Model Predictive Control (MPC) of an Artificial Pancreas with Data-Driven Learning of Multi-Step-Ahead Blood Glucose Predictors

We present the design and \textit{in-silico} evaluation of a closed-loop insulin delivery algorithm to treat type 1 diabetes (T1D) consisting in a data-driven multi-step-ahead blood glucose (BG) predictor integrated into a Linear Time-Varying (LTV) Model Predictive Control (MPC) framework. Instead of identifying an open-loop model of the glucoregulatory system from available data, we propose to directly fit the entire BG prediction over a predefined prediction horizon to be used in the MPC, as a nonlinear function of past input-ouput data and an affine function of future insulin control inputs. For the nonlinear part, a Long Short-Term Memory (LSTM) network is proposed, while for the affine component a linear regression model is chosen. To assess benefits and drawbacks when compared to a traditional linear MPC based on an auto-regressive with exogenous (ARX) input model identified from data, we evaluated the proposed LSTM-MPC controller in three simulation scenarios: a nominal case with 3 meals per day, a random meal disturbances case where meals were generated with a recently published meal generator, and a case with 25$\%$ decrease in the insulin sensitivity. Further, in all the scenarios, no feedforward meal bolus was administered. For the more challenging random meal generation scenario, the mean $\pm$ standard deviation percent time in the range 70-180 [mg/dL] was 74.99 $\pm$ 7.09 vs. 54.15 $\pm$ 14.89, the mean $\pm$ standard deviation percent time in the tighter range 70-140 [mg/dL] was 47.78$\pm$8.55 vs. 34.62 $\pm$9.04, while the mean $\pm$ standard deviation percent time in sever hypoglycemia, i.e., $<$ 54 [mg/dl] was 1.00$\pm$3.18 vs. 9.45$\pm$11.71, for our proposed LSTM-MPC controller and the traditional ARX-MPC, respectively. Our approach provided accurate predictions of future glucose concentrations and good closed-loop performances of the overall MPC controller.Comment: 10 pages, 5 Figures, 2 Table

Treatment of type 2 diabetes with saxagliptin: a pharmacoeconomic evaluation in Argentina

Background: The increasing prevalence of diabetes and its inadequate management results in a heavy burden of the disease for patients, the health and the productive systems and the community. Consequently, it is necessary to have new effective drugs to treat people with diabetes to decrease such burden. DPP-4 inhibitors can help to cope with this demand, but their use is challenged by their apparently high cost. The aim of the current study was to compare a simulated cost-effectiveness ratio of metformin (MET) plus one drug of the DPP-4 inhibitors family, saxagliptin (SAXA), or sulfonylurea (SU) treatment during a 20-year period, from the perspective of the social security system, in a cohort of people with Type 2 diabetes (T2DM) who did not attain glycosylated hemoglobin treatment target values only with MET. Methods: A discrete event simulation model (Cardiff diabetes model) based on UKPDS 68 was used to simulate disease progression and to estimate the economic and health treatment consequences in people with T2DM. The clinical efficacy parameters for SAXA administration were obtained from the literature; local standard costs were considered for drug acquisition, adverse events (AEs), and micro/macrovascular complications.Costs were expressed in United States dollars (2009) with an annual 3.5% discount and a 20-year time horizon. Results: The SAXA+MET treated group had a lower number of non-fatal events than the SU+MET treated group. The model also predicted a lower number of fatal macrovascular events for the SAXA+MET group (149.6 vs. 152.8). The total cost of the SAXA+MET cohort was 15% higher than that of the SU+MET cohort. Treatment with SAXA+MET resulted in a higher number of quality-adjusted life years (QALYs) (9.54 vs. 9.32) and life-years gained (LYGs) (20.84 vs. 20.76) compared to those treated with SU+MET. The incremental cost per QALY and LYG gained was $7,374 and$20,490, respectively. Conclusions: According to the criteria proposed by the Commission on Macroeconomics and Health, the use of the combination SAXA+MET is highly cost-effective in Argentina.Fil: Elgart, Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina. Universidad Nacional de la Plata; ArgentinaFil: Caporale, Joaquin E.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina. Universidad Nacional de la Plata; ArgentinaFil: Gonzalez, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina. Universidad Nacional de la Plata; ArgentinaFil: Aiello, Eleonora. Bristol-Myers Squibb; ArgentinaFil: Waschbusch, Maximiliano. Bristol-Myers Squibb; ArgentinaFil: Gagliardino, Juan Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico La Plata. Centro de Endocrinologia Experimental y Aplicada (i); Argentina. Universidad Nacional de la Plata; Argentin

