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Health related quality of life (HRQoL) is one of the most important outcomes to measure effectiveness of an intervention, especially for islet transplantation in which benefits should outweigh risks of long-term immunosuppression. This study aimed to evaluate long-term effects of islet transplantation and to outline possible influential factors.Forty islet transplant recipients who completed 344 Health Status Questionnaires (HSQ 2.0) and 384 Diabetes Quality of Life Questionnaires (DQoL) between 2000 and 2007 were retrospectively reviewed. Assessments were analyzed in pretransplantation period, then every 3 months after the first infusion for 18 months and every 6 months thereafter. The mean follow-up posttransplantation was 40.8±21.9 months (9–72 months).Sustained improvement in DQoL-impact score was observed at all time-points posttransplantation. Similarly, worry and satisfaction scales were significantly better than pretransplant evaluation for most time-points. Four of eight HSQ 2.0 scales demonstrated a significant improvement at some time-points. Longitudinal analysis, after adjustments for potential confounding factors, showed significantly sustained improvement in impact scale up to 72 months. Longer diabetes duration, higher insulin dosage, and occurrence of adverse events had negative effects on HRQoL. Single islet infusion or islet after kidney transplant recipients showed the lowest values in HSQ 2.0. In contrast, subjects on exenatide therapy had significantly higher HSQ 2.0 scores.Islet transplantation is associated with long-term improvement in HRQoL. Exenatide usage had a positive effect whereas single islet infusion, islet after kidney transplantation, longer diabetes duration, higher insulin dosage, and adverse events had a negative impact on HRQoL scores.