Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer.

BACKGROUND: In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits. METHODS: In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization. RESULTS: Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of -0.3 percentage points (two-sided 90% CI, -2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported. CONCLUSIONS: In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years. (Funded by the French National Cancer Institute; ESTIMABL2 ClinicalTrials.gov number, NCT01837745.).

Islets-on-Chip: A Tool for Real-Time Assessment of Islet Function Prior to Transplantation.

Islet transplantation improves metabolic control in patients with unstable type 1 diabetes. Clinical outcomes have been improving over the last decade, and the widely used beta-score allows the evaluation of transplantation results. However, predictive pre-transplantation criteria of islet quality for clinical outcomes are lacking. In this proof-of-concept study, we examined whether characterization of the electrical activity of donor islets could provide a criterion. Aliquots of 8 human donor islets from the STABILOT study, sampled from islet preparations before transplantation, were characterized for purity and split for glucose-induced insulin secretion and electrical activity using multi-electrode-arrays. The latter tests glucose concentration dependencies, biphasic activity, hormones, and drug effects (adrenalin, GLP-1, glibenclamide) and provides a ranking of CHIP-scores from 1 to 6 (best) based on electrical islet activity. The analysis was performed online in real time using a dedicated board or offline. Grouping of beta-scores and CHIP-scores with high, intermediate, and low values was observed. Further analysis indicated correlation between CHIP-score and beta-score, although significance was not attained (R = 0.51, p = 0.1). This novel approach is easily implantable in islet isolation units and might provide means for the prediction of clinical outcomes. We acknowledge the small cohort size as the limitation of this pilot study.

Slow potentials encode intercellular coupling and insulin demand in pancreatic beta cells.

AIMS/HYPOTHESIS: Ion fluxes constitute a major integrative signal in beta cells that leads to insulin secretion and regulation of gene expression. Understanding these electrical signals is important for deciphering the endogenous algorithms used by islets to attain homeostasis and for the design of new sensors for monitoring beta cell function. METHODS: Mouse and human islets were cultured on multielectrode arrays (MEAs) for 3-13 days. Extracellular electrical activities received on each electrode were continuously amplified and recorded for offline characterisation. RESULTS: Differential band-pass filtering of MEA recordings of mouse islets showed two extracellular voltage waveforms: action potentials (lasting 40-60 ms) and very robust slow potentials (SPs, lasting 800-1,500 ms), the latter of which have not been described previously. The frequency of SPs directly correlated with glucose concentration, peaked at 10 mmol/l glucose and was further augmented by picomolar concentrations of glucagon-like peptide-1. SPs required the closure of ATP-dependent potassium channels as they were induced by glucose or glibenclamide but were not elicited by KCl-induced depolarisation. Pharmacological tools and the use of beta cell specific knockout mice showed that SPs reflected cell coupling via connexin 36. Moreover, increasing and decreasing glucose ramps showed hysteresis with reduced glucose sensitivity during the decreasing phase. SPs were also observed in human islets and could be continuously recorded over 24 h. CONCLUSIONS/INTERPRETATION: This novel electrical signature reflects the syncytial function of the islets and is specific to beta cells. Moreover, the observed hysteresis provides evidence for an endogenous algorithm naturally present in islets to protect against hypoglycaemia.

Strategies of radioiodine ablation in patients with low-risk thyroid cancer.

BACKGROUND: It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care. METHODS: In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework. RESULTS: There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods. CONCLUSIONS: The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; ClinicalTrials.gov number, NCT00435851; INCa number, RECF0447.).

Influence of glycemic control on gain in VO2 peak, in patients with type 2 diabetes enrolled in cardiac rehabilitation after an acute coronary syndrome. The prospective DARE study.

