Sex differences on peak oxygen uptake in heart failure

Women represent nearly half of the adult heart failure (HF) population and they remain underrepresented in HF studies. We aimed to evaluate the evidence about peak oxygen uptake (peak VO2) for clinical stratification in women with HF. This narrative review summarizes (i) the evidence endorsing the value of cardiopulmonary exercise testing for clinical stratification and phenotyping HF population; (ii) the determinants of a person’s functional aerobic capacity to understand predicted values for patients with chronic HF; and (iii) sex differences on peak VO2 data in different forms of HF. Lastly, based on existing data in patients with HF, we provide a perspective on how to improve existing gaps about the utility of peak VO2 in clinical stratification in women. Peak VO2 provides prognosis information in patients with HF; however, its use has been limited for a reduced number of patients excluding women, elderly, and HF patients with preserved ejection fraction. Further studies will help to fill the wide gender gap about the utility of cardiopulmonary exercise testing in the risk assessment and management in women with HF

Essays in Education Policies in Latin America

Education is often perceived as a key to development and growth, consequently, in the last decades, many countries have increased education coverage in all education levels. The creation of international education quality measurement programs, such as OECD’s Programme for International Student Assessment (PISA) or the Trends in International Mathematics and Science Study (TIMSS), have further led to a focus on improving education quality. For these reasons, the last decades have seen an increase in the importance of education in the political debate. This has been particularly relevant in Latin America, where, additionally, education has been used, sometimes, to fight traditionally high levels of income inequality, with a significant rise in education expenditure and coverage. The evaluation of education policies that aim to increase education coverage, quality or equity is, however, generally difficult. Many education policies are large-scale policies and are likely to affect all students or workers in the population, even those not directly benefiting from the policy. For example, students not participating in some education policy could still experience changes in their classmate characteristics that could affect their achievement. The presence of possible spillovers may change the direction of the effects of large-scale education policies when all the population is included in the analysis. Therefore, analyzing solely the effects on students participating in the policy may not give a complete picture of the effects of large-scale education policies. This dissertation focuses on the effects that three large-scale education policies that aimed to improve education equity, quality and coverage, respectively, had on students and workers affected differently by the policies. Particularly, each chapter analyzes the aggregate effects for the population of each education policy and decomposes these effects on the impact suffered by different groups of students or workers. In Chapter 1, I analyze the effects on test scores of a policy that aimed to increase education equity in Chile. I study the effects of an increase in school choice for low-income students by examining a 2008 reform that made the value of Chile’s (previously flat, universal) school voucher a step function of student income. This policy increased the proportion of private schools that low income, eligible children could access free of charge from 0.5 to 0.7. In order to identify aggregate effects and the impact within groups of students, I combine the introduction of the policy with variation from a date of birth enrollment cutoff for 1st grade. I show that the differentiated voucher lowered the probability that students used public schools by a small fraction and that these students shifted out of low achievement public schools to enroll in low achievement private schools. Nonetheless, private schools where these students enrolled had better test scores and socioeconomic composition at baseline, and less experienced teachers and smaller class sizes than public schools where they would have enrolled in the absence of the program. Despite the improvement in some school observable characteristics, I do not find any increase in test scores for students more likely to move to private schools. Further analysis suggests a rise in test scores for students most likely to stay in public schools. These results suggest that the policy had an overall modest positive effect on test scores, but that this positive effect was caused by responses from public schools instead of by students responding to the increase in school choice. In Chapter 2, I study the impact on test scores of a policy that aimed to improve education quality by increasing transparency of school performance in Chile. Particularly, I look at the effects of the distribution of school performance information to all families in Chile in 2011. Since I am interested in identifying effects for different groups of students, I define a control group within each group of students by using variation in enrollment year. Due to the presence of a date of birth enrollment cutoff for 1st grade enrollment there is variation in enrollment year for students born a few days apart. I combine this variation together with the timing of the distribution of information to identify the effects of the policy. I show that the distribution of information increased enrollment in high-performing schools, particularly for students in the third quartile of the municipality socioeconomic distribution. Thanks to this policy, students in the third quartile were exposed to a better socioeconomic composition of peers. Test score results suggest that there was an overall positive effect on verbal test scores, particularly for students in the third quartile, seemingly caused by an improvement in peer characteristics. However, there does not seem to be any significant change in test scores for students less likely to change enrollment decisions in response to the new information. Finally, Chapter 3, examines the effects of a policy that increased tertiary education coverage in Colombia on wages. I identify the effects on the distribution of wages using two different empirical strategies: the DiNardo, Fortin and Lemieux (1996) reweighting method and a differences-indifferences strategy. My results suggest that the overall distribution of wages remained constant, once labor demand shifts and productivity changes are taken into account. In contrast, wages increased for workers that were not at the margin of studying tertiary education, workers with primary education or less, and the density of wages at high levels of the distribution decreased for high school and tertiary education graduates. However, there were no effects on average wages for workers with any of the education levels. These results suggest that the policy had heterogeneous effects within the wage distribution and between education levels that were not captured by changes in average wages. These three chapters show that large-scale education policies can, sometimes, have effects on achievement or wages of students that are not participating in the policy, and that these effects are not always visible in the aggregate effects. Therefore, policy-makers and researchers should take into account the presence of spillovers or strategic responses when designing or analyzing large-scale education policies