Treatment of type 2 diabetes with saxagliptin: a pharmacoeconomic evaluation in Argentina

Background: The increasing prevalence of diabetes and its inadequate management results in a heavy burden of the disease for the patients, the health and the productive system and the overall community. Consequently, it is necessary to have new effective drugs to treat people with diabetes to decrease such burden. DPP-4 inhibitors can help to cope with this demand, but its usage is challenged by its apparent high cost. The aim of the current study was to compare a simulated cost-effectiveness ratio of metformin (MET) plus one drug of the DPP-4 inhibitors family, saxagliptin (SAXA) or sulfonylurea (SU) treatment during a 20-year period, from the perspective of the social security system, in a cohort of people with Type 2 diabetes (T2DM) who did not attain glycosylated hemoglobin treatment target values only with MET. Methods: A discrete event simulation model (Cardiff diabetes model) based on UKPDS 68 was used to simulate disease progression and to estimate the economic and health treatment consequences in people with T2DM. The clinical efficacy parameters for SAXA administration were obtained from the literature; local standard costs were considered for drug acquisition, adverse events (AEs), and micro/macrovascular complications. Costs were expressed in US dollars (2009) with an annual 3.5% discount and a 20-year time horizon. Results: The SAXA + MET treated group had a lower number of non-fatal events than the SU + MET treated group. The model also predicted a lower number of fatal macrovascular events for the SAXA + MET group (149.6 vs. 152.8). The total cost of the SAXA + MET cohort was 15% higher than that of the SU + MET cohort. Treatment with SAXA + MET resulted in a higher number of quality-adjusted life years (QALYs) (9.54 vs. 9.32) and life-years gained (LYGs) (20.84 vs. 20.76) compared to those treated with SU + MET. The incremental cost per QALY and LYG gained was $7,374 and$20,490, respectively. Conclusions: According to the criteria proposed by the Commission on Macroeconomics and Health, the use of the combination SAXA+ MET is highly cost-effective in Argentina.Centro de Endocrinología Experimental y Aplicad

Spotting Frozen Curd in PDO Buffalo Mozzarella Cheese Through Insights on Its Supramolecular Structure Acquired by 1H TD-NMR Relaxation Experiments

The addition of frozen curd (FC) during the production process of \u201cMozzarella di Bufala Campana\u201d, an Italian cheese with Protected Designation of Origin (PDO), is a common fraud not involving modifications of the chemical composition in the final product. Its detection cannot thus be easily obtained by common analytical methods, which are targeted at changes in concentrations of diagnostic chemical species. In this work, the possibility of spotting this fraud by focusing on the modifications of the supramolecular structure of the food matrix, detected by time domain nuclear magnetic resonance (TD-NMR) experiments, was investigated. Cheese samples were manufactured in triplicate, according to the PDO disciplinary of production, except for using variable amounts of FC (i.e., 0, 15, 30, and 50% w/w). Relaxation data were analysed through different approaches: (i) Discrete multi-exponential fitting, (ii) continuous Laplace inverse fitting, and (iii) chemometrics approach. The strategy that lead to best detection results was the chemometrics analysis of raw Carr-Purcell-Meiboom-Gill (CPMG) decays, allowing to discriminate between compliant and adulterated samples, with as low as 15% of FC addition. The strategy is based on the use of machine learning for projection on latent structures of raw CPMG data and classification tasks for fraud detection, using quadratic discriminant analysis. By coupling TD-NMR raw decays with machine learning, this work opens the way to set up a system for detecting common food frauds modifying the matrix structure, for which no official authentication methods are yet availabl