BACKGROUND: Gain in VO2 peak after cardiac rehabilitation (CR) following an acute coronary syndrome (ACS), is associated with reduced mortality and morbidity. We have previously shown in CR, that gain in VO2 peak is reduced in Type 2 diabetic patients and that response to CR is impaired by hyperglycemia. METHODS: We set up a prospective multicenter study (DARE) whose primary objective was to determine whether good glycemic control during CR may improve the gain in VO2 peak. Sixty four type 2 diabetic patients, referred to CR after a recent ACS, were randomized to insulin intensive therapy or a control group with continuation of the pre-CR antidiabetic treatment. The primary objective was to study the effect of glycemic control during CR on the improvement of peak VO2 by comparing first the 2 treatment groups (insulin intensive vs. control) and second, 2 pre-specified glycemic control groups according to the final fructosamine level (below and above the median). RESULTS: At the end of the CR program, the gain in VO2 peak and the final fructosamine level (assessing glycemic level during CR) were not different between the 2 treatment groups. However, patients who had final fructosamine level below the median value, assessing good glycemic control during CR, showed significantly higher gain in VO2 peak (3.5 ± 2.4 vs. 1.7 ± 2.4 ml/kg/min,p = 0.014) and ventilatory threshold (2.7 ± 2.5 vs. 1.2 ± 1.9 ml/kg/min,p = 0.04) and a higher proportion of good CR-responders (relative gain in VO2 peak ≥ 16 %): 66 % vs. 36 %, p = 0.011. In multivariate analysis, gain in VO2 peak was associated with final fructosamine level (p = 0.010) but not with age, gender, duration of diabetes, type of ACS, insulin treatment or basal fructosamine. CONCLUSIONS: The DARE study shows that, in type 2 diabetes, good glycemic control during CR is an independent factor associated with gain in VO2 peak. This emphasizes the need for good glycemic control in CR for type 2 diabetic patients. TRIAL REGISTRATION: Trial registered as NCT00354237 (19 July 2006).

Adsorption of microgels at an oil-water interface: correlation between packing and 2D elasticity.

The aim of this paper is to determine how microgels adsorb at a model oil-water interface and how they adapt their conformation to compression, which gives rise to surface elasticity depending on the microgel packing. The structure of the film is determined by the Langmuir films approach (forced compression) and compared to spontaneous adsorption using the pendant drop method. The behaviour of microgels differs significantly from that of non-deformable particles but resembles that of linear polymers or proteins. We also correlate the properties of microgels spontaneously adsorbed at model interfaces to their forced adsorption during emulsification. Finally we propose a route to easily control a posteriori the microgel packing at the surface of droplets and the flow properties of emulsions stabilised by the microgels.

Readily prepared dynamic hydrogels by combining phenyl boronic acid- and maltose-modified anionic polysaccharides at neutral pH.

Dynamic covalent hydrogels are facilely prepared from biocompatible polysaccharides in physiological conditions by the formation of phenylboronate ester cross-links. This is based on the simple mixing of carboxylate-containing polysaccharides (i.e., hyaluronic acid or carboxymethylcellulose) modified with phenylboronic acid and maltose moieties according to mild coupling reactions performed in aqueous solution. The formation of dynamic networks based on reversible boronic-ester cross-links is demonstrated by analyzing their rheological behavior. This study shows that these gels can adapt their structure in response to chemical stimuli such as variations in pH or addition of glucose and self-heal.

[Diabetes, obesity and heart complications]. / Diabète, obésité et complications cardiaques.

Although epidemiologic analyses suggest a correlation between higher rates of cardiovascular disease and chronic hyperglycemia, to date, no randomized clinical trial has convincingly demonstrated a beneficial effect of intensive therapy on macrovascular outcomes in individuals with long-standing type 2 diabetes. In contrast, intensive initial control in individuals with newly diagnosed diabetes has long-term benefit in decreasing the risk of myocardial infarction, diabetes-related death, and overall death. There is strong, consistent evidence that the relationship between blood glucose levels and cardiovascular risk extends into the no diabetic range and obesity. Therefore, multifactorial risk reduction should be a top priority for prevention of macrovascular complications. We should keep in mind that obesity and diabetes also increase the risk of heart failure independent of coronary heart disease and hypertension and may cause a cardiomyopathy, a frequent, forgotten, and often fatal complication. This multifactorial disease should be treated by a multidisciplinary team.

Five-Year Efficacy and Safety of TiNO-Coated Stents Versus Drug-Eluting Stents in Acute Coronary Syndrome: A Meta-Analysis.

