CGM based basal-insulin titration in insulin-naïve type 2 diabetic subjects: an in-silico study

openLa fisiopatologia del diabete di tipo 2 (T2D) consiste in un malfunzionamento dei circuiti di feedback che coinvolgono la secrezione di insulina (disfunzione delle cellule β) e/o l'azione dell'insulina (stato di resistenza insulinica), il quale malfunzionamento porta il soggetto in uno stato di iperglicemia (livello di glucosio nel sangue elevato). Con la progressione della malattia (T2D in stato avanzato), i soggetti possono richiedere la somministrazione di insulina esogena per controllare la glicemia: l’azione combinata di insuline ad azione rapida per il controllo durante i pasti ed insuline ad azione prolungata per il controllo della concentrazione glicemica pre-prandiale e postprandiale. L’attuale procedura per determinare la dose ottimale di insulina basale in soggetti che non hanno mai utilizzato in precedenza l’insulina per il trattamento del diabete (naïve all’insulina) consiste in una regola di titolazione non personalizzata. Secondo le linee guida ADA, i soggetti devono iniziare la titolazione con una dose di insulina bassa che viene fatta variare seguendo incrementi e decrementi predefiniti: tali variazioni sono basate sull’automonitoraggio (SMBG) a digiuno della glicemia; lo scopo è di raggiungere un livello target di glicemia a digiuno (FPG). Lo scopo di questa tesi è sviluppare una regola di titolazione dell'insulina basale personalizzata basata sui bisogni specifici di insulina dei soggetti. In particolare, è stato utilizzato il monitoraggio continuo del glucosio (CGM) e delle relative metriche temporali ricavate da tale segnale, le quali sono utilizzate dai medici per valutare la qualità del controllo glicemico: il tempo speso al di sopra dell'intervallo glicemico target (TAR), tempo speso nell'intervallo glicemico target (TIR) e tempo sotto l'intervallo glicemico target (TBR). La popolazione utilizzata è composta da 300 soggetti virtuali, ai quali è stata somministrata lo stato dell’arte delle regole per la titolazione dell’insulina basale (DUAL I). I soggetti sono stati quindi classificati utilizzando un modello di regressione logistica precedentemente addestrato. In particolare, sono stati divisi in base alla loro dose finale di insulina tra alto fabbisogno insulinico (HIN) e basso fabbisogno insulinico (LIN). I soggetti classificati come HIN sono stati titolati utilizzando i quattro nuovi algoritmi. Le metriche temporali del segnale GCM ottenute dalle nuove regole di titolazione sono state confrontate con quelle ottenute utilizzando DUAL I. Tra i nuovi algoritmi testati il migliore risulta essere la quarta versione. Tale risultato è il prodotto di una selezione che ha considerato la correlazione tra la dose finale di insulina somministrata da DUAL I e quella di ciascun algoritmo di titolazione (per il quarto algoritmo: ρ= 0,82, pvalue<10-8). L’applicazione del nuovo algoritmo ha mostrato un aumento statisticamente e clinicamente significativo del TIR, nonché una diminuzione significativa del TAR accompagnata da una riduzione significativa del FPG. Lo svantaggio principale è stato un aumento statisticamente significativo della TBR fino al terzo mese; tuttavia, dopo questo periodo questa differenza non è risultata più significativa. Nonostante i buoni risultati complessivamente ottenuti, potrebbero essere apportati miglioramenti in futuro. Nella fattispecie, si possono considerare gli altri trend per aggiungere informazioni significative che migliorino il processo decisionale. Inoltre, si potrebbero condurre altri studi su come regolare l’aggressività degli algoritmi oggetto di questa tesi.The pathophysiology of the type 2 diabetes (T2D) consists in a malfunctioning of the feedback loops between insulin secretion (β-cell disfunction) and/or insulin action (insulin resistance state) leading to an abnormally high blood glucose level. With the progression of the disease (advance stage T2D), subjects may need exogenous insulin to control their glycaemia, using fast acting insulins during meals and/or long-acting insulins, to control fasting (pre-breakfast) and postprandial glucose concentration. The current procedure to determine the optimal basal insulin dose in subjects who have never previously used insulin to treat diabetes (insulin-naïve) consists in a non-personalized titration rule. According to ADA guidelines, subjects must start the titration with a low insulin dose that is progressively adjusted, following predefined increments/decrements, based only on self-monitoring blood glucose (SMBG) pre-breakfast measurements (Gpre), to reach a target fasting glucose level. The aim of this thesis is to develop a more personalized basal insulin titration rule based on subjects’ specific insulin needs, continuous glucose monitoring (CGM) and common CGM metrics used by clinician to assess the quality of glucose control i.e., time above range (TAR), time in range (TIR), and time below range (Tb). We used a dataset consisting of 300 in silico subjects who underwent a literature titration rule (DUAL I). Subjects were then classified as high insulin needs (HIN) and low insulin needs (LIN), based on their final insulin dose, using a literature logistic regression model. The classified HIN subjects underwent four new rules and their GCM time metrics were compared with the ones obtained using DUAL I. Among the new tested rules, the best one, which is selected in terms of higher correlation with DUAL I final insulin dose (ρ=0.85, p-value<10-8), showed a statistically and clinically significant increase of TIR, as well as a significant decrease of TAR accompanied by a significant reduction in the GPre. The main drawback was a statistically significant increase in the Tb until the third month, anyway after this period this difference was not significant anymore. Despite the overall good results achieved, improvements could be made in the future, looking if other trends can add significant features which improve the decision process, but also making studies on how to tune the aggressiveness of the rules object of this thesis

