Evolución a medio plazo de los fenotipos metabólicos de riesgo en pacientes cardiovasculares sometidos a una intervención dietética: dieta mediterránea o dieta baja en grasas (Estudio CORDIOPREV)

BACKGROUND: Obesity is a complex disease, with a wide, heterogeneous and, to a certain extent, not clear aetiology, with an alarmingly increasing incidence. Its big health implications go beyond its associated risk of increasing cardiovascular diseases; so it has also been associated with cancer, renal dysfunction and dementia, among others. Obesity also has enormous socioeconomic consequences, as the reduction of quality of life, or the association with a higher unemployment rate, lower productivity and higher health care costs. In this sense, it could be crucial the identification of obese individuals at risk of developing these comorbidities, some of them potentially fatal. Although the Body Mass Index (BMI) is the most widely used tool for measuring obesity, it has some limitations, such as the heterogeneous cardiovascular risk associated with the same BMI value . As a result, the concept of metabolic phenotypes of obesity emerged, combining metabolic health status and quantitative measurement of excess fat, giving rise to the definition of the Metabolically Healthy Obese (MHO) and the Metabolically Unhealthy Obese (MUO). Although divergent data exist, MHO has traditionally been defined as a transient and unstable phenotype over time whose natural evolution is to progress to MUO. This MUO appears to be a stable phenotype. To date, there are no long-term studies reporting the effects of diet on the evolution of obesity phenotypes in patients with established coronary artery disease. Our hypothesis is that we can identify the existence of biological variables whose changes are associated with the evolution of metabolic phenotypes after the consumption for 5 years of two healthy dietary patterns, one Mediterranean and the other Low in Fat. The null hypothesis is that our study fails to demonstrate the existence of any characteristic associated with the evolution of the metabolic phenotypes of obesity, with the dietary patterns used. OBJECTIVES: Main Objective: - To evaluate the existence of baseline characteristics that differentiate both phenotypes: MHO and MUO. To determine the evolution of the metabolic phenotypes, in cardiovascular patients in the CORDIOPREV study, after long-term consumption, 5 years, of a Mediterranean diet [ 55% carbohydrates]. To study the characteristics that could determine the evolution towards metabolic health or disease, determining 4 phenotypes subgroups: MHO-Non- Progressors, MHO-Progressors, MUO-Responders, and MUO-Non-Responders. Secondary Objectives: 1. To evaluate the existence of key variables associated with less progression to metabolic disease in MHO after long-term consumption of both dietary patterns. 2. To evaluate the existence of variables associated with a recovery of the metabolic disease state in MUO, after long-term consumption of healthy dietary patterns. 3. To evaluate the similarities and differences between the two dietary patterns (Mediterranean diet and Low-Fat diet) in the evolution of obesity phenotypes. POPULATION, DESIGN AND METHODOLOGY: Our research was conducted in the context of the CORDIOPREV study. The CORDIOPREV study was a randomized clinical trial in patients with established coronary artery disease, in which a long-term dietary intervention was performed with two healthy diets: Mediterranean and Low-Fat. In the specific project of this thesis, only obese patients were selected at the beginning of the dietary intervention. Metabolic disease is defined as the presence of two or more cardiometabolic abnormalities (including the criteria for metabolic syndrome, except for waist circumference, and the addition of markers of insulin resistance and systemic inflammation). These patients were classified into Metabolically Healthy Obese (MHO) and Metabolically Unhealthy Obese (MUO). Anthropometric and analytical variables were evaluated both at baseline and after 5 years of dietary intervention, and the evolution of metabolic phenotypes and other related variables were assessed. RESULTS: At the beginning of the study, 562 obese patients were identified from among the 1002 patients who were randomized. After 5 years, 476 obese patients were still on dietary intervention. A total of 28.2% of the MHO at baseline (n=71 participants) maintained their metabolic health (MHO-Non-Progressors). Among the characteristics assessed, these patients decreased their BMI more than 5% from baseline (p=0.033), and their liver fat content more than 15% from baseline (p= 0.045). The remaining 71.8% of MHO patients progressed to metabolic disease (MHO-Progressors), and an increase in insulin resistance (p= 55% carbohidratos]. Estudiar qué características podrían determinar una evolución hacia salud o enfermedad metabólica, determinando 4 subgrupos de fenotipo: OMS-No-Progresadores, OMS-Progresadores, OMERespondedores, OME-No-Respondedores. Objetivos Secundarios: 1. Evaluar la existencia de variables clave asociadas a una menor progresión hacia la enfermedad metabólica en OMS (OMS-No-Progresadores), tras el consumo a largo plazo de ambos patrones dietéticos. 