TV medical dramas: health sciences students' viewing habits and potential for teaching issues related to bioethics and professionalism.

BACKGROUND: Medical dramas have been popular since their inception, especially among medical students. We hypothesized that the recent increase in the availability of TV medical series through online streaming platforms has probably changed health science students' viewing habits as well as the representation of bioethical conflicts and health professionals. METHODS: We invited undergraduate students of medicine, nursing, and human biology to complete a self-administered questionnaire about their viewing habits and perceptions of the depictions of bioethical issues and professionalism in TV medical series. RESULTS: Of the 355 respondents, 98.6 % had watched TV in the last year, 93.5 % watched TV series, and 49.6 % watched medical dramas more than once a week. The most-viewed medical dramas were The Good Doctor, House MD, and Grey's Anatomy. The most-remembered bioethical topics were medical errors, inappropriate professional behaviors, and death. Most students considered that ideals of professionalism were depicted positively and professionals were portrayed as intelligent, professionally qualified, and competent. CONCLUSIONS: Medical dramas are very popular with health science students and are potentially useful as teaching tools for discussing issues related to bioethics and professionalism.

Parameters of the Mouse Embryo Assay that affect detection of peroxides in mineral oil.

RESEARCH QUESTION: Can culture conditions influence the sensitivity of a Mouse Embryo Assay and its potential to detect peroxide-related toxicity in mineral oil samples? DESIGN: Protein type and concentration, embryo density and culture dish design were selected as the variables in the culture system with the potential to influence the assay's sensitivity. Fresh 1-cell mouse embryos were cultured under mineral oil samples with known peroxide concentrations. Protein type (human serum albumin [HSA] + α/ß-Globulins versus HSA versus bovine serum albumin [BSA]), concentration (5 mg/ml versus 0.5 mg/ml), embryo density (25 versus 3 µl/embryo) and culture dish (Petri versus micro-well dish) were adjusted to define the culture conditions with the highest sensitivity. RESULTS: High concentrations of peroxides can be easily detected by current quality control standards. However, for oil samples with a lower concentration of peroxides, supplementing the culture medium with 5 mg/ml of HSA + alpha/beta-globulins or with HSA resulted in an increased detection of embryo toxicity compared with when BSA was used as the protein supplement. The sensitivity of the assay was greatly reduced when embryos were cultured in groups and when certain micro-well dishes were used. CONCLUSIONS: Current quality control protocols may not be sensitive enough to identify low concentrations of peroxides, which, if undetected, can increase over time and become potentially harmful during gamete and embryo culture. The different parameters established in this study allow the sensitivity of the Mouse Embryo Assays to be optimized to specifically detect peroxides in mineral oil samples prior to their release into the market and their broad use in human IVF.

DNA methylation biomarkers of myocardial infarction and cardiovascular disease.

BACKGROUND: The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identified biomarkers is still limited. We aimed to identify differentially methylated loci associated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers. RESULTS: We designed a case-control, two-stage, epigenome-wide association study on AMI (ndiscovery = 391, nvalidation = 204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. We performed a fixed-effects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n ~ 1800 and n ~ 2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infinium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic influence and therefore the results were not conclusive. CONCLUSIONS: We have identified 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.

Genetic variation in the KCNMA1 potassium channel alpha subunit as risk factor for severe essential hypertension and myocardial infarction.

OBJECTIVE: The large conductance Ca2+ -dependent potassium channel plays a critical role in the control of vascular tone, coupling local increases in intracellular Ca2+ to membrane hyperpolarization and vascular relaxation. It also impacts blood pressure by modulating the renin-angiotensin-aldosterone system. Previous studies have shown that a polymorphism in the beta1 regulatory subunit of the Ca2+ -dependent potassium channel modulates the risk of diastolic hypertension in humans. METHODS: We have studied polymorphisms in the pore-forming alpha subunit gene (KCNMA1) and their association to hypertension and myocardial infarction. RESULTS: Sequencing of the KCNMA1 gene revealed two genetic variants (polymorphisms C864T and IVS17) in population-based epidemiological studies (4786 participants). We detected a significant increase in the frequency of the IVS17+37T>C polymorphism with severe systolic hypertension (48.3% for normotensive vs. 69% for severe systolic hypertension, P=0.03) and with severe general hypertension (48.7 vs. 65.8%, P=0.04), although the adjusted odd ratios did not reach statistical significance. Four C864T/IVS17 haplotypes were identified. Haplotype 4 (encompassing the C allele of the IVS17 polymorphism and the T allele of the C864T polymorphism) was related with increased severity of systolic and general hypertension as well as increased risk of myocardial infarction. CONCLUSION: Our study provides genetic evidence that highlights the relevance of the Ca2+ -dependent potassium channel in the control of human blood pressure and its impact on cardiovascular disease.

Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension.

Hypertension is the most prevalent risk factor for cardiovascular diseases, present in almost 30% of adults. A key element in the control of vascular tone is the large-conductance, Ca(2+)-dependent K(+) (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting alpha subunit and a regulatory beta(1) subunit, which couples local increases in intracellular Ca(2+) to augmented channel activity and vascular relaxation. Our large population-based genetic epidemiological study has identified a new single-nucleotide substitution (G352A) in the beta(1) gene (KCNMB1), corresponding to an E65K mutation in the protein. This mutation results in a gain of function of the channel and is associated with low prevalence of moderate and severe diastolic hypertension. BK-beta(1E65K) channels showed increased Ca(2+) sensitivity, compared with wild-type channels, without changes in channel kinetics. In conclusion, the BK-beta(1E65K) channel might offer a more efficient negative-feedback effect on vascular smooth muscle contractility, consistent with a protective effect of the K allele against the severity of diastolic hypertension.

Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk.

The E65K polymorphism in the beta1-subunit of the large-conductance, Ca2+-dependent K+ (BK) channel, a key element in the control of arterial tone, has recently been associated with low prevalence of diastolic hypertension. We now report the modulatory effect of sex and age on the association of the E65K polymorphism with low prevalence of diastolic hypertension and the protective role of E65K polymorphism against cardiovascular disease. We analyzed the genotype frequency of the E65K polymorphism in 3924 participants selected randomly in two cross-sectional studies. A five-year follow-up of the cohort was performed to determine whether cardiovascular events had occurred since inclusion. Estrogen modulation of wild-type and mutant ion channel activity was assessed after heterologous expression and electrophysiological studies. Multivariate regression analyses showed that increasing age upmodulates the protective effect of the K allele against moderate-to-severe diastolic hypertension in the overall group of participants (odds ratio [OR], 0.35; P=0.006). The results remained significant when analyses were restricted to women (OR, 0.18; P=0.02) but not men (OR, 0.46; P=0.09). This effect was independent of the reported acute modulation of BK channels by estrogen. A five-year follow-up study also demonstrated a reduced age- and sex-adjusted hazard ratio of 0.11, 95% CI, 0.01 to 0.79 of K-carriers for "combined cardiovascular disease" (myocardial infarction and stroke) compared with EE homozygotes. Our study provides the first genetic evidence for the different impact of the BK channel in the control of human blood pressure in men and women, with particular relevance in aging women, and highlights the E65K polymorphism as one of the strongest genetic factors associated thus far to protection against myocardial infarction and stroke.

DNA methylation and obesity traits: An epigenome-wide association study. The REGICOR study.

Obesity is associated with increased risk of several diseases and has become epidemic. Obesity is highly heritable but the genetic variants identified by genome-wide association studies explain only limited variability. Epigenetics could contribute to explain the missing variability. The study aim was to discover differential methylation patterns related to obesity. We designed an epigenome-wide association study with a discovery phase in a subsample of 641 REGICOR study participants, validated by analysis of 2,515 participants in the Framingham Offspring Study. Blood DNA methylation was assessed using Illumina HumanMethylation450 BeadChip. Next, we meta-analyzed the data using the fixed effects method and performed a functional and pathway analysis using the Ingenuity Pathway Analysis software. We were able to validate 94 CpGs associated with body mass index (BMI) and 49 CpGs associated with waist circumference, located in 95 loci. In addition, we newly discovered 70 CpGs associated with BMI and 33 CpGs related to waist circumference. These CpGs explained 25.94% and 29.22% of the variability of BMI and waist circumference, respectively, in the REGICOR sample. We also evaluated 65 of the 95 validated loci in the GIANT genome-wide association data; 10 of them had Tag SNPs associated with BMI. The top-ranked diseases and functions identified in the functional and pathway analysis were neurologic, psychological, endocrine, and metabolic.

