Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Volatile Compound Screening Using HS-SPME-GC/MS on Saccharomyces eubayanus Strains under Low-Temperature Pilsner Wort Fermentation

The recent isolation of the yeast Saccharomyces eubayanus has opened new avenues in the brewing industry. Recent studies characterized the production of volatile compounds in a handful set of isolates, utilizing a limited set of internal standards, representing insufficient evidence into the ability of the species to produce new and diverse aromas in beer. Using Headspace solid-phase microextraction followed by gas chromatography-mass spectrometry (HS-SPME-GC-MS), we characterized for the first time the production of volatile compounds in 10 wild strains under fermentative brewing conditions and compared them to a commercial lager yeast. S. eubayanus produces a higher number of volatile compounds compared to lager yeast, including acetate and ethyl esters, together with higher alcohols and phenols. Many of the compounds identified in S. eubayanus are related to fruit and floral flavors, which were absent in the commercial lager yeast ferment. Interestingly, we found a significant strain &times; temperature interaction, in terms of the profiles of volatile compounds, where some strains produced significantly greater levels of esters and higher alcohols. In contrast, other isolates preferentially yielded phenols, depending on the fermentation temperature. This work demonstrates the profound fermentation product differences between different S. eubayanus strains, highlighting the enormous potential of this yeast to produce new styles of lager beers

Características operativas de dos pruebas ELISAs para la detección de anticuerpos de VHE en donantes del banco de sangre de referencia de Bogotá – Colombia

Introducción: El virus de la Hepatitis E (VHE), generalmente es transmitido por vía fecal-oral y por zoonosis, sin embargo, se ha identificado una nueva vía de es la transfusión de productos sanguíneos contaminados siendo un riesgo potencial para la seguridad de la sangre. En Colombia, no existen estudios que validen el uso de las diferentes herramientas diagnosticas utilizadas en el tamizaje de VHE y que así mismo documenten la seroprevalencia en donantes de sangre. Objetivo: Comparar el desempeño de dos pruebas de tamizaje comerciales Dia.pro y Mikrogen frente a un Gold Estándar para la detección de anticuerpos IgG e IgM del Virus de Hepatitis E en donantes de Sangre de un banco de referencia para Bogotá. Metodología: Se obtuvieron 766 muestras de suero de donantes de sangre entre el año 2015-2017. Se realizaron pruebas serológicas para la detección de anticuerpos anti-VHE de tipo IgG e IgM a partir de dos ensayos comerciales. Además, se aplicó westerblot que es una prueba más sensible considerada de referencia para anticuerpos anti VHE. Resultados: Se analizó un total de 766 sueros de donantes de sangre de las cuales 16 fueron positivas (Prevalencia del 2.09%; IC95%: 1.2% to 3.4%) para el anticuerpo IgM y 47 fueron positivas (Prevalencia = 6.14%; IC95%: 4.54% to 8.08%) para el anticuerpo IgG. Al comparar las AUC de Dia.pro y Mikrogen se ha considerado que ambas curvas de las características de funcionamiento están correlacionadas. No se encontraron diferencias estadísticamente significativas Conclusiones: Este trabajo es el primer análisis comparativo de la eficiencia de dos pruebas comerciales para detección de anticuerpos IgM e IgG contra el virus de la hepatitis E en población donante de sangre, sugiriendo la mejor herramienta de tamizaje diagnóstico para estimar la seroprevalencia del VHE. En cuanto a la comparación entre pruebas se confirma que la seroprevalencia del virus, es altamente influenciado por las características analíticas de las pruebas serológicas y que la circulación del virus de la hepatitis E en donantes de sangre esta latente en Bogotá y, por ello, es necesario tomar medidas de contingencia.Magíster en EpidemiologíaMaestrí

Effects of Chronic Carvedilol Administration on Blood Pressure Variability and Target Organ Injury in Rats with Sinoaortic Denervation

