Effectiveness of new technologies in promoting healthy lifestyles and weight loss. Evident 3 randomized clinical trial

Tesis por compendio de publicaciones[ES]Antecedentes: Existe evidencia de que las intervenciones sobre estilos de vida que aborden varios componentes, como la dieta, la actividad física y el cambio de comportamiento, son eficaces para inducir una pérdida de peso clínicamente significativa, y se asocian con mejoras en la salud y el estado psicosocial. En este contexto, el uso de las Tecnologías de la Información y Comunicación (TICs) podría mejorar la autogestión de la salud y la eficacia de estas intervenciones al ofrecer una mayor adaptación al usuario. Objetivos: El objetivo principal es evaluar el impacto de añadir una aplicación para Smartphone y una pulsera de actividad al consejo estándar sobre estilos de vida en la pérdida de peso en sujetos con sobrepeso u obesidad. Como objetivos secundarios de esta tesis se incluyen cambios en la actividad física, la ingesta calórica y la composición corporal, así como establecer los determinantes psicológicos más relevantes para los cambios a corto plazo de la actividad física. Métodos: Ensayo clínico aleatorio de dos grupos paralelos, multicéntrico y doble ciego. Se incluyó un total de 650 participantes, que fueron asignados aleatoriamente al grupo intervención (app + pulsera + consejo) (n = 318) o al grupo control (sólo consejo) (n = 332) después de la visita inicial. La intervención estuvo compuesta por una app (EVIDENT 3) y una pulsera de actividad (Mi Band 2), para su uso durante 3 meses. Se realizaron dos visitas de seguimiento a los 3 y 12 meses. Resultados: El grupo intervención (GI) obtuvo una mayor pérdida de peso en comparación con el grupo control (GC) a corto plazo, pero esta tendencia descendente no se mantuvo a los 12 meses. Aunque ambos grupos redujeron otras variables antropométricas, el GI mostró una mayor tendencia a reducirlas en la visita de 3 meses. El GI aumentó el tiempo de actividad física ligera auto informada en comparación con el GC en ambas visitas. Ambos grupos redujeron la ingesta calórica diaria y aumentaron la adherencia a la dieta mediterránea, sin diferencias entre los grupos. Sin embargo, el GI aumentó la ingesta de pan y cereales integrales y disminuyó la ingesta de colesterol y de productos lácteos enteros. Por último, se estableció que la motivación y la autoeficacia fueron los determinantes más relevantes para los cambios en la actividad física. Conclusión: La intervención mHealth del estudio Evident 3 mostró beneficios en las variables principales del estudio en la visita de los 3 meses, momento en el que se recogieron los dispositivos, pero no se mantuvo su efecto en el seguimiento a los 12 meses[EN]Background: There is evidence that lifestyle interventions that address several components, such as diet, physical activity and behavior change, are effective in inducing clinically significant weight loss and are associated with improvements in health and psychosocial status. In this context, the use of Information and Communication Technologies (ICTs) could improve self-management of health and the effectiveness of these interventions by providing greater user tailoring. Objectives: The main objective is to evaluate the impact of adding a smartphone application and a smart band to standard lifestyle advice on weight loss in overweight or obese participants. Secondary objectives of this thesis include changes in physical activity, caloric intake and body composition, as well as establishing the psychological determinants most relevant to short-term changes in physical activity. Methods: Randomized, double-blind, multicenter, parallel two-group clinical trial. 650 participants were randomly assigned to the intervention group (app + wristband + advice) (n = 318) or the control group (advice only) (n = 332) after the baseline visit. The intervention combined an app (EVIDENT 3) and an activity tracker wristband (Mi Band 2), to be used for 3 months. Two follow-up visits were conducted at 3 and 12 months. Results: The intervention group (IG) showed a greater weight loss compared to the control group (CG) in the short term, but this downward trend was not maintained at 12 months. Although both groups reduced other anthropometric variables, IG showed a greater tendency to reduce them at a 3-month follow-up. IG increased self-reported light physical activity time compared with CG at both visits. Both groups reduced daily caloric intake and increased adherence to the Mediterranean diet, with no differences between groups. However, the IG increased the intake of whole meal bread and whole-grain cereals and decreased the intake of cholesterol and full-fat dairies. Finally, it was established that motivation and self-efficacy were the most relevant determinants of changes in physical activity. Conclusion: The mHealth intervention of the Evident 3 study showed benefits in the main study variables at the 3-month visit when the devices were collected, but its effect was not maintained at the 12-month follow-up