A model-driven transformation approach for the modelling of processes in clinical practice guidelines

Clinical Practice Guidelines (CPGs) include recommendations aimed at optimising patient care, informed by a review of the available clinical evidence. To achieve their potential benefits, CPG should be readily available at the point of care. This can be done by translating CPG recommendations into one of the languages for Computer-Interpretable Guidelines (CIGs). This is a difficult task for which the collaboration of clinical and technical staff is crucial. However, in general CIG languages are not accessible to non-technical staff. We propose to support the modelling of CPG processes (and hence the authoring of CIGs) based on a transformation, from a preliminary specification in a more accessible language into an implementation in a CIG language. In this paper, we approach this transformation following the Model-Driven Development (MDD) paradigm, in which models and transformations are key elements for software development. To demonstrate the approach, we implemented and tested an algorithm for the transformation from the BPMN language for business processes to the PROforma CIG language. This implementation uses transformations defined in the ATLAS Transformation Language. Additionally, we conducted a small experiment to assess the hypothesis that a language such as BPMN can facilitate the modelling of CPG processes by clinical and technical staff.Funding for open access charge: CRUE-Universitat Jaume

Dysregulation of H/ACA ribonucleoprotein components in chronic lymphocytic leukemia

Telomeres are protective repeats of TTAGGG sequences located at the end of human chromosomes. They are essential to maintain chromosomal integrity and genome stability. Telomerase is a ribonucleoprotein complex containing an internal RNA template (hTR) and a catalytic subunit (hTERT). The human hTR gene consists of three major domains; among them the H/ACA domain is essential for telomere biogenesis. H/ACA ribonucleoprotein (RNP) complex is composed of four evolutionary conserved proteins, including dyskerin (encoded by DKC1 gene), NOP10, NHP2 and GAR1. In this study, we have evaluated the expression profile of the H/ACA RNP complex genes: DKC1, NOP10, NHP2 and GAR1, as well as hTERT and hTR mRNA levels, in patients with chronic lymphocytic leukemia (CLL). Results were correlated with the number and type of genetic alteration detected by conventional cytogenetics and FISH (fluorescence in situ hybridization), IGHV (immunoglobulin heavy chain variable region) mutational status, telomere length (TL) and clinico pathological characteristics of patients. Our results showed significant decreased expression of GAR1, NOP10, DKC1 and hTR, as well as increased mRNA levels of hTERT in patients compared to controls (p=0.04). A positive correlation between the expression of GAR1-NHP2, GAR1-NOP10, and NOP10-NHP2 (p=0.0001), were observed. The analysis taking into account prognostic factors showed a significant increased expression of hTERT gene in unmutated-IGHV cases compared to mutated-CLL patients (p = 0.0185). The comparisons among FISH groups exhibited increased expression of DKC1 in cases with two or more alterations with respect to no abnormalities, trisomy 12 and del13q14, and of NHP2 and NOP10 compared to those with del13q14 (p = 0.03). The analysis according to TL showed a significant increased expression of hTERT (p = 0.0074) and DKC1 (p = 0.0036) in patients with short telomeres compared to those with long TL. No association between gene expression and clinical parameters was found. Our results suggest a role for these telomere associated genes in genomic instability and telomere dysfunction in CLL.Fil: Dos Santos, Patricia Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Panero, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Stanganelli, Carmen Graciela. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Palau Nagore, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Stella, Flavia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bezares, Raimundo F.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Los desafíos del profesorado clínico en la educación médica

