Association between tomato consumption and blood pressure in an older population at high cardiovascular risk: observational analysis of PREDIMED trial

Aims: Clinical studies have produced conflicting evidence on the effects of the consumption of tomatoes on blood pressure, and there are limited data from epidemiologic studies. This study assesses whether tomato consumption (Solanum lycopersicum L.) is associated with Systolic (SBP) and Diastolic Blood Pressure (DBP), and the risk of hypertension in a prospective 3-year longitudinal study in older adults at high cardiovascular risk.Methods: The present study was carried out within the PREDIMED (Prevención con Dieta Mediterránea) trial involving 7,056 (82.5% hypertensive) participants. The consumption of tomato (g/d) was measured using a validated Food Frequency Questionnaire (FFQ) and categorized into 4 groups: lowest (110 g). Multilevel linear mixed models examined blood pressure and tomato consumption association. Cox proportional-hazards models analyzed hypertension risk in 1,097 non-hypertensive participants, studying risk reductions versus the lowest tomato consumers.Results: An inverse association between tomato consumption and diastolic blood pressure was observed between the intermediate group β = -0.65 mmHg [95% CI:-1.20, -0.10] and the lowest consumption group. A significant inverse association was observed for blood pressure in grade 1 hypertension participants in the intermediate tomato consumption group. The risk of hypertension decreased with consumption of >110 g/d tomato (highest vs lowest consumption; HR, 0.64 [95% CI, 0.51-0.89]).Conclusions: Tomato consumption, including tomato-based products, is beneficial in preventing and managing hypertension. Higher tomato intake reduces hypertension risk by 36%, and moderate consumption lowers blood pressure, especially in grade 1 hypertension.</p

Water intake, hydration status and 2-year changes in cognitive performance: a prospective cohort study

BackgroundWater intake and hydration status have been suggested to impact cognition; however, longitudinal evidence is limited and often inconsistent. This study aimed to longitudinally assess the association between hydration status and water intake based on current recommendations, with changes in cognition in an older Spanish population at high cardiovascular disease risk.MethodsA prospective analysis was conducted of a cohort of 1957 adults (aged 55-75) with overweight/obesity (BMI between >= 27 and = 300 mmol/L (dehydrated). Water intake was assessed as total drinking water intake and total water intake from food and beverages and according to EFSA recommendations. Global cognitive function was determined as a composite z-score summarizing individual participant results from all neuropsychological tests. Multivariable linear regression models were fitted to assess the associations between baseline hydration status and fluid intake, continuously and categorically, with 2-year changes in cognitive performance.ResultsThe mean baseline daily total water intake was 2871 +/- 676 mL/day (2889 +/- 677 mL/day in men; 2854 +/- 674 mL/day in women), and 80.2% of participants met the ESFA reference values for an adequate intake. Serum osmolarity (mean 298 +/- 24 mmol/L, range 263 to 347 mmol/L) indicated that 56% of participants were physiologically dehydrated. Lower physiological hydration status (i.e., greater serum osmolarity) was associated with a greater decline in global cognitive function z-score over a 2-year period (beta: - 0.010; 95% CI - 0.017 to - 0.004, p-value = 0.002). No significant associations were observed between water intake from beverages and/or foods with 2-year changes in global cognitive function.ConclusionsReduced physiological hydration status was associated with greater reductions in global cognitive function over a 2-year period in older adults with metabolic syndrome and overweight or obesity. Future research assessing the impact of hydration on cognitive performance over a longer duration is needed

Impact of COVID-19 pandemic on the PREDIMED-Plus randomized clinical trial: Effects on the interventions, participants follow-up, and adiposity