Cardiovascular Risk Factors and Ischemic Heart Disease: Is the Confluence of Risk Factors Greater Than the Parts? A Genetic Approach.

BACKGROUND: Cardiovascular risk factors tend to aggregate. The biological and predictive value of this aggregation is questioned and genetics could shed light on this debate. Our aims were to reappraise the impact of risk factor confluence on ischemic heart disease (IHD) risk by testing whether genetic risk scores (GRSs) associated with these factors interact on an additive or multiplicative scale, and to determine whether these interactions provide additional value for predicting IHD risk. METHODS AND RESULTS: We selected genetic variants associated with blood pressure, body mass index, waist circumference, triglycerides, type-2 diabetes mellitus, high-density lipoprotein and low-density lipoprotein cholesterol, and IHD to create GRSs for each factor. We tested and meta-analyzed the impact of additive (synergy index) and multiplicative (ßinteraction) interactions between each GRS pair in 1 case-control (n=6042) and 4 cohort studies (n=17 794) and evaluated the predictive value of these interactions. We observed 2 multiplicative interactions: GRSLDL·GRSTriglycerides (ßinteraction=-0.096; SE=0.028) and nonpleiotropic GRSIHD·GRSLDL (ßinteraction=0.091; SE=0.028). Inclusion of these interaction terms did not improve predictive capacity. CONCLUSIONS: The confluence of low-density lipoprotein cholesterol and triglycerides genetic risk load has an additive effect on IHD risk. The interaction between low-density lipoprotein cholesterol and IHD genetic load is more than multiplicative, supporting the hazardous impact on atherosclerosis progression of the combination of inflammation and increased lipid levels. The capacity of risk factor confluence to improve IHD risk prediction is questionable. Further studies in larger samples are warranted to confirm and expand our results.

Prevalencia del síndrome de burnout entre los estudiantes de medicina y su relación con variables demográficas, personales y académicas / The prevalence of burnout syndrome among medical students and its relationship with demographic, personal and academic variables

Introducción: Recientes estudios muestran que el síndrome de burnout puede aparecer en estudiantes de medicina antes incluso de empezar su vida laboral y puede tener potenciales consecuencias, tanto en la salud de los futuros médicos como en la calidad asistencial. Objetivo: Analizar la prevalencia de burnout en los estudiantes de medicina del grado conjunto UPF/UAB y su relación con características demográficas y personales. Sujetos y métodos: Se llevaron a cabo dos estudios transversales en estudiantes de medicina de la Facultad de Ciencias de la Salud y de la Vida (UPF/UAB) en Barcelona, en 2018 y 2019. Se recogieron datos demográficos, personales y de burnoutmediante cuestionarios que incluían el Maslach Burnout Inventory-Student Survey. Resultados: La prevalencia de burnout fue del 33,6% en la cohorte de 2018 y del 38% en la de 2019. Se observó un incremento estadísticamente significativo en los estudiantes de sexto curso (60,5%) respecto a los estudiantes de primero (20,6%). No se encontraron asociaciones significativas entre el burnouty las variables demográficas y personales estudiadas. Los cursos académicos más elevados mostraron un incremento significativo de la prevalencia del síndrome en ambas cohortes. Conclusiones: Existe una alta prevalencia de burnout entre los estudiantes de medicina del grado conjunto UPF/UAB. Aunque no se relacionó con las variables estudiadas, los resultados del presente estudio muestran que la prevalencia del síndrome de burnout en los estudiantes se incrementa significativamente a medida que se avanza en los estudios de medicina

Introduction: Recent studies show that burnout syndrome can appear in medical students even before starting their working life, and it can have potential consequences, both in the health of future doctors and in the quality of care. Aim: To analyze the prevalence of burnout in medical students of the UPF/UAB joint degree and its relationship with demographic and personal characteristics. Subjects and methods: Two cross-sectional studies were carried out in Medicine students of the Faculty of Health and Life Sciences (UPF/UAB) in Barcelona, in 2018 and 2019. Demographic, personal and burnout data were collected through questionnaires which included the Maslach Burnout Inventory-Student Survey. Results: The present study shows that the prevalence of burnout was 33.6% in the 2018 cohort and 38% in the 2019 cohort. A statistically significant increase was observed in sixth grade students (60.5%) with respect to first-year students (20.6%). No significant associations were found between burnout and the demographic and personal variables studied. The highest academic courses showed a significant increase in the prevalence of the syndrome in both cohorts. Conclusions: There is a high prevalence of burnout among UPF/UAB medical students. Although it was not related to the variables studied, the results of the present study show that the prevalence of burnout syndrome in students significantly increases with advancing academic course

Antioxidant paraoxonase 1 activity in the metabolic syndrome.

