Effect of polyphenol intake on biomarkers and cardiovascular risk

174 p.[ES] Introducción La enfermedad cardiovascular es la principal causa de muerte en todo el mundo y, a pesar de las estrategias preventivas llevadas a cabo, continúa siendo un problema de salud pública. La dieta mediterránea ha demostrado numerosos beneficios cardiosaludables dada su riqueza en moléculas antioxidantes y antiinflamatorias y, muy especialmente, en polifenoles. Estos compuestos bioactivos han mostrado beneficios a nivel cardiovascular debido a sus propiedades antitrombóticas, antiinflamatorias y antiagregantes. Sin embargo, el estudio de su potencial en humanos es limitado. Dado el gran número de compuestos que existen, y, por ende, sus variadas biodisponibilidades y mecanismos de acción, aún hay muchos puntos que necesitan ser esclarecidos. Por este motivo, el objetivo principal de la presente tesis doctoral es evaluar la asociación entre el consumo de polifenoles, y el riesgo y biomarcadores de riesgo cardiovascular (RCV). Metodología Se utilizó la información disponible de 6.633 participantes del estudio PREDIMED-Plus, un ensayo clínico aleatorizado multicéntrico, que recopiló información sobre hábitos alimentarios y estilos de vida, así como muestras sanguíneas para análisis bioquímicos. El consumo de polifenoles se estimó utilizando los datos de consumo de alimentos del cuestionario semicuantitativo de frecuencia alimentaria de 143 ítems y el contenido de polifenoles de cada alimento contenido en la base de datos Phenol-Explorer. Los consumos estimados se ajustaron por la ingesta total de energía de acuerdo al método de residuales. Mediante modelos de regresión lineal multivariante, se evaluó la asociación entre la ingesta de polifenoles y el RCV (estimado mediante ecuaciones de riesgo). Además, se evaluó la asociación entre la ingesta de polifenoles y, el ácido úrico (mediante regresión lineal multivariante) y, mediante modelos de regresión de Cox con un tiempo de seguimiento constante (t=1) se estimó los Prevalence Ratio de la hiperuricemia. Por otro lado, se establecieron patrones de consumo de polifenoles mediante análisis factorial y análisis clúster, comparando ambos métodos y relacionando la adherencia a cada patrón con el RCV estimado. Todos los análisis se realizaron para hombres y mujeres por separado, además de en la población total. Resultados La ingesta total de polifenoles (βQ5vs.Q1= 0,10, IC 95%: 0,04 a 0,17) y flavonoides (βQ5vs.Q1= 0,17, IC 95%: 0,10 a 0,24) se asoció directa y significativamente con una mejor salud cardiovascular óptima (Life’s Simple 7). Se encontraron asociaciones inversas entre el consumo de la clase otros polifenoles y, el RCV estimado mediante Framingham (βQ5vs.Q1= -1,22%, IC 95%: -2,37 a -0,07) y SCORE (βQ5vs.Q1=-0,32, IC 95%: -2,37 a -0,07). En las mujeres, las asociaciones entre el consumo de polifenoles y todas las ecuaciones de riesgo, tienden a ser protectoras. La ingesta de ácidos fenólicos (βQ5vs.Q1= -0,17, IC 95%: -0,27 a -0,06), ácidos hidroxicinámicos (βQ5vs.Q1= -0,19, IC 95%: -0,3 a -0,09), alquilmetoxifenoles (βQ5vs.Q1= 0,2, IC 95%: -0,31 a -0. 1) y metoxifenoles (βQ5vs.Q1= -0,24, IC 95%: -0,34 a -0,13) -0,24, IC 95%: -0,34 a -0,13) mostró una asociación inversa con los niveles de ácido úrico en suero y, la hiperuricemia (PRQ5vs.Q1=0,82, IC 95%:0,71-0,95; PRQ5vs.Q1=0,82, IC 95%:0,71-0,95; PRQ5vs.Q1=0,80, IC 95%:0,70-0,92 y PR=0,79, IC 95%:0,69-0,91, respectivamente). Los patrones de polifenoles revelaron diferencias entre hombres y mujeres, así como en su asociación con el RCV. Respecto a aquellos derivados del análisis factorial: para el total de la muestra, y los hombres, el patrón 3 (aceitunas y aceite de oliva) se asoció positivamente con el RCV, también presentaron, mayor prevalencia de diabetes y mayores consumos de sodio. El patrón 4 formado por el café en todos los grupos, también se asoció con mayor RCV. En cuanto al análisis clúster, el clúster 2 en el total y en hombres, caracterizados por consumo de polifenoles del café y las aceitunas y aceite de oliva, también mostraron mayor RCV. Conclusiones La clase otros polifenoles mostró asociaciones inversas con el riesgo cardiovascular estimado, encontrándose resultados similares con las ecuaciones de Framingham, Framingham-REGICOR y Life’s Simple 7 (después de eliminar el componente de dieta) y diferentes con la SCORE, pero los predictores que se incluyen en esta herramienta son escasos. Una mayor ingesta subclases de polifenoles presentes en el café: ácidos hidroxicinámicos, alquilmetoxifenoles y metoxifenoles se asoció de forma inversa a los niveles de ácido úrico y la hiperuricemia. Encontramos diferencias en los patrones de ingesta de polifenoles entre hombres y mujeres, y en sus asociaciones con la RCV. Estas diferencias de sexo pueden explicarse por el hecho de que llevan estilos de vida diferentes, ya que un patrón no se refiere sólo a los hábitos dietéticos. Además, los sujetos que presentaban un mayor riesgo al inicio del estudio podrían sentirse más motivados para mejorar su hábito dietético (causalidad inversa). Nuestros hallazgos añaden nuevos conocimientos en el estudio de los compuestos fenólicos, destacando la importancia de analizarlos por sexo y de estudiar los determinantes de las elecciones alimentarias y los patrones dietéticos en relación con la percepción de riesgo y los estilos de vida específicos.