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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 (energyreduced 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., 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, Especial Action Project, European Research Council (ERC) European Commission 340918 2013ACUP00194, Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018, Center for Forestry Research & Experimentation (CIEF) PROMETEO/2017/017 PROMETEO 21/2021, Department of Health of the Generalitat de Catalunya SLT006/17/00246, Spanish Government FPU 17/01925, Fundacion Francisco Soria Melguizo, ICREA under the ICREA Academia programme, Canadian Institutes of Health Research (CIHR), A European Regional Development Fund 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, The European Regional Development Fund 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

Background: Metabolic syndrome (MetS) worsens quality of life and increases mortality. Dissatisfaction with weight in patients with MetS may modify the effect of lifestyle interventions to achieve changes in health-related behaviors. Objective: To assess 1-year changes in cardiovascular risk scores, self-perceived general health and health-related behaviors according to observed changes in desired weight loss during the first year of intervention in a large cardiovascular prevention trial. Design: Prospective analysis of the PREDIMED-PLUS trial, including 5,499 adults (55-75 years old) with overweight or obesity at baseline. Methods: The desired weight loss was the difference between ideal and measured weight. Tertiles of change in desired weight loss (1 year vs. baseline) were defined by the following cut-off points: >= 0.0 kg (T1, n = 1,638); 0.0 to -4.0 kg (T2, n = 1,903), European Research Council (ERC) European Commission 20132018 340918, Spanish government, ISCIII, through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund 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, Especial Action Project entitled: Implementacion y evaluacion de una intervencion intensive sobre la actividad fisica Cohorte PREDIMED-Plus grant, Recercaixa Grant 2013ACUP00194, Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018, Center for Forestry Research & Experimentation (CIEF), European Commission PROMETEO/2017/017 European Cooperation in Science and Technology (COST) European Commission CA16112, Balearic Islands Health Research Institute (IDISBA), European Commission CIBEROBN CB06/03 CB12/03 European Commission European Commission Joint Research Centre EAT2BENICE_H2020_SFS2016, Fundacio La Marato TV3 201630.10, Fernando Tarongi Bauza Grant, 'Spanish government, ISCIII, through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund' 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, the Spanish government, ISCIII, through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund 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 PI19/01226, "Spanish government, ISCIII, through the Fondo de Investigacion para la Salud (FIS) - European Regional Development Fund" PI19/00781 PI19/01560 PI19/01332 PI20/01802 PI20/00138 PI20/01532 PI20/00456 PI20/00339 PI20/00557 PI20/00886 PI20/01158

[eng] BACKGROUND: Bariatric surgery (BS) is the most effective long-term therapy for the treatment of severe obesity. Benefits of BS include a reduction of overall and cardiovascular mortality, incidence of first occurrence of fatal- or nonfatal-cardiovascular events, prevention and remission of type 2 diabetes mellitus, and improved quality of life. Nonetheless, BS is associated with potential complications amongst which micronutrient deficiencies are relevant. AIM: Against this background, the overall aim of this PhD project was to better understand the increased risk for nutritional deficiencies and protein status in subjects undergoing BS. METHODS: We prospectively evaluated the nutritional status of obese individuals prior to BS, and following the drastic reduction of daily energy intake, anatomical changes, and massive weight loss associated with the two currently most commonly performed surgical techniques [gastric bypass (GBP) and sleeve gastrectomy (SG)]. Additionally, to gain insight specifically on how to address the high prevalence of vitamin D (VD) deficiency, we performed two open-label, prospective studies aiming at evaluating the efficacy and safety of achieving 25-hydroxy VD (25(OH)D) levels ≥75 nmol/L with two different supplementation algorithms. Similarly, we gained insight on the reported high prevalence of iron deficiency by characterizing iron status with the evaluation of indices of systemic inflammation. Finally, we performed two observational prospective studies to evaluate the effects of dietary protein