Background: There is a unique particularity of clinical teaching in medical education that isbeyond knowledge, skills or teaching methods of each clinician: this is clinical teaching context.This study aimed to analyze the main barriers in clinical teaching in a single medical school in Spain. Methods: This was a descriptive study in which all the clinical teachers (all of them associateprofessors) of a single and novel faculty of medicine were asked to answer an online, anonymousand voluntary questionnaire about aspects of support to clinical work, promotion of clinicalresearch and recognition of their professional careers. The questionnaires were organized andanalyzed into these three main issues.Results: 61 clinical teachers (42%) answered the questionnaire. The main findings that emergedwere: (i) lack of protected time for practical teaching at hospital; (ii) lack of support for clinicalresearch from hospital or faculty; and (iii) lack of recognition of their professional careers.Conclusions: The clinical teaching in medical education is a continuing challenge for busyclinicians. Further studies on this topic are needed.Antecedentes: La enseñanza clínica en la educación médica tiene una particularidad única:el contexto clínico. Este estudio tiene como objetivo analizar las principales barreras de laense˜nanza clínica en una facultad joven de Medicina de Espa˜na.Métodos: Se trata de un estudio transversal descriptivo en el que se solicitó a todos losprofesores clínicos (todos ellos profesores asociados) de una facultad joven de Medicina que res-pondieran a un cuestionario en línea, anónimo y voluntario sobre aspectos de carga asistencial,promoción de la investigación clínica y reconocimiento de sus carreras profesionales.Resultados: Sesenta y un profesores (42%) respondieron al cuestionario. Los principales hallaz-gos que se obtuvieron fueron: 1) la falta de tiempo protegido para la ense˜nanza práctica en lainstitución sanitaria; 2) el escaso apoyo para la investigación clínica por parte de la instituciónsanitaria o de la facultad; y 3) el escaso de reconocimiento de la carrera profesional.Conclusiones: La ense˜nanza clínica en la educación médica es un desafío continuo para elclínico. Son necesarios futuros estudios que analicen estos aspectos de forma más exhaustiva

Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction—a substudy of the DAPA-VO2 study

Dapagliflozin; Fibroblast growth factor 23; Functional capacityDapagliflozin; Factor de crecimiento de fibroblastos 23; Capacidad funcionalDapagliflozin; Factor de creixement de fibroblasts 23; Capacitat funcionalThe klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%–p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8–72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5–37.8), 67.4 ml/min/1.73 m2 (50.7–82.8), 1,285 pg/ml (898–2,305), 623.4 pg/ml (533.5–736.6), and 72.6 RU/ml (62.6–96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9–37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ−4.6, (−1.7 to −5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.This work was supported in part by an unrestricted grant from Astra Zeneca (ESR-17-13447), Unidad de Investigación Clínica y Ensayos Clínicos INCLIVA Health Research Institute, Spanish Clinical Research Network (SCReN; PT17/0017/0003 y PT20/00100), RICORS2040 (RD21/0005/0013), and CIBER Cardiovascular [grant number 16/11/00420]

Heart rate response and functional capacity in patients with chronic heart failure with preserved ejection fraction

Aims: The mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) are not yet elucidated. Chronotropic incompetence has emerged as a potential mechanism. We aimed to evaluate whether heart rate (HR) response to exercise is associated to functional capacity in patients with symptomatic HFpEF. Methods and results We prospectively studied 74 HFpEF patients [35.1% New York Heart Association Class III, 53% fe- male, age (mean ± standard deviation) 72.5 ± 9.1 years, and 59.5% atrial fi brillation]. Functional performance was assessed by peak oxygen consumption (peak VO 2 ). The mean (standard deviation) peak VO 2 was 10 ± 2.8 mL/min/kg. The following chronotropic parameters were calculated: Delta-HR (HR at peak exercise - HR at rest), chronotropic index (CI) = (HR at peak exercise - resting HR)/[(220 - age) - resting HR], and CI according to the equation developed by Keteyian et al . (CIK) (HR at peak exercise - HR at rest)/[119 + (HR at rest/2) (age/2) - 5 - HR at rest]. In a bivariate setting, peak VO 2 was positively and signi fi cantly correlated with Delta-HR ( r = 0.35, P = 0.003), CI ( r = 0.27, P = 0.022), CIK ( r = 0.28, P = 0.018), and borderline with HR at peak exercise ( r = 0.22, P = 0.055). In a multivariable linear regression analysis that included clinical, analytical, echocardiographic, and functional capacity covariates, the chronotropic parameters were positively associated with peak VO 2 . We found a linear relationship between Delta-HR and peak VO 2 ( β coef fi cient of 0.03; 95% con fi dence interval: 0.004 – 0.05; P = 0.030); conversely, the association among CIs and peak VO 2 was exponen- tially shaped. Conclusions In patients with chronic HFpEF, the HR response to exercise was positively associated to patient ’ s functional capacity