Paraoxonase (PON1) is an antioxidant enzyme closely associated with high-density lipoproteins. Low PON1 has been shown in oxidative stress-associated processes such as dyslipidemia, diabetes mellitus, advancing age, and smoking. Indeed, oxidative stress is related to the degree of insulin resistance, a key component of the metabolic syndrome. Therefore, the possible relationship between PON1 activity and the metabolic syndrome was investigated. From 1364 randomly recruited subjects, 285 were found to have the metabolic syndrome, according to the guidelines published by the National Cholesterol Education Program, Adult Treatment Panel III. PON1 activity, lipid peroxides, and PON1 codon 192 genotypes, which strongly modulate PON1 activity, were determined. Serum PON1 activity levels were found to be significantly lower, and lipid peroxide concentrations significantly higher, in subjects with the metabolic syndrome compared with unaffected subjects (P = 0.033 and < 0.001, respectively). Study subjects showed a significant decreasing trend in PON1 activity levels and a significant increasing trend in lipid peroxide concentrations, with the increase in the number of metabolic disturbances. No differences in the prevalence of PON1 codon 192 genotypes were found among the categories of metabolic abnormalities. In conclusion, a greater degree of severity of the metabolic syndrome is associated with a progressively worse antioxidant/oxidant balance, which is consistent with increased oxidative stress and lower antioxidant PON1 enzymatic capacity.

High oxidative stress in patients with stable coronary heart disease.

Oxidized low density lipoprotein (oxLDL) plays a pivotal role in the development of atherosclerosis. The aim of the study was to investigate the relationship between oxLDL and other oxidative stress biomarkers with stable coronary heart disease (CHD). We compared the degree of oxidative stress in patients with CHD and sex-matched healthy control subjects in a case-control study. The study included 64 male subjects: 32 patients with stable CHD and 32 normal control subjects. Levels of circulating oxLDL were measured by a monoclonal antibody 4E6-based competition ELISA. Comparison of oxidative stress marker levels between cases and controls, adjusted for age, revealed significantly higher plasma oxLDL levels (63.32+/-25.49 vs. 37.73+/-20.58 U/l, P=0.001), lower serum levels of autoantibodies against oxLDL (341.53+/-350.46 vs. 796.45+/-1034.2 mU/ml, P=0.021), higher activities of the antioxidant enzymes superoxide dismutase in erythrocytes (951+/-70.2 vs. 771.6+/-191.2 U/g, P=0.032) and glutathione peroxidase in whole blood (GSH-Px: 10714.4+/-3705.4 vs. 5512.2+/-1498.1 U/l, P<0.001). The risk of having CHD was 20.6-fold greater (95% CI, 1.86-228.44, P=0.014) in the highest tertile of the oxLDL distribution than in the lowest, determined by logistic regression analysis on the combined study population after adjustment for age and other potential confounding factors. When the risk associated with GSH-Px levels was calculated, the odds ratio was 305.3 (95% CI, 5.07-18369.95, P=0.006) in the highest tertile compared with the lowest. Our results showed that an oxidative stress occurs in patients with CHD despite being clinically stable and under medical treatment. The combination of oxLDL levels and GSH-Px activity may be useful for the identification of patients with stable CHD.

[The antioxidant function of high density lipoproteins: a new paradigm in atherosclerosis]. / Función antioxidante de las lipoproteínas de alta densidad: un nuevo paradigma en la arteriosclerosis.

