A Simulation Study of an Inverse Controller for Closed and Semiclosed-Loop Control in Type 1 Diabetes

Background: Closed-loop control algorithms in diabetes aim to calculate the optimum insulin delivery to maintain the patient in a normoglycemic state, taking the blood glucose level as the algorithm's main input. The major difficulties facing these algorithms when applied subcutaneously are insulin absorption time and delays in measurement of subcutaneous glucose with respect to the blood concentration. Methods: This article presents an inverse controller (IC) obtained by inversion of an existing mathematical model and validated with synthetic patients simulated with a different model and is compared with a proportional-integral-derivative controller. Results: Simulated results are presented for a mean patient and for a population of six simulated patients. The IC performance is analyzed for both full closed-loop and semiclosed-loop control. The IC is tested when initialized with the heuristic optimal gain, and it is compared with the performance when the initial gain is deviated from the optimal one (±10%). Conclusions: The simulation results show the viability of using an IC for closed-loop diabetes control. The IC is able to achieve normoglycemia over long periods of time when the optimal gain is used (63% for the full closed-loop control, and it is increased to 96% for the semiclosed-loop control

The impact of telehealth remote patient monitoring on glycemic control in type 2 diabetes: a systematic review and meta-analysis of systematic reviews of randomised controlled trials

Background There is a growing body of evidence to support the use of telehealth in monitoring HbA1c levels in people living with type 2 diabetes. However, the overall magnitude of effect is yet unclear due to variable results reported in existing systematic reviews. The objective of this study is to conduct a systematic review and meta-analysis of systematic reviews of randomised controlled trials to create an evidence-base for the effectiveness of telehealth interventions on glycemic control in adults with type 2 diabetes. Methods Electronic databases including The Cochrane Library, MEDLINE, EMBASE, HMIC, and PsychINFO were searched to identify relevant systematic reviews published between 1990 and April 2016, supplemented by references search from the relevant reviews. Two independent reviewers selected and reviewed the eligible studies. Of the 3279 references retrieved, 4 systematic reviews reporting in total 29 unique studies relevant to our review were included. Both conventional pairwise meta-analyses and network meta-analyses were performed. Results Evidence from pooling four systematic reviews found that telehealth interventions produced a small but significant improvement in HbA1c levels compared with usual care (MD: -0.55, 95% CI: -0.73 to − 0.36). The greatest effect was seen in telephone-delivered interventions, followed by Internet blood glucose monitoring system interventions and lastly interventions involving automatic transmission of SMBG using a mobile phone or a telehealth unit. Conclusion Current evidence suggests that telehealth is effective in controlling HbA1c levels in people living with type 2 diabetes. However there is need for better quality primary studies as well as systematic reviews of RCTs in order to confidently conclude on the impact of telehealth on glycemic control in type 2 diabetes

In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern

Neutralization of pathogenic beta1-receptor autoantibodies by aptamers in vivo: the first successful proof of principle in spontaneously hypertensive rats

Autoantibodies (AABs) against the second extracellular loop of the beta1-receptor (beta1(II)-AABs) are found as a pathogenic driver in patients with idiopathic dilated cardiomyopathy, Chagas cardiomyopathy, peripartum cardiomyopathy, and myocarditis, and have been increasingly seen as a treatment target. We recently identified an aptamer (single short DNA strand) that specifically binds and neutralizes beta1(II)-AABs. Via application of this aptamer, a new treatment strategy for diseases associated with the cardio-pathogenic beta1(II)-AABs could be developed. Spontaneously hypertensive rats (SHR) positive for beta1(II)-AABs were treated five times at weekly intervals (bolus application of 2 mg/kg body weight followed by an infusion of the same amount over 20 min). SHR responded to aptamer treatment with a strong reduction in the cardio-pathogenic beta1(II)-AABs. The AABs did not substantially return within the study period. No signs for aptamer toxicity were observed by visual examination of the heart, liver, and kidney, or by measurement of plasma CK, ALT, and creatinine. The aptamer's potential for beta1(II)-AAB neutralization and consequently for cardiomyopathy treatment has been shown for the first time in vivo