intake (PI) on fat free mass (FFM, as assessed from bioelectrical impedance or DEXA) and protein status changes after BS-induced weight loss. As further step in this research path, a randomized control trial proposal has been designed to determine the effect of two levels of PI (standard versus high) after BS on the nitrogen balance, body composition, energy expenditure, perceived satiety, and plasma levels of branched chain amino acids (BCAA) and insulin sensitivity, as well as the feasibility of protein supplementation up to one year after BS. This translational research protocol integrates mechanistic, metabolic, and energy homeostasis outcomes. Preliminary results of a pilot study of that trial are presented as part of this thesis project to demonstrate feasibility of the protocol. RESULTS: Nutritional deficiencies are commonly found in a Mediterranean severely obese population undergoing BS, with those deficiencies being more prevalent than in normal weight individuals. Of note, SG- and GBP-patients experience similar long-term changes in dietary intake. Indeed, when micronutrient intake from supplements was not taken into account, mean daily dietary intake of all evaluated micronutrients was below current dietary reference intakes (DRIs). Interestingly, SG and GBP carry comparable post-surgical nutritional risk. Low VD and elevated PTH levels were the most prevalent nutritional abnormalities after BS. In clinical practice, a single fixed high dose (2,000 IU) of VD supplementation is as effective and safe as an individualized daily dose of cholecalciferol to achieve 25(OH)D levels ≥75 nmol/L after BS. When considering hs-CRP as inflammatory marker, impaired iron status could be identified in two thirds of BS candidates. Protein supplements are helpful in achieving the PI goal after BS, with PI thresholds of >60 g/d or 1.1 g/kg Ideal Body Weight/day being associated with better FFM retention. The results of our pilot study support feasibility for a larger Randomized Control Trial with to address the association between PI and NB, BCAA, body compositions changes, REE, glucose homeostasis, and satiety after BS. CONCLUSION: Our data underscores the need for the evaluation of nutritional parameters prior to- and following-BS. We deem results of this PhD project significantly contribute to improve knowledge in the area of nutrition and body composition after BS., [spa] INTRODUCCIÓN: La cirugía bariátrica (CB) es el método más eficaz para el tratamiento de la obesidad grave a largo plazo. Sin embargo, la CB se asocia a déficits de micronutrientes. OBJETIVO: aumentar el conocimiento del riesgo de deficiencias nutricionales y del estado proteico en sujetos candidatos a CB. MÉTODOS: Se evaluó prospectivamente el estado nutricional de los pacientes antes y después de la CB (bypass gástrico (BPG) y gastrectomía tubular (GT)]. Se evaluó, mediante dos estudios prospectivos la eficacia y la seguridad de normalizar los niveles de 25-hydroxy VD (25 (OH) D) mediante dos algoritmos de suplementación distintos. Obtuvimos información sobre la alta prevalencia de deficiencia de hierro al caracterizar el estado de hierro con la evaluación de índices de inflamación sistémica. Finalmente, se realizaron dos estudios observacionales prospectivos para evaluar los efectos de la ingesta proteica (IP) sobre la masa libre de grasa (MLG) y los cambios en el estatus proteico después de la pérdida de peso inducida por BS. Finalmente, se diseñó un estudio aleatorizado y controlado para determinar el efecto de dos niveles de IP (estándar versus alto) después de CB sobre el balance de nitrógeno, la composición corporal, el gasto energético, saciedad y los niveles plasmáticos de aminoácidos de cadena ramificada, así como el efecto de la suplementación proteica a largo plazo. RESULTADOS: Los déficits nutricionales son frecuentes en nuestra población candidata a CB. La GT y BPG conllevan un riesgo nutricional comparable. Una dosis fija (2.000 UI) de suplementos de VD es tan eficaz y segura como una dosis diaria individualizada para normalizar niveles. Al considerar hs-CRP como marcador inflamatorio, el déficit de hierro podría ser identificado en dos tercios de los candidatos a CB. Los suplementos proteicos son útiles para alcanzar el objetivo proteico tras CB. IP de> 60 g / día o 1,1 g / kg de peso ideal / día se asocia con una mejor retención de MLG. Los resultados del estudio piloto apoyan la viabilidad del protocolo propuesto. CONCLUSIÓN: Nuestros datos subrayan la necesidad de la evaluación de parámetros nutricionales antes y después de la CB. Consideramos que los resultados de este proyecto contribuyen significativamente a mejorar el conocimiento en el área de nutrición y composición corporal después de la CB.