Synthesis and antimicrobial activity of new 1-R-3-(2-Piridyl)-4-nitroso-5 carboxiethyl-1H-Pyrazoles

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NEW 1-R-3-(2-PIRIDYL)- 4-NITROSO- 5-CARBOXIETHYL-1H-PYRAZOLES. Stefania Aielloa , Carmelo Massimo Maidab, Fabio Venturellab, Diego Planetac Marco Giammancod, M.Milicib a Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, Università degli Studi di Palermo bDipartimento di Scienze per la Promozione della Salute G. D’ Alessandro, Università degli Studi di Palermo cDipartimento dei Sistemi Agro-Abientali,Università degli Studi di Palermo d Dipartimednto di Studi Giuridici, Economici, Biomedici e Psicosociopedagogici delle Scienze Motorie e Sportive, Università degli Studi di Palermo Corresponding author: Stefania Aiello, Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy; tel:+39.091 23896802; email: [email protected] In recent years, epidemiological studies confirm the significant impact on human health by infections caused by pathogenic fungi. In fact, although the Candida genus is commensal and a constituent of the normal gut flora, it is responsible for opportunistic infections and can become pathogenic secondary to predisposing factors related to the host, like a comprimised immune system (AIDS, anti-cancer therapy, transplants), excessive prophylaxis with antimicrobial agents, and use of invasive catheters. Large-scale surveillance for fungal infections has demonstrated an increasing incidence of drug-resistant fungal pathogens. As a matter of fact, a significant number of fungi species (especially Candida glabrata and Candida krusei) exhibited primary resistance to Fluconazole or were less susceptible to Amphotericin B. Furthermore, as a consequence of the toxicity of the currently used polyene antifungal drugs, which leads to interrupt the therapy, and the emergence of Candida species resistance to azole-based agents, there is an urgent need for developing alternative drug therapies. In our previous study we have disclosed the synthesis and antifungal activity of a series of 4-nitrosopyrazoles that mainly displayed in vitro potent antifungal activity at no cytotoxic concentrations and that some of these compounds were 4 times more potent than Amphotericine B and Fluconazole respectively against Cryptococcus neoformans and Candida Krusei [1-4] As part of our Structure Activity Relationships studies, we were interested in learning the influence of the steric and electronic effects of the substituent in position 5 of the 4-nitrosopyrazoles which had already showed powerful antimycotic activity. Therefore, we synthetized title compounds and evaluated their antimycotic activity (fig1). NNNCOOC2H5ONR R: a=H, b= CH3, c=C2H5 Fig 1. Synthetized compounds The 5-carboxiethylester group has made the antimycotic actity dramatically decay, confirming the necessity, for a good antimicotic activity, of derivatives in which the position 5 is free or substituted with little groups as a methyl shown the best antifungal activity. [1] E. Aiello, S. Aiello, F. Mingoia, A. Bacchi, G. Pelizzi, C. Musiu, M. G. Setzu, A. Pani, P. La Colla and M. E. Marongiu. Synthesis and Antimicrobial activity of New 3-(1-R -3-methyl-4-nitroso-1H-5-pyrazolyl)-5-methylisoxazole derivatives, Bioorganic and Medicinal Chemistry, 2000, 8, 2719-2728 [2] Stefania Aiello; Enrico Aiello, Marica Orioli, Marina Carini, 3-(1-R-3-methyl-4-nitroso-1H-5-pyrazolyl)-5-methylisoxazoles: a new class of antifungal compounds. In vitro metabolism by rat liver:LC and LC-MS studies. Convegno Nazionale, Sorrento 18-22 Settembre 2002. [3] S. Aiello, E. Aiello and M. Milici: “Synthesis and Antifungal Activity of new 3(5)-methyl-5(3)-(2-thiophenyl) and -(2-quinolyl)-1H-1-R-4-nitrosopyrazoles.Part V”. Polish-Austrian-German-Hungarian-Italian Joint Meeting on Medicinal Chemistry, Krakow, October 15-18, 2003 [4] Stefania Aiello, Antonio Macchiarulo, Maria Milici and Enrico Aiello, Sintesi e studi QSAR di nuovi derivati 3(5)-(2-X)-1R-1H-4-nitrosopirazoli: una classe di composti con potente attività antifungina in vitro. Parte VI XVII Convegno Nazionale della Divisione di Chimica Farmaceutica della SCI, Pisa 6-10 settembre 2004