Long-Term Effectiveness of a Smartphone App and a Smart Band on Arterial Stiffness and Central Hemodynamic Parameters in a Population with Overweight and Obesity (Evident 3 Study): Randomised Controlled Trial

Background: mHealth technologies could help to improve cardiovascular health; however, their effect on arterial stiffness and hemodynamic parameters has not been explored to date. Objective: To evaluate the effect of a mHealth intervention, at 3 and 12 months, on arterial stiffness and central hemodynamic parameters in a sedentary population with overweight and obesity. Methods: Randomised controlled clinical trial (Evident 3 study). 253 subjects were included: 127 in the intervention group (IG) and 126 in the control group (CG). The IG subjects were briefed on the use of the Evident 3 app and a smart band (Mi Band 2, Xiaomi) for 3 months to promote healthy lifestyles. All measurements were recorded in the baseline visit and at 3 and 12 months. The carotid-femoral pulse wave velocity (cfPWV) and the central hemodynamic parameters were measured using a SphigmoCor System® device, whereas the brachial-ankle pulse wave velocity (baPWV) and the Cardio Ankle Vascular Index (CAVI) were measured using a VaSera VS-2000® device. Results: Of the 253 subjects who attended the initial visit, 237 (93.7%) completed the visit at 3 months of the intervention, and 217 (85.3%) completed the visit at 12 months of the intervention. At 12 months, IG showed a decrease in peripheral augmentation index (PAIx) (−3.60; 95% CI −7.22 to −0.00) and ejection duration (ED) (−0.82; 95% CI −1.36 to −0.27), and an increase in subendocardial viability ratio (SEVR) (5.31; 95% CI 1.18 to 9.44). In CG, cfPWV decreased at 3 months (−0.28 m/s; 95% CI −0.54 to −0.02) and at 12 months (−0.30 m/s, 95% CI −0.54 to −0.05), central diastolic pressure (cDBP) decreased at 12 months (−1.64 mm/Hg; 95% CI −3.19 to −0.10). When comparing the groups we found no differences between any variables analyzed. Conclusions: In sedentary adults with overweight or obesity, the multicomponent intervention (Smartphone app and an activity-tracking band) for 3 months did not modify arterial stiffness or the central hemodynamic parameters, with respect to the control group. However, at 12 months, CG presented a decrease of cfPWV and cDBP, whereas IG showed a decrease of PAIx and ED and an increase of SEVR

Combined use of smartphone and smartband technology in the improvement of lifestyles in the adult population over 65 years: study protocol for a randomized clinical trial (EVIDENT-Age study)

Background The increasing use of smartphones by older adults also increases their potential for improving different aspects of health in this population. Some studies have shown promising results in the improvement of cognitive performance through lifestyle modification. All this may have a broad impact on the quality of life and carrying out daily living activities. The objective of this study is to evaluate the effectiveness of combining the use of smartphone and smartband technology for 3 months with brief counseling on life habits, as opposed to providing counseling only, in increasing physical activity and improving adherence to the Mediterranean diet. Secondary objectives are to assess the effect of the intervention on body composition, quality of life, independence in daily living activities and cognitive performance. Methods This study is a two-arm cluster-randomized trial that will be carried out in urban health centers in Spain. We will recruit 160 people aged between 65 and 80 without cardiovascular disease or cognitive impairment (score in the Mini-mental State Examination ≥24). On a visit to their center, intervention group participants will be instructed to use a smartphone application for a period of 3 months. This application integrates information on physical activity received from a fitness bracelet and self-reported information on the patient’s daily nutritional composition. The primary outcome will be the change in the number of steps measured by accelerometer. Secondary variables will be adherence to the Mediterranean diet, sitting time, body composition, quality of life, independence in daily living activities and cognitive performance. All variables will be measured at baseline and on the assessment visit after 3 months. A telephone follow-up will be carried out at 6 months to collect self-reported data regarding physical activity and adherence to the Mediterranean diet. Discussion Preventive healthy aging programs should include health education with training in nutrition and lifestyles, while stressing the importance of and enhancing physical activity; the inclusion of new technologies can facilitate these goals. The EVIDENT-AGE study will incorporate a simple, accessible intervention with potential implementation in the care of older adults.This study was supported in part by grants funded by the Instituto de Salud Carlos III, Institute of Biomedical Research of Salamanca (IBSAL)-IBY17/00003, and the Spanish Research Network for Preventive Activities and Health Promotion in Primary Care (REDIAPP)-RD16/0007

