Model Free iPID Control for Glycemia Regulation of Type-1 Diabetes.

OBJECTIVE: The objective is to design a fully automated glycemia controller of Type-1 Diabetes (T1D) in both fasting and postprandial phases on a large number of virtual patients. METHODS: A model-free intelligent proportional-integral-derivative (iPID) is used to infuse insulin. The feasibility of iPID is tested in silico on two simulators with and without measurement noise. The first simulator is derived from a long-term linear time-invariant model. The controller is also validated on the UVa/Padova metabolic simulator on 10 adults under 25 runs/subject for noise robustness test. RESULTS: It was shown that without measurement noise, iPID mimicked the normal pancreatic secretion with a relatively fast reaction to meals as compared to a standard PID. With the UVa/Padova simulator, the robustness against CGM noise was tested. A higher percentage of time in target was obtained with iPID as compared to standard PID with reduced time spent in hyperglycemia. CONCLUSION: Two different T1D simulators tests showed that iPID detects meals and reacts faster to meal perturbations as compared to a classic PID. The intelligent part turns the controller to be more aggressive immediately after meals without neglecting safety. Further research is suggested to improve the computation of the intelligent part of iPID for such systems under actuator constraints. Any improvement can impact the overall performance of the model-free controller. SIGNIFICANCE: The simple structure iPID is a step for PID-like controllers since it combines the classic PID nice properties with new adaptive features.

Manual Closed-Loop Insulin Delivery Using a Saddle Point Model Predictive Control Algorithm: Results of a Crossover Randomized Overnight Study.

BACKGROUND: The purpose was to assess the efficacy of a new closed-loop algorithm (Saddle Point Model Predictive Control, SP-MPC) in achieving nocturnal normoglycemia while reducing the risk of hypoglycemia in patients with type 1 diabetes. METHOD: In this randomized crossover study, 10 adult patients (mean hemoglobin A1c 7.35 ± 1.04%) were assigned to be treated overnight by open loop using sensor-augmented pump therapy (open-loop SAP) or manual closed-loop delivery. During closed loop, insulin doses were calculated using the SP-MPC algorithm and administered as manual boluses every 15 minutes from 9:00 pm to 8:00 am. Patients consumed a self-selected meal (65-125 g of carbohydrates) at 7:00 pm accompanied by their usual prandial bolus. Blood glucose was measured every 30 minutes. The primary endpoints were the time spent in target (70-145 mg/dl) and time spent below 70 mg/dl from 11:00 pm to 8:00 am. RESULTS: Time spent in target did not differ between closed-loop and open-loop SAP. The number of hypoglycemic events (<70 mg/dl) was reduced 2.8-fold in closed loop (n = 5, median = 0/patient/hour; interquartile range: 0-0.11) as compared to open-loop SAP (n = 14, median = 0.22/patient/hour, 0.02-0.22) ( P = .02). The area under the curve for sensor glucose values >145 mg/dl was significantly lower during closed-loop than during open-loop SAP ( P = .03) as well as HBGI ( P = .02). CONCLUSIONS: This pilot study suggests that the use of the SP-MPC algorithm may improve mean overnight glucose control and reduce the number of hypoglycemic events as compared to SAP therapy.

Insulin Pump Failures: Has There Been an Improvement? Update of a Prospective Observational Study.

BACKGROUND: Insulin pump failures had been assessed in our center by a prospective observational study from 2001 to 2007. The aim of this study was to update our data since 2008 and to determine whether there exist specific risk factors for insulin pump failures. METHODS: All insulin pump defects were prospectively collected between 2008 and 2013 in a monocentric cohort of 350 new pumps. Clinical consequences were recorded. Brand and model of pumps and type of defects and patients' characteristics (gender, type of diabetes, age at diabetes diagnosis, age at first pump, pump treatment duration, number of previous pumps, and number of previous pump failures) were tested for possible association with insulin pump failure. RESULTS: Malfunctions occurred in 239 (68%) pumps. The incidence rate was 33/100 pump-years. There were 28 (12%) complete failures, 17 (7%) alarms, 83 (35%) mechanical defects, and 105 (44%) minor defects. Survival curves did not differ according to pump brand and model. Hyperglycemia occurred in 2.9% of cases. In multivariate analysis, only patient age less than 40 years at the initiation of pump therapy was associated with higher risk of malfunction (hazard ratio 1.64; 95% confidence interval 1.19-2.24; P = 0.002). CONCLUSIONS: Pump malfunctions remain common with modern pumps. We report less complete failures than in our previous study. This could be because of improvement in quality of pumps or to our strategy of systematic screening and replacement in case of mechanical defects.

A Long-Term Model of the Glucose-Insulin Dynamics of Type 1 Diabetes.

A new glucose-insulin model is introduced which fits with the clinical data from in- and outpatients for two days. Its stability property is consistent with the glycemia behavior for type 1 diabetes. This is in contrast to traditional glucose-insulin models. Prior models fit with clinical data for a few hours only or display some nonnatural equilibria. The parameters of this new model are identifiable from standard clinical data as continuous glucose monitoring, insulin injection, and carbohydrate estimate. Moreover, it is shown that the parameters from the model allow the computation of the standard tools used in functional insulin therapy as the basal rate of insulin and the insulin sensitivity factor. This is a major outcome as they are required in therapeutic education of type 1 diabetic patients.

A closed-loop artificial pancreas using a proportional integral derivative with double phase lead controller based on a new nonlinear model of glucose metabolism.

BACKGROUND: Most closed-loop insulin delivery systems rely on model-based controllers to control the blood glucose (BG) level. Simple models of glucose metabolism, which allow easy design of the control law, are limited in their parametric identification from raw data. New control models and controllers issued from them are needed. METHODS: A proportional integral derivative with double phase lead controller was proposed. Its design was based on a linearization of a new nonlinear control model of the glucose-insulin system in type 1 diabetes mellitus (T1DM) patients validated with the University of Virginia/Padova T1DM metabolic simulator. A 36 h scenario, including six unannounced meals, was tested in nine virtual adults. A previous trial database has been used to compare the performance of our controller with their previous results. The scenario was repeated 25 times for each adult in order to take continuous glucose monitoring noise into account. The primary outcome was the time BG levels were in target (70-180 mg/dl). RESULTS: Blood glucose values were in the target range for 77% of the time and below 50 mg/dl and above 250 mg/dl for 0.8% and 0.3% of the time, respectively. The low blood glucose index and high blood glucose index were 1.65 and 3.33, respectively. CONCLUSION: The linear controller presented, based on the linearization of a new easily identifiable nonlinear model, achieves good glucose control with low exposure to hypoglycemia and hyperglycemia.

Markers of recurrence and long-term morbidity in craniopharyngioma: a systematic analysis of 171 patients.

CONTEXT: Craniopharyngiomas are often associated with an unfavorable prognosis, but data on their long-term consequences are sparse. OBJECTIVE: The aim of the study was to identify markers of recurrence and factors associated with compromised social rehabilitation and altered quality of life in a large cohort of patients with either childhood-onset (CO) or adult-onset craniopharyngioma. METHODS: Retrospective analysis was performed for 171 patients treated for craniopharyngioma in two academic centers in France between 1972 and 2009. For each subject, data were collected concerning clinical presentation, imaging features, visual sequelae, endocrine and metabolic impact, treatment modalities (surgery, radiotherapy), recurrence-free survival rate, and social insertion, as well as answers to the WHO-QOL BREF questionnaire. RESULTS: A total of 65 CO and 106 adult-onset patients were reviewed. If CO was diagnosed before the age of 10 yr, this was associated with a higher incidence of obesity, blindness, and panhypopituitarism, and only 40.7% of subjects had adequate work or school attendance compared to 72.4% of patients with later disease onset. Initial symptoms of intracranial hypertension (SIHT), pterional surgery, and multiple surgery were associated with obesity and poorer social insertion. No determinant of quality of life was identified. In the subgroup of patients treated in the 1990s and later, the progression rate was 59.4% in patients with residual tumor on magnetic resonance imaging compared with a 19.8% recurrence rate in the group with apparently complete resection. Recurrence/progression correlates significantly with male gender, early onset (before 10 yr), and SIHT, but only SIHT at presentation remained a significant predictor with multivariate analysis. CONCLUSIONS: Craniopharyngioma continues to be associated with severe outcomes. Higher morbidity rates are found in patients with early-onset disease (before 10 yr), initial SIHT, or in whom pterional surgery was required. Markers of recurrence are difficult to identify, with SIHT being the most powerful predictor.

Chronic hepatic cytolysis revealing a pheochromocytoma.

We report here the first case of chronic cytolysis that led to the diagnosis of pheochromocytoma, in a 48-year-old woman with a recent onset of hypertension. The etiological research ruled out the common causes of raised transaminase levels, and led to the discovery of a left adrenal pheochromocytoma. The sustained normalization of liver function tests after the removal of the tumour strongly suggests that hepatocyte injury was due to catecholamine hyperproduction. The present original clinical case, linking pheochromocytoma and liver dysfunction, raises important mechanistic questions concerning the relationship between catecholamines and liver function. It may also have clinical implications. Indeed, pheochromocytoma should be considered as a possible cause in case of unexplained transaminase increase associated with the recent onset of hypertension.

Differential evolution of thyroid peroxidase and thyrotropin receptor antibodies in Graves' disease: thyroid peroxidase antibody activity reverts to pretreatment level after carbimazole withdrawal.

In this study, we compared the evolution of thyroid peroxidase antibody (TPOAb) and thyroid-stimulating antibody (TSAb) activities before, during, and after treatment of Graves' disease (GD) with carbimazole. TPOAb and TSAb were measured in sera from 75 patients with GD, during an 18-month block-replace regimen and after drug withdrawal (12, 24, and 36 months). At diagnosis, TPOAb were present in 85% of the patients versus 99% for TSAb. During the treatment, TPOAb values and prevalence significantly decreased, as observed with TSAb. After drug withdrawal, TPOAb levels increased once again to reach the pretreatment values, whereas TSAb remained unchanged. TPOAb values and prevalence at drug withdrawal were not significantly different between patients who remained euthyroid and those who had a relapse of hyperthyroidism. In contrast, TSAb values and prevalence were higher at drug withdrawal in relapse patients. In conclusion, TPOAb and TSAb changes are similar during GD treatment by carbimazole but diverge after drug withdrawal. TPOAb might reflect autoimmune perturbations independently of the clinical status and of the thyroid-stimulating activity.

Choreic syndrome due to Hashimoto's encephalopathy.

We report on the instructive case of an elderly woman who became encephalopathic and concurrently developed chorea. Thyroid antibody studies were abnormal. She responded extremely well to oral corticosteroids.