2. Evaluar la existencia de variables que se asocien con una recuperación del estado de la enfermedad metabólica en OME (OME-Respondedores), tras el consumo a largo plazo de ambos patrones dietéticos. 3. Evaluar las semejanzas y diferencias entre estos dos modelos de alimentación (Dieta Baja en Grasas y Dieta Mediterránea) en la evolución de los fenotipos de obesidad. POBLACIÓN, DISEÑO Y METODOLOGÍA: Nuestra investigación se realizó en el contexto del estudio CORDIOPREV. El estudio CORDIOPREV fue un ensayo clínico, aleatorizado, con pacientes con enfermedad coronaria establecida, en el que se realizó una intervención dietética a largo plazo con dos dietas saludables: Mediterránea y Baja en grasas. En el Proyecto específico de esta tesis, se seleccionaron únicamente los pacientes obesos al inicio de la intervención dietética. La enfermedad metabólica está definida como la presencia de dos o más anormalidades cardiometabólicas (incluyendo los criterios del Síndrome Metabólica, excepto el perímetro cintura, añadiendo marcadores de resistencia a la insulina, e inflamación sistémica). Estos pacientes fueron clasificados en obesos metabólicamente sanos y obesos metabólicamente enfermos. Se evaluaron variables antropométricas y analíticas tanto al inicio del estudio como tras 5 años de intervención dietética, y se evaluó la evolución de los fenotipos metabólicos y otras variables relacionadas. RESULTADOS: Al inicio del estudio se identificaron 562 pacientes obesos de entre los 1002 pacientes que fueron aleatorizados. Después de 5 años, 476 pacientes obesos seguían en intervención dietética. Un 28.2% de los OMS al inicio del estudio (n=71 participantes) mantuvieron su salud metabólica (OMS-No-Progresadores). Entre las características evaluadas, estos pacientes disminuyeron su IMC más del 5% del basal (p=0.033), y su contenido de grasa hepática más del 15% del basal (p= 0.045). El restante 71.8% de los pacientes OMS progresaron hacia enfermedad metabólica (OMS-Progresadores), y se evidenció en ellos un aumento en la resistencia a la insulina (p=<0.001), un aumento del porcentaje de pacientes con hiperglucemia (p<0.001) y una disminución de HDL-c (p<0.001), sin cambios en la acumulación grasa. Un 8% de los OME consiguieron responder a la intervención dietética y revertir su estado de enfermedad metabólica (OME-Respondedores). En estos pacientes se observó una disminución del IMC mayor del 5% del basal (p=0.001), una reducción de su contenido de grasa hepática mayor del 15% del basal (p=0.002), y experimentaron una mejoría de la sensibilidad a la insulina (p=0.014). La mayoría de los pacientes OME (92%) mantuvieron su enfermedad metabólica (OME-No-Respondedores). Este último grupo a pesar de disminuir su IMC en torno al 1.5% del inicio (p=0.001) y su estado de inflamación (p=0.022), empeoraron su resistencia a la insulina (p<0.001). Se encontraron diferencias entre dietas, en la evolución de la glucemia en el grupo de los OMS-No-Progresadores, con mejores resultados en la dieta Mediterránea. Y también se hallaron diferencias entre dietas en OME-No-Respondedores en cuanto al descenso de IMC y la presión sistólica arterial, siendo mayores en la dieta baja en grasa. CONCLUSIONES: Conclusión Principal: El obeso metabólicamente sano es un estado transitorio e inestable en el tiempo, con una tendencia hacia la progresión de estados no saludables, a pesar de ello, cerca de un tercio consiguió mantener su salud metabólica (OMS-No-Progresadores). Por otro lado, el obeso metabólicamente enfermo es un estado estable en el tiempo manteniéndose enfermo, no obstante, logramos un 8% de tasa de reversión de salud metabólica (OME-Respondedores). Existen variables basales que podrían diferencian los fenotipos de obesidad, identificando sujetos de alto riesgo cardiovascular. El exceso de adiposidad generalizada, medido mediante IMC, con una distribución anómala hepática, determinado a través del FLI, y con una disfunción del tejido adiposo desencadenando un estado de resistencia insulina e inflamación crónica, son las principales variables identificadas. Conclusiones Secundarias: - Las variables clave que evitaron la progresión hacia la enfermedad metabólica en OMS, tras el consumo a largo plazo de ambos patrones dietéticos, fueron un descenso de la adiposidad general, medida por IMC, mayor del 5% y una disminución de la adiposidad ectópica, representado por FLI, mayor del 15%. •Las variables que promueven revertir el estado de enfermedad metabólica en OME, tras el consumo a largo plazo de ambos patrones dietéticos, fueron un descenso de la adiposidad general, medida por IMC, mayor del 5% y una disminución de la adiposidad ectópica, representado por FLI, mayor del 15%. Adicionalmente, existió un descenso en la presión sistólica arterial, triglicéridos, resistencia a la insulina e inflamación sistémica. - Los dos patrones de alimentación (dieta baja en grasas y dieta mediterránea) tuvieron un impacto similar en la disminución del IMC y de FLI tanto en los OMS-No- Progresadores como entre los OME-Respondedores. Se encontraron diferencias entre dietas, en la evolución de la glucemia en el grupo de los OMS-Progresadores, siendo mayor en la dieta Mediterránea. Y también se hallaron diferencias entre dietas entre OME-No-Respondedores y el descenso de IMC y de presión sistólica arterial, siendo mayor en la dieta baja en grasa