Gut microbiota composition and arterial stiffness measured by pulse wave velocity: Case-control study protocol (MIVAS study)

[Introduction]: Intestinal microbiota is arising as a new element in the physiopathology of cardiovascular diseases. A healthy microbiota includes a balanced representation of bacteria with health promotion functions (symbiotes). The aim of this study is to analyse the relationship between intestinal microbiota composition and arterial stiffness. [Methods and analysis]: An observational case—control study will be developed. Cases will be defined by the presence of at least one of the following: carotid-femoral pulse wave velocity (cf-PWV), Cardio-Ankle Vascular Index (CAVI), brachial ankle pulse wave velocity (ba or ba-PWV) above the 90th percentile, for age and sex, of the reference population. Controls will be selected from the same population as cases. The study will be developed in Primary Healthcare Centres. We will select 500 subjects (250 cases and 250 controls), between 45 and 74 years of age. Cases will be selected from a database that combines data from EVA study (Spain) and Guimarães/Vizela study (Portugal). Measurements: cf-PWV will be measured using the SphygmoCor system, CAVI, ba-PWV and Ankle-Brachial Index will be determined using VaSera device. Gut microbiome composition in faecal samples will be determined by 16S ribosomal RNA sequencing. Lifestyle will be assessed by food frequency questionnaire, adherence to the Mediterranean diet and IPAQ (International Physical Activity Questionnaire). Body composition will be evaluated by bioimpedance. [Ethics and dissemination]: The study has been approved by ‘Committee of ethics of research with medicines of the health area of Salamanca’ on 14 December 2018 (cod. 2018-11-136) and the ’Ethics committee for health of Guimaraes’ (Portugal) on 15 October 2019 (ref: 67/2019).All study participants will sign an informed consent form agreeing to participate in the study, in compliance with the Declaration of Helsinki and the WHO standards for observational studies. The results of this study will allow a better description of gut microbiota in patients with arterial stiffness.The project has been funded by the Carlos III Health Institute (Spain) through the Network of preventive activities and health promotion (redIAPP, RD16/0007), co-financed with European funds for regional development (FEDER) and the Autonomous Government of Castilla y León (GRS 1820/B/18; GRS 1944/B/19 and intensification programme)

The relationship of the atlantic diet with cardiovascular risk factors and markers of arterial stiffness in adults without cardiovascular disease

[EN]Abstract: Background: Studying the adherence of the population to the Atlantic Diet (AD) could be simplified by an easy and quickly applied dietary index. The aim of this study is to analyse the relationship of an index measuring compliance with recommendations regarding the Atlantic diet and physical activity with cardiovascular disease risk factors, cardiovascular risk factors, obesity indexes and arterial stiffness markers. Methods: We included 791 individuals from the EVIDENT study (lifestyles and arterial ageing), (52.3 ± 12 years, 61.7% women) without cardiovascular disease. Compliance with recommendations on AD was collected through the responses to a food frequency questionnaire, while physical activity was measured by accelerometer. The number of recommendations being met was estimated using a global scale between 0 and 14 points (a higher score representing greater adherence). Blood pressure, plasma lipid and glucose values and obesity rates were measured. Cardiovascular risk was estimated with the Framingham equation. Results: In the overall sample, 184 individuals (23.3%) scored between 0–3 on the 14-point index we created, 308 (38.9%) between 4 and 5 points, and 299 (37.8%) 6 or more points. The results of multivariate analysis yield a common tendency in which the group with an adherence score of at least 6 points shows lower figures for total cholesterol (p = 0.007) and triglycerides (p = 0.002). Similarly, overall cardiovascular risk in this group is the lowest (p < 0.001), as is pulse wave velocity (p = 0.050) and the mean values of the obesity indexes studied (p < 0.05 in all cases). Conclusion: The rate of compliance with the Atlantic diet and physical activity shows that greater adherence to these recommendations is linked to lower cardiovascular risk, lower total cholesterol and triglycerides, lower rates of obesity and lower pulse wave velocity values.This study was funded by the Spanish Ministry of Science and Innovation (MICINN) and the Carlos III Health Institute/European Regional Development Fund (ERDF) (FIS: PI13/00618, PI13/01526, PI13/00058, PI13/01635, PI13/02528, PI12/01474; RETICS: RD12/0005, RD16/0007), the Regional Health Administration of Castilla and León (GRS 1191/B/15, GRS 909/B/14, GRS 770/B/13) and the Infosalud Foundation. None of the funders were involved in the design, implementation, analysis or interpretation of the data