(1) Background: Percutaneous coronary interventions (PCI) in patients with acute coronary syndrome (ACS) are performed with titanium-nitride-oxide-coated stents (TiNOSs) or drug-eluting stents (DESs). The initial completion of this prospective systematic literature review (SLR) of prospective randomized controlled trials (RCTs) showed that TiNOSs are non-inferior to DESs in major adverse cardiac event (MACE) rates and present a lower risk of recurrent myocardial infarction (MI) at 1-year follow-up. This iteration of the SLR protocol performs the critical assessment of 5-year follow-up outcomes with clinical validity and generalizability assessments. (2) Methods: The previously described SLR and meta-analysis protocol, per PRISMA, Cochrane methods, and GRADE, was applied to 5-year follow-up outcomes. (3) Results: Three RCTs were eligible, comprising 1620 patients with TiNOS vs. 1123 with DES. The pooled risk ratios (RRs) and 95% confidence intervals were MACE 0.82 [0.68, 0.99], MI 0.58 [0.44, 0.78], cardiac death (CD) 0.46 [0.28, 0.76], ischemia-driven target lesion revascularization (TLR) 1.03 [0.79, 1.33], probable or definite stent thrombosis (ST) 0.32 [0.21, 0.59], and all-cause mortality (TD) 0.84 [0.63, 1.12]. The evidence certainty was high in MACE, CD, MI, and ST, and moderate in TLR and TD. (4) Conclusions: TiNOSs in ACS at 5-year follow-up appear safer than DESs and equally efficacious. The pooled RRs stratified by clinical presentation and stent type will be required to test this meta-analysis's clinical validity and generalize its results to patient populations with varying proportions of clinical presentations and DES options.

Performance and patients' satisfaction with the A7+TouchCare insulin patch pump system: A randomized controlled non-inferiority study.

BACKGROUND: We assessed the performance and patient satisfaction of a new insulin patch pump, the A7+TouchCare (Medtrum), compared with the Omnipod system. METHODS: This multicenter, randomized, open-label, controlled study enrolled 100 adult patients with type 1 or type 2 diabetes mellitus (A1C ≥ 6.5% and ≤ 9.5%, i.e., 48 to 80 mmol/mol) who were assigned with the Omnipod or with the A7+TouchCare pump for 3 months. The primary study outcome was the glucose management indicator (GMI) calculated with continuous glucose monitoring (CGM). RESULTS: Premature withdrawals occurs respectively in 2 and 9 participants in the Omnipod and TouchCare groups. In the Per Protocol analysis, the difference in GMI between groups was 0.002% (95% confidence interval -0.251; 0.255). The non-inferiority was demonstrated since the difference between treatments did not overlap the pre-defined non-inferiority margin (0.4%). There was no significant difference in CGM parameters between groups. On average, patients in both groups were satisfied/very satisfied with the insulin pump system. Patients preferred Omnipod as an insulin management system and especially the patch delivery system but preferred the A7+TouchCare personal diabetes manager to control the system. CONCLUSIONS: This study showed that the A7+TouchCare insulin pump was as efficient as the Omnipod pump in terms of performance and satisfaction. CLINICAL TRAIL REGISTRATION: The study was registered in the ClinicalTrials.gov protocol register (NCT04223973).

Non-invasive long-term and real-time analysis of endocrine cells on micro-electrode arrays.

Non-invasive high-throughput and long-term monitoring of endocrine cells is important for drug research, phenotyping, tissue engineering and pre-transplantation quality control. Here we report a novel approach to obtain simultaneous long-term electrical recordings of different islet cell types using multi-electrode arrays. We implemented wavelet transforms to resolve the low signal/noise ratio inherent to these measurements and extracted on-line a signature specific of cell activity. The architecture employed allows multiplexing a large number of electrodes for high-throughput screening. This method should be of considerable advantage in endocrine research and may be extended to other excitable cells previously not accessible to the technique.

Integrating an Islet-Based Biosensor in the Artificial Pancreas: In Silico Proof-of-Concept.