Diferencias entre los métodos de determinación de 2.a y 3.a generación de la parathormona sérica sobre la mortalidad en el paciente en hemodiálisis

Parathormone plays a key role in controlling mineral metabolism. PTH is considered a uremic toxin causing cardiovascular damage and cardiovascular mortality in dialysis patients. There are two different assays to measure PTH called 2nd generation or intact PTH (iPTH) and 3rd generation or bioPTH (PTHbio). Objective: To evaluate the differences in mortality of dialysis patients between both assays to measure PTH, as well as the possible prognostic role of the PTHbio/iPTH ratio. Methods: 145 haemodialysis patients were included with 2-year monitoring including baseline laboratory test and annually thereafter. Results: 21 patients died in the first year and 28 in the second. No correlation was found between PTH, PTHbio and PTHbio/iPTH ratio with mortality. Both PTH have a perfect correlation between them and correlate similarly with other molecules of the mineral metabolism. The extreme baseline values of PTH are those of higher mortality. In survival by iPTH intervals (according to guidelines and COSMOS study), a J curve is observed. When iPTH increases, the ratio decreases, possibly when increasing fragments no. 1–84. There is no greater prognostic approximation on mortality with PTHbio than PTHi. There was also no difference in mortality when progression ratio PTHbio/PTHi was analysed. Conclusions: We didn’t find any advantages to using bioPTH vs. PTHi as a marker of mortality. BioPTH limits of normality must be reevaluated because its relationship with iPTH is not consistent. Not knowing these limits affects its prognostic valueLa paratohormona tiene un papel fundamental en el control del metabolismo mineral. Además es considerada como una toxina urémica al originar dan˜ o cardiovascular e influir en la mortalidad cardiovascular del paciente en diálisis. Existen dos métodos de medición denominados de 2.a generación o PTH intacta (PTHi) y de 3.a generación o bioPTH (PTHbio). Objetivo: Evaluar las diferencias en la mortalidad del paciente en diálisis entre ambas formas de medición de PTH, así como el posible papel pronóstico de su cociente. Métodos: Se incluyeron 145 pacientes en hemodiálisis con un seguimiento de 2 an˜ os con determinación analítica basal y posteriormente de forma anual. Resultados: Veintiún pacientes fallecieron el primer an˜ o y 28 el segundo. No se encontró correlación entre PTHi, PTHbio y cociente PTHbio/PTHi con la mortalidad. Ambas PTH tienen una buena correlación entre ellas y correlacionan de manera similar con otras moléculas del metabolismo mineral. Los valores basales de PTH extremos son los de mayor mortalidad. En la supervivencia por tramos de PTHi (según guías y estudio COSMOS) se observa una curva en J. A mayor aumento de PTHi el cociente desciende, posiblemente al aumentar los fragmentos no 1-84. No existe una mayor aproximación pronóstica sobre mortalidad con PTHbio que con PTHi. No se observan diferencias en el valor predictivo del cociente sobre la mortalidad. Tampoco hubo diferencias en mortalidad cuando se analiza la progresión del cociente PTHbio/PTHi. Conclusiones: No encontramos ventajas en la utilización de PTHbio sobre la PTHi como marcador de mortalidad. Se deben reevaluar los límites de la PTHbio pues su relación con la PTHi no es constante. El no conocer esos límites condiciona su utilidad pronósticaOur thanks to Maribel Villarino for the help with the development of the study. L.R.-O. is a Health Professional on Research Training “Rio Hortega r” (CM13/00131), Ministry of Education, Government of Spain. R.V.B. is a professional with postdoctoral contract “Sara Borrell” (CD14/00198) and a project (SAF2014- 60699-JIN) of the Ministry of Economy (MINECO) and FEDER funds. PI14/00386. PI16/01298. FEDER funds ISCIII-RETIC REDinREN/ RD06/0016, RD12/002

