhibitors. Here, we show that concurrent loss of PTEN and activation of the Notch pathway is associated with poor response to the ERK inhibitor SCH772984, and that co-inhibition of Notch and ERK decreased viability in BRAF-V600E melanomas. Additionally, patients with low PTEN and Notch activation had significantly shorter progression free survival when treated with BRAF inhibitors. Our studies provide a rationale to further develop combination strategies with Notch antagonists to maximize the efficacy of MAPK inhibition in melanoma. Our findings should prompt the evaluation of combinations co-targeting MAPK/ERK and Notch as a strategy to improve current therapies and warrant further evaluation of co-occurrence of aberrant PTEN and Notch activation as predictive markers of response to therapy.

Impact and economic evaluations of a combination prevention programme for men who have sex with men in Mexico.

BACKGROUND: Despite the high-profile support for combination prevention programmes (CPPs) since 2008, there is little rigorous evidence on their impact and cost-effectiveness. In 2010, Mexico received funds from the Global Fund to implement a series of behavioural, biomedical, and structural interventions over 3 years targeted to men who have sex with men. The aims of the study were to estimate the impact of the programme across a range of outcomes and cost-effectiveness. METHODS: A quasi-experiment was designed before the implementation of the CPP, in which 24 cities were randomly selected for impact evaluation and 12 pairs of cities were matched. In practice, though, implementation of the programme was staggered over 1 year. Therefore, we used two different approaches to estimate impact: a difference-in-difference estimation comparing both groups and a dose-response approach using time exposure to the programme at the city level. FINDINGS: Results from the difference-in-difference estimation showed modest impact on condom use. However, the dose­response findings revealed a 7.5% increase in HIV testing per additional year exposed to the programme, relative to baseline coverage; an increase in awareness of HIV status among HIV-positive individuals of 6.3%; a 6.7% increase in HIV-positive individuals on treatment; and a 7% reduction in the perception of stigma/discrimination from healthcare personnel. The cost per person not exposed to an untreated HIV-positive individual was gauged to be US$400. CONCLUSIONS: The study provides evidence of the effectiveness and cost of a CPP along the HIV treatment cascade: access to HIV tests, awareness of HIV status, and antiretroviral therapy initiation.

Thrombosis in leukemia: incidence, causes, and practical management.

In patients with acute leukemia (AL), coagulation disorders, which include both thrombotic and hemorrhagic events, are part of the clinical spectrum both at diagnosis and during its evolution. The incidence of these events has been reported by several authors in the range of 1-36 %. This heterogeneity appears to be related to the type of patients included, the study design, and patient-related factors as well as the treatment used. The pathophysiology of thrombosis in AL is complex and multifactorial and includes a myriad of factors that contribute to cancer procoagulant state: synthesis of procoagulant factors by circulating blasts, cellular microparticles, use of endovascular devices (catheters), type of chemotherapy used (L-asparaginase) to name a few. Currently, treatment relies in the use of heparin, followed by vitamin K antagonists for 3 to 6 months. However, randomized controlled studies are required in patients with AL and thrombosis to confirm its safety, duration, and effectiveness.

Development of organometallic S6K1 inhibitors.

Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC50 value in the low nanomolar range at 100 µM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, αC helix, and αD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications.

Life stress as a determinant of emotional well-being: development and validation of a Spanish-Language Checklist of Stressful Life Events.

Objectives: To develop a screening instrument for investigating the prevalence and impact of stressful life events in Spanish-speaking Peruvian adults. Background: Researchers have demonstrated the causal connection between life stress and psychosocial and physical complaints. The need for contextually relevant and updated instruments has been also addressed. Methods: A sequential exploratory design combined qualitative and quantitative information from two studies: first, the content validity of 20 severe stressors (N = 46); then, a criterion-related validity process with affective symptoms as criteria (Hopkins Symptom Checklist (HSCL-25), N = 844). Results: 93% of the participants reported one to eight life events (X = 3.93, Mdn = 3, SD = 7.77). Events increase significantly until 60 years of age (Mdn = 6). Adults born in inland regions (Mdn = 4) or with secondary or technical education (Mdn = 5) reported significantly more stressors than participants born in Lima or with higher education. There are no differences by gender. Four-step hierarchical models showed that life stress is the best unique predictor (ß) of HSCL anxiety, depression and general distress (p < .001). Age and gender are significant for the three criteria (p < .01, p < .001); lower education and unemployment are significant unique predictors of general distress and depression (p < .01; p < .05). Previously, the two-factor structure of the HSCL-25 was verified (Satorra-Bentler chi-square, root-mean-square error of approximation = 0.059; standardized root-mean-square residual = 0.055). Conclusion: The Spanish-Language Checklist of Stressful Life Events is a valid instrument to identify adults with significant levels of life stress and possible risk for mental and physical health (clinical utility).

Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma.

Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.

Incidence of thrombosis in adults with acute leukemia: a single center experience in Mexico.

BACKGROUND: Acute leukemias are hematopoietic malignancies that may be accompanied by hemostatic abnormalities. In general, information on the frequency of thrombotic events, their clinical characteristics and survival in adult patients with acute leukemia is still scarce and controversial. OBJECTIVES: To describe the frequency of thrombotic events, their clinical characteristics and survival of adult patients with acute leukemia at the Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City. MATERIAL AND METHODS: A patient cohort, diagnosed and treated between October 2003 and December 2009, was retrospectively analyzed in terms of thrombotic events, frequencies and survival curves. RESULTS: We analyzed 181 patients with a median age of 33 years, 80 were female (44.2%). Fifteen cases with thrombosis (8.3%) were documented and in 53.3% of cases, they were related to the use of a central venous catheter. The median time to development of thrombosis was 92 days; 33.3% of events occurred during the first 30 days after diagnosis. The incidence of thrombosis in patients receiving L-asparaginase was 15%. Of the 15 patients with thrombosis, 27% were alive and without evidence of disease at last follow-up, and 73% had died; disease progression was the most common cause of death (81.8%). None of the thrombotic events had an impact on mortality. Median overall survival (OS) was 349 days. CONCLUSIONS: The incidence of thrombosis in this adult acute leukemia population is comparable to that reported in the literature. Only a third of cases occurred during the first month after diagnosis; however, 93.3% of patients developed a thrombotic event during the first year after the diagnosis of acute leukemia. All cases were symptomatic and central venous catheter-related thrombosis was the most frequent presentation in this group. Survival curves comparing patients with and without thrombosis were similar. Prospective studies are necessary in order to assess the risk factors fostering thrombosis in adult patients with acute leukemia.

Comparative zymographic analysis of metallopeptidase of Leishmania (Viannia) peruviana and Leishmania (Viannia) braziliensis isolates from Peru.

American tegumentary leishmaniasis (ATL) in Peru is mainly associated with Leishmania (Viannia) peruviana and L. (V.) braziliensis. These parasites are genetically related, and their characterization as distinct species is controversial. Despite their genetic similarity, each species is associated with different clinical manifestations of ATL; L. (V.) peruviana causes only cutaneous leishmaniasis, whereas L. (V.) braziliensis can cause both cutaneous and mucocutaneous leishmaniasis. Because the primary cutaneous lesions caused by infection with these species are indistinguishable, it is necessary to develop a suitable method to differentiate them in order to prevent possible metastasis to oropharyngeal mucosa. In the present study, we investigated the proteolytic profile of L. (V.) peruviana and L. (V.) braziliensis isolates from Peru by zymographic analysis in SDS-PAGE copolymerized with gelatin. Enzymes were characterized according to their pH range of activity and sensitivity to distinct peptidase inhibitors. We observed that L. (V.) peruviana isolates displayed three proteolytic bands with molecular masses ranging from 55 to 80 kDa, whereas L. (V.) braziliensis isolates showed six proteolytic activities between 55 and 130 kDa. Using specific inhibitors, we determined that these proteolytic activities are due to metallopeptidases and present optimal activity between the pH range 5.5 and 10.0. Our results suggest that the expression of metallopeptidases in L. (V.) peruviana and L. (V.) braziliensis isolates from Peru is species-specific.

Self-collection of vaginal specimens for human papillomavirus testing in cervical cancer prevention (MARCH): a community-based randomised controlled trial.