The one disease associated with the greatest morbidity and mortality in industrialized countries is coronary heart disease (CHD). High density lipoprotein (HDL) is one of the most important independent protective factors for the arteriosclerosis which underlies CHD. Paraoxonase 1 (PON1) is an enzyme that confers antioxidant properties to HDL. In vitro, PON1 hydrolyzes a large variety of endogenous or exogenous substrates, some of which are clearly involved in the progression of arteriosclerosis. A close relationship between PON1 deficiency and accelerated progression of arteriosclerosis has been found in animal models. Moreover, PON1 activity is reduced in high oxidative stress diseases such as CHD, dyslipoproteinemias, inflammatory processes, diabetes and certain neuropathies. Reduced PON1 enzyme activity is associated with several arteriosclerosis-related diseases. The most thoroughly studied genetic variant of PON1 is PON1-192, in which the R allele is associated with elevated paraoxonase activity. This allele, present in 24.8% of the Italian population, is found in up to 78.9% of the population of Ecuadorian Cayapa Indians. A metaanalysis of studies on the relationship between CHD and the R allele showed the latter to be an independent risk factor for this disease, with an odds ratio of 1.18 (95% confidence interval, 1.10-1.27). The PON1 enzyme is a potentially useful new qualitative indicator in addition to the well known reverse cholesterol transport capacity associated with high plasma levels of HDL.

[Paraoxonase 1 gene 192 polymorphism, physical activity and lipoprotein in women]. / Polimorfismo 192 del gen de la paraoxonasa 1, actividad física y lipoproteínas de alta densidad en la mujer.

BACKGROUND AND OBJECTIVE: Regular physical activity is associated with an increase in high-density lipoprotein cholesterol (HDL-C), whose antioxidant and protective effect for coronary artery disease is well known. Paraoxonase-1 (PON1) is an enzyme related with the antioxidant activity of HDL. The PON1 gene has several genetic polymorphisms; one of them locates in codon 192, whose alleles Q and R are associated with low and high PON1-activity, respectively. The objective of this study was to determine whether physical activity has different effects on the lipid profile in women depending on the PON1-192 genotype. PATIENTS AND METHOD: Six hundred and fifty-one women from a cross-sectional risk-factor study were included in this retrospective cohort study. We analyzed anthropometrical characteristics, serum lipids and lipoproteins, blood pressure, PON1-192 genotypes and menopause. We used the Minnesota Leisure Time Physical Activity Questionnaire to assess the daily physical activity in the previous year. RESULTS: Women included in the study were classified into three categories by tertiles of daily physical activity. Although no differences in the lipidic parameters were found, we observed an increasing trend in HDL-C concentration and a decreasing trend in log-triglyceride-to-HDL-cholesterol ratio with increasing physical activity in RR homozygous women. In subgroup analyses, we observed that the association of high physical activity and increased HDL-C concentration or decreased log-triglyceride-to-HDL-cholesterol ratio were exclusive for RR homozygous non-menopausal women. CONCLUSIONS: The results of this study suggest that PON1-192 polymorphism could modulate the effect of physical activity on HDL-C concentration and on triglyceride-rich lipoprotein catabolism in non-menopausal women.

La enseñanza de la relación mutua entre ciencias biomédicas y sociedad. La experiencia de biomedicina, sociedad y cultura / The mutual relationship between biomedical sciences and society. The experience of biomedicine, society and culture

INTRODUCCIÓN: Los avances biomédicos de los últimos 2 siglos han tenido una repercusión importante en la sociedad. Sin embargo, la docencia de esta relación mutua en el ámbito universitario es una tarea pendiente. MATERIAL Y MÉTODOS: Se describe las características de la asignatura Biomedicina, sociedad y cultura dirigida a presentar la interacción de la biomedicina con la historia, la economía, la sociología y la cultura a los estudiantes de máster. Se presentan los resultados de los 3 primeros años (2015-2017) de su impartición mediante un cuestionario de evaluación cualitativo tipo Likert de 5 puntos para los aspectos generales del curso y cuantitativo para el interés de los diversos temas (0-5), que completaron los estudiantes. RESULTADOS: La cursaron 51 estudiantes. La mayoría (89%) provenía de estudios biomédicos. Los estudiantes expresaron con puntuaciones máximas (totalmente de acuerdo) que la asignatura había cumplido sus expectativas, que la recomendarían y que había aumentado sus conocimientos sobre la relación entre biomedicina y aspectos sociales y culturales. Los temas de mayor interés fueron los aspectos históricos (4,5 ± 0,6), las implicaciones sociológicas (4,6 ± 0,7) y las consideraciones bioéticas (4,5 ± 0,6), y el menos valorado fue los aspectos culturales (3,9 ± 1,0). DISCUSIÓN: La asignatura descrita puede contribuir de forma importante a que los graduados comprendan cómo se ejerce la relación mutua entre ciencia biomédica y elementos sociales. Materias similares pueden ayudar a la contextualización de los avances científicos en un área tan sensible como es la biomedicina