[EN] Introduction Cardiovascular disease is the leading cause of death worldwide and, despite preventive strategies, continues to be a public health problem. The Mediterranean diet has demonstrated numerous benefits in this regard given its richness in antioxidant and anti-inflammatory molecules, and most especially, in polyphenols. These bioactive compounds have shown cardiovascular benefits due to their antithrombotic, anti-inflammatory and antiplatelet properties. However, the study of their potential in humans is limited. Given the large number of compounds that exist and, therefore, their varied bioavailability and mechanisms of action, there are still many points that need to be clarified. For this reason, the main objective of this doctoral thesis is to evaluate the association between polyphenol intake and cardiovascular risk (CVR) and biomarkers. Methods The information available from 6,633 participants in the PREDIMED-Plus study was used, it is a multicenter randomized clinical trial, which collected information on dietary habits and lifestyles, as well as blood samples for biochemical analysis. Polyphenol intakes were estimated using food consumption data from the 143-item semi-quantitative food frequency questionnaire and the polyphenol content of each food contained in the Phenol-Explorer database. Estimated intakes were adjusted for total energy intake according to the residuals method. The association between polyphenol intake and CVR (estimated using risk equations) was evaluated using multivariate linear regression models. In addition, the association between polyphenol intake and uric acid was evaluated (using multivariate linear regression) and, using Cox regression models with a constant follow-up time (t=1), the prevalence ratio of hyperuricemia was estimated. On the other hand, polyphenol consumption patterns were established by factor analysis and cluster analysis, comparing both methods and relating adherence to each pattern with the estimated CVR. All analyses were performed for men and women separately, as well as in the total population. Results Total polyphenol (βQ5vs.Q1= 0.10, 95% CI: 0.04 to 0.17) and flavonoid (βQ5vs.Q1= 0.17, 95% CI: 0.10 to 0.24) intakes were directly and significantly associated with improved optimal cardiovascular health (Life's Simple 7). Inverse associations were found between other polyphenols class intake and, CVR estimated by Framingham (βQ5vs.Q1= -1.22%, 95% CI: -2.37 to -0.07) and SCORE (βQ5vs.Q1=-0.32, 95% CI: -2.37 to -0.07). In women, the associations between polyphenol intake and all risk equations tended to be protective. The intake of phenolic acids (βQ5vs.Q1= -0.17, 95% CI: -0.27 to -0.06), hydroxycinnamic acids (βQ5vs.Q1= -0.19, 95% CI: -0.3 to -0.09), alkylmethoxyphenols (βQ5vs.Q1= 0.2, 95% CI: -0.31 to -0. 1) and methoxyphenols (βQ5vs.Q1= -0.24, 95% CI -0.34 to -0.13) showed an inverse association with serum uric acid levels and, hyperuricemia (PRQ5vs.Q1=0.82, 95% CI:0.71-0.95; PRQ5vs.Q1=0.82, 95% CI:0.71-0.95; PRQ5vs.Q1=0.80, 95% CI:0.70-0.92 and PRQ5vs.Q1=0.79, 95% CI:0.69-0.91, respectively). The polyphenol patterns revealed differences between men and women, as well as, in their association with CVR. Regarding those derived from the factorial analysis: for the total sample and the men, pattern 3 (olives and olive oil poyphenols) was positively associated with CVR, they also had a higher prevalence of diabetes and higher sodium intake. Pattern 4, formed by coffee polyphenols in all groups, was also associated with higher CVR. As for the cluster analysis, cluster 2 in the total and in men, characterized by consumption of coffee polyphenols and olives and olive oil, also showed higher CVR. Conclusions The other polyphenols class showed inverse associations with estimated cardiovascular risk, finding similar results with the Framingham, Framingham-REGICOR and Life's Simple 7 equations (after eliminating the diet component), and different with the SCORE, but predictors included in this scale are scarce. Higher intakes of polyphenols present in coffee: hydroxycinnamic acids, alkylmethoxyphenols, and methoxyphenols, were inversely associated with serum uric acid levels and hyperuricemia. We found differences in polyphenol intake patterns between men and women, and in their associations with CVR. These sex differences may be explained by the fact that they lead different lifestyles, since a pattern does not refer only to dietary habits. Moreover, subjects who were at higher risk at baseline might be more motivated to improve their dietary habit (reverse causality). Our findings add new insights in the study of phenolic compounds, highlighting the importance of analyzing them by sex and studying the determinants of food choices and dietary patterns in relation to risk perception and specific lifestyles