Rehospitalization burden and morbidity risk in patients with heart failure with mid-range ejection fraction

Heart failure with mid-range ejection fraction (HFmrEF) has been proposed as a distinct HF phenotype, but whether patients on this category fare worse, similarly, or better than those with HF with reduced EF (HFrEF) or preserved EF (HFpEF) in terms of rehospitalization risks over time remains unclear. We prospectively included 2961 consecutive patients admitted for acute HF (AHF) in our institution. Of them, 158 patients died during the index admission, leaving the sample size to be 2803 patients. Patients were categorized according to their EF: HFrEF if EF ≤ 40% (n = 908, 32.4%); HFmrEF if EF = 41-49% (n = 449, 16.0%); and HFpEF if EF ≥ 50% (n = 1446, 51.6%). Covariate-adjusted incidence rate ratios (IRRs) were used to evaluate the association between EF status and recurrent all-cause and HF-related admissions. At a median follow-up of 2.6 years (inter-quartile range: 1.0-5.3), 1663 (59.3%) patients died, and 6035 all-cause readmissions were registered in 2026 patients (72.3%), 2163 of them HF related. Rates of all-cause readmission per 100 patients-years of follow-up were 150.1, 176.9, and 163.6 in HFrEF, HFmrEF, and HFpEF, respectively (P = 0.097). After multivariable adjustment, when compared with that of patients with HFrEF and HFpEF, HFmrEF status was not significantly associated with a different risk of all-cause readmissions (IRR = 0.99; 95% confidence interval [CI], 0.77-1.27; P = 0.926; and IRR = 0.93; 95% CI, 0.74-1.18; P = 0.621, respectively) or HF-related readmissions (IRR = 1.06; 95% CI, 0.77-1.46; P = 0.725; and IRR = 1.11; 95% CI, 0.82-1.50; P = 0.511, respectively). Following an admission for AHF, patients with HFmrEF had a similar rehospitalization burden and a similar risk of recurrent all-cause and HF-related admissions than had patients with HFrEF or HFpEF. Regarding morbidity risk, HFmrEF seems not to be a distinct HF phenotype

Right Ventricular Dysfunction Staging System for Mortality Risk Stratifiction in Heart Failure with Preserved Ejection Fraction

Right ventricular dysfunction (RVD) parameters are increasingly important features in heart failure with preserved ejection fraction (HFpEF). We sought to evaluate the prognostic impact of a progressive RVD staging system by combining the tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (TAPSE/PASP) ratio with functional tricuspid regurgitation (TR) severity. We prospectively included 1355 consecutive HFpEF patients discharged for acute heart failure (HF). Of them, in 471 (34.7%) patients, PASP could not be accurately measured, leaving the final sample size to be 884 patients. Patients were categorized as Stage 1: TAPSE/PASP ≥ 0.36 without significant TR; stage 2: TAPSE/PASP ≥ 0.36 with significant TR; stage 3: TAPSE/PASP < 0.36 without significant TR; and stage 4: TAPSE/PASP < 0.36 with significant TR. By the 1 year follow-up, 207 (23.4%) patients had died. We found a significant and graded association between RVD stages and mortality rates (15.8%, 25%, 31.2%, and 45.4% from stage 1 to stage 4, respectively; log-rank test, p < 0.001). After multivariable adjustment, and compared to stage 1, stages 3 and 4 were independently associated with mortality risk (HR: 1.8219; 95% CI 1.308-2.538; p < 0.001 and HR = 2.2632; 95% CI 1.540-3.325; p < 0.001, respectively). A RVD staging system, integrating TAPSE/PASP and TR, provides a comprehensive and widely available tool for risk stratification in HFpEF

Caracterização de pacientes adultos mais velhos com epilepsia em dois hospitais de Bogotá (Colômbia)