Treatment of type 2 diabetes with saxagliptin: a pharmacoeconomic evaluation in Argentina

Background: The increasing prevalence of diabetes and its inadequate management results in a heavy burden of the disease for the patients, the health and the productive system and the overall community. Consequently, it is necessary to have new effective drugs to treat people with diabetes to decrease such burden. DPP-4 inhibitors can help to cope with this demand, but its usage is challenged by its apparent high cost. The aim of the current study was to compare a simulated cost-effectiveness ratio of metformin (MET) plus one drug of the DPP-4 inhibitors family, saxagliptin (SAXA) or sulfonylurea (SU) treatment during a 20-year period, from the perspective of the social security system, in a cohort of people with Type 2 diabetes (T2DM) who did not attain glycosylated hemoglobin treatment target values only with MET. Methods: A discrete event simulation model (Cardiff diabetes model) based on UKPDS 68 was used to simulate disease progression and to estimate the economic and health treatment consequences in people with T2DM. The clinical efficacy parameters for SAXA administration were obtained from the literature; local standard costs were considered for drug acquisition, adverse events (AEs), and micro/macrovascular complications. Costs were expressed in US dollars (2009) with an annual 3.5% discount and a 20-year time horizon. Results: The SAXA + MET treated group had a lower number of non-fatal events than the SU + MET treated group. The model also predicted a lower number of fatal macrovascular events for the SAXA + MET group (149.6 vs. 152.8). The total cost of the SAXA + MET cohort was 15% higher than that of the SU + MET cohort. Treatment with SAXA + MET resulted in a higher number of quality-adjusted life years (QALYs) (9.54 vs. 9.32) and life-years gained (LYGs) (20.84 vs. 20.76) compared to those treated with SU + MET. The incremental cost per QALY and LYG gained was $7,374 and$20,490, respectively. Conclusions: According to the criteria proposed by the Commission on Macroeconomics and Health, the use of the combination SAXA+ MET is highly cost-effective in Argentina.Centro de Endocrinología Experimental y Aplicad

Costo efectividad de Abatacept en comparación con otras terapias biológicas para el tratamiento de la artritis reumatoide moderada a severamente activa en pacientes que han fallado al tratamiento con metotrexato en EsSalud para el año 2010

Objetivo: Estimar la costo efectividad de Abatacept combinado con Metotrexato (MTX) en comparación a otras DARMEs biológicas, en combinación con MTX, en pacientes con AR moderada a severamente activa. Materiales y métodos: Se adaptó un modelo de secuencias de tratamiento para la representación de la invalidez en términos del índice HAQ en un horizonte de 5 años de enfermedad para una cohorte de 1 000 pacientes. Abatacept en combinación con MTX se comparó contra etanercept, rituximab, infliximab, adalimumab y tocilizumab, todas asociadas a MTX. Resultados: El costo de tratamiento con Abatacept es de S/. 169 263 y su efectividad es de 1.96 AVAC. Respecto a etanercept, adalimumab, infliximab y tocilizumab, abatacept se ha mostrado más efectivo en términos de AVACs y menos costoso. Respecto a rituximab, abatacept presenta un índice de costo efectividad incremental de S/ 75 493 por AVAC ganado. Conclusiones: Abatacept es dominante frente a Etanercept, Adalimumab, Infliximab y Tocilizumab, desde la perspectiva del Seguro Social de Salud (EsSalud) para el tratamiento de pacientes con AR moderada a severamente activa que han fallado a MTX