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

BACKGROUND: 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. METHODS AND RESULTS: This cross-sectional analysis involved baseline data of 6332 participants. Food polyphenol content 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 associated 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. CONCLUSIONS: In individuals with metabolic syndrome, a higher intake of some polyphenol subclasses (hydroxycinnamic acids, alkylmethoxyphenol, and methoxyphenol) was inversely associated with serum uric acid levels and hyperuricemia. Nevertheless, our findings warrant further research.European Research Council (ERC) European Commission 2013-2018 340918official funding agency for biomedical research of the Spanish government Instituto de Salud Carlos IIIEuropean 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 PI14/01919Especial Action ProjectLa Caixa Foundation 2013ACUP00194Consejo Interinstitucional de Ciencia y Tecnologia (CICYT) AGL2016-75329-RCenter for Forestry Research & Experimentation (CIEF)European Commission PROMETEO/2017/017Generalitat de Catalunya SGR-2019Junta de Andalucia PI0458/2013 PS0358/2016 PI0137/2018SEMERGEN (Sociedad Espanola de Medicos de Atencion Primaria)European Cooperation in Science and Technology (COST)IDISBA (Instituto de Investigacion Sanitaria Islas Baleares)European Commission CIBEROBN CB06/03 CB12/03European Commission European Commission Joint Research Centre EAT2BENI-CE_H2020_SFS2016Spanish Ministry of Science, Innovation and Universities for the Formacion de Profesorado Universitario FPU17/00785Instituto de Salud Carlos III, through the Fondo de Investigacion para la Salud - European Regional Development Fund 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 PI16/00473Instituto de Salud Carlos III European Commission PI14/00853 PI14/01374 PI14/00972 PI19/00386 PI19/00309 PI19/01032 PI19/00576 PI19/00017 PI19/01226 PI19/00781 PI19/01560 PI16/00662 PI16/01873 PI16/01094 PI19/01332 PI14/00728 PI14/0147