INTRODUCTION: Biomedical progress in the last two centuries has had a significant effect on society. However, the teaching on the mutual relationship between bioscience and society is still lacking in most universities. MATERIAL AND METHODS: A description is presented on the characteristics of the subject Biomedicine, society and culture. This is devoted to introduce, the interaction of biomedicine with history, economy, sociology, and culture, to graduate students of masters programs. The evaluation of the first three years (2015-2017) of the experience is reported. Student beliefs and opinions were evaluated by means of a questionnaire that used a five point Likert type scale for the agreement with some statements, and a quantitative scale (zero to five) for their opinion with the contents of the subject. RESULTS: The questionnaire on the experience was completed by 51 students. Most of them (89%) were graduates of biomedical disciplines. They gave the highest score (Fully agree) to the statements that the subject had fulfilled their expectations, that they would recommend it to other students, and the fact that the subject had increased their knowledge on the mutual relationship between biomedicine and social and cultural factors. The topics that they scored the highest were historical aspects (4.5 ± 0.6), sociological implications (4.6 ± 0.7) and bioethical considerations (4.5 ± 0.6), whereas the lowest was cultural aspects (3.9 ± 1.0) DISCUSSION: The subject described here may contribute to enhancing the understanding of the importance of a mutual relationship between biomedicine and society by postgraduate students. Similar initiatives may help in establishing the context of scientific progress in an important area such biomedicine

Assessment of the value of a genetic risk score in improving the estimation of coronary risk.

BACKGROUND: The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS improves the predictive capacity of the Framingham risk function. METHODS AND RESULTS: Using eight genetic variants associated with CHD but not with classical cardiovascular risk factors (CVRFs), we generated a multi-locus GRS, and found it to be linearly associated with CHD in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537) (meta-analyzed HR [95%CI]: ~1.13 [1.01-1.27], per unit). Inclusion of the GRS in the Framingham risk function improved its discriminative capacity in the Framingham sample (c-statistic: 72.81 vs.72.37, p=0.042) but not in the REGICOR sample. According to both the net reclassification improvement (NRI) index and the integrated discrimination index (IDI), the GRS improved re-classification among individuals with intermediate coronary risk (meta-analysis NRI [95%CI]: 17.44 [8.04; 26.83]), but not overall. CONCLUSIONS: A multi-locus GRS based on genetic variants unrelated to CVRFs was associated with a linear increase in risk of CHD events in two distinct populations. This GRS improves risk reclassification particularly in the population at intermediate coronary risk. These results indicate the potential value of the inclusion of genetic information in classical functions for risk assessment in the intermediate risk population group.

Hypothesis-based analysis of gene-gene interactions and risk of myocardial infarction.

The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3-2.0, depending on allele frequency and interaction model).

Factores predictores de resultados en la prueba MIR en las universidades públicas. Análisis de la cohorte 2008-2014 / Factors that may predict the success in the MIR exam in public Spanish universities. An analysis of the 2008-2014 cohort

Objetivo: Analizar la influencia de algunos factores que podrían asociarse con el rendimiento y éxito de los médicos en la prueba MIR. Sujetos y métodos: Se analizaron los resultados obtenidos por los aspirantes médicos en la prueba MIR de la convocatoria 2014-2015 originarios de 29 facultades de medicina. Las variables de análisis incluidas fueron la nota de acceso a la universidad para el curso 2008-2009, el tamaño de las promociones de entrada, el número total de los presentados a la convocatoria MIR, la diferencia entre los presentados a la convocatoria y el tamaño de la promoción de entrada, y las variables de éxito, como el porcentaje de aspirantes que superaron la prueba y su distribución en los percentiles 23 y 73. Resultados: Ni la nota de acceso a la universidad ni el tamaño de la promoción de entrada se asociaron con las variables de éxito en los resultados. La diferencia entre presentados a la prueba y estudiantes de la promoción fue un indicador significativamente negativo del éxito en la prueba. Conclusiones: El principal y único factor determinante del éxito de los resultados en la prueba MIR es la diferencia entre el número de presentados a la prueba y el de los estudiantes de la cohorte inicial. Esta diferencia representa en su mayor parte a aquellos estudiantes que difieren su candidatura a la prueba por no obtener plaza en la convocatoria natural o que prefieren cambiar la obtenida en años anteriores