Increased phospho-mTOR expression in megakaryocytic cells derived from CD34+ progenitors of essential thrombocythaemia and myelofibrosis patients

n/

PMN-MDSC frequency discriminates active versus latent tuberculosis and could play a role in counteracting the immune-mediated lung damage in active disease

: Tuberculosis (TB), due to Mycobacterium tuberculosis infection, is still the principal cause of death caused by a single infectious agent. The balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. Factors defining this variety are unclear and likely involve both mycobacterial and immunological components. Myeloid derived suppressor cells (MDSC) have been shown to be expanded during TB, but their role in human TB pathogenesis is not clear. We evaluated the frequency of circulating MDSC by flow-cytometry in 19 patients with active TB, 18 with latent TB infection (LTBI), and 12 healthy donors (HD) as control. Moreover, we investigated the capacity of MDSC to modulate the mycobactericidal activity of monocytes. The association between MDSC level and TB chest X-ray severity score was analyzed. We observed that, unlike active TB, polymorphonuclear (PMN)-MDSC are not expanded in LTBI patients, and, by performing a receiver operating characteristic (ROC) curve analysis, we found that PMN-MDSC frequency supported the discrimination between active disease and LTBI. Interestingly, we observed an association between PMN-MDSC levels and the severity of TB disease evaluated by chest X-ray. Specifically, PMN-MDSC frequency was higher in those classified with a low/mild severity score compared to those classified with a high severity score. Moreover, PMN-MDSC can impact mycobacterial growth by inducing ROS production in Bacillus Calmette et Guerin (BCG)-infected monocytes. This effect was lost when tested with M. tuberculosis (MTB), In conclusion, our data indicate that the elevated frequency of PMN-MDSC in IGRA-positive individuals is associated with active TB. Our findings also pointed out a beneficial role of PMN-MDSC during human active TB, most likely associated with the limitation of inflammation-induced tissue damage

A quantitative and T‐pattern analysis of anxiety‐like behavior in male GAERS, NEC, and Wistar rats bred under the same conditions, against a commercially available Wistar control group in the hole board and elevated plus maze tests

Aim: The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbred polygenic model of childhood absence epilepsy (CAE), which, as their non‐epileptic control (NEC) rats, are derived from Wistar rats. While the validity of GAERS in reproducing absence seizures is well established, its use as a model for CAE psychiatric comorbidities has been subject to conflicting findings. Differences in colonies, experimental procedures, and the use of diverse controls from different breeders may account for these disparities. Therefore, in this study, we compared GAERS, NEC, and Wistar bred in the same animal facility with commercially available Wistar (Cm Wistar) as a third control. Methods: We performed hole board (HB) and elevated plus maze (EPM) tests that were analyzed with standard quantitative and T‐pattern analysis in male, age‐matched Cm Wistar and GAERS, NEC, and Wistar, bred under the same conditions, to rule out the influence of different housing factors and provide extra information on the structure of anxiety‐like behavior of GAERS rats. Results: Quantitative analysis showed that GAERS and NEC had similar low anxiety‐like behavior when compared to Cm Wistar but not to Wistar rats, although a higher hole‐focused exploration was revealed in NEC. T‐pattern analysis showed that GAERS, NEC, and Wistar had a similar anxiety status, whereas GAERS and NEC exhibited major differences with Cm Wistar but not Wistar rats. EPM results indicated that GAERS and NEC also have similar low anxiety compared to Cm Wistar and/or Wistar rats. Nevertheless, the analysis of the T‐pattern containing open‐arm entry showed GAERS and Wistar to be less anxious than NEC and Cm Wistar rats. Conclusion: To summarize, comorbid anxiety may not be present in male GAERS rats. This study also highlighted the importance of including a control Wistar group bred under the same conditions when evaluating their behavior, as using Wistar rats from commercial breeders can lead to misleading results