Family history of first degree as a risk factor for colorectal cancer

Objetivo: El objetivo de este estudio es evaluar la asociación entre antecedentes familiares (AF) de primer grado y cáncer colorrectal (CCR).Método: Se incluyeron 2857 controles y 1360 casos de CCR, del estudio MCC-Spain. La odds ratio (OR)y el intervalo de confianza del 95% (IC95%) de los AF de primer grado y el CCR se estimaron mediante regresión logística no condicional según la localización tumoral en los casos. Resultados: Los AF de primer grado duplicaron el riesgo de CCR (OR: 2,19; IC95%: 1,80-2,66), incrementándose en aquellos que presentaban dos o más (OR: 4,22; IC95%: 2,29-7,78) y en aquellos cuyos familiares fueron diagnosticados antes de los 50 años (OR: 3,24; IC95%: 1,52-6,91). Presentar AF se relacionó con estilos de vida como un menor consumo de vegetales. En cuanto a la asociación de los AF con la localización no se observaron diferencias significativas entre colon y recto, pero sí en la relación de estas con la edad de diagnóstico, presentando más AF los diagnosticados antes de los 50 años (OR: 4,79; IC95%:2,65-8,65).Conclusiones: Presentar AF de primer grado de CCR aumenta las probabilidades de desarrollar este cáncer, y también se elevan cuando el familiar es diagnosticado a edad temprana. Por ello, debe ser una población diana sobre la que incrementar las medidas de prevención.Objective To evaluate the association between first-degree family history and colorectal cancer (CRC). Method We analyzed data from 2857 controls and 1360 CRC cases, collected in the MCC-Spain project. The adjusted odds ratio (OR) and 95% confidence interval (95% CI) of association with the family history of CRC was estimated by non-conditional logistic regression. Results First-degree relatives doubled the risk of CRC (OR: 2.19; 95% CI: 1.80–2.66), increasing in those with two or more (OR: 4.22; 95% CI: 2.29–7.78) and in those whose relatives were diagnosed before 50 years (OR: 3.24; 95% CI: 1.52–6.91). Regarding the association of the family history with the location, no significant differences were observed between colon and rectum, but there were in the relation of these with the age of diagnosis, having more relatives those diagnosed before 50 years (OR: 4.79; 95% CI: 2.65–8.65). Conclusions First-degree relatives of CRC increase the chances of developing this tumor, they also increase when the relative is diagnosed at an early age. Therefore, it must be a target population on which to carry out prevention measures

Clinical Validation of a 3-Dimensional Ultrafast Cardiac Magnetic Resonance Protocol Including Single Breath-Hold 3-Dimensional Sequences

Objectives: This study sought to clinically validate a novel 3-dimensional (3D) ultrafast cardiac magnetic resonance (CMR) protocol including cine (anatomy and function) and late gadolinium enhancement (LGE), each in a single breath-hold. Background: CMR is the reference tool for cardiac imaging but is time-consuming. Methods: A protocol comprising isotropic 3D cine (Enhanced sensitivity encoding [SENSE] by Static Outer volume Subtraction [ESSOS]) and isotropic 3D LGE sequences was compared with a standard cine+LGE protocol in a prospective study of 107 patients (age 58 ± 11 years; 24% female). Left ventricular (LV) mass, volumes, and LV and right ventricular (RV) ejection fraction (LVEF, RVEF) were assessed by 3D ESSOS and 2D cine CMR. LGE (% LV) was assessed using 3D and 2D sequences. Results: Three-dimensional and LGE acquisitions lasted 24 and 22 s, respectively. Three-dimensional and LGE images were of good quality and allowed quantification in all cases. Mean LVEF by 3D and 2D CMR were 51 ± 12% and 52 ± 12%, respectively, with excellent intermethod agreement (intraclass correlation coefficient [ICC]: 0.96; 95% confidence interval [CI]: 0.94 to 0.97) and insignificant bias. Mean RVEF 3D and 2D CMR were 60.4 ± 5.4% and 59.7 ± 5.2%, respectively, with acceptable intermethod agreement (ICC: 0.73; 95% CI: 0.63 to 0.81) and insignificant bias. Both 2D and 3D LGE showed excellent agreement, and intraobserver and interobserver agreement were excellent for 3D LGE. Conclusions: ESSOS single breath-hold 3D CMR allows accurate assessment of heart anatomy and function. Combining ESSOS with 3D LGE allows complete cardiac examination in less than 1 min of acquisition time. This protocol expands the indication for CMR, reduces costs, and increases patient comfort. (J Am Coll Cardiol Img 2021;14:1742–1754)Funding included Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund (ERDF) Grants DTS17/00136 to Dr. Ibáñez and PI19/01704 to Dr. Fernandez-Jimenez; Spanish Society of Cardiology Translational Research Grant 2016 to Dr. Ibáñez; European Research Council ERC-CoG 819775-MATRIX to Dr. Ibáñez; Comunidad de Madrid S2017/BMD-3867-RENIM-CM to Drs. Desco and Ibáñez; and Ministerio de Ciencia e Innovación (MICINN) RETOS2019-107332RB-I00 to Dr. Ibáñez. Dr. Fernandez-Jimenez received funding from the European Union Horizon 2020 research and innovation programme under Marie Sklodowska-Curie Hrant Agreement No. 707642. The CNIC is supported by the ISCIII, the MICINN, and the Pro CNIC Foundation. Drs. Fernandez-Jimenez, Nothnagel, Fuster, Ibáñez, and Javier Sánchez-González are inventors of a joint patent (Philips/CNIC) for the new cine imaging method here described and validated/protected under the IP #2014P00960EP. Drs. Nothnagel, Kouwenhoven, Clemence, and Javier Sánchez-González are Philips employees. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose

Vocabulario de medicina [galego-español-inglés-portugués]

Consellaría de Sanidade. Xunta de Galici

Association between Polyphenol Intake and Gastric Cancer Risk by Anatomic and Histologic Subtypes: MCC-Spain

Several anticancer properties have been largely attributed to phenolics in in vivo and in vitro studies, but epidemiologic evidence is still scarce. Furthermore, some classes have not been studied in relation to gastric cancer (GC). The aim of this study was to assess the relationship between the intake of phenolic acids, stilbenes, and other phenolics and the risk of developing GC and its anatomical and histological subtypes. We used data from a multi-case-control study (MCC-Spain) obtained from different regions of Spain. We included 2700 controls and 329 GC cases. Odds ratios (ORs) were calculated using mixed effects logistic regression considering quartiles of phenolic intake. Our results showed an inverse association between stilbene and lignan intake and GC risk (ORQ4 vs. Q1 = 0.47; 95% CI: 0.32-0.69 and ORQ4 vs. Q1 = 0.53; 95% CI: 0.36-0.77, respectively). We found no overall association between total phenolic acid and other polyphenol class intake and GC risk. However, hydroxybenzaldehydes (ORQ4 vs. Q1 = 0.41; 95% CI: 0.28-0.61), hydroxycoumarins (ORQ4 vs. Q1 = 0.49; 95% CI: 0.34-0.71), and tyrosols (ORQ4 vs. Q1 = 0.56; 95% CI: 0.39-0.80) were inversely associated with GC risk. No differences were found in the analysis by anatomical or histological subtypes. In conclusion, a diet high in stilbenes, lignans, hydroxybenzaldehydes, hydroxycoumarins, and tyrosols was associated with a lower GC risk. Further prospective studies are needed to confirm our results

Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab

Ustekinumab has shown efficacy in Crohn's Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients' data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index <= 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission

Prospective associations between a priori dietary patterns adherence and kidney function in an elderly Mediterranean population at high cardiovascular risk

