Novel Immune Features of the Systemic Inflammation Associated with Primary Hypercholesterolemia: Changes in Cytokine/Chemokine Profile, Increased Platelet and Leukocyte Activation

Primary hypercholesterolemia (PH) is associated with a low grade systemic inflammation that is likely the main driver of premature atherosclerosis. Accordingly, we characterized the immune cell behaviour in PH and its potential consequences. Whole blood from 22 PH patients and 21 age-matched controls was analysed by flow cytometry to determine the percentage of leukocyte immunophenotypes, activation, and platelet-leukocyte aggregates. Plasma markers were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). The adhesion of platelet-leukocyte aggregates to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium was investigated using the dynamic model of the parallel-plate flow chamber. PH patients presented greater percentage of Mon 3 monocytes, Th2 and Th17 lymphocytes, activated platelets, and leukocytes than controls. The higher percentages of circulating platelet-neutrophil, monocyte and lymphocyte aggregates in patients caused increased platelet-leukocyte adhesion to dysfunctional arterial endothelium. Circulating CXCL8, CCL2, CX3CL1, and IL-6 levels positively correlated with key lipid features of PH, whereas negative correlations were found for IL-4 and IL-10. We provide the first evidence that increased platelet and leukocyte activation leads to elevated platelet-leukocyte aggregates in PH and augmented arterial leukocyte adhesiveness, a key event in atherogenesis. Accordingly, modulation of immune system behavior might be a powerful target in the control of further cardiovascular disease in PH

Increased dosage of tumor suppressors limits the tumorigenicity of iPS cells without affecting their pluripotency

Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a promising therapeutic tool for many diseases, including aged tissues and organs at high risk of failure. However, the intrinsic self-renewal and pluripotency of ES and iPS cells make them tumorigenic, and hence, the risk of tumor development hinders their clinical application. Here, we present a novel approach to limit their tumorigenicity and increase their safety through increased copy number of tumor suppressors. iPS containing an extra copy of the p53 or Ink4a/ARF locus show normal pluripotency, as determined by in vitro and in vivo differentiation assays. Yet, while retaining full pluripotency, they also possess an improved engagement of the p53 pathway during teratocarcinoma formation, which leads to a reduced tumorigenic potential in various in vitro and in vivo assays. Furthermore, they show an improved response to anticancer drugs, which could aid in their elimination in case tumors arise with no adverse effects on cell function or aging. Our system provides a model for studying tumor suppressor pathways during reprogramming, differentiation, and cell therapy applications. This offers an improved understanding of the pathways involved in tumor growth from engrafted pluripotent stem cells, which could facilitate the use of ES and iPS cells in regenerative medicine

Famílies botàniques de plantes medicinals

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia, Assignatura: Botànica Farmacèutica, Curs: 2013-2014, Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són els recull de 175 treballs d’una família botànica d’interès medicinal realitzats de manera individual. Els treballs han estat realitzat per la totalitat dels estudiants dels grups M-2 i M-3 de l’assignatura Botànica Farmacèutica durant els mesos d’abril i maig del curs 2013-14. Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pel professor de l’assignatura i revisats i finalment co-avaluats entre els propis estudiants. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings

Study of the systemic inflammation associated to primary hypercholesterolemia, its modulation and its impact in atherosclerosis. Role of CXCL16/CXCR6 axis in abdominal aortic aneurysm formation

La hipercolesterolemia primaria (HP) es un desorden metabólico caracterizado por unos elevados niveles circulantes de lipoproteínas de baja densidad (LDL), así como por una inflamación sistémica de bajo grado, que puede finalmente dar lugar al desarrollo de aterosclerosis. Debido a la escasa información que se tiene de la enfermedad a nivel inmunológico, hemos caracterizado el comportamiento de diferentes mediadores solubles y celulares de la inflamación y sus posibles consecuencias. Para ello se ha empleado sangre completa de 22 pacientes con HP y 21 controles de semejante edad. En todos ellos se ha analizado la sangre por citometría de flujo para determinar la activación leucocitaria y plaquetaria, la proporción de las distintas subpoblaciones leucocitarias, así como la formación de agregados plaqueta-leucocito, junto con la determinación de los niveles plasmáticos de diferentes marcadores solubles. De hecho, los pacientes con HP presentaron mayores porcentajes de monocitos de tipo 3 (Mon 3), linfocitos Th2 y Th17 y plaquetas y leucocitos activados que los controles. Asimismo, se detectaron mayores niveles circulantes de interleucina (IL)-8/CXCL8, CCL2, fractalquina/CX3CL1 e IL-6 que se correlacionaron positivamente con los niveles de lípidos característicos de la HP: apolipoproteína B (apoB), LDL y colesterol total (CT). Sin embargo, los pacientes con HP mostraron niveles plasmáticos inferiores de las citocinas anti-inflamatorias IL-4 e IL-10 que los correspondientes controles. Por otro lado, la disfunción endotelial constituye una de las primeras etapas de la aterogénesis, promoviendo la adhesión y posterior migración leucocitaria hacia el foco inflamatorio. El factor de necrosis tumoral α (TNFα) es una de las citocinas principales en la hipercolesterolemia; por esta razón se han explorado las consecuencias funcionales de la presencia de elevados niveles de TNFα en los pacientes con HP. Así, se ha estudiado mediante cámara de flujo la adhesión plaqueta-leucocito y leucocito sobre el endotelio arterial estimulado o no con TNFα, observándose una mayor adhesión leucocitaria al endotelio disfuncional en los pacientes con HP. Ello sugiriere una posible asociación entre la inflamación sistémica y el desarrollo de enfermedades cardiovasculares en este desorden metabólico. Al mismo tiempo, y para saber si la ingesta de una sobrecarga lipídica oral de una preparación comercial de triglicéridos de cadena larga con una proporción ω6/ω3 >20/1, logra disminuir la inflamación sistémica, se administró a pacientes con HP y se repitió el estudio de todos los parámetros anteriores a las 4 horas de su ingesta, observándose una disminución de la activación plaquetaria así como una disminución en la adhesión leucocitaria al endotelio disfuncional. Se pudo observar que la administración de esta sobrecarga lipídica tuvo un efecto beneficioso en el estado protrombótico y proinflamatorio en los pacientes con HP. Así mismo, se detectaron elevados niveles circulantes de eotaxina-1/CCL11 y eotaxina-3/CCL26 en los pacientes con HP. Ya que ambas quimiocinas señalizan exclusivamente a través del receptor CCR3, el cual se expresa de manera constitutiva en los eosinófilos, se llevó a cabo un estudio en profundidad de la expresión del receptor en diferentes poblaciones leucocitarias, tanto en pacientes como en controles. La aterosclerosis es una de las principales causas de morbilidad y mortalidad en países desarrollados que presenta varias similitudes histopatológicas con la inflamación crónica. Para entender el papel que desempeña en su desarrollo el eje CCL11/CCR3, se generaron ratones deficientes en apolipoproteína E (apoE−/−) y el receptor de eotaxina-1 (CCR3; apoE−/−CCR3−/−). Se evaluó el impacto de una dieta aterogénica en la formación de la placa de ateroma en ratones apoE−/−CCR3+/+ y ratones apoE−/−CCR3−/−. Los ratones apoE−/−CCR3+/+ y apoE−/−CCR3−/− sometidos a una dieta hipercolesterolémica durante dos meses mostraron un claro desarrollo de lesión aterosclerótica en aorta caracterizada por un mayor contenido en colágeno, core necrótico, células de la musculatura lisa vascular, macrófagos y linfocitos T que aquellos sometidos a una dieta control. Los ratones apoE−/−CCR3−/− sometidos a dieta aterogénica mostraron mayor lesión aterosclerótica y mayor contenido en colágeno e infiltración de macrófagos y linfocitos T que los ratones que presentaban el receptor CCR3 (apoE−/−CCR3+/+). La expresión de eotaxina-1 en la lesión de los ratones apoE−/−CCR3+/+ en ambiente hipercolesterolémico fue mucho mayor que la detectada en los ratones apoE−/−CCR3−/− en las mismas condiciones. Esto sugieren que el eje eotaxina-1 (CCL11)/CCR3 podría ejercer un efecto protector en el desarrollo del proceso aterosclerótico. El aneurisma aórtico abdominal (AAA) es una importante causa de muerte en nuestro país, afectando principalmente a varones mayores de 65 años de edad. Actualmente no existe tratamiento preventivo ya que la falta de conocimiento sobre los mecanismos responsables de la iniciación, propagación y ruptura del AAA aún hoy en día son desconocidos. Uno de los causantes de la patología es la angiotensina-II (Ang-II), principal péptido efector del sistema renina-angiotensina, la cual es utilizada in vivo para inducir la enfermedad en modelos experimentales de ratones apoE−/−. En el estudio se ha empleado el fármaco antihipertensivo losartán, el cual actúa como antagonista selectivo del receptor de Ang-II de tipo 1 (AT1), a la dosis de 30 mg/kg/día. Tras 28 días de tratamiento, se pudo comprobar cómo la dosis de 30 mg/kg/día lograba atenuar la formación, el desarrollo y el diámetro del AAA inducida con Ang-II, así como la infiltración de linfocitos T, macrófagos, la neovascularización, células CXCR6+ y la expresión de ARNm de quimiocinas y mediadores proangiogénicos como Mcp-1/Ccl2, Vegf, Cxcl16 y su receptor Cxcr6. Estos resultados nos inducen a sugerir que una monoterapia con losartán a una dosis de 30 mg/kg/día podría ser susceptible de convertirse en una nueva y segura herramienta terapéutica en el control del AAA. Para estudiar el papel del eje CXCL16/CXCR6 en el desarrollo del AAA, se generaron ratones con el receptor CXCR6 no funcional (apoE−/−CXCR6GFP/GFP). En aquellos animales deficientes en la función de CXCR6 se observaron resultados similares a los ratones apoE−/− tratados con losartán. Por tanto, la modulación farmacológica del eje CXCL16/CXCR6 podría impactar beneficiosamente en el desarrollo del AAA asociado a alteraciones del sistema renina-angiotensina.Primary hypercholesterolemia (PH) is a metabolic disease characterized by high circulating levels of low-density lipoproteins (LDL), as well as a low-grade of systemic inflammation, which can eventually lead to the development of atherosclerosis. Due to the limited information of the immunological component of the disease, we have characterized the behavior of different immunological cell populations, the soluble inflammatory mediators and their possible consequences in PH. Whole blood of 21 age-matched controls and 22 patients with PH was used. In all of them, the blood was analyzed by flow cytometry to determine platelet, and leukocyte activation, percentage of leukocyte subpopulations, the formation of platelet-leukocyte aggregates as well as the circulating levels of different soluble inflammatory mediators. PH patients presented a higher percentage of type 3 monocytes (Mon 3), Th2 and Th17 lymphocytes, activated platelets, and leukocytes than controls. Similarly, circulating interleukin (IL)-8/CXCL8, CCL2, fractalkine/CX3CL1, and IL-6 levels positively correlated with key lipid features of PH: apolipoprotein B (apoB), LDL and total cholesterol (TC); whereas negative correlations were found for IL-4 and IL-10. Endothelial dysfunction is one of the first stages of atherogenesis, promoting the adhesion and the subsequent leukocyte migration to the inflammatory focus. Tumor necrosis factor α (TNFα) is one of the central cytokines in hypercholesterolemia; for this reason, the functional consequences of high levels of TNFα in PH patients have been studied. Thus, platelet-leukocyte and leukocyte adhesion on the arterial endothelium stimulated or not with TNFα have been assessed using a flow chamber. Indeed, greater leukocyte adherence to the dysfunctional endothelium was observed in patients than in control subjects suggesting a possible link between systemic inflammation and the development of cardiovascular diseases in this metabolic disorder. To explore whether the intake of an oral fat load (OFL) with a commercial preparation of long-chain triglycerides (ω6/ω3 ratio >20/1) has an impact on inflammation, this OFL was administered to PH patients, and the different parameters were determined 4 hours later. A decrease in platelet activation as well as in leukocyte adhesion to the dysfunctional endothelium was detected. Therefore, the administration of this OFL may have a beneficial impact on the control of the pro-thrombotic and proinflammatory state in patients with PH. Likewise, high circulating levels of eotaxin-1/CCL11 and eotaxin-3/CCL26 were detected in patients with PH. Both mediators signal exclusively through the CCR3 receptor, which is expressed constitutively in eosinophils. Therefore, an in-depth study of the expression of the receptor in different leukocyte populations was carried out, both in PH patients and in control volunteers. Atherosclerosis is one of the leading causes of morbidity and mortality in developed countries that presents several histopathological similarities with chronic inflammation. To understand the role of the CCL11/CCR3 axis in its development, mice deficient in apolipoprotein E (apoE−/−) and the eotaxin-1 receptor (CCR3; apoE−/−CCR3−/−) were generated. The impact on the atheroma plaque formation of an atherogenic diet was evaluated in apoE−/−CCR3+/+ and apoE−/−CCR3−/− mice. The apoE−/−CCR3+/+ and apoE−/−CCR3−/− mice under a hypercholesterolemic diet for two months showed a clear development of atherosclerotic lesion in the aorta characterized by a higher content of collagen, necrotic core, vascular smooth muscle cells, macrophages, and T lymphocytes than those subjected to a control diet. The apoE−/−CCR3−/− mice subjected to an atherogenic diet showed greater atherosclerotic lesion and higher collagen content and infiltration of macrophages and T lymphocytes than the mice that express the CCR3 receptor (apoE−/−CCR3+/+). The expression of eotaxin-1 in the lesion of the apoE−/−CCR3+/+ mice in a hypercholesterolemic environment was much higher than that detected in the apoE−/−CCR3−/− mice under the same conditions. This suggests that the eotaxin-1 (CCL11)/CCR3 axis may exert a protective effect in the development of the atherosclerotic process. Abdominal aortic aneurysm (AAA) is an important cause of death in developed countries, affecting mainly men over 65 years old. Currently, there is no preventive treatment because of the lack of knowledge regarding the mechanisms involved in AAA initiation, progression, and rupture. One of the causes of this pathology is linked to angiotensin-II (Ang-II), the main effector peptide of the renin-angiotensin system. Ang-II is used in vivo to induce the disease in experimental models of apoE−/− mice. The study has used the anti-hypertensive drug losartan, which acts as a selective antagonist of the Ang-II receptor type 1 (AT1), at a dose of 30 mg/kg/day. After 28 days of treatment, losartan was able to reduce Ang-II-induced AAA formation and diameter. The infiltration of T lymphocytes, macrophages, neovascularization, CXCR6+ cells, and the mRNA expression of pro-angiogenic mediators such as Mcp-1/Ccl2, Vegf, Cxcl16, and its receptor, Cxcr6 were clearly impaired. These results suggest that a monotherapy with losartan at a dose of 30 mg/kg/day may become a new and safe therapeutic tool in the control of AAA. In order to study the role of the CXCL16/CXCR6 axis in the development of AAA, mice deficient in CXCR6 receptor function (apoE−/−CXCR6GFP/GFP) were generated. In those animals deficient in CXCR6 functionality, similar results to those observed in apoE−/− mice treated with losartan were detected. Therefore, pharmacological modulation of CXCL16/CXCR6 axis may positively affect AAA development linked to disorders associated with the renin-angiotensin system

Increased dosage of tumor suppressors limits the tumorigenicity of iPS cells without affecting their pluripotency

Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a promising therapeutic tool for many diseases, including aged tissues and organs at high risk of failure. However, the intrinsic self-renewal and pluripotency of ES and iPS cells make them tumorigenic, and hence, the risk of tumor development hinders their clinical application. Here, we present a novel approach to limit their tumorigenicity and increase their safety through increased copy number of tumor suppressors. iPS containing an extra copy of the p53 or Ink4a/ARF locus show normal pluripotency, as determined by in vitro and in vivo differentiation assays. Yet, while retaining full pluripotency, they also possess an improved engagement of the p53 pathway during teratocarcinoma formation, which leads to a reduced tumorigenic potential in various in vitro and in vivo assays. Furthermore, they show an improved response to anticancer drugs, which could aid in their elimination in case tumors arise with no adverse effects on cell function or aging. Our system provides a model for studying tumor suppressor pathways during reprogramming, differentiation, and cell therapy applications. This offers an improved understanding of the pathways involved in tumor growth from engrafted pluripotent stem cells, which could facilitate the use of ES and iPS cells in regenerative medicine

Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort.

Objective:To develop and validate a prediction model (STOMA score) for 1-year stoma-free survival in patients with rectal cancer (RC) with anastomotic leakage (AL).Background:AL after RC resection often results in a permanent stoma.Methods:This international retrospective cohort study (TENTACLE-Rectum) encompassed 216 participating centres and included patients who developed AL after RC surgery between 2014 and 2018. Clinically relevant predictors for 1-year stoma-free survival were included in uni and multivariable logistic regression models. The STOMA score was developed and internally validated in a cohort of patients operated between 2014 and 2017, with subsequent temporal validation in a 2018 cohort. The discriminative power and calibration of the models' performance were evaluated.Results:This study included 2499 patients with AL, 1954 in the development cohort and 545 in the validation cohort. Baseline characteristics were comparable. One-year stoma-free survival was 45.0% in the development cohort and 43.7% in the validation cohort. The following predictors were included in the STOMA score: sex, age, American Society of Anestesiologist classification, body mass index, clinical M-disease, neoadjuvant therapy, abdominal and transanal approach, primary defunctioning stoma, multivisceral resection, clinical setting in which AL was diagnosed, postoperative day of AL diagnosis, abdominal contamination, anastomotic defect circumference, bowel wall ischemia, anastomotic fistula, retraction, and reactivation leakage. The STOMA score showed good discrimination and calibration (c-index: 0.71, 95% CI: 0.66-0.76).Conclusions:The STOMA score consists of 18 clinically relevant factors and estimates the individual risk for 1-year stoma-free survival in patients with AL after RC surgery, which may improve patient counseling and give guidance when analyzing the efficacy of different treatment strategies in future studies