Background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both inhypertensive and normotensive subjects, so its reduction should be considered as a new therapeutic goal.Objective: The aim of this study was to evaluate the effect of long-term oral carvedilol treatment on blood pressure, bloodpressure variability and target organ injury in the left ventricle and thoracic aorta in a model of blood pressure liability.Methods: Twelve male Wistar rats submitted to sinoaortic denervation were treated during 8 weeks with a single dose ofcarvedilol 30 mg/kg or vehicle. At the end of treatment, echocardiographic evaluation and blood pressure and short-term variabilitymeasurements were performed. Left ventricular and thoracic aortic weights were determined and histological sampleswere prepared from both tissues. Metalloproteinase MMP-2 and transforming growth factor b (TGF-b) were quantified in theleft ventricle and thoracic aorta.Results: Carvedilol reduced systolic blood pressure and its variability in sinoaortic-denervated rats compared with the controlgroup (126±5 vs. 142±11 mmHg, p<0.05; SD: 2.9±0.5 vs. 6.0±0.5 mmHg; p<0.05). A lower amount of connective tissue wasfound in carvedilol-treated animals. The expression of TGF-b decreased in both organs after carvedilol treatment.Conclusions: Chronic carvedilol treatment significantly reduces systolic blood pressure and its short-term variability insinoaortic-denervated rats, decreasing the degree of left ventricular fibrosis.El objetivo del presente trabajo fue evaluar el efecto del tratamiento a largo plazo con carvedilol sobre la presión arterial, la variabilidad a corto plazo de la presión arterial y el daño de órgano blanco en ventrículo izquierdo y aorta torácica en el modelo de la labilidad de presión. Se incluyeron 12 ratas Wistar macho sometidas a desnervación sinoaórtica, las cuales fueron tratadas durante 8 semanas con una única administración diaria de carvedilol 30 mg/kg o vehículo. Al final del tratamiento se realizó la medición de la presión arterial y de su variabilidad a corto plazo y la evaluación ecocardiográfica. La variación a corto plazo fue establecida por el desvío estándar (DE) del registro contínuo de la presión arterial directa. Se determinó el peso del ventrículo y de la aorta torácica y se realizaron preparados histológicos sobre ambos tejidos. Finalmente se cuantificó la expresión de proteínas profibróticas, metaloproteinasas MMP-2 y factor de crecimiento transformante β (TGF-b) en homogenatos de ventrículo izquierdo y aorta torácica. El tratamiento oral con carvedilol redujo la presión arterial sistólica de ratas SAD en comparación con el control (126±5 vs. 142±11 mmHg, p<0,05). La variabilidad de la presión arterial  fue significativamente inferior en ratas SAD tratadas con carvedilol en comparación con el control (DE: 2,9±0,5 vs. 6,0±0,5 mmHg; p<0,05). No se documentaron diferencias significativas en el peso del ventrículo izquierdo y de la aorta torácica entre las ratas DSA tratadas crónicamente con carvedilol respecto del grupo control. Tampoco se encontraron diferencias en los parámetros ecocardiográficos entre el grupo carvedilol y el control. Los estudios histológicos evidenciaron menor cantidad de tejido conectivo en ratas tratadas con carvedilol en comparación con el grupo control. La expresión de TGF-b en homogenatos de ventrículo izquierdo y aorta fue menor en ratas SAD tratadas con carvedilol respecto del grupo que recibió vehículo. En conclusión, el tratamiento crónico con carvedilol reduce de manera significativa la presión arterial y la variabilidad de la presión arterial a corto plazo en ratas con SAD, disminuyendo el grado de fibrosis del ventrículo izquierdo.

Management of eosinophil-associated inflammatory diseases: the importance of a multidisciplinary approach

Elevated eosinophil counts in blood and tissue are a feature of many pathological processes. Eosinophils can migrate and accumulate in a wide variety of tissues and, by infiltrating a target organ, can mediate the development of several inflammatory diseases. The normalization of eosinophilia is a common biomarker of a treatable trait and can also be used as a prognostic and predictive biomarker since it implies a reduction in type 2 inflammation that contributes to disease pathogenesis. Biological therapies targeting this cell type and its proinflammatory mediators have been shown to be effective in the management of a number of eosinophilic diseases, and for this reason they constitute a potential common strategy in the treatment of patients with various multimorbidities that present with type 2 inflammation. Various biological options are available that could be used to simultaneously treat multiple target organs with a single drug, bearing in mind the need to offer personalized treatments under the umbrella of precision medicine in all patients with eosinophil-associated diseases (EADs). In addition to reviewing these issues, we also discuss a series of perspectives addressing the management of EAD patients from a multidisciplinary approach, with the collaboration of health professionals from different specialties who manage the different multimorbidities that frequently occur in these patients. We examine the basic principles of care that this multidisciplinary approach must cover and present a multidisciplinary expert opinion regarding the ideal management of patients with EADs, from diagnosis to therapeutic approach and follow-up

Microplastic concentration, distribution and dynamics along one of the largest Mediterranean-climate rivers: A whole watershed approach

Microplastics (MPs) have been recognized as one of the most ubiquitous environmental pollutants globally. They have been found in all ecosystems studied to date, threatening biological diversity, ecosystem functioning and human health. The present study aimed to elucidate the environmental and anthropogenic drivers of MP dynamics in the whole catchment of the Biotin) river, one of the largest rivers in South America. MP concentration and characteristics were analysed in 18 sites subjected to different sources of pollution and other human-related impacts. The sampling sites were classified in relation to altitudinal zones (highland, midland and lowland) and ecosystem types (fluvial and reservoir), and different water and territorial environmental variables were further collated and considered for analysis. Seven types of micmplastic polymers were identified in the samples analysed, with a catchment mean (+/- SE) MP concentration of 22 +/- 0.4 particles m(-3) 5 and MP presence being significantly higher in lowlands (26 +/- 2 particle m(-3)) and in reservoirs (42 +/- 14 particle m(-3)). The most abundant type of MP was fragments (84%), with a mean concentration of 37 +/- 6 particles m(-3). Overall, MP concentrations were low compared to those found in other studies, with a strong influence of human population size