Purpose To assess the association between three different a priori dietary patterns adherence (17-item energy reduced-Mediterranean Diet (MedDiet), Trichopoulou-MedDiet and Dietary Approach to Stop Hypertension (DASH)), as well as the Protein Diet Score and kidney function decline after one year of follow-up in elderly individuals with overweight/obesity and metabolic syndrome (MetS). Methods We prospectively analyzed 5675 participants (55-75 years) from the PREDIMED-Plus study. At baseline and at one year, we evaluated the creatinine-based estimated glomerular filtration rate (eGFR) and food-frequency questionnaires-derived dietary scores. Associations between four categories (decrease/maintenance and tertiles of increase) of each dietary pattern and changes in eGFR (ml/min/1.73m(2)) or >= 10% eGFR decline were assessed by fitting multivariable linear or logistic regression models, as appropriate. Results Participants in the highest tertile of increase in 17-item erMedDiet Score showed higher upward changes in eGFR (beta: 1.87 ml/min/1.73m(2); 95% CI: 1.00-2.73) and had lower odds of >= 10% eGFR decline (OR: 0.62; 95% CI: 0.47-0.82) compared to individuals in the decrease/maintenance category, while Trichopoulou-MedDiet and DASH Scores were not associated with any renal outcomes. Those in the highest tertile of increase in Protein Diet Score had greater downward changes in eGFR (beta: - 0.87 ml/min/1.73m(2); 95% CI: - 1.73 to - 0.01) and 32% higher odds of eGFR decline (OR: 1.32; 95% CI: 1.00-1.75). Conclusions Among elderly individuals with overweight/obesity and MetS, only higher upward change in the 17-item erMedDiet score adherence was associated with better kidney function after one year. However, increasing Protein Diet Score appeared to have an adverse impact on kidney health. Trial Registration Number: ISRCTN89898870 (Data of registration: 2014).Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work 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 (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: Implementacion y evaluacion de una intervencion intensiva sobre la actividad fisica Cohorte PREDIMED-Plus grant to JS-S; the European Research Council (Advanced Research Grant 2014-2019; agreement #340918) granted to MAMG.; the Recercaixa (number 2013ACUP00194) grant to JS-S; grants from the Consejeria de Salud de la Junta de Andalucia (PI0458/2013, PS0358/2016, PI0137/2018); the PROMETEO/2017/017 and the PROMETEO 21/2021 grant from the Generalitat Valenciana; the SEMERGEN grant; the Boosting young talent call grant program for the development of IISPV research projects 2019-2021 (Ref.: 2019/IISPV/03 grant to AD-L); the Societat Catalana d'Endocrinologia i Nutricio (SCEN) Clinical-Research Grant 2019 (IPs: JS-S and AD-L). Collaborative Nutrition and/or Obesity Project for Young Researchers 2019 supported by CIBEROBN entitled: Lifestyle Interventions and Chronic Kidney Disease: Inflammation, Oxidative Stress and Metabolomic Profile (LIKIDI study) grant to AD-L. Jordi Salas-Salvado, gratefully acknowledges the financial support by ICREA under the ICREA Academia programme. M.R.-G., is supported by the Ministry of Education of Spain (FPU17/06488). 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

Family History and Gastric Cancer Risk: A Pooled Investigation in the Stomach Cancer Pooling (STOP) Project Consortium

Although there is a clear relationship between family history (FH) and the risk of gastric cancer (GC), quantification is still needed in relation to different histological types and anatomical sites, and in strata of covariates. The objective was to analyze the risk of GC according to first-degree FH in a uniquely large epidemiological consortium of GC. This investigation includes 5946 cases and 12,776 controls from 17 studies of the Stomach Cancer Pooling (StoP) Project consortium. Summary odds ratios (OR) and the corresponding 95% confidence intervals (CIs) were calculated by pooling study-specific ORs using fixed-effect model meta-analysis techniques. Stratified analyses were carried out by sex, age, tumor location and histological type, smoking habit, socioeconomic status, alcohol intake and fruit consumption. The pooled OR for GC was 1.84 (95% CI: 1.64-2.04; I2 = 6.1%, P heterogeneity = 0.383) in subjects with vs. those without first-degree relatives with GC. No significant differences were observed among subgroups of sex, age, geographic area or study period. Associations tended to be stronger for non-cardia (OR = 1.82; 95% CI: 1.59-2.05 for subjects with FH) than for cardia GC (OR = 1.38; 95% CI: 0.98-1.77), and for the intestinal (OR = 1.92; 95% CI: 1.62-2.23) than for the diffuse histotype (OR = 1.62; 95% CI: 1.28-1.96). This analysis confirms the effect of FH on the risk of GC, reporting an approximately doubled risk, and provides further quantification of the risk of GC according to the subsite and histotype. Considering these findings, accounting for the presence of FH to carry out correct prevention and diagnosis measures is of the utmost importance

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice