Estrés celular y acción de antibióticos sobre bacterias productoras de toxinas

Escherichia coli productor de toxina Shiga (STEC) es un patógeno emergente transmitido por alimentos, asociado frecuentemente a casos de Síndrome Urémico Hemolítico (SUH). En Argentina es endémico con un promedio de 450 a 500 casos por año, siendo el país del mundo con mayor incidencia de esta enfermedad.STEC posee diversos factores de virulencia, pero la acción de la toxina Shiga (Stx) es determinante para la patología del SUH. Recientemente se ha descripto la capacidad de formar biofilms y esto podría ser considerado un factor de virulencia adicional como estrategia de supervivencia.Hasta el presente no existe una terapia específica para el tratamiento de las infecciones por STEC y aunque es susceptible a los antibióticos (ATBs) usados comunmente, la utilización de terapia antimicrobiana es controvertida debido al efecto sobre la inducción del ciclo lítico del fago que contiene los genes que codifican para Stx. Recientes publicaciones sugieren que los ATBs convencionales aumentan el riesgo de SUH en pacientes infectados con STEC debido a que desencadenan en estas bacterias una respuesta SOS que promueve la liberación de Stx. Se ha demostrado que ciertos ATBs no sólo inducen la replicación y expresión de los genes stx, sino que como consecuencia de la lisis bacteriana, también aumentan la liberación de Stx. Sin embargo, estudios clínicos han revelado resultados contradictorios y sigue siendo un tema muy controvertido.Cada vez hay más evidencias de que el mecanismo de muerte celular iniciada por algunos ATBs incluye la producción de especies reactivas del oxígeno (ERO) como mecanismo secundario al mecanismo principal, incluso existen antecedentes que han indicado que el estrés oxidativo constituye una posible causa del daño bacteriano generado por distintos antimicrobianos.En esta tesis doctoral se planteó como objetivo principal esclarecer aspectos metabólicos y fisiológicos en relación al estrés celular que sufren las células del biofilm de STEC al ser sometidas a diferentes condiciones de cultivo. Además, se propuso evaluar la existencia de factores que podrían modificar la liberación de Stx desde el biofilm y la acción de la toxina sobre células sensibles.Los resultados obtenidos permitieron demostrar que diferentes condiciones de cultivo tuvieron influencia sobre la formación del biofilm y se pudo observar que esta formación estuvo directamente relacionada al estrés oxidativo. En condiciones de cultivo que resultaron favorables para la formación del biofilms, como el agregado de glúcidos (glucosa, manosa y maltosa) o un medio reductor (con y sin agregado de azúcares), se evidenció una disminución de ERO y especies reactivas del nitrógeno (ERN) con niveles de enzimas antioxidantes tales como superóxido dismutasa (SOD) y catalasa (CAT) bajos. En condiciones de cultivo desfavorables como el uso de un agente estresante exógeno o en presencia de ATBs tales como ciprofloxacina (CIP), rifaximina (RIF) y fosfomicina (FOS), la biomasa del biofilms disminuyó; siendo CIP capaz de reducir la misma en mayor medida. También hubo una disminución en las ERO y ERN con aumentos marcados en la actividad de las enzimas SOD y CAT sugiriendo que el desarrollo del biofilm de STEC estaría influenciado por la producción de metabolitos oxidantes y la respuesta de las defensas antioxidantes. Los tres ATBs utilizados mostraron diferencias significativas tanto en la reducción del biofilm como en el desbalance oxidativo siendo más marcado este desbalance con CIP.El uso de secuestrantes utilizados para evaluar el estrés oxidativo causado por CIP en los biofilms de STEC, permitió observar una variación dosis dependiente de la biomasa del biofilm. En presencia de un secuestrante específico de anión superóxido como el Tirón, se evidenció un aumento significativo en la formación del biofilm en todas las concentraciones de CIP estudiadas con respecto al basal sin agregado de antioxidante. Glutatión (un antioxidante no enzimático preformado en las células) y ácido ascórbico (un compuesto capaz de oxidarse cediendo sus electrones y evitando la oxidación de otros compuestos) también disminuyeron el estrés oxidativo generado por CIP. La utilización de estos tres antioxidantes permitió observar un aumento en los niveles de nitritos lo cual indicaría que las ERN también estarían involucradas en la generación del estrés oxidativo inducido por CIP.Además, se evidenció que el biofilm de STEC fue capaz de liberar Stx y esto incrementó cuando éste fue expuesto a una condición estresante (agregado de CIP) ya que el efecto citotóxico de Stx sobre células sensibles como las Vero, aumentó significativamente con el incremento del estrés oxidativo. Se observaron diferencias en la liberación de toxina desde los biofilms de STEC expuestos a los ATBs utilizados, siendo mayor con CIP, mientras que RIF y FOS no modificaron la liberación de toxina o incluso en algunas concentraciones la disminuyeron. Estos resultados corroboran lo encontrado por otros investigadores en bacterias planctónicas quienes describen que los ATBs que actúan sobre la síntesis de ADN aumentan la producción de Stx, mientras que los que actúan sobre la síntesis de proteínas y de la pared celular inhiben la producción de Stx. Por otro lado, indican que la inducción de la replicación de profagos que contienen genes stx ocurre no solo en presencia de ATBs que interfieren con el ADN sino también bajo condiciones de estrés oxidativo. En este trabajo de tesis, la liberación de toxinas pudo ser revertida, al menos parcialmente por agentes exógenos secuestrantes o inhibidores de ERO con un marcado aumento de óxido nítrico, posiblemente porque este último reduce drásticamente la expresión de recA suprimiendo la respuesta SOS bacteriana inducida por agentes que dañan el ADN y de esta manera inhibe la replicación del fago y la expresión de Stx en STEC.En los distintos capítulos de esta tesis doctoral se comprueba el rol del estrés oxidativo en la formación del biofilm de STEC y la liberación de toxina Shiga, concluyendo que existe una relación entre ellos. El estudio de diferentes efectores implicados en la liberación de toxinas durante la formación de biofilms podría contribuir a una mejor comprensión de la patogénesis de STEC.publishedVersionFil: Villegas, Natalia Angel. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Paraje, María Gabriela. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Escuela de Biología; Argentina.Fil: Paraje, María Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Multidisciplinario de Biología Vegetal ; Argentina.Fil: Becerra, María Cecilia. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Ciencias Farmacéuticas; Argentina.Fil: Becerra, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Multidisciplinario de Biología Vegetal; Argentina.Fil: Genti de Raimondi, Susana Del Valle. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina.Fil: Genti de Raimondi, Susana Del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina.Fil: Smania, Andrea María. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.Fil: Smania, Andrea María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina.Fil: Demo, Mirta. Universidad Nacional de Río IV; Argentina.Tesis (Doctora en Ciencias Químicas) - - Universidad Nacional de Córdoba. Facultad de Ciencias Químicas, 201

Antioxidant status in rabbit aqueous humor after instillation of ascorbyl laurate-based nanostructures

The aim of this work was evaluate the antioxidant effect of ascorbyl laurate (ASC12) based nanostructures applied topically to the cornea of ocular normotensive and hypertensive rabbits. The ASC12 was chosen for its capacity to form liquid lyotropic crystal and keeps its free radical trapping power.MethodsThe hypertension model was performed in six rabbits and was obtained by the application of intracameral injections of alpha-chymotrypsin in the right eye. A single 50 mL dose of ascorbyl laurate coagel 2% w/v (COA-ASC12) was applied topically to the cornea of six normotensive and six hypertensive rabbits. The aqueous humor samples were obtained before and after instillation of COA-ASC12 at different times (2 h and 4 h). Antioxidant capacity was determined via the reduction reaction with iron and tripyridyltriazine (FRAP) and the total proteins were measured using the Bradford reagent.ResultsThe kinetic antioxidant capacity in the aqueous humor of normotensive and hypertensive rabbits showed a maxim increment at 4 hours instillation. Also, the antioxidant capacity in the aqueous humor of hypertensive rabbits was ten times lower than in normotensive rabbits. This type of nanostructures has the potential to significantly improve the topical formulation for the prophylaxis and treatment of several eye diseases.Fil: Angel Villegas, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Tartara, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Caballero, Gabriela. Universidad Nacional de Córdoba; ArgentinaFil: Campana, Vilma. Universidad Nacional de Córdoba; ArgentinaFil: Allemandi, Daniel Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Palma, Santiago Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentin

Relevance of biofilms in the pathogenesis of Shiga-toxin-producing Escherichia coli infection

The present study was designed to determine the relationships among biofilm formation, cellular stress and release of Shiga toxin (Stx) by three different clinical Shiga toxin-producing Escherichia coli (STEC) strains. The biofilm formation was determined using crystal violet stain in tryptic soy broth or thioglycollate medium with the addition of sugars (glucose or mannose) or hydrogen peroxide. The reactive oxygen species (ROSs) were detected by the reduction of nitro blue tetrazolium and reactive nitrogen intermediates (RNI) determined by the Griess assay. In addition, the activities of two antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), were studied. For the cytotoxicity studies, Vero cells were cultured with Stx released of STEC biofilms. The addition of sugars in both culture mediums resulted in an increase in biofilm biomass, with a decrease in ROS and RNI production, low levels of SOD and CAT activity, and minimal cytotoxic effects. However, under stressful conditions, an important increase in the antioxidant enzyme activity and high level of Stx production were observed. The disturbance in the prooxidantantioxidant balance and its effect on the production and release of Stx evaluated under different conditions of biofilm formation may contribute to a better understanding of the relevance of biofilms in the pathogenesis of STEC infection.Fil: Angel Villegas, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina;Fil: Baronetti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas.Centro Científico Tecnológico - CONICET - Cordoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina;Fil: Albesa, Inés. Universidad Nacional de Cordoba. Facultad de Cs.Quimicas; Argentina;Fil: Polifroni, Rosana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Nacional Patagonico; Argentina;Fil: Parma, Alberto Ernesto. Universidad Nacional del Centro de la Provincia de Bs.as.. Facultad de Cs.veterinarias. Departamento de Sanidad Animal y Medicina Preventiva. Laboratorio de Inmunoquimica y Biotecnologia; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;Fil: Etcheverría, Analía Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina;Fil: Becerra, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina;Fil: Padola, Nora Lía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina;Fil: Paraje, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina

DESIGN AND ANALYSIS OF AN EFFICIENT GLAUCOMA MODEL FOR EVALUATION OF PHARMACOLOGICAL TRIALS

Glaucoma is a multifactorial progressive optic neuropathy whose main risk factor is intraocular hypertension (IOH). It generates a loss of nerves and is the primary cause of irreversible blindness worldwide. The objective of this work was to develop a glaucoma model in rabbits and analyze the anatomical, functional and biochemical changes over time through intraocular pressure (IOP), electroretinography (ERG), and antioxidant capacity with FRAP essay. in aqueous humor (AH), and histopathology with quantification of retinal ganglion cells (RGC). 24 female New Zealand white rabbits were used. In 12 animals, glaucoma was induced by injection of ∝-chymotrypsin. During the postoperative period, the treatment and control groups were examined weekly. 7 days after surgery, IOP (mmHg) was 18.30 ± 1.75 in the treatment group and 13.59 ± 0.63 in the control (p<0.02). The most important rise was at 14 days (treatment 27 ± 2.64 vs. controls 15.78 ± 0.86) (p<0.001), remaining stable thereafter. In the ERG, the analysis of the latency of A and B waves in ms with a stimulus intensity of 15 LUX showed a difference between treatment and controls (p ≤ 0.05). The FRAP values (µM FeSO4 /mg of proteins) were 520.3 ± 44 in the treatment group, and 2851.3 ± 178.7 in the control (p<0.0001). The RGC count per field was 15 ± 2.20 in the control group and 5.52 ± 0.77 in the treatment group (p<0.001). The glaucoma model enabled the analysis of anatomical, functional, and biochemical changes as a function of time

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Red “Universidad, género, docencia e igualdad”

La Red de investigación en docencia universitaria “Universidad, docencia, genero e igualdad” persigue avanzar en la calidad e innovación de las enseñanzas universitarias a partir de la inclusión de la perspectiva de género. Se busca dar cumplimiento a las directrices generales de los nuevos planes de estudio respecto del principio de igualdad de oportunidades entre hombres y mujeres en la formación universitaria (Real Decreto 1393/2007. BOE nº 260, 30 de octubre de 2007). En la quinta edición de la Red, y dada su composición multidisciplinar, se ha trabajado en tres líneas de investigación: 1) mantenimiento del “Portal web con recursos docentes con perspectiva de género”, proyecto financiado por el Instituto de la Mujer (PACUI, 2012) e iniciado en el curso 2012-2013; 2) desarrollo de la primera versión de “iLengUA”, una herramienta informática para un discurso inclusivo e igualitario; y 3) diseño de una Guía de recomendaciones para la inclusión de la perspectiva de género en la docencia universitaria

Long-term outcomes of the global tuberculosis and COVID-19 co-infection cohort

Background: Longitudinal cohort data of patients with tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are lacking. In our global study, we describe long-term outcomes of patients affected by TB and COVID-19. Methods: We collected data from 174 centres in 31 countries on all patients affected by COVID-19 and TB between 1 March 2020 and 30 September 2022. Patients were followed-up until cure, death or end of cohort time. All patients had TB and COVID-19; for analysis purposes, deaths were attributed to TB, COVID-19 or both. Survival analysis was performed using Cox proportional risk-regression models, and the log-rank test was used to compare survival and mortality attributed to TB, COVID-19 or both. Results: Overall, 788 patients with COVID-19 and TB (active or sequelae) were recruited from 31 countries, and 10.8% (n=85) died during the observation period. Survival was significantly lower among patients whose death was attributed to TB and COVID-19 versus those dying because of either TB or COVID-19 alone (p&lt;0.001). Significant adjusted risk factors for TB mortality were higher age (hazard ratio (HR) 1.05, 95% CI 1.03-1.07), HIV infection (HR 2.29, 95% CI 1.02-5.16) and invasive ventilation (HR 4.28, 95% CI 2.34-7.83). For COVID-19 mortality, the adjusted risks were higher age (HR 1.03, 95% CI 1.02-1.04), male sex (HR 2.21, 95% CI 1.24-3.91), oxygen requirement (HR 7.93, 95% CI 3.44-18.26) and invasive ventilation (HR 2.19, 95% CI 1.36-3.53). Conclusions: In our global cohort, death was the outcome in &gt;10% of patients with TB and COVID-19. A range of demographic and clinical predictors are associated with adverse outcomes

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

New Century, Old Disparities: Gender and Ethnic Wage Gaps in Latin America

This paper surveys gender and ethnic wage gaps in 18 Latin American countries, decomposing differences using matching comparisons as a non-parametric alternative to the Blinder-Oaxaca (BO) decomposition. It is found that men earn 9-27 percent more than women, with high cross-country heterogeneity. The unexplained pay gap is higher among older, informal and self-employed workers and those in small firms. Ethnic wage differences are greater than gender differences, and educational attainment differentials play an important role in explaining the gap. Higher ethnic wage gaps are found among males, singleincome generators of households and full-time workers, and in rural areas. An important share of the ethnic wage gap is due to the scarcity of minorities in highpaid positions