GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is a 36-center unmasked, parallel treatment group, randomized controlled trial evaluating four diabetes medications added to metformin in people with type 2 diabetes (T2DM). We report baseline characteristics and compare GRADE participants to a National Health and Nutrition Examination Survey (NHANES) cohort. RESEARCH DESIGN AND METHODS Participants were age ‡30 years at the time of diagnosis, with duration of T2DM <10 years, HbA 1c 6.8-8.5% (51-69 mmol/mol), prescribed metformin monotherapy, and randomized to glimepiride, sitagliptin, liraglutide, or insulin glargine. RESULTS At baseline, GRADE's 5,047 randomized participants were 57.2 6 10.0 years of age, 63.6% male, with racial/ethnic breakdown of 65.7% white, 19.8% African American, 3.6% Asian, 2.7% Native American, 7.6% other or unknown, and 18.4% Hispanic/ Latino. Duration of diabetes was 4.2 6 2.8 years, with mean HbA 1c of 7.5 6 0.5% (58 6 5.3 mmol/mol), BMI of 34.3 6 6.8 kg/m 2 , and metformin dose of 1,944 6 204 mg/day. Among the cohort, 67% reported a history of hypertension, 72% a history of hyperlipidemia, and 6.5% a history of heart attack or stroke. Applying GRADE inclusion criteria to NHANES indicates enrollment of a representative cohort with T2DM on metformin monotherapy (NHANES cohort average age, 57.9 years; mean HbA 1c , 7.4% [57 mmol/mol]; BMI, 33.2 kg/m 2 ; duration, 4.2 6 2.5 years; and 7.2% with a history of cardiovascular disease). CONCLUSIONS The GRADE cohort represents patients with T2DM treated with metformin requiring a second diabetes medication. GRADE will inform decisions about the clinical effectiveness of the addition of four classes of diabetes medications to metformin. The optimal medication management of hyperglycemia in type 2 diabetes (T2DM) is not established. In addition to lifestyle intervention, metformin is the recommended initial medication in T2DM due to its glycemic effectiveness, lack of associated hypoglycemia or weight gain, low cost, and evidence of long-term benefit and safety

Learning about a moving visual stimulus was examined in zebrafish larvae using an automated imaging system and a t1-t2 design. In three experiments, zebrafish larvae were exposed to one of two inputs at t1 (either a gray bouncing disk or an identical but stationary disk) followed by a common test at t2 (the gray bouncing disk). Using 7 days post-fertilization (dpf) larvae and 12 stimulus exposures, Experiment 1 established that these different treatments produced differential responding to the moving disk during testing. Larvae familiar with the moving test stimulus were significantly less likely to be still in its presence than larvae that had been exposed to the identical but stationary stimulus. Experiment 2 confirmed this result in 7 dpf larvae and extended the finding to 5 and 6 dpf larvae. Experiment 3 found differential responding to the moving test stimulus with 4 or 8 stimulus exposures but not with just one exposure in 7 dpf larvae. These results provide evidence for learning in very young zebrafish larvae. The merits and challenges of the t1-t2 framework to study learning are discussed.

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