OBJECTIVE: Current treatment of type 1 diabetes by closed-loop therapy depends on continuous glucose monitoring. However, glucose readings alone are insufficient for an artificial pancreas to truthfully restore nutrient homeostasis where additional physiological regulators of insulin secretion play a considerable role. Previously, we have developed an electrophysiological biosensor of pancreatic islet activity, which integrates these additional regulators through electrical measurements. This work aims at investigating the performance of the biosensor in a blood glucose control loop as potential in silico proof-of-concept. METHODS: Two islet algorithm models were identified on experimental data recorded with the biosensor. First, we validated electrical measurement as a means to exploit the inborn regulation capabilities of islets for intravenous glucose measurement and insulin infusion. Subsequently, an artificial pancreas integrating the islet-based biosensor was compared to standard treatment approaches using subcutaneous routes. The closed-loop simulations were performed in the UVA/Padova T1DM Simulator where a series of realistic meal scenarios were applied to virtual diabetic patients. RESULTS: With intravenous routes, the endogenous islet algorithms successfully restored glucose homeostasis for all patient categories (mean time in range exceeds 90%) while mitigating the risk of adverse glycaemic events (mean BGI < 2). Using subcutaneous routes, the biosensor-based artificial pancreas was as efficient as standard treatments, and outperformed them under challenging conditions. CONCLUSION: This work validates the concept of using inborn pancreatic islets algorithms in an artificial pancreas in silico. SIGNIFICANCE: Pancreatic islet endogenous algorithms obtained via an electrophysiological biosensor successfully regulate blood glucose levels of virtual type 1 diabetic patients.

Towards the Integration of an Islet-Based Biosensor in Closed-Loop Therapies for Patients With Type 1 Diabetes.

In diabetes mellitus (DM) treatment, Continuous Glucose Monitoring (CGM) linked with insulin delivery becomes the main strategy to improve therapeutic outcomes and quality of patients' lives. However, Blood Glucose (BG) regulation with CGM is still hampered by limitations of algorithms and glucose sensors. Regarding sensor technology, current electrochemical glucose sensors do not capture the full spectrum of other physiological signals, i.e., lipids, amino acids or hormones, relaying the general body status. Regarding algorithms, variability between and within patients remains the main challenge for optimal BG regulation in closed-loop therapies. This work highlights the simulation benefits to test new sensing and control paradigms which address the previous shortcomings for Type 1 Diabetes (T1D) closed-loop therapies. The UVA/Padova T1DM Simulator is the core element here, which is a computer model of the human metabolic system based on glucose-insulin dynamics in T1D patients. That simulator is approved by the US Food and Drug Administration (FDA) as an alternative for pre-clinical testing of new devices and closed-loop algorithms. To overcome the limitation of standard glucose sensors, the concept of an islet-based biosensor, which could integrate multiple physiological signals through electrical activity measurement, is assessed here in a closed-loop insulin therapy. This investigation has been addressed by an interdisciplinary consortium, from endocrinology to biology, electrophysiology, bio-electronics and control theory. In parallel to the development of an islet-based closed-loop, it also investigates the benefits of robust control theory against the natural variability within a patient population. Using 4 meal scenarios, numerous simulation campaigns were conducted. The analysis of their results then introduces a discussion on the potential benefits of an Artificial Pancreas (AP) system associating the islet-based biosensor with robust algorithms.

Glycaemic Variability and Hyperglycaemia as Prognostic Markers of Major Cardiovascular Events in Diabetic Patients Hospitalised in Cardiology Intensive Care Unit for Acute Heart Failure.

(1) Background: Hyperglycaemia and hypoglycaemia are both emerging risk factors for cardiovascular disease. Nevertheless, the potential effect of glycaemic variability (GV) on mid-term major cardiovascular events (MACE) in diabetic patients presenting with acute heart failure (AHF) remains unclear. This study investigates the prognostic value of GV in diabetic patients presenting with acute heart failure (AHF). (2) Methods: this was an observational study including consecutive patients with diabetes and AHF between January 2015 and November 2016. GV was calculated using standard deviation of glycaemia values during initial hospitalisation in the intensive cardiac care unit. MACE, including recurrent AHF, new-onset myocardial infarction, ischaemic stroke and cardiac death, were recorded. The predictive effects of GV on patient outcomes were analysed with respect to baseline characteristics and cardiac status. (3) Results: In total, 392 patients with diabetes and AHF were enrolled. During follow-up (median (interquartile range) 29 (6−51) months), MACE occurred in 227 patients (57.9%). In total, 92 patients died of cardiac causes (23.5%), 107 were hospitalised for heart failure (27.3%), 19 had new-onset myocardial infarction (4.8%) and 9 (2.3%) had an ischaemic stroke. Multivariable logistic regression analysis showed that GV > 50 mg/dL (2.70 mmol/L), age > 75 years, reduced left ventricular ejection fraction (LVEF < 30%) and female gender were independent predictors of MACE: hazard ratios (HR) of 3.16 (2.25−4.43; p < 0.001), 1.54 (1.14−2.08; p = 0.005), 1.47 (1.06−2.07; p = 0.02) and 1.43 (1.05−1.94; p = 0.03), respectively. (4) Conclusions: among other well-known factors of HF, a GV cut-off value of >50 mg/dL was the strongest independent predictive factor for mid-term MACE in patients with diabetes and AHF.