La obesidad mórbida es un problema de salud creciente. La cirugía bariátrica es actualmente el tratamiento más eficaz para la pérdida de peso, sin embargo esta pérdida de peso es súmamente variable. En alrededor del 20% de los pacientes intervenidos la pérdida de peso es insuficiente, las causas de esta gran variabilidad no están bien definidas. Las hipótesis planteadas en esta tesis son las siguientes, 1. La variabilidad en la pérdida de peso tras la cirugía bariátrica puede ilustrarse en un número limitado de trayectorias ponderales con significación clínica. 2. La variabilidad en la pérdida de peso puede explicarse por lo menos en parte por la variabilidad en el efecto de las hormonas gastrointestinales. Los objetivos son los siguientes, 1. Describir la presencia de diferentes patrones de pérdida de peso en una cohorte de individuos operados mediante bypass gástrico y gastrectomía vertical con 5 años de seguimiento y evaluar los predictores clínicos de cada trayectoria ponderal. 2. Comparar la respuesta de las hormonas gastrointestinales en los grupos de fracaso y éxito en la pérdida de peso tras el bypass gástrico. 3. Comparar los niveles plasmáticos de citrina, marcador de la masa entérica, en los grupos de fracaso y éxito en la pérdida de peso tras el bypass gástrico. 4. Valorar el rol causal de las hormonas gastrointestinales sobre la ingesta y su repercusión sobre la respuesta ponderal en los diferentes grupos de fracaso y éxito tras el bypass gástrico a través del bloqueo de la secreción de hormonas gastrointestinales con octreótido. Los resultados y conclusiones derivadas de esta tesis se resumen en los siguientes puntos, 1- La cirugía bariátrica logra una pérdida de peso muy variable, sus efectos se atenúan y su variabilidad aumenta con el transcurso del tiempo. 2. Se pueden identificar dos trayectorias clínicamente diferentes en los que presentan escasa pérdida de peso. El fracaso primario ó resistencia a la pérdida de peso y, el fracaso secundario o mayor tendencia a reganancia de peso. 3. La cirugía bariátrica se asocia una menor pérdida del exceso de peso en los pacientes con obesidad extrema. 4. El mayor cumplimiento de las visitas de seguimiento se asocia con mayor respuesta a la cirugía bariátrica. 5. El bypass y la gastrectomía vertical consiguen resultados similares a corto y mediano plazo, sin embargo la gastrectomía vertical se asocia con mayor reganancia ponderal a medio plazo. 6. El éxito en la pérdida de peso tras el bypass gástrico se asocia a un perfil hormonal más anorexígeno en comparación con el fracaso. 7. Las hormonas gastrointestinales ejercen un papel importante en el control fisiológico de la ingesta calórica también tras el BPG. 8. Las hormonas gastrointestinales no juegan un papel crítico en las diferencias en la ingesta entre personas con éxito o fracaso secundario en la pérdida de peso tras el bypass gástrico. 9. Tras el bypass gástrico sucede una adaptación intestinal que es progresiva en el tiempo. 10. Los datos disponibles sugieren que la adaptación intestinal no ejerce un rol determinante del éxito en la pérdida de peso tras el bypass gástrico., Morbidly obesity is a growing health problem. Bariatric surgery is currently the most effective treatment for weight loss, however its results are highly variable. In about 20% of individuals weight loss is insufficient, the causes of this high variability are not well defined. The hypotheses made in this thesis are as follows, 1. Variability in weight loss after bariatric surgery can be illustrated in a limited number of weight loss patterns with clinical significance. 2. Variability in weight loss can be explained at least partly by the effect of variability in the gastrointestinal hormones. The aims were to, 1. Describe the presence of different patterns of weight loss in a cohort of individuals operated by gastric bypass and vertical gastrectomy with 5 years of follow up and evaluate clinical predictors of each weight loss path. 2. Compare the response of gastrointestinal hormones in groups of failure and success in weight loss after gastric bypass. 3. Compare the plasma levels of citrulline, marker enteric mass in groups of failure and success in weight loss after gastric bypass. 4. Assess the causal role of gastrointestinal hormones on food intake and its impact on the weight response in different groups of failure and success after gastric bypass by blocking the secretion of gastrointestinal hormones with octreotide. The results and conclusions from this thesis are summarized in the following points, 1- Bariatric surgery achieves weight loss with high variability, its effects are mitigated and variability increases with the passage of time. 2. We can identify two clinically different paths in those with low weight loss. The primary failure or resistance to weight loss, and secondary failure or greater tendency to regain weight. 3. Bariatric surgery is associated with a lower loss of excess weight in patients with extreme obesity. 4. Greater compliance with follow-up visits is associated with increased response to bariatric surgery. 5. The bypass and vertical gastrectomy get similar short and medium term results, however gastrectomy is associated with increased weight regain at medium term. 6. Successful weight loss after gastric bypass is associated with a more anorectic hormone profile compared with failure. 7. The gastrointestinal hormones play an important role in the physiological control of calorie intake also after gastric bypass. 8. Gastrointestinal hormones do not play a critical role in the differences in intake among people with secondary success or failure in weight loss after gastric bypass. 9. After gastric bypass intestinal adaptation occurs, it is progressive over time. 10. The available data suggest that intestinal adaptation does not play a decisive role to success in weight loss after gastric bypass.

La polineuropatía diabética es una complicación muy frecuente en la diabetes tipo 2, el factor de riesgo más importante de ulcera y está involucrada en la mayoría de amputaciones no traumáticas del pie. Su evolución es lenta y silenciosa y, una vez establecida, es sustancialmente irreversible. Disponer de más factor tiempo para una prevención secundaria de la polineuropatía diabética realmente efectiva requiere nuevos enfoques en la investigación de sus marcadores de riesgo. OBJETIVOS: Investigar posibles marcadores de riesgo, innovadores o poco estudiados, de polineuropatía diabética. METODOLOGIA. Se realizaron tres estudios observacionales en muestras aleatorias de personas con diabetes tipo 2: 1) Descriptivo transversal para evaluar la relación entre los niveles circulantes del Transforming Growth Factor Beta 1 (TGF-beta-1) total y la presencia de polineuropatía diabética; 2) Prospectivo de seguimiento a tres años explorando el polimorfismo ("I/D" inserción/ delección) del gen del enzima conversor de la angiotensina (ACE) como factor de riesgo de desarrollar polineuropatía diabética; 3) Prospectivo de seguimiento a diez años, analizando la presencia previa de enfermedad cardiovascular y su relación con la aparición posterior de polineuropatía diabética. RESULTADOS: El TGF-beta-1 aparece como una molécula biomarcadora importante para la detección de polineuropatía diabética. El genotipo (D/I) del gen del ACE se erige como un factor protector en el desarrollo de la polineuropatía diabética. A los diez años de seguimiento, las personas con diabetes tipo 2 y enfermedad cardiovascular al inicio del estudio presentaron mayor riesgo de desarrollar polineuropatía diabética. CONCLUSIONES: Los tres estudios aportan resultados orientados a identificar personas susceptibles de desarrollar polineuropatía diabética. La posibilidad de que dicha identificación se lleve a cabo antes de sus manifestaciones clínicas permitiría anticipar las medidas de prevención secundaria e intensificar las actuaciones sobre sus factores de riesgo., La polineuropatia diabètica és una complicació molt freqüent en la diabetis tipus 2, el factor de risc més important d'úlcera i està involucrada en la majoria d'amputacions no traumàtiques del peu. La seva evolució es lenta i silenciosa i, una vegada establerta, és substancialment irreversible. Disposar de més factor temps per una prevenció secundària de la polineuropatia diabètica realment efectiva exigeix nous enfocaments en la investigació dels seus marcadors de risc. OBJECTIUS: Investigar possibles marcadors de risc, innovadors o poc estudiats, de polineuropatia diabètica. METODOLOGIA: Es varen fer tres estudis observacionals en mostres aleatòries de persones amb diabetis tipus 2: 1) Descriptiu transversal per avaluar la relació entre els nivells circulants del Transforming Growth Factor Beta 1 (TGF-beta-1) total i la presència de polineuropatia diabètica; 2) Prospectiu de seguiment a tres anys explorant el polimorfisme ("I/D" inserció/delecció) del gen de l'enzim conversor de l'angiotensina (ACE) com a factor de risc de desenvolupar polineuropatia diabètica; 3) Prospectiu de seguiment a deu anys, analitzant la presència prèvia de malaltia cardiovascular i la seva relació amb l'aparició posterior de polineuropatia diabètica. RESULTATS: El TGF-beta-1 apareix com una molècula biomarcadora important per la detecció de polineuropatia diabètica. El genotip (D/I) del gen de l'ACE s'erigeix com un factor protector en el desenvolupament de la polineuropatia diabètica. Als deu anys de seguiment, les persones amb diabetis tipus 2 i malaltia cardiovascular a l'inici de l'estudi presentaren major risc de desenvolupar polineuropatia diabètica. CONCLUSIONS: Els tres estudis aporten resultats orientats a identificar persones susceptibles de desenvolupar polineuropatia diabètica. La possibilitat que aquesta identificació es dugui a terme abans de les seves manifestacions clíniques permetria anticipar les mesures de prevenció secundària i intensificar les actuacions envers els seus factors de risc., Diabetic Polyneuropathy (DPN) is the commonest of its microangiopathic complications. It is the main risk factor for ulcers and is involved in the majority of non-traumatic lower extremity amputations. Its natural history is silent and insidious; nevertheless, once established it substantially irreversible. Hence, new research strategies on DPN risk factors are needed to provide health practitioners with more time for a more efficient secondary prevention. OBJETIVES: To look after for novel or surrogate DPN risk factors METHODOLOGY: three observational studies were performed on randomly selected samples of patients with Type 2 Diabetes mellitus (T2DM): 1) Descriptive cross-sectional study designed to evaluate the relationship between circulating plasma Transforming Growth Factor Beta 1 (TGF-beta-1) and the presence of DPN; 2) Prospective (three years of follow-up) study exploring the Angiotensin-converting enzyme (ACE) gene single polymorphism ("I/D" insertion/ deletion) as a genetic biomarker of the risk factor for DPN development; 3) Prospective (10 years of follow-up) study assessing the relationship between DPN development and a history of previous cardio-vascular disease (CVD). RESULTS: TGF-beta-1 appears as an important biomarker molecule for DPN screening. The (D/I) genotype of the ACE gene polymorphism stands as a protective factor in the development of DPN. After ten year of follow-up, those T2DM patients with prior history of CVD disclose a higher risk of developing DPN. CONCLUSIONS: the three aforementioned studies provide results oriented at identifying potential candidates to develop DPN. This identification is likely to be performed prior to the development of DPN clinical manifestations. The latter would allow implementation of secondary prevention measures and intensify the treatment of its risk factors.