Lifestyles, arterial aging, and its relationship with the intestinal and oral microbiota (MIVAS III study): a research protocol for a cross-sectional multicenter study

The microbiota is increasingly recognized as a significant factor in the pathophysiology of many diseases, including cardiometabolic diseases, with lifestyles probably exerting the greatest influence on the composition of the human microbiome. The main objectives of the study are to analyze the association of lifestyles (diet, physical activity, tobacco, and alcohol) with the gut and oral microbiota, arterial aging, and cognitive function in subjects without cardiovascular disease in the Iberian Peninsula. In addition, the study will examine the mediating role of the microbiome in mediating the association between lifestyles and arterial aging as well as cognitive function.Methods and analysisMIVAS III is a multicenter cross-sectional study that will take place in the Iberian Peninsula. One thousand subjects aged between 45 and 74 years without cardiovascular disease will be selected. The main variables are demographic information, anthropometric measurements, and habits (tobacco and alcohol). Dietary patterns will be assessed using a frequency consumption questionnaire (FFQ) and the Mediterranean diet adherence questionnaire. Physical activity levels will be evaluated using the International Physical Activity Questionnaire (IPAQ), Marshall Questionnaire, and an Accelerometer (Actigraph). Body composition will be measured using the Inbody 230 impedance meter. Arterial aging will be assessed through various means, including measuring medium intimate carotid thickness using the Sonosite Micromax, conducting analysis with pulse wave velocity (PWA), and measuring pulse wave velocity (cf-PWV) using the Sphygmocor System. Additional cardiovascular indicators such as Cardio Ankle Vascular Index (CAVI), ba-PWV, and ankle-brachial index (Vasera VS-2000®) will also be examined. The study will analyze the intestinal microbiota using the OMNIgene GUT kit (OMR−200) and profile the microbiome through massive sequencing of the 16S rRNA gene. Linear discriminant analysis (LDA), effect size (LEfSe), and compositional analysis, such as ANCOM-BC, will be used to identify differentially abundant taxa between groups. After rarefying the samples, further analyses will be conducted using MicrobiomeAnalyst and R v.4.2.1 software. These analyses will include various aspects, such as assessing α and β diversity, conducting abundance profiling, and performing clustering analysis.DiscussionLifestyle acts as a modifier of microbiota composition. However, there are no conclusive results demonstrating the mediating effect of the microbiota in the relationship between lifestyles and cardiovascular diseases. Understanding this relationship may facilitate the implementation of strategies for improving population health by modifying the gut and oral microbiota

Effectiveness of a multiple health-behaviour-change intervention in increasing adherence to the Mediterranean Diet in adults (EIRA study): a randomized controlled hybrid trial

Background: The present study describes the efectiveness of a complex intervention that addresses multiple lifestyles to promote healthy behaviours in increasing adherence to the Mediterranean diet (MD). Methods: Cluster-randomised, hybrid clinical trial controlled with two parallel groups. The study was carried out in 26 primary Spanish healthcare centres. People aged 45–75 years who presented at least two of the following crite‑ ria were included: smoker, low adherence to the MD or insufcient level of physical activity. The intervention group (IG) had three diferent levels of action: individual, group, and community, with the aim of acting on the behaviours related to smoking, diet and physical activity at the same time. The individual intervention included personalised recommendations and agreements on the objectives to attain. Group sessions were adapted to the context of each healthcare centre. The community intervention was focused on the social prescription of resources and activities performed in the environment of the community of each healthcare centre. Control group (CG) received brief advice given in the usual visits to the doctor’s ofce. The primary outcome was the change, after 12 months, in the number of participants in each group with good adherence to the MD pattern. Secondary outcomes included the change in the total score of the MD adherence score (MEDAS) and the change in some cardiovascular risk factors. Results: Three thousand sixty-two participants were included (IG=1,481, CG=1,581). Low adherence to the MD was present in 1,384 (93.5%) participants, of whom 1,233 initiated the intervention and conducted at least one individual visit with a healthcare professional. A greater increase (13.7%; 95% CI, 9.9–17.5; p<0.001) was obtained by IG in the number of participants who reached 9 points or more (good adherence) in the MEDAS at the fnal visit. Moreover, the efect attributable to the intervention obtained a greater increase (0.50 points; 95% CI, 0.35 to 0.66; p<0.001) in IG. Conclusions: A complex intervention modelled and carried out by primary healthcare professionals, within a real clinical healthcare context, achieved a global increase in the adherence to the MD compared to the brief advice