Background: The COVID-19 pandemic has affected the implementation of most ongoing clinical trials worldwide including the PREDIMED-Plus study. The PREDIMED-Plus is an ongoing, multicenter, controlled intervention trial, aimed at weight-loss and cardiovascular disease prevention, in which participants were randomized (1:1 ratio) to an intervention group (energy-reduced Mediterranean diet, promotion of physical activity, and behavioral support) or to a control group (Mediterranean diet with usual care advice). When the pandemic began, the trial was in the midst of the planned intervention. The objective of this report was to examine the effects of the pandemic on the delivery of the intervention and to describe the strategies established to mitigate the possible adverse effects of the pandemic lockdown on data collection and adiposity. Methods: We assessed the integrity of the PREDIMED-Plus trial during 5 identified periods of the COVID-19 pandemic determined according to restrictions dictated by the Spanish government authorities. A standardized questionnaire was delivered to each of the 23 PREDIMED-Plus recruiting centers to collected data regarding the trial integrity. The effect of the restrictions on intervention components (diet, physical activity) was evaluated with data obtained in the three identified lockdown phases: pre lockdown, lockdown proper, and post lockdown. Results: During the lockdown (March/2020-June/2021), 4,612 participants (48% women, mean age 65y) attended pre-specified yearly follow-up visits to receive lifestyle recommendations and obtain adiposity measures. The overall mean (SD) of the proportions reported by each center showed that 40.4% (25.4) participants had in-person visits, 39.8% (18.2) participants were contacted by telephone and 35% (26.3) by electronic means. Participants' follow-up and data collection rates increased across lockdown periods (from ≈10% at onset to ≈80% at the end). Compared to pre-lockdown, waist circumference increased during (0.75 cm [95% CI: 0.60-0.91]) and after (0.72 cm [95% CI: 0.56-0.89]) lockdown. Body weight did not change during lockdown (0.01 kg [95% CI: -0.10 to 0.13) and decreased after lockdown (-0.17 kg [95% CI: -0.30 to -0.04]). Conclusion: Mitigating strategies to enforce the intervention and patient's follow-up during lockdown have been successful in preserving the integrity of the trial and ensuring its continuation, with minor effects on adiposity. Clinical trial registration: https://doi.org/10.1186/ISRCTN89898870, identifier ISRCTN89898870. Keywords: COVID-19; Mediterraean diet; PREDIMED-Plus; clinical trial; lockdown; weight-loss. Copyright © 2023 Paz-Graniel, Fitó, Ros, Buil-Cosiales, Corella, Babio, Martínez, Alonso-Gómez, Wärnberg, Vioque, Romaguera, López-Miranda, Estruch, Tinahones, Lapetra, Serra-Majem, Bueno-Cavanillas, Tur, Martín-Sánchez, Pintó, Gaforio, Matía-Martín, Vidal, Vázquez, Daimiel, García-Gavilán, Toledo, Nishi, Sorlí, Castañer, García-Ríos, García de la Hera, Barón-López, Ruiz-Canela, Morey, Casas, Garrido-Garrido, Tojal-Sierra, Fernández-García, Vázquez-Ruiz, Fernández-Carrión, Goday, Peña-Orihuela, Compañ-Gabucio, Schröder, Martínez-Gonzalez and Salas-Salvadó. Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

Association Among Polyphenol Intake, Uric Acid, and Hyperuricemia: A CrossSectional Analysis in a Population at High Cardiovascular Risk