Whole-brain vasculature reconstruction at the single capillary level

The distinct organization of the brain’s vascular network ensures that it is adequately supplied with oxygen and nutrients. However, despite this fundamental role, a detailed reconstruction of the brain-wide vasculature at the capillary level remains elusive, due to insufficient image quality using the best available techniques. Here, we demonstrate a novel approach that improves vascular demarcation by combining CLARITY with a vascular staining approach that can fill the entire blood vessel lumen and imaging with light-sheet fluorescence microscopy. This method significantly improves image contrast, particularly in depth, thereby allowing reliable application of automatic segmentation algorithms, which play an increasingly important role in high-throughput imaging of the terabyte-sized datasets now routinely produced. Furthermore, our novel method is compatible with endogenous fluorescence, thus allowing simultaneous investigations of vasculature and genetically targeted neurons. We believe our new method will be valuable for future brain-wide investigations of the capillary network

Design and efficiency analysis of an LCL Capacitive Power Transfer system with Load-Independent ZPA

This paper proposes a design procedure of an LCL compensation circuit for a capacitive power transfer (CPT) system. The design enables the achievement of load independent zero phase angle (ZPA) operation in order to increase the overall efficiency of the system by using a minimum number of compensation components. The proposed approach is supported and validated by circuital simulations and confirmed by the results of experimental tests carried out on a specifically designed prototype

Rapid decline of fasting glucose in HCV diabetic patients treated with direct-acting antiviral agents

Association between HCV infection and diabetes has been widely postulated. Little is known about the impact of direct acting antiviral agents (DAAs) on glycemic control. Aim of our study was to evaluate the glycemic control modifications in a case series of HCV+ diabetic population receiving DAAs. We retrospectively evaluated 149 HCV+ patients in two different institutions affiliated to the Sapienza University: Policlinico Umberto I of Rome and Ospedale Santa Maria Goretti of Latina. We were able to identify 29 patients with T2DM (19% of total population) who were receiving different IFN-free regimens. During-treatment fasting glucose values were available for 21 patients and analysis showed a statistically significant reduction (p=0,007), the reduction mean value was -52,86 mg/dl. An A1C value during treatment (week 4 or week 8 or week 12) was available for 10 patients and the analysis showed a statistically significant reduction (p=0,021) with a reduction mean value of -1,95%. 6 patients (23%) needed to reduce hypoglycemic drugs, 8 of 10 patients showed reduction of A1C, 14 of 21 patients (67%) showed reduced FG during treatment. FG and A1C reductions values were independent from which DAA was present in the regimen, HCV genotype, BMI and HIV status. In order to avoid hypoglycemic events, diabetic patients undergoing DAAs should be closely monitorized for reduction of hypoglycemic drugs. Furthermore, diabetes could be considered, in our opinion, as an element to prioritize treatment in those patients with no apparent liver disease

Systemic adipokines, hepatokines and interleukin-6 in HCV-monoinfected and HCV/HIV coinfected patients treated with direct antiviral agents (DAAs)

In this study, we demonstrated that that altered levels ofadipokines/hepatokines in HCV-infected patients, including HIV coinfected, can be restored by treatment with direct antiviral agents (DAAs), thus indicating the important metabolic changes occurring during the eradication of this viral infection

