Effet préventif de la milrinone inhalée chez les patients avec hypertension pulmonaire subissant une chirurgie cardiaque sous circulation extracorporelle : une approche pharmacométrique

La circulation extracorporelle (CEC) est une technique utilisée en chirurgie cardiaque effectuée des milliers de fois chaque jour à travers le monde. L’instabilité hémodynamique associée au sevrage de la CEC difficile constitue la principale cause de mortalité en chirurgie cardiaque et l’hypertension pulmonaire (HP) a été identifiée comme un des facteurs de risque les plus importants. Récemment, une hypothèse a été émise suggérant que l'administration prophylactique (avant la CEC) de la milrinone par inhalation puisse avoir un effet préventif et faciliter le sevrage de la CEC chez les patients atteints d’HP. Toutefois, cette indication et voie d'administration pour la milrinone n'ont pas encore été approuvées par les organismes réglementaires. Jusqu'à présent, la recherche clinique sur la milrinone inhalée s’est principalement concentrée sur l’efficacité hémodynamique et l'innocuité chez les patients cardiaques, bien qu’aucun biomarqueur n’ait encore été établi. La dose la plus appropriée pour l’administration par nébulisation n'a pas été déterminée, de même que la caractérisation des profils pharmacocinétiques (PK) et pharmacodynamiques (PD) suite à l'inhalation. L'objectif de notre recherche consistait à caractériser la relation exposition-réponse de la milrinone inhalée administrée chez les patients subissant une chirurgie cardiaque sous CEC. Une méthode analytique par chromatographie liquide à haute performance couplée à un détecteur ultraviolet (HPLC-UV) a été optimisée et validée pour le dosage de la milrinone plasmatique suite à l’inhalation et s’est avérée sensible et précise. La limite de quantification (LLOQ) était de 1.25 ng/ml avec des valeurs de précision intra- et inter-dosage moyennes (CV%) <8%. Des patients souffrant d’HP pour lesquels une chirurgie cardiaque sous CEC était prévue ont d’abord été recrutés pour une étude pilote (n=12) et, par la suite, pour une étude à plus grande échelle (n=28) où la milrinone (5 mg) était administrée par inhalation pré-CEC. Dans l'étude pilote, nous avons comparé l'exposition systémique de la milrinone peu après son administration avec un nébuliseur pneumatique ou un nébuliseur à tamis vibrant. L’efficacité des nébuliseurs en termes de dose émise et dose inhalée a également été déterminée in vitro. Dans l'étude à plus grande échelle conduite en utilisant exclusivement le nébuliseur à tamis vibrant, la dose inhalée in vivo a été estimée et le profil pharmacocinétique de la milrinone inhalée a été pleinement caractérisé aux niveaux plasmatique et urinaire. Le ratio de la pression artérielle moyenne sur la pression artérielle pulmonaire moyenne (PAm/PAPm) a été choisi comme biomarqueur PD. La relation exposition-réponse de la milrinone a été caractérisée pendant la période d'inhalation en étudiant la relation entre l'aire sous la courbe de l’effet (ASCE) et l’aire sous la courbe des concentrations plasmatiques (ASC) de chacun des patients. Enfin, le ratio PAm/PAPm a été exploré comme un prédicteur potentiel de sortie de CEC difficile dans un modèle de régression logistique. Les expériences in vitro ont démontré que les doses émises étaient similaires pour les nébuliseurs pneumatique (64%) et à tamis vibrant (68%). Cependant, la dose inhalée était 2-3 fois supérieure (46% vs 17%) avec le nébuliseur à tamis vibrant, et ce, en accord avec les concentrations plasmatiques. Chez les patients, en raison des variations au niveau des facteurs liés au circuit et au ventilateur causant une plus grande dose expirée, la dose inhalée a été estimée inférieure (30%) et cela a été confirmé après récupération de la dose de milrinone dans l'urine 24 h (26%). Les concentrations plasmatiques maximales (Cmax: 41-189 ng/ml) et l'ampleur de la réponse maximale ΔRmax-R0 (0-65%) ont été observées à la fin de l'inhalation (10-30 min). Les données obtenues suite aux analyses PK sont en accord avec les données publiées pour la milrinone intraveineuse. Après la période d'inhalation, les ASCE individuelles étaient directement reliées aux ASC (P=0.045). Enfin, notre biomarqueur PD ainsi que la durée de CEC ont été identifiés comme des prédicteurs significatifs de la sortie de CEC difficile. La comparaison des ASC et ASCE correspondantes a fourni des données préliminaires supportant une preuve de concept pour l'utilisation du ratio PAm/PAPm comme biomarqueur PD prometteur et justifie de futures études PK/PD. Nous avons pu démontrer que la variation du ratio PAm/PAPm en réponse à la milrinone inhalée contribue à la prévention de la sortie de CEC difficile.