Dietary polyphenol intake has been associated with a decreased risk of hyperuricemia, but most of this knowledge comes from preclinical studies. The aim of the present study was to assess the association of the intake of different classes of polyphenols with serum uric acid and hyperuricemia. This cross- sectional analysis involved baseline data of 6332 participants. Food polyphenol con- tent was estimated by a validated semiquantitative food frequency questionnaire and from the Phenol-Explorer database. Multivariable-adjusted linear regression models with serum uric acid (milligrams per deciliter) as the outcome and polyphenol intake (quintiles) as the main independent variable were fitted. Cox regression models with constant follow-up time (t=1) were performed to estimate the prevalence ratios (PRs) of hyperuricemia (≥7 mg/dL in men and ≥6 mg/dL in women). An inverse association between the intake of the phenolic acid class (β coefficient, −0.17 mg/dL for quintile 5 versus quintile 1 [95% CI, −0.27 to −0.06]) and hydroxycinnamic acids (β coefficient, −0.19 [95% CI, −0.3 to −0.09]), alkylmethoxyphenols (β coefficient, −0.2 [95% CI, −0.31 to −0.1]), and methoxyphenols (β coefficient, −0.24 [95% CI, −0.34 to −0.13]) subclasses with serum uric acid levels and hyperuricemia (PR, 0.82 [95% CI, 0.71– 0.95]; PR, 0.82 [95% CI, 0.71– 0.95]; PR, 0.80 [95% CI, 0.70– 0.92]; and PR, 0.79 [95% CI, 0.69– 0.91]; respectively) was found. The intake of hydroxybenzoic acids was directly and significantly as- sociated with mean serum uric acid levels (β coefficient, 0.14 for quintile 5 versus quintile 1 [95% CI, 0.02– 0.26]) but not with hyperuricemia

Integrative development of a short screening questionnaire of highly processed food consumption (sQ-HPF)

Background: Recent lifestyle changes include increased consumption of highly processed foods (HPF), which has been associated with an increased risk of non-communicable diseases (NCDs). However, nutritional information relies on the estimation of HPF consumption from food-frequency questionnaires (FFQ) that are not explicitly developed for this purpose. We aimed to develop a short screening questionnaire of HPF consumption (sQ-HPF) that integrates criteria from the existing food classification systems. Methods: Data from 4400 participants (48.1% female and 51.9% male, 64.9 +/- 4.9 years) of the Spanish PREDIMED-Plus (PREvention with MEDiterranean DIet) trial were used for this analysis. Items from the FFQ were classified according to four main food processing-based classification systems (NOVA, IARC, IFIC and UNC). Participants were classified into tertiles of HPF consumption according to each system. Using binomial logistic regression, food groups associated with agreement in the highest tertile for at least two classification systems were chosen as items for the questionnaire. ROC analysis was used to determine cut-off points for the frequency of consumption of each item, from which a score was calculated. Internal consistency of the questionnaire was assessed through exploratory factor analysis (EFA) and Cronbach's analysis, and agreement with the four classifications was assessed with weighted kappa coefficients. Results: Regression analysis identified 14 food groups (items) associated with high HPF consumption for at least two classification systems. EFA showed that items were representative contributors of a single underlying factor, the HPF dietary pattern (factor loadings around 0.2). We constructed a questionnaire asking about the frequency of consumption of those items. The threshold frequency of consumption was selected using ROC analysis. Comparison of the four classification systems and the sQ-HPF showed a fair to high agreement. Significant changes in lifestyle characteristics were detected across tertiles of the sQ-HPF score. Longitudinal changes in HPF consumption were also detected by the sQ-HPF, concordantly with existing classification systems. Conclusions: We developed a practical tool to measure HPF consumption, the sQ-HPF. This may be a valuable instrument to study its relationship with NCDs

Pro-vegetarian food patterns and cardiometabolic risk in the PREDIMED-Plus study: a cross-sectional baseline analysis