Large-scale automated identification of mouse brain cells in confocal light sheet microscopy images

Motivation: Recently, confocal light sheet microscopy has enabled high-throughput acquisition of whole mouse brain 3D images at the micron scale resolution. This poses the unprecedented challenge of creating accurate digital maps of the whole set of cells in a brain. Results: We introduce a fast and scalable algorithm for fully automated cell identification. We obtained the whole digital map of Purkinje cells in mouse cerebellum consisting of a set of 3D cell center coordinates. The method is accurate and we estimated an F(1) measure of 0.96 using 56 representative volumes, totaling 1.09 GVoxel and containing 4138 manually annotated soma centers. Availability and implementation: Source code and its documentation are available at http://bcfind.dinfo.unifi.it/. The whole pipeline of methods is implemented in Python and makes use of Pylearn2 and modified parts of Scikit-learn. Brain images are available on request. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Unveiling Oxygen Redox Activity in P2-Type NaxNi0.25Mn0.68O2 High-Energy Cathode for Na-Ion Batteries

Na-ion batteries are emerging as convenient energy-storage devices for large-scale applications. Enhanced energy density and cycling stability are key in the optimization of functional cathode materials such as P2-type layered transition metal oxides. High operating voltage can be achieved by enabling anionic reactions, but irreversibility of O2–/O2n–/O2 evolution still limits this chance, leading to extra capacity at first cycle that is not fully recovered. Here, we dissect this intriguing oxygen redox activity in Mn-deficient NaxNi0.25Mn0.68O2 from first-principles, by analyzing the formation of oxygen vacancies and dioxygen complexes at different stages of sodiation. We identify low-energy intermediates that release molecular O2 at high voltage, and we show how to improve the overall cathode stability by partial substitution of Ni with Fe. These new atomistic insights on O2 formation mechanism set solid scientific foundations for inhibition and control of this process toward the rational design of new anionic redox-active cathode materials

Tailored sample mounting for light-sheet fluorescence microscopy of clarified specimens by polydimethylsiloxane casting

The combination of biological tissue clearing methods with light-sheet fluorescence microscopy (LSFM) allows acquiring images of specific biological structures of interest at whole organ scale and microscopic resolution. Differently to classical epifluorescence techniques, where the sample is cut into slices, LSFM preserves the whole organ architecture, which is of particular relevance for investigations of long-range neuronal circuits. This imaging modality comes with the need of new protocols for sample mounting. Gel matrix, hooks, tips, glues, and quartz cuvettes have been used to keep whole rodent organs in place during image acquisitions. The last one has the advantage of avoiding sample damage and optical aberrations when using a quartz refractive index (RI) matching solution. However, commercially available quartz cuvettes for such large samples are expensive. We propose the use of polydimethylsiloxane (PDMS) for creating tailor-made cuvettes for sample holding. For validation, we compared PDMS and quartz cuvettes by measuring light transmittance and performing whole mouse-brain imaging with LSFM. Moreover, imaging can be performed using an inexpensive RI matching solution, which further reduces the cost of the imaging process. Worth of note, the RI matching solution used in combination with PDMS leads to a moderate expansion of the sample with respect to its original size, which may represent an advantage when investigating small components, such as neuronal processes. Overall, we found the use of custom-made PDMS cuvettes advantageous in term of cost, image quality, or preservation of sample integrity with respect to other whole-mouse brain mounting strategies adopted for LSFM

Multidimensional non-linear laser imaging of Basal Cell Carcinoma

We have used a multidimensional non-linear laser imaging approach to visualize ex-vivo samples of basal cell carcinoma (BCC). A combination of several non-linear laser imaging techniques involving fluorescence lifetime, multispectral two-photon and second-harmonic generation imaging has been used to image different skin layers. This approach has elucidated some morphological (supported by histopathological images), biochemical, and physiochemical differences of the healthy samples with respect to BCC ones. In particular, in comparison with normal skin, BCC showed a blue-shifted fluorescence emission, a higher fluorescence response at 800 nm excitation wavelength and a slightly longer mean fluorescence lifetime. Finally, the use of aminolevulinic acid as a contrast agent has been demonstrated to increase the constrast in tumor border detection. The results obtained provide further support for in-vivo non-invasive imaging of Basal Cell Carcinoma