BACKGROUND: Vaginal self-sampling for human papillomavirus (HPV) DNA testing could increase rates of screening participation. In clinic-based settings, vaginal HPV testing is at least as sensitive as cytology for detecting cervical intraepithelial neoplasia (CIN) grade 2 or worse; however, effectiveness in home settings is unknown. We aimed to establish the relative sensitivity and positive predictive value for HPV screening of vaginal samples self-collected at home as compared with clinic-based cervical cytology. METHODS: We did a community-based, randomised equivalence trial in Mexican women of low socioeconomic status aged 25-65 years. Participants came from 540 medically underserved, predominantly rural communities in Morelos, Guerrero, and the state of Mexico. Our primary endpoint was CIN 2 or worse, detected by colposcopy. We used a computer-generated randomisation sequence to randomly allocate patients to HPV screening or cervical cytology. Eight community nurses who were masked to patient allocation received daily lists of the women's names and addresses, and did the assigned home visits. We referred women with positive results in either test to colposcopy. We did per-protocol and intention-to-screen analyses. This trial was registered with the Instituto Nacional de Salud Pública, Mexico, INSP number 590. FINDINGS: 12,330 women were randomly allocated to HPV screening and 12,731 to cervical cytology; 9202 women in the HPV screening group adhered to the protocol, as did 11,054 in the cervical cytology group. HPV prevalence was 9·8% (95% CI 9·1-10·4) and abnormal cytology rate was 0·38% (0·23-0·45). HPV testing identified 117·4 women with CIN 2 or worse per 10,000 (95·2-139·5) compared with 34·4 women with CIN 2 or worse per 10,000 (23·4-45·3) identified by cytology; the relative sensitivity of HPV testing was 3·4 times greater (2·4-4·9). Similarly, HPV testing detected 4·2 times (1·9-9·2) more invasive cancers than did cytology (30·4 per 10,000 [19·1-41·7] vs 7·2 per 10,000 [2·2-12·3]). The positive predictive value of HPV testing for CIN 2 or worse was 12·2% (9·9-14·5) compared with 90·5% (61·7-100) for cytology. INTERPRETATION: Despite the much lower positive predictive value for HPV testing of self-collected vaginal specimens compared with cytology, such testing might be preferred for detecting CIN 2 or worse in low-resource settings where restricted infrastructure reduces the effectiveness of cytology screening programmes. Because women at these sites will be screened only a few times in their lives, the high sensitivity of a HPV screen is of paramount importance. FUNDING: Instituto Nacional de Salud Pública, the Health Ministry of Mexico, QiAGEN Corp.

Perspectiva futura del Perú y el nivel de satisfacción con él / Future perspective of Peru and level of satisfaction with him

Se trata de explorar lo que un grupo de ciudadanos desea para el futuro del Perú, las actitudes que muestran frente al futuro, presente y pasado del mismo y los niveles de satisfacción con él. Se evaluaron 482 hombres y mujeres entre 15 y 80 años de tres niveles socioeconómicos. Se utilizó una adaptación del Método de Inducción Motivacional y de la Escala de Actitudes Temporales de Nuttin y una adaptación del SWLS de Diener. Los deseos de los participantes se orientan principalmente a temas como la paz, justicia, honestidad y condiciones de vida, se muestran insatisfechos con el país y con una actitud cauta frente al futuro, aunque con un cierto matiz de esperanza en relación al presente.

This research explores the wishes of a group of citizens for the future of Peru, what their attitudes towards the future, present and past of the country are and the level of satisfaction with it. 482 men and women, between 15 and 80 years old were surveyed. They belonged to three socioeconomic strata. An adaptation of the Motivational Induction Method, the Temporal Attitudes Scale of Nuttin and an adaptation of Diener SWL Scale were used in the investigation. Findings revealed that citizens’ wishes for the country are mainly of peace, justice, honesty and better life conditions; they feel dissatisfied with the country and display a cautious attitude towards the future, although feeling some hope related to current times.

Migration and AIDS in Mexico: an overview based on recent evidence.

OBJECTIVES: Provide an overview of the relation between migration to the United States and AIDS cases in Mexico. Characterize the sexual behaviors of Mexican migrants. Describe HIV/AIDS prevention and clinical attention actions developed. METHODS: The following were analyzed: AIDS cases databases, various prevalence studies, the migrants survey, and information of the Ministries of the Interior and of Health. A documental analysis was undertaken of works published between 1992 and 2000 on migration and AIDS. RESULTS: In terms of their sexual practices, migrants in the past year had more sexual partners, tended to use a condom in their most recent relation in greater proportion, and had greater use of injected medicines and drugs. Two bi-national programs undertake epidemiological surveillance activities, while several initiatives have used innovative formats to provide prevention information to migrants. Imminent universal coverage leaves the challenge to assure quality of attention for migrants. CONCLUSIONS: Studies to evaluate the impact of international migration on distribution of infected persons will be indispensable to establish priorities in prevention and attention among migrants. More information is needed on bi-national health projects to understand the impact they may have in prevention, while continuity of the prevention initiatives must be guaranteed. Attention to migrants in bi-national contexts requires information exchange agreements on migrants living with the HIV/AIDS.