Designed glucose-responsive microgels with selective shrinking behavior.

We report on the synthesis of various glucose-responsive microgels based on N-alkylacrylamide derivatives and phenylboronic acid (PBA) as a glucose sensing moiety. Depending on their chemical composition, the microgels exhibit opposite behaviors in response to glucose concentration increase: they can either swell or shrink, using two different mechanisms for glucose recognition. Both behaviors may be suitable for glucose sensing and insulin delivery. When glucose binds a single boronate receptor, the microgel swells as glucose concentration increases. This mechanism can be used to deliver a drug by diffusion through the network. In other cases, glucose binds specifically to two boronates, which creates additional cross-links within the network and provokes shrinkage. Such systems are promising for the development of sensors with improved selectivity and also as potential "intelligent" valves in microfabricated delivery systems. By a rational choice of the constituting units of the network structure, we show how to favor one or the other type of response to glucose variation. Therefore, glucose-swelling microgels operating under physiological conditions have been obtained by copolymerization with an appropriate choice of alkylacrylamide monomer and boronate derivative. At a pH above the pK(a) of the boronic acid derivative, the same structures shrink in response to glucose concentration. The nature of the cross-linker is a key parameter to enable this dual behavior. In other microgels, an amine group is introduced in the vicinity of the boronic acid, which lowers its pK(a) and favors microgel contraction at physiological pH. This work has allowed us to give some general rules to control the swelling/shrinking behavior of glucose-responsive microgels.

[Biomarkers in diabetes mellitus: contributions and discrepancies of new technologies. A case report]. / Marqueurs biologiques du diabète : apports et discordances des nouvelles technologies. À propos d'un cas clinique.

Potential discrepancies between laboratory and estimated (from Continuous Glucose Monitoring (CGM)) glycated hemoglobin (HbA1c) have been reported by diabetologists. CGM devices produce an eA1c derived from average glucose and correlated with Time-in-Range (TIR, %) which is the relative time spent in a range of normal glycaemia. Through a case report, we studied the potential causes for these discrepancies. CGM devices estimate eA1c during the lifespan of the sensor, that is replaced every 14 days and HbA1c is a retrospective data of exposure to hyperglycemia over 8 to 12 weeks. In our case report, the patient had a poor glycemic control resulting in 9% eA1c compared to 7,4% HbA1c got by delocalized immune-assay (Siemens DCA-Vantage®), confirmed at 7,7% by HPLC (Variant II Turbo). On top of the CGM data, an increased labile A1c (LA1c) fraction was found on the patient's HbA1c HPLC profile, both in favor of a recently altered glycemic control. Thus, recent and/or substantial variations in glycemic control will increase the gap between HbA1c and eA1c, being a potential source of therapeutic errors. The differences of those markers, particularly the time window during which it is estimated, make them hardly comparable. As the use of CGM is becoming widespread, it is important to understand and harness its data and biomarkers.

Dynamic Uni- and Multicellular Patterns Encode Biphasic Activity in Pancreatic Islets.

Biphasic secretion is an autonomous feature of many endocrine micro-organs to fulfill physiological demands. The biphasic activity of islet ß-cells maintains glucose homeostasis and is altered in type 2 diabetes. Nevertheless, underlying cellular or multicellular functional organizations are only partially understood. High-resolution noninvasive multielectrode array recordings permit simultaneous analysis of recruitment, of single-cell, and of coupling activity within entire islets in long-time experiments. Using this unbiased approach, we addressed the organizational modes of both first and second phase in mouse and human islets under physiological and pathophysiological conditions. Our data provide a new uni- and multicellular model of islet ß-cell activation: during the first phase, small but highly active ß-cell clusters are dominant, whereas during the second phase, electrical coupling generates large functional clusters via multicellular slow potentials to favor an economic sustained activity. Postprandial levels of glucagon-like peptide 1 favor coupling only in the second phase, whereas aging and glucotoxicity alter coupled activity in both phases. In summary, biphasic activity is encoded upstream of vesicle pools at the micro-organ level by multicellular electrical signals and their dynamic synchronization between ß-cells. The profound alteration of the electrical organization of islets in pathophysiological conditions may contribute to functional deficits in type 2 diabetes.