[Purpose]: We explored the cross-sectional association between the adherence to three different provegetarian (PVG) food patterns defined as general (gPVG), healthful (hPVG) and unhealthful (uPVG), and the cardiometabolic risk in adults with metabolic syndrome (MetS) of the PREDIMED-Plus randomized intervention study. [Methods]: We performed a cross-sectional analysis of baseline data from 6439 participants of the PREDIMED-Plus randomized intervention study. The gPVG food pattern was built by positively scoring plant foods (vegetables/fruits/legumes/grains/potatoes/nuts/olive oil) and negatively scoring, animal foods (meat and meat products/animal fats/eggs/fish and seafood/dairy products). The hPVG and uPVG were generated from the gPVG by adding four new food groups (tea and coffee/fruit juices/sugar-sweetened beverages/sweets and desserts), splitting grains and potatoes and scoring them differently. Multivariable-adjusted robust linear regression using MM-type estimator was used to assess the association between PVG food patterns and the standardized Metabolic Syndrome score (MetS z-score), a composed index that has been previously used to ascertain the cardiometabolic risk, adjusting for potential confounders. [Results]: A higher adherence to the gPVG and hPVG was associated with lower cardiometabolic risk in multivariable models. The regression coefficients for 5th vs. 1st quintile were − 0.16 (95% CI: − 0.33 to 0.01) for gPVG (p trend: 0.015), and − 0.23 (95% CI: − 0.41 to − 0.05) for hPVG (p trend: 0.016). In contrast, a higher adherence to the uPVG was associated with higher cardiometabolic risk, 0.21 (95% CI: 0.04 to 0.38) (p trend: 0.019). [Conclusion]: Higher adherence to gPVG and hPVG food patterns was generally associated with lower cardiovascular risk, whereas higher adherence to uPVG was associated to higher cardiovascular risk.This work was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación para la Salud (FIS), which is co-funded by the European Regional Development Fund (six coordinated FIS projects leaded by JS-S and JVi, including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332, PI20/01802, PI20/00138, PI20/01532, PI20/00456, PI20/00339, PI20/00557, PI20/00886, PI20/01158); the Especial Action Project entitled: Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus grant to JS-S; the European Research Council (Advanced Research Grant 2014–2019; agreement #340918) granted to MÁM-G.; the Recercaixa (number 2013ACUP00194) grant to JS-S; grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013, PS0358/2016, PI0137/2018); the PROMETEO/2017/017 grant from the Generalitat Valenciana; the SEMERGEN grant; None of the funding sources took part in the design, collection, analysis, interpretation of the data, or writing the report, or in the decision to submit the manuscript for publication

Dietary intake of polychlorinated dibenzo-p-dioxins and furans, adiposity and obesity status

Introduction: The principal source of exposure to Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) in humans comes from food intake. PCDD/Fs, are a family of potential endocrine disruptors and have been associated with different chronic diseases such as diabetes and hypertension. However, studies assessing the relationship between dietary exposure to PCDD/Fs and adiposity or obesity status in a middle-aged population are limited. Objective: To assess cross-sectionally and longitudinally the associations between estimated dietary intake (DI) of PCDD/Fs and body mass index (BMI), waist circumference, and the prevalence/incidence of obesity and abdominal obesity in a middle-aged population. Methods: In 5899 participants aged 55-75 years (48% women) living with overweight/obesity from the PREDIMED-plus cohort, PCDD/Fs DI was estimated using a 143-item validated food-frequency questionnaire, and the levels of food PCDD/F expressed as Toxic Equivalents (TEQ). Consequently, cross-sectional and prospective associations between baseline PCDD/Fs DI (in pgTEQ/week) and adiposity or obesity status were assessed at baseline and after 1-year follow-up using multivariable cox, logistic or linear regression models. Results: Compared to participants in the first PCDD/F DI tertile, those in the highest tertile presented a higher BMI (β-coefficient [confidence interval]) (0.43kg/m2 [0.22; 0.64]; P-trend <0.001), a higher waist circumference (1.11 cm [0.55; 1.66]; P-trend <0.001), and a higher prevalence of obesity and abdominal obesity (1.05 [1.01; 1.09] and 1.02 [1.00; 1.03]; P-trend = 0.09 and 0.027, respectively). In the prospective analysis, participants in the top PCDD/F DI baseline tertile showed an increase in waist circumference compared with those in the first tertile after 1-year of follow-up (β-coefficient 0.37 cm [0.06; 0.70]; P-trend = 0.015). Conclusion: Higher DI of PCDD/Fs was positively associated with adiposity parameters and obesity status at baseline and with changes in waist circumference after 1-year of follow-up in subjects living with overweight/obesity. Further large prospective studies using a different population with longer follow-up periods are warranted in the future to strengthen our results. Keywords: Abdominal obesity; Adiposity; Endocrine disrupting chemicals; Obesity; Polychlorinated dibenzo-p-furans (PCDD/F)