COVID-19 infection and digestive symptoms. Analysis of an outpatient geriatric population

Introducción: Aunque la principal sintomatología de COVID19 es de tipo respiratorio, muchos pacientes presentan síntomas digestivos, que pueden servir para orientar diagnósticos más precoces, adelantando las medidas de aislamiento y la instauración de tratamiento. Dado que los sujetos de mayor edad son lo que presentan formas más severas de COVID 19, llegando incluso a comprometer su vida, estás medidas son más relevantes entre la población anciana. Material y métodos: En el presente trabajo se analizan 147 casos con infección por el SarsCov-2 identificados en una residencia de ancianos durante marzo y abril de 2020. Objetivos: Describir la presentación clínica de síntomas y evolución del cuadro en estos pacientes. Como objetivo secundario demostrar la importancia de los síntomas digestivos en la COVID-19. Resultados: En 71 pacientes (48,3%) se detectó datos de infección por el COVID-19 por PCR y/o test rápido de anticuerpos específicos. El 39,4 % cursaron de forma asintomática. El 72,1% de los pacientes positivos fueron mujeres y la media de edad fue de 80,8 años (DE=16,7). El síntoma más frecuente fue la diarrea (48,8%), seguido de la tos (41,9%) y la fiebre (39,5%). La diarrea se detectó el primer día del cuadro en el 90,4%. En 33,3% se asoció a otros síntomas y en el 16,6% curso de forma aislada. La duración media del cuadro fue de 11,7 días. El 30,2% precisó ingreso hospitalario. El 16,2% falleció por complicaciones respiratorias o sepsis. Conclusiones: Los síntomas gastrointestinales pueden ser frecuentes en la infección por COVID-19 y ser incluso la primera manifestación de la enfermedad. Este grupo de pacientes cursó con una menor proporción de complicaciones y letalidad de la habitual. No obstante, es necesario verificar con estudios de mayor tamaño muestral el papel de los síntomas digestivos en la infección por COVID-19.Introduction: Although the main symptomatology of COVID19 is respiratory, many patients present digestive symptoms, which can be used to guide earlier diagnosis, anticipating isolation measures and the establishment of treatment. Given that older subjects present more severe forms of COVID 19, even compromising their lives, these measures are more relevant among the elderly population. Methods: In the present study, 147 cases with SarsCov-2 infection identified in a nursing home during March and April 2020 were analyzed. Aims: To analyze cases with SarsCov-2 infection identified in a nursing home, as well as to describe the clinical presentation of symptoms and the evolution of the condition in these patients. The secondary objective is to demonstrate the importance of digestive symptoms in COVID-19. Results: In 71 patients (48.3%) data of COVID-19 infection were detected by PCR and/or rapid test for specific antibodies. 39.4% were asymptomatic. Of the positive patients, 72.1% were women and the mean age was 80.8 years (SD=16.7). The most frequent symptom was diarrhea (48.8%), followed by cough (41.9%) and fever (39.5%). Diarrhea was detected on the first day of illness in 90.4%. In 33.3% it was associated with other symptoms and in 16.6% it was isolated. The mean duration of the symptoms was 11.7 days. Hospital admission was required in 30.2% of patients. 16.2% died due to respiratory complications or sepsis. Conclusions: Gastrointestinal symptoms may be frequent in COVID-19 infection and may even be the first manifestation of the disease. This group of patients had a lower proportion of complications and case fatality than usual. However, the role of digestive symptoms in COVID-19 infection needs to be verified with larger studies