Effectiveness of an mHealth Intervention Combining a Smartphone App and Smart Band on Body Composition in an Overweight and Obese Population: Randomized Controlled Trial (EVIDENT 3 Study)

[EN]Background: Mobile health (mHealth) is currently among the supporting elements that may contribute to an improvement in health markers by helping people adopt healthier lifestyles. mHealth interventions have been widely reported to achieve greater weight loss than other approaches, but their effect on body composition remains unclear. Objective: This study aimed to assess the short-term (3 months) effectiveness of a mobile app and a smart band for losing weight and changing body composition in sedentary Spanish adults who are overweight or obese. Methods: A randomized controlled, multicenter clinical trial was conducted involving the participation of 440 subjects from primary care centers, with 231 subjects in the intervention group (IG; counselling with smartphone app and smart band) and 209 in the control group (CG; counselling only). Both groups were counselled about healthy diet and physical activity. For the 3-month intervention period, the IG was trained to use a smartphone app that involved self-monitoring and tailored feedback, as well as a smart band that recorded daily physical activity (Mi Band 2, Xiaomi). Body composition was measured using the InBody 230 bioimpedance device (InBody Co., Ltd), and physical activity was measured using the International Physical Activity Questionnaire. Results: The mHealth intervention produced a greater loss of body weight (–1.97 kg, 95% CI –2.39 to –1.54) relative to standard counselling at 3 months (–1.13 kg, 95% CI –1.56 to –0.69). Comparing groups, the IG achieved a weight loss of 0.84 kg more than the CG at 3 months. The IG showed a decrease in body fat mass (BFM; –1.84 kg, 95% CI –2.48 to –1.20), percentage of body fat (PBF; –1.22%, 95% CI –1.82% to 0.62%), and BMI (–0.77 kg/m2, 95% CI –0.96 to 0.57). No significant changes were observed in any of these parameters in men; among women, there was a significant decrease in BMI in the IG compared with the CG. When subjects were grouped according to baseline BMI, the overweight group experienced a change in BFM of –1.18 kg (95% CI –2.30 to –0.06) and BMI of –0.47 kg/m2 (95% CI –0.80 to –0.13), whereas the obese group only experienced a change in BMI of –0.53 kg/m2 (95% CI –0.86 to –0.19). When the data were analyzed according to physical activity, the moderate-vigorous physical activity group showed significant changes in BFM of –1.03 kg (95% CI –1.74 to –0.33), PBF of –0.76% (95% CI –1.32% to –0.20%), and BMI of –0.5 kg/m2 (95% CI –0.83 to –0.19). Conclusions: The results from this multicenter, randomized controlled clinical trial study show that compared with standard counselling alone, adding a self-reported app and a smart band obtained beneficial results in terms of weight loss and a reduction in BFM and PBF in female subjects with a BMI less than 30 kg/m2 and a moderate-vigorous physical activity level. Nevertheless, further studies are needed to ensure that this profile benefits more than others from this intervention and to investigate modifications of this intervention to achieve a global effect.[EN]This study was funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, and co-funded by the European Union (ERDF/ESF, “Investing in your future”) (RD12/0005/0001, RD16/0007/0003, RD16/0007/0005, RD16/0007/0008, RD16/0007/0009 and PI16/00101, PI16/00952, PI16/00765, PI16/00659, PI16/00421, PI16/00170, FI17/00040). Gerencia Regional de Salud de Castilla y Leon (GRS 1277/B/16) also collaborated in the funding of this study. They played no role in the study design, data analysis, reporting results, or decision to submit the manuscript for publication

Metabolic Syndrome Including Glycated Hemoglobin A1c in Adults: Is It Time to Change?