La prevalencia global de la epilepsia en Colombia es del 1,13% y en pacientes mayores de 65 años puede estar cercana al 1,5%. El objetivo de este trabajo ha sido el de describir las características demográficasy clínicas de la población mayor de 65 años que presenta epilepsia. Materiales y métodos: estudio descriptivo, de corte transversal en dos hospitales en Bogotá (Colombia), durante los años 2005-2008. Se revisaron las bases de datos y se seleccionaron las historias clínicas de los pacientes mayores de 65 años con epilepsia. Resultados: se revisaron 211 historias clínicas y se seleccionaron 179. La edad media fue de 75 años (65-98) y el inicio de la epilepsia fue a los 67,5 (7-93); el 64,4% inició la enfermedad después de los 65 años. El 84% de las crisis fueron clasificadas como focales. El diagnóstico más frecuente fue epilepsia focal sintomática (94,4%). 61 pacientes tuvieron como etiología una enfermedad cerebro-vascular. Los antiepilépticos de primera generación, especialmente fenitoína, fueron los más utilizados (99%), aunque 81 de 104 pacientes tratados no estaban libres de crisis. Conclusiones: la mayoría de las crisis son resultado de una epilepsia focal sintomática como consecuencia de una lesión vascular, por lo que se debe considerar el tratamiento farmacológico desde la primera crisis. Es recomendable iniciar el tratamiento con antiepilépticos de segunda generación como lamotrigina, gabapentin, levetiracetam, para minimizar efectos secundarios, y mantener el principio de inicio con dosis bajas y mantenimiento con dosis bajas. Si las condiciones económicas no lo permiten, se puede usar fenitoína o carbamacepina con precaución.Epilepsy’s overall prevalence in Colombia is 1.13%. Its prevalence in patients aged over 65 could be around 1.5%. Objective: describe demographic and clinical characteristics of patients older than 65 years of age with epilepsy. Materials and methods: A cross-sectional descriptive study was carried out in two high complexity hospitals in Bogotá, Colombia during 2005-2008. Demographic data were compiled and patients characterized regarding the type, frequency and diagnosis of seizures (based on ILAE classification), probable etiology, having a family background of epilepsy, and current pharmacological management. Results: 211 clinical histories were reviewed and 179 of them selected. Mean patient age was 75 (65-98) and average age at onset of epilepsy was 67.5 (7-93). 84% of the seizures were classified as being focal. The most frequently occurring diagnosis was symptomatic focal epilepsy (94.4%). 74 cases (41.3%) had an etiological diagnosis. The most important cause was cerebrovascular disease (61 patients). First generation anti-epileptic drugs were the most used ones (99%). 81/104 patients were found not to be free from epileptic episodes. Conclusions: Most seizures have a partial beginning, resulting from symptomatic partial epilepsy as a consequence of a vascular lesion. Pharmacological treatment must be considered following the first seizure. Treatment with second generation anti-epileptic drugs such as Lamotrigine, Gabapentin, Levetiracetam and Topiramate must be begun for minimizing secondary effects and low doses must be maintained from the start of treatment. Costs may limit the use of the above antiepileptic drugs, in such cases Phenytoin and Carbamazepine may be used with extreme caution.A prevalência global da epilepsia na Colômbia é 1,13% e em pacientes maiores de 65 anos pode estar próxima a 1,5%. O objetivo deste trabalho tem sido descrever as características demográficas e clínicas da população maior de 65 anos que apresenta epilepsia. Materiais e métodos: estudo descritivo, de corte transversal em dois hospitais em Bogotá, Colômbia, durante os anos 2005-2008. Revisaram-se as bases de dados e se selecionaram as histórias clínicas dos pacientes maiores de 65 anos com epilepsia. Resultados: Se revisaram 211 histórias clínicas e se selecionaram 179. A idade média foi de 75 anos (65-98) e o inicio da epilepsia foi aos 67,5 (7-93); 64,4% iniciaram a doença depois dos 65 anos. 84% das crises foram classificadas como focais. O diagnóstico mais freqüente foi epilepsia focal sintomática (94.4%). 61 pacientes tiveram como etiologia uma doença cardiovascular. Os antiepilépticos de primeira geração, especialmente Fenitoína, foram os mais utilizados (99%) ainda que 81 de 104 pacientes tratados não estivessem livres de crises. Conclusões:a maioria das crises é resultado de uma epilepsia focal sintomática como conseqüência de uma lesão vascular pelo que se deve considerar o tratamento farmacológico desde a primeira crise. É recomndável iniciar o tratamento com antiepilépticos de segunda geração como Lamotrigina, Gabapentin, Levetiracetam para minimizar os efeitos secundários e, manter no princípio o início com doses baixas e conservação com doses baixas. Se as condições econômicas não o permitem, pode-se usar Fenitoína ou Carbamacepina com precaução