Evolution of Metabolic Phenotypes of Obesity in Coronary Patients after 5 Years of Dietary Intervention: From the CORDIOPREV Study

Background: Obesity phenotypes with different metabolic status have been described previously. We analyzed metabolic phenotypes in obese coronary patients during a 5-year follow-up, and examined the factors influencing this evolution. Methods: The CORDIOPREV study is a randomized, long-term secondary prevention study with two healthy diets: Mediterranean and low-fat. All obese patients were classified as either metabolically healthy obese (MHO) or metabolically unhealthy obese (MUO). We evaluated the changes in the metabolic phenotypes and related variables after 5 years of dietary intervention. Results: Initially, 562 out of the 1002 CORDIOPREV patients were obese. After 5 years, 476 obese patients maintained their clinical and dietary visits; 71.8% of MHO patients changed to unhealthy phenotypes (MHO-Progressors), whereas the MHO patients who maintained healthy phenotypes (MHO-Non-Progressors) lost more in terms of their body mass index (BMI) and had a lower fatty liver index (FLI-score) (p < 0.05). Most of the MUO (92%) patients maintained unhealthy phenotypes (MUO-Non-Responders), but 8% became metabolically healthy (MUO-Responders) after a significant decrease in their BMI and FLI-score, with improvement in all metabolic criteria. No differences were found among dietary groups. Conclusions: A greater loss of weight and liver fat is associated with a lower progression of the MHO phenotype to unhealthy phenotypes. Likewise, a marked improvement in these parameters is associated with regression from MUO to healthy phenotypes

Statins in Non-alcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease. The range is extensive, including hepatocellular carcinoma, cirrhosis, fibrosis, fatty liver, and non-alcoholic steatohepatitis (NASH). NASH is a condition related to obesity, overweight, metabolic syndrome, diabetes, and dyslipidemia. It is a dynamic condition that can regress to isolated steatosis or progress to fibrosis and cirrhosis. Statins exert anti-inflammatory, proapoptotic, and antifibrotic effects. It has been proposed that these drugs could have a relevant role in NASH. In this review, we provide an overview of current evidence, from mechanisms of statins involved in the modulation of NASH to human trials about the use of statins to treat or attenuate NASH.Ye