Mediator framework for inserting xDRs into hadoop

During the last decades, we assisted to what is called “information explosion”. With the advent of the new technologies and new contexts, the volume, velocity and variety of data has increased exponentially, becoming what is known today as big data. Among them, we emphasize telecommunications operators, which gather, using network monitoring equipment, millions of network event records, the Call Detail Records (CDRs) and the Event Detail Records (EDRs), commonly known as xDRs. These records are stored and later processed to compute network performance and quality of service metrics. With the ever increasing number of collected xDRs, its generated volume needing to be stored has increased exponentially, making the current solutions based on relational databases not suited anymore. To tackle this problem, the relational data store can be replaced by Hadoop File System (HDFS). However, HDFS is simply a distributed file system, this way not supporting any aspect of the relational paradigm. To overcome this difficulty, this paper presents a framework that enables the current systems inserting data into relational databases, to keep doing it transparently when migrating to Hadoop. As proof of concept, the developed platform was integrated with the Altaia - a performance and QoS management of telecommunications networks and services.

Protecting databases from schema disclosure: a CRUD-based protection model

Database schemas, in many organizations, are considered one of the critical assets to be protected. From database schemas, it is not only possible to infer the information being collected but also the way organizations manage their businesses and/or activities. One of the ways to disclose database schemas is through the Create, Read, Update and Delete (CRUD) expressions. In fact, their use can follow strict security rules or be unregulated by malicious users. In the first case, users are required to master database schemas. This can be critical when applications that access the database directly, which we call database interface applications (DIA), are developed by third party organizations via outsourcing. In the second case, users can disclose partially or totally database schemas following malicious algorithms based on CRUD expressions. To overcome this vulnerability, we propose a new technique where CRUD expressions cannot be directly manipulated by DIAs any more. Whenever a DIA starts-up, the associated database server generates a random codified token for each CRUD expression and sends it to the DIA that the database servers can use to execute the correspondent CRUD expression. In order to validate our proposal, we present a conceptual architectural model and a proof of concept.

Multi-purpose adaptable business tier components based on Call Level Interfaces

Call Level Interfaces (CLI) play a key role in business tiers of relational and on some NoSQL database applications whenever a fine tune control between application tiers and the host databases is a key requirement. Unfortunately, in spite of this significant advantage, CLI are low level API, this way not addressing high level architectural requirements. Among the examples we emphasize two situations: a) the need to decouple or not to decouple the development process of business tiers from the development process of application tiers and b) the need to automatically adapt business tiers to new business and/or security needs at runtime. To tackle these CLI drawbacks, and simultaneously keep their advantages, this paper proposes an architecture relying on CLI from which multi-purpose business tiers components are built, herein referred to as Adaptable Business Tier Components (ABTC). Beyond the reference architecture, this paper presents a proof of concept based on Java and Java Database Connectivity (an example of CLI).

ABTC: multi-purpose adaptable business tier components based on Call Level Interfaces

Call Level Interfaces (CLI) are low level API that play a key role in database applications whenever a fine tune control between application tiers and the host databases is a key requirement. Unfortunately, in spite of this significant advantage, CLI were not designed to address organizational requirements and contextual runtime requirements. Among the examples we emphasize the need to decouple or not to decouple the development process of business tiers from the development process of application tiers and also the need to automatically adapt to new business and/or security needs at runtime. To tackle these CLI drawbacks, and simultaneously keep their advantages, this paper proposes an architecture relying on CLI from which multi-purpose business tiers components are built, herein referred to as Adaptable Business Tier Components (ABTC). This paper presents the reference architecture for those components and a proof of concept based on Java and Java Database Connectivity (an example of CLI).

Uma API criptográfica para aplicações embarcadas

This document presents GEmSysC, an unified cryptographic API for embedded systems. Software layers implementing this API can be built over existing libraries, allowing embedded software to access cryptographic functions in a consistent way that does not depend on the underlying library. The API complies to good practices for API design and good practices for embedded software development and took its inspiration from other cryptographic libraries and standards. The main inspiration for creating GEmSysC was the CMSIS-RTOS standard, which defines an unified API for embedded software in an implementation-independent way, but targets operating systems instead of cryptographic functions. GEmSysC is made of a generic core and attachable modules, one for each cryptographic algorithm. This document contains the specification of the core of GEmSysC and three of its modules: AES, RSA and SHA-256. GEmSysC was built targeting embedded systems, but this does not restrict its use only in such systems – after all, embedded systems are just very limited computing devices. As a proof of concept, two implementations of GEmSysC were made. One of them was built over wolfSSL, which is an open source library for embedded systems. The other was built over OpenSSL, which is open source and a de facto standard. Unlike wolfSSL, OpenSSL does not specifically target embedded systems. The implementation built over wolfSSL was evaluated in a Cortex- M3 processor with no operating system while the implementation built over OpenSSL was evaluated on a personal computer with Windows 10 operating system. This document displays test results showing GEmSysC to be simpler than other libraries in some aspects. These results have shown that both implementations incur in little overhead in computation time compared to the cryptographic libraries themselves. The overhead of the implementation has been measured for each cryptographic algorithm and is between around 0% and 0.17% for the implementation over wolfSSL and between 0.03% and 1.40% for the one over OpenSSL. This document also presents the memory costs for each implementation.