(1) Background: To assess the suitability of replacing conventional markers used for insulin resistance and dysglycemia by HbA1c in both the quantitative and qualitative metabolic syndrome (MetS) definition criteria; (2) Methods: Confirmatory factorial analysis was used to compare three quantitative definitions of MetS that consisted of many single-factor models, one of which included HbA1c as the dysglycemia indicator. After that, the model with the better goodness-of-fit was selected. Furthermore, a new MetS qualitative definition was proposed by replacing fasting plasma glucose with HbA1c &gt; 5.7% in the International Diabetes Federation (IDF) definition. The clinical performance of these two MetS criteria (IDF and IDF-modified including HbA1c as the dysglycemia indicator) to predict vascular damage (pulse wave velocity [PWv], intima media thickness [IMT] and albumin-to-creatinine ratio [ACR]) was estimated; (3) Results: The single-factor model including HbA1c showed the better goodness-of-fit (&chi;2 = 2.45, df = 2, p = 0.293, CFI = 0.999, SRMR = 0.010). Additionally, the IDF-modified criteria gained in clinical performance to predict vascular damage (diagnostic Odds Ratio: 6.94, 1.34 and 1.90) for pulse wave velocity (PWv), intima media thickness (IMT) and albumin-to-creatinine ratio (ACR), respectively; and (4) Conclusions: These data suggest that HbA1c could be considered as a useful component to be included in the MetS definition

Long-term Effectiveness of a Smartphone App Combined With a Smart Band on Weight Loss, Physical Activity, and Caloric Intake in a Population With Overweight and Obesity (Evident 3 Study): Randomized Controlled Trial

[EN]Background: Multicomponent mobile health approaches can improve lifestyle intervention results, although little is known about their long-term effectiveness. Objective: This study aims to evaluate the long-term effectiveness (12 months) of a multicomponent mobile health intervention—combining a smartphone app, an activity tracker wristband, and brief counseling, compared with a brief counseling group only—on weight loss and improving body composition, physical activity, and caloric intake in Spanish sedentary adults with overweight or obesity. Methods: We conducted a randomized controlled, multicenter clinical trial (Evident 3). A total of 650 participants were recruited from 5 primary care centers, with 318 participants in the intervention group (IG) and 332 in the control group (CG). All participants were briefly counseled about a healthy diet and physical activity at the baseline visit. For the 3-month intervention period, the IG received training to use the app to promote healthy lifestyles and the smart band (Mi Band 2, Xiaomi). All measurements were performed at baseline and at 3 and 12 months. Physical activity was measured using the International Physical Activity Questionnaire–Short Form. Nutritional habits were assessed using the Food Frequency Questionnaire and Adherence to Mediterranean diet questionnaire. Results: Of the 650 participants included, 563 (86.6%) completed the 3-month visit and 443 (68.2%) completed the 12-month visit. After 12 months, the IG showed net differences in weight (−0.26, 95% CI −1.21 to 0.70 kg; P=.02), BMI (−0.06, 95% CI −0.41 to 0.28 points; P=.01), waist-height ratio (−0.25, 95% CI −0.94 to 0.44; P=.03), body adiposity index (−0.33, 95% CI −0.77 to 0.11; P=.03), waist circumference (−0.48, 95% CI −1.62 to 0.66 cm, P=.04) and hip circumference (−0.69, 95% CI –1.62 to 0.25 cm; P=.03). Both groups lowered daily caloric intake and increased adherence to the Mediterranean diet, with no differences between the groups. The IG increased light physical activity time (32.6, 95% CI −30.3 to 95.04 min/week; P=.02) compared with the CG. Analyses by subgroup showed changes in body composition variables in women, people aged >50 years, and married people. Conclusions: The low-intensity intervention of the Evident 3 study showed, in the IG, benefits in weight loss, some body composition variables, and time spent in light physical activity compared with the CG at 3 months, but once the devices were collected, the downward trend was not maintained at the 12-month follow-up. No differences in nutritional outcomes were observed between the groups.This study was funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III and cofunded by the European Union (ERDF/ESF, “Investing in your future”; RD16/0007/0003, RD16/0007/0005, RD16/0007/0008, and RD16/0007/0009; and PI16/00101, PI16/00952, PI16/00765, PI16/00659, PI16/00421, PI16/00170, and FI17/00040; REDIAPP). Gerencia Regional de Salud de Castilla y Leon (GRS 1277/B/16 and GRS 1580/B/17) also collaborated with the funding of this study. They played no role in the study design, data analysis, reporting results, or the decision to submit the manuscript for publication