Circulating carotenoids are associated with favorable lipid and fatty acid profiles in an older population at high cardiovascular risk

Carotenoid intake has been reported to be associated with improved cardiovascular health, but there is little information on actual plasma concentrations of these compounds as biomarkers of cardiometabolic risk. The objective was to investigate the association between circulating plasma carotenoids and different cardiometabolic risk factors and the plasma fatty acid profile. This is a cross-sectional evaluation of baseline data conducted in a subcohort (106 women and 124 men) of an ongoing multi-factorial lifestyle trial for primary cardiovascular prevention. Plasma concentrations of carotenoids were quantified by liquid chromatography coupled to mass spectrometry. The associations between carotenoid concentrations and cardiometabolic risk factors were assessed using regression models adapted for interval-censored variables. Carotenoid concentrations were cross-sectionally inversely associated with serum triglyceride concentrations [-2.79 mg/dl (95% CI: -4.25, -1.34) and -5.15 mg/dl (95% CI: -7.38, -2.93), p-values = 0.0002 and <0.00001 in women and men, respectively], lower levels of plasma saturated fatty acids [-0.09% (95% CI: -0.14, -0.03) and -0.15 % (95% CI: -0.23, -0.08), p-values = 0.001 and 0.0001 in women and men, respectively], and higher levels of plasma polyunsaturated fatty acids [(0.12 % (95% CI: -0.01, 0.25) and 0.39 % (95% CI: 0.19, 0.59), p-values = 0.065 and 0.0001 in women and men, respectively] in the whole population. Plasma carotenoid concentrations were also associated with higher plasma HDL-cholesterol in women [0.47 mg/dl (95% CI: 0.23, 0.72), p-value: 0.0002], and lower fasting plasma glucose in men [-1.35 mg/dl (95% CI: -2.12, -0.59), p-value: 0.001]. Keywords: Mediterranean diet; PREDIMED-plus study; cardiovascular health; liquid chromatography; mass spectrometry; plasma carotenoids

Fruit and Vegetable Consumption is Inversely Associated with Plasma Saturated Fatty Acids at Baseline in Predimed Plus Trial