Tuning of an Artificial Pancreas Controller: an in silico methodology based on clinically-relevant criteria.

This paper presents a methodology to tune an artificial pancreas controller by minimizing the time spent in endangering glycaemic ranges (hypo- and hyperglycaemia). The risk associated to the patient's glycaemia is evaluated with an objective metric (the blood glucose risk index), which has an established clinical relevance. The tuned controller is validated in the UVA/Padova environment where the resulting artificial pancreas achieves minimal glucose risk index in realistic 24-hour long scenarios with unannounced glucose intake.

The effects of Rituximab on Graves'orbitopathy: A retrospective study of 14 patients.

PURPOSE: Management of Graves' ophthalmopathy remains challenging. Over the last decade, previous studies have shown promising results for Rituximab in the treatment of Graves' ophthalmopathy. We present the response of 14 individuals with active moderate-to-severe Graves' ophthalmopathy to Rituximab, representing one of the largest retrospective case series reported to date. METHODS: Rituximab was administered intravenously, 1000 mg twice at a 2-week interval. The primary end point was a clinical activity score reduction (improvement by ⩾ 2 points or disease inactivation: clinical activity score < 3) at 24 weeks. Secondary end points included clinical activity score improved by ⩾ 2 points or inactivation of Graves' ophthalmopathy at 12 weeks, improvement in each item of the clinical activity score, in proptosis, in severity disease by the total eye score and in diplopia according to the Gorman score. RESULTS: A limited improvement in clinical activity score was observed (median improvement at 24 weeks by 1 point, p = 0.002, (5/14 patients, 35.7%). Disease inactivation occurred in 50% of patients (7/14 patients). At 12 weeks, clinical activity score improved by ⩾ 2 points in 2/14 patients (14.3%) and inactivation of Graves' ophthalmopathy occurred in four patients (28.6%). Improvement in proptosis and total eye score was observed in 3/9 patients (33%) and in 4/14 patients (28.6%) at 24 weeks, respectively. Only one patient experienced moderate adverse event. CONCLUSION: Rituximab is a well-tolerated treatment with a good safety profile, but offered limited and partial improvement for active moderate-to-severe Graves' ophthalmopathy with a long duration of disease.

DIABEO System Combining a Mobile App Software With and Without Telemonitoring Versus Standard Care: A Randomized Controlled Trial in Diabetes Patients Poorly Controlled with a Basal-Bolus Insulin Regimen.

Background: The DIABEO® system (DS) is a telemedicine solution that combines a mobile app for patients with a web portal for health care providers. DS allows real-time monitoring of basal-bolus insulin therapy as well as therapeutic decision-making, integrating both basal and bolus dose calculation. Real-life studies have shown a very low rate of use of mobile health applications by patients. Therefore, we conducted a large randomized controlled trial study to investigate the efficacy of DS in conditions close to real life (TELESAGE study). Methods: TELESAGE was a multicenter, randomized, open study with three parallel arms: arm 1 (standard care), arm 2 (DIABEO alone), and arm 3 (DIABEO+telemonitoring by trained nurses). The primary outcome assessed the reduction in HbA1c levels after a 12-month follow-up. Results: Six hundred sixty-five patients were included in the study. Participants who used DIABEO once or more times a day (DIABEO users) showed a significant and meaningful reduction of HbA1c versus standard care after a 12-month follow-up: mean difference -0.41% for arm 2-arm 1 (P = 0.001) and -0.51% for arm 3-arm 1 (P ≤ 0.001). DIABEO users included 25.1% of participants in arm 2 and 37.6% in arm 3. In the intention-to-treat population, HbA1c changes and incidence of hypoglycemia were comparable between arms. Conclusions: A clinical and statistically significant reduction in HbA1c levels was found in those patients who used DIABEO at least once a day.