Differences between 2nd and 3rd generation seric parathormone determination methods on mortality in haemodialysis patients

Parathormone plays a key role in controlling mineral metabolism. PTH is considered a uremic toxin causing cardiovascular damage and cardiovascular mortality in dialysis patients. There are two different assays to measure PTH called 2nd generation or intact PTH (iPTH) and 3rd generation or bioPTH (PTHbio). Objective: To evaluate the differences in mortality of dialysis patients between both assays to measure PTH, as well as the possible prognostic role of the PTHbio/iPTH ratio. Methods: 145 haemodialysis patients were included with 2-year monitoring including baseline laboratory test and annually thereafter. Results: 21 patients died in the first year and 28 in the second. No correlation was found between PTH, PTHbio and PTHbio/iPTH ratio with mortality. Both PTH have a perfect correlation between them and correlate similarly with other molecules of the mineral metabolism. The extreme baseline values of PTH are those of higher mortality. In survival by iPTH intervals (according to guidelines and COSMOS study), a J curve is observed. When iPTH increases, the ratio decreases, possibly when increasing fragments no. 1–84. There is no greater prognostic approximation on mortality with PTHbio than PTHi. There was also no difference in mortality when progression ratio PTHbio/PTHi was analysed. Conclusions: We didn’t find any advantages to using bioPTH vs. PTHi as a marker of mortality. BioPTH limits of normality must be reevaluated because its relationship with iPTH is not consistent. Not knowing these limits affects its prognostic value

The 2022 Seismic Hazard Model for Costa Rica

Costa Rica is located at the boundary of four tectonic plates where the regularity of destruc tive earthquakes highlights the necessity of seismic hazard estimations. This study contains the most recent Probabilistic Seismic Hazard Assessment (PSHA) for Costa Rica, calculated with the largest and the most updated earthquake database from both—the Earthquake Engineering Laboratory and the National Seismological Network of the University of Costa Rica. For the PSHA, we updated the seismicity parameters for the upper plate, sub duction interplate, and intraslab tectonic domains, characterized the upper-plate zones by percentages of fault types, and used weighted ground-motion models for each of the tec tonic domains. The resulted maps of peak ground acceleration (PGA) at return periods of 475 yr (PGA-475) and 2475 yr, as well as the spectral accelerations, show geographic trends that allow for the division of the country in four seismic hazard levels: (1) extremely high for the Nicoya, Osa, and Burica peninsulas, situated directly above the subduction interplate, where the PGA-475 could be 0.55–1.20g; (2) very high for most of the Guanacaste Province, where the PGA-475 may be 0.55–0.70g; (3) high for most of the country ( ∼41%) with PGA-475 values of 0.40–0.55g, including Central Costa Rica and the capital city of San Jose; and (4) moderate for the Talamanca Cordillera and Northern Costa Rica, with PGA-475 up to 0.40g. These ground-motion values are 0.1–0.6g higher than the previous PSHA for the Pacific peninsulas, Guanacaste, and the southeastern Caribbean. Further, hazard curves, uni form hazard spectra, and a hazard disaggregation indicate that the seismic hazard is lower but more complex in San Jose than in Liberia—the largest city in Guanacaste.Universidad de Costa Rica/[731-B9-780]/UCR/Costa RicaUniversidad de Costa Rica/[113-B5-704]/UCR/Costa RicaUniversidad de Costa Rica/[113-B9-911]/UCR/Costa RicaUCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela Centroamericana de GeologíaUCR::Vicerrectoría de Docencia::Ingeniería::Facultad de Ingeniería::Escuela de Ingeniería CivilUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ingeniería::Laboratorio Nacional de Materiales y Modelos Estructurales (LanammeUCR)UCR::Vicerrectoría de Docencia::Ciencias Sociales::Facultad de Ciencias Sociales::Escuela de PsicologíaUCR::Vicerrectoría de Docencia::Ciencias Sociales::Facultad de Ciencias Sociales::Escuela de Trabajo Socia

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health