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

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

The effects of runoff on the physiology of Enteromorpha intestinalis: implications for use as a bioindicator of freshwater and nutrient influx to estaurine and coastal areas

Southern California is a highly populated region with developed watersheds. Thus there is increased risk of pollution reaching coastal waters and estuaries: more runoff reaches marine environments in urbanized areas, and there is year-round influx of treated wastewater effluent entering a system typically exposed to freshwater during the rainy season. A major limitation of current methods of freshwater and nutrient measurement is the samples are discrete. Therefore an integrative way to quantify terrestrial inputs to marine communities is necessary. The green macroalga Enteromorpha intestinalis has the potential to be an indicator of water quality. This alga is tolerant of a variety of environmental conditions and responds to decreased salinity and increased nutrient supply on the cellular level.The focus of this project is to quantify the response of E. intestinalis to factors associated with terrestrial influx of freshwater and nutrients in order to assess its usefulness as a bioindicator. We will measure tissue water content and potassium concentration to examine short-term effects of reduced salinity, and nutrient content (nitrate, ammonium) of tissue and water to see how salinity decrease, temperature change and light availability affect nutrient uptake. Labeled nitrogen (15N) will be used to determine the preferred form of nitrogen (nitrate, ammonium) taken up. Finally, the natural abundance of stable isotopes (5N/'4 N) will be used to determine where the nutrients available to the algae come from (sewage, terrestrial or marine derived).The benefits from the results of this research include understanding how short-term environmental changes affect macroalgae, and learning about nutrient uptake and which sources of nutrients are most utilized by algae in the field. With these data we can begin development of a biological indicator to measure runoff in marine and estuarine environments, thus providing an inexpensive, easy way to measure water quality in areas subject to runoff influence

A Simple, Inexpensive, and Field-Relevant Microcosm Tidal Simulator for Use in Marsh Macrophyte Studies

Premise of the study: A microcosm unit with tidal simulation was developed to address the challenge of maintaining ecologically relevant tidal regimes while performing controlled greenhouse experiments on smooth cordgrass, Spartina alterniflora. Methods and Results: We designed a simple, inexpensive, easily replicated microcosm unit with tidal simulation and tested whether S. alterniflora growth in microcosms with tidal simulation was similar to that of tidally influenced plants in the field on Sapelo Island, Georgia. After three months of exposure to either natural or simulated tidal treatment, plants in microcosms receiving tidal simulation had similar stem density, height, and above- and belowground biomass to plants in field plots. Conclusions: The tidal simulator developed may provide an inexpensive, effective method for conducting studies on S. alterniflora and other tidally influenced plants in controlled settings to be used not only to complement field studies, but also in locations without coastal access

Land Use and Environmental Variables Influence Tetracycline-Resistant Bacteria Occurrence in Southeastern Coastal Plain Streams

The global presence of antimicrobial resistance (AMR) in aquatic systems has the potential to influence public health by reducing antibiotic efficacy, and the environment by altering the structure and activity of microbial communities. Wastewater treatment plant (WWTP) discharge, agricultural runoff, and variables such as precipitation, warm temperatures, and nutrient availability are thought to increase AMR occurrence in the environment. In this study, we examined relationships between tetracycline-resistant Escherichia coli counts and land use, precipitation, temperature, and nutrient availability within the Ogeechee River basin in Georgia. Due to its widespread use in agriculture and medicine, tetracycline was selected as a pathway for AMR occurrence in the study area. Tetracycline-resistant E. coli levels were compared across WWTP effluent, agricultural runoff, and reference sites over 13 wk. Discharge from WWTPs had tetracycline-resistant E. coli counts 2 to 50 times greater than reference sites. Tetracycline-resistant E. coli counts were positively correlated with temperature and precipitation, indicating that environmental factors and runoff were significant contributors to the presence of AMR in this study. Furthermore, increased precipitation appeared to enhance the spatial scale of AMR in the Ogeechee River system; elevated levels of tetracycline-resistant E. coli occurred at reference sites after a major precipitation event, but not during drier months. Results from this study suggest that considering both environmental conditions and land use could be useful for managing AMR in surface waters. Core Ideas Agricultural runoff and wastewater effluent increased fecal bacteria in the river. Wastewater treatment plant (WWTP) discharge increased tetracycline-resistant bacteria levels. Bacteria with antimicrobial resistance were transported farther after heavy precipitation. Temperature and nutrients positively correlated with tetracycline-resistant bacteria. WWTP inputs to surface waters should be monitored for antimicrobial resistance

Evaluating Relationships between Mercury Concentrations in Air and in Spanish Moss

Measurement of mercury vapor is essential given that it is transported globally, and once deposited can be converted to methylmercury, a dangerous neurotoxin. A study was conducted in southeastern Georgia and northern Florida, USA to determine whether Spanish moss, an epiphytic vascular plant common to the southeastern United States, has the ability to retain mercury in its tissues over time, and to detect atmospheric mercury at relatively low concentrations from nonpoint sources. Spanish moss plants exposed to 10× and 100× ambient concentrations of mercury vapor increased tissue concentrations by 13.7 ± 11% and 74.1 ± 17% respectively, and then retained the mercury over two weeks following removal from the source. There was a strong trend of increasing Spanish moss mercury concentrations with increasing air concentration in resident populations across urban, rural inland, coastal and industrial sites. Transplanted Spanish moss around an industrial site contaminated with mercury exhibited a 164.8 ± 8.7% increase in mercury concentration after two weeks. Mercury concentration of Spanish moss transplanted to rural inland sites also increased after two weeks, while the change in transplant concentration at coastal sites was more variable. This study shows that Spanish moss possesses characteristics important for use as a bioindicator of atmospheric mercury, and can potentially be adapted as a tool for obtaining time-integrated atmospheric mercury data to add to existing atmospheric mercury monitoring programs

Using Spanish Moss to Quantify Atmospheric Mercury Concentrations

Abstract not available