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OBJECTIVE--To evaluate the effect of continuous glucose monitoring (CGM) on the frequency of severe hypoglycemia (SH) in patients with established hypoglycemia unawareness. RESEARCH DESIGN AND METHODS--We conducted a retrospective audit of 35 patients with type 1 diabetes and problematic hypoglycemia unawareness, despite optimized medical therapy (continuous subcutaneous insulin infusion/multiple daily insulin injections), who used CGM for >1 year. RESULTS--Over a 1-year follow-up period, the median rates of SH were reduced from 4.0 (interquartile range [IQR] 0.75-7.25) episodes/patient-year to 0.0 (0.0-1.25) episodes/patient-year (P < 0.001), and the mean (±SD) rates were reduced from 8.1 ± 13 to 0.6 ± 1.2 episodes/year (P = 0.005). HbA[sub 1c] was reduced from 8.1 ± 1.2% to 7.6 ± 1.0% over the year (P = 0.005). The mean Gold score, measured in 19 patients, did not change: 5.1 ± 1.5 vs. 5.2 ± 1.9 (P = 0.67). CONCLUSIONS--In a specialist experienced insulin pump center, in carefully selected patients, CGM reduced SH while improving HbA[sub 1c] but failed to restore hypoglycemia awareness. [ABSTRACT FROM AUTHOR]

TCR-gene-transfer is an efficient strategy to produce therapeutic T cells of defined antigen specificity. However, there are substantial variations in the cell surface expression levels of human TCRs, which can impair the function of engineered T cells. Here we demonstrate that substitutions of 3 amino acid residues in the framework of the TCR variable domains consistently increase the expression of human TCRs on the surface of engineered T cells.The modified TCRs mediate enhanced T cell proliferation, cytokine production and cytotoxicity, while reducing the peptide concentration required for triggering effector function up to 3000-fold. Adoptive transfer experiments in mice show that modified TCRs control tumor growth more efficiently than wild-type TCRs. Our data indicate that simple variable domain modifications at a distance from the antigen-binding loops lead to increased TCR expression and improved effector function. This finding provides a generic platform to optimize the efficacy of TCR gene therapy in humans. Increasing TCR cell surface expression can potentiate T cell responses to low-concentrations of antigen. Here the authors identify aminoacids in human TCR variable domains that impact its surface expression, and demonstrate how editing these residues can improve T cell activation and effector function without altering antigen specificity. [ABSTRACT FROM AUTHOR]