Aim: To analyze the influence of some factors on the performance and success of physicians in the MIR test. Subjects and methods: The results obtained by medical aspirants in the 2014-015 MIR test call from 29 medical schools were analyzed. The analysis variables were the access mark to university for 2008-2009, the size of the input promotions, the total number of the presented to the MIR call, the difference between presented to the call and the size of the input promotion, and success variables such as the percentage of applicants who passed the test and their distribution in the 23 and 73 percentiles. Results: Neither the access cut-off to the university nor the size of the entry cohort was associated with successful results. The difference between those presented to the test and those from the input promotion was a significant negative predictor of success in the test. Conclusions: The single biggest determinant of successful outcomes in the MIR test is the difference between the number of submitted for testing and the students of the initial cohort. This difference largely represents students who delay their application to the test by not getting square or prefer to change it

Post-genomic update on a classical candidate gene for coronary artery disease: ESR1.

BACKGROUND: After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated. METHODS AND RESULTS: We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87,000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ERα in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex. CONCLUSIONS: We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

A gain-of-function SNP in TRPC4 cation channel protects against myocardial infarction.

AIMS: The TRPC4 non-selective cation channel is widely expressed in the endothelium, where it generates Ca(2+) signals that participate in the endothelium-mediated vasodilatory response. This study sought to identify single-nucleotide polymorphisms (SNPs) in the TRPC4 gene that are associated with myocardial infarction (MI). METHODS AND RESULTS: Our candidate-gene association studies identified a missense SNP (TRPC4-I957V) associated with a reduced risk of MI in diabetic patients [odds ratio (OR) = 0.61; confidence interval (CI), 0.40-0.95, P= 0.02]. TRPC4 was also associated with MI in the Wellcome Trust Case-Control Consortium's genome-wide data: an intronic SNP (rs7319926) within the same linkage disequilibrium block as TRPC4-I957V showed an OR of 0.86 (CI, 0.81-0.94; P =10(-4)). Functional studies of the missense SNP were carried out in HEK293 and CHO cells expressing wild-type or mutant channels. Patch-clamp studies and measurement of intracellular [Ca(2+)] in response to muscarinic agonists and direct G-protein activation showed increased channel activity in TRPC4-I957V-transfected cells compared with TRPC4-WT. Site-directed mutagenesis and molecular modelling of TRPC4-I957V suggested that the gain of function was due to the presence of a less bulky Val-957. This permits a firmer interaction between the TRPC4 and the catalytic site of the tyrosine kinase that phosphorylates TRPC4 at Tyr-959 and facilitates channel insertion into the plasma membrane. CONCLUSION: We provide evidence for the association of a TRPC4 SNP with MI in population-based genetic studies. The higher Ca(2+) signals generated by TRPC4-I957V may ultimately facilitate the generation of endothelium- and nitric oxide-dependent vasorelaxation, thereby explaining its protective effect at the vasculature.

Additive effect of multiple genetic variants on the risk of coronary artery disease.

INTRODUCTION AND OBJECTIVES: Coronary artery disease (CAD) has a substantial genetic component and, in recent years, a number of genetic variants associated with the disease have been identified. The objective of this study was to evaluate the magnitude of the association between a genetic risk score, which is based on the accumulated number of risk alleles in all genetic variants of interest, and the presence of CAD. METHODS: The study involved in silico data from the Wellcome Trust Case-Control Consortium on 1988 patients with CAD and 5380 controls. The association between the genetic risk score and CAD was assessed using logistic regression analysis. RESULTS: Nine genetic variants independently associated with CAD irrespective of other cardiovascular risk factors were selected. There was a linear association between the number of risk alleles and the risk of presenting with CAD (odds ratio [OR] for an increase of one allele=1.18; 95% confidence interval [CI], 1.15-1.22; P=2 x 10-16). The OR for CAD for the last quintile of the accumulated number of risk alleles relative to the first was 2.21 (95%CI, 1.87-2.61; P=5 x 10-21). CONCLUSIONS: A genetic risk score based on nine genetic variants independently associated with CAD irrespective of other cardiovascular risk factors was associated with the presence of the disease. Cohort studies are needed to determine whether this genetic risk score can improve the predictive capacity or the risk classification of classical risk functions.