I.D.-L. is supported by the [FI_B 00256] from the FI-AGAUR Research Fellowship Program, Generalitat de Catalunya and M.M.-M is supported by the FPU17/00513 grant. a.-H. is supported by the [CD17/00122] grant and S.K.N. is supported by a Canadian Institutes of Health Research (CIHR) Fellowship. We also thank all the volunteers for their participation in and the personnel for their contribution to the PREDIMED-Plus trial. This research was funded by CiCYT [AGL2016-75329-R] and CIBEROBN from the Instituto de Salud Carlos III, ISCIII from the Ministerio de Ciencia, Innovacion y Universidades, (AEI/FEDER, UE), Generalitat de Catalunya (GC) [2017SGR196]. The PREDIMED-Plus trial was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigacion para la Salud (FIS), which is co-funded by the European Regional Development Fund (four coordinated Fondo de Investigaciones Sanitarias projects lead by J.S.-S. and J.V., including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926 and PI19/00781), the Especial Action Project entitled Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grant to J.S.-S., European Research Council (Advanced Research Grant 2014-2019, 340918) to M.a.M.-G., the Recercaixa grant to J.S.-S. (2013ACUP00194), grants from the Consejeria de Salud de la Junta de Andalucia (PI0458/2013, PS0358/2016, and PI0137/2018), a grant from the Generalitat Valenciana (PROMETEO/2017/017), a SEMERGEN grant, Fundacio la Marato de TV3 (PI044003), 2017 SGR 1717 from Generalitat de Catalunya, a CICYT grant provided by the Ministerio de Ciencia, Innovacion y Universidades (AGL2016-75329-R), and funds from the European Regional Development Fund (CB06/03 and CB12/03). Food companies Hojiblanca (Lucena, Spain) and Patrimonio Comunal Olivarero (Madrid, Spain) donated extra virgin olive oil, and the Almond Board of California (Modesto, CA, USA), American Pistachio Growers (Fresno, CA, USA), and Paramount Farms (Wonderful Company, LLC, Los Angeles, CA, USA) donated nuts. J.K. was supported by the "FOLIUM" program within the FUTURMed project entitled Talent for the medicine within the future from the Fundacio Institut d'Investigacio Sanitaria Illes Balears. This call was co-financed at 50% with charge to the Operational Program FSE 2014-2020 of the Balearic Islands. This work is partially supported by ICREA under the ICREA Academia programme to J.S.-S.Scope: Plasma fatty acids (FAs) are associated with the development of cardiovascular diseases and metabolic syndrome. The aim of our study is to assess the relationship between fruit and vegetable (F&V) consumption and plasma FAs and their subtypes. Methods and Results: Plasma FAs are assessed in a cross-sectional analysis of a subsample of 240 subjects from the PREDIMED-Plus study. Participants are categorized into four groups of fruit, vegetable, and fat intake according to the food frequency questionnaire. Plasma FA analysis is performed using gas chromatography. Associations between FAs and F&V consumption are adjusted for age, sex, physical activity, bodymass index (BMI), total energy intake, and alcohol consumption. Plasma saturated FAs are lower in groups with high F&V consumption (-1.20 mg cL−1 [95% CI: [-2.22, - 0.18], p-value = 0.021), especially when fat intake is high (-1.74 mg cL−1 [95% CI: [-3.41, -0.06], p-value = 0.042). Total FAs and n-6 polyunsaturated FAs tend to be lower in high consumers of F&V only in the high-fat intake groups. Conclusions: F&V consumption is associated with lower plasma saturated FAs when fat intake is high. These findings suggest that F&V consumption may have different associations with plasma FAs depending on their subtype and on the extent of fat intake.Generalitat de Catalunya FI_B 00256Canadian Institutes of Health Research (CIHR)Consejo Interinstitucional de Ciencia y Tecnologia (CICYT)European Commission AGL2016-75329-RCIBEROBN from the Instituto de Salud Carlos III ISCIII from the Ministerio de Ciencia, Innovacion y Universidades, (AEI/FEDER, UE)Generalitat de Catalunya 2017SGR196CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn)Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigacion para la Salud (FIS)European Commission PI13/00673 PI13/00492 PI13/00272 PI13/01123 PI13/00462 PI13/00233 PI13/02184 PI13/00728 PI13/01090 PI13/01056 PI14/01722 PI14/00636 PI14/00618 PI14/00696 PI14/01206 PI14/01919 PI14/00853 PI14/01374Especial Action Project entitled Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grantEuropean Research Council (ERC) European Commission 340918Recercaixa grant 2013ACUP00194Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018Generalitat Valenciana European Commission PROMETEO/2017/017SEMERGEN grant, Fundacio la Marato de TV3 PI044003Generalitat de Catalunya 2017 SGR 1717Ministerio de Ciencia, Innovacion y Universidades AGL2016-75329-R"FOLIUM" program within the FUTURMed project within Fundacio Institut d'Investigacio Sanitaria Illes BalearsICREA under the ICREA Academia programmeThe European Regional Development Fund PI17/01347 PI17/00525 PI17/01827 PI17/00532 PI17/00215 PI17/01441 PI17/00508 PI17/01732 PI17/00926 PI19/00781 CB06/03 CB12/03European Commission PI14/00972 PI14/00728 PI14/01471 PI16/00473 PI16/00662 PI16/01873 PI16/01094 PI16/00501 PI16/00533 PI16/00381 PI16/00366 PI16/01522 PI16/01120 PI17/00764 PI17/01183 PI17/00855 FPU17/00513 CD17/0012