Front end development for building automation systems using JavaScript Frameworks

Automation technologies are widely acclaimed to have the potential to significantly reduce energy consumption and energy-related costs in buildings. However, despite the abundance of commercially available technologies, automation in domestic environments keep on meeting commercial failures. The main reason for this is the development process that is used to build the automation applications, which tend to focus more on technical aspects rather than on the needs and limitations of the users. An instance of this problem is the complex and poorly designed home automation front-ends that deter customers from investing in a home automation product. On the other hand, developing a usable and interactive interface is a complicated task for developers due to the multidisciplinary challenges that need to be identified and solved. In this context, the current research work investigates the different design problems associated with developing a home automation interface as well as the existing design solutions that are applied to these problems. The Qualitative Data Analysis approach was used for collecting data from research papers and the open coding process was used to cluster the findings. From the analysis of the data collected, requirements for designing the interface were derived. A home energy management functionality for a Web-based home automation front-end was developed as a proof-of-concept and a user evaluation was used to assess the usability of the interface. The results of the evaluation showed that this holistic approach to designing interfaces improved its usability which increases the chances of its commercial success.

Motion compensation with minimal residue dispersion matching criteria

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Tecnoloigia, 2016.

A pilot study to determine the normal haematological indices for young Malawian adults in Blantyre, Malawi

Aim To determine the distribution of haematological parameters in healthy individuals residing in Blantyre, Malawi. We also examined the effect of sociodemographic and nutritional factors on the haematological variables. Methods We conducted a proof-of-concept cross-sectional study, involving 105 healthy blood donors at Malawi Blood Transfusion Service in Blantyre. Eligible participants were HIV-negative males and females, aged 19 to 35 years, who did not have any evidence of acute or chronic illness, or bloodborne infection. We performed the haematological tests at the Malawi-Liverpool Wellcome Trust laboratory in Blantyre, and the screening tests at Malawi Blood Transfusion Service laboratories. Results Out of 170 consenting healthy volunteers, haematological results were available for 105 participants. The proportions of results which were below the lower limit of the manufacturer’s reference ranges were 35.2% (37/105) for haemoglobin, 15.2% (16/105) for neutrophils, 23.8% (25/105) for eosinophils, and 88.6 % (93/105) for basophils. The proportions of results that were above the upper limit of the manufacturer’s reference ranges were 9.5% (10/105) for platelets and 12.4% (13/105) for monocytes. We also observed that the mean leucocyte and basophil counts were significantly higher in males than females (p = 0.042 and p = 0.015, respectively). There were no statistically significant differences in haematological results observed among different ethnic, age, and body mass index groups. Conclusions Over half of otherwise healthy study participants had at least one abnormal haematological result, using previously established foreign standards. More detailed studies are needed to establish locally relevant normal ranges for different age groups and other demographic characteristics of the Malawian population. This will lead to accurate interpretation of laboratory results.

Fluidic flow delay by ionogel passive pumps in microfluidic paper-based analytical devices

[EN] A new concept for fluid flow manipulation in microfluidic paper-based analytical devices (m-PADs) is presented by introducing ionogel materials as passive pumps. m-PADs were fabricated using a new doubleside contact stamping process and ionogels were precisely photopolymerised at the inlet of the m-PADs.The ionogels remain mainly on the surface of the paper and get absorbed in the superficial paper-fibers allowing for the liquid to flow from the ionogel into the paper easily. As a proof of concept the fluid flowand mixing behaviour of two different ionogels mPADs were compared with the non-treated mPADs.It was demonstrated that both ionogels highly affect the fluid flow by delaying the flow due to their different physical and chemical properties and water holding capacities.

Holistic Design In High-Speed Optical Interconnects

Integrated circuit scaling has enabled a huge growth in processing capability, which necessitates a corresponding increase in inter-chip communication bandwidth. As bandwidth requirements for chip-to-chip interconnection scale, deficiencies of electrical channels become more apparent. Optical links present a viable alternative due to their low frequency-dependent loss and higher bandwidth density in the form of wavelength division multiplexing. As integrated photonics and bonding technologies are maturing, commercialization of hybrid-integrated optical links are becoming a reality. Increasing silicon integration leads to better performance in optical links but necessitates a corresponding co-design strategy in both electronics and photonics. In this light, holistic design of high-speed optical links with an in-depth understanding of photonics and state-of-the-art electronics brings their performance to unprecedented levels. This thesis presents developments in high-speed optical links by co-designing and co-integrating the primary elements of an optical link: receiver, transmitter, and clocking.

In the first part of this thesis a 3D-integrated CMOS/Silicon-photonic receiver will be presented. The electronic chip features a novel design that employs a low-bandwidth TIA front-end, double-sampling and equalization through dynamic offset modulation. Measured results show -14.9dBm of sensitivity and energy efficiency of 170fJ/b at 25Gb/s. The same receiver front-end is also used to implement source-synchronous 4-channel WDM-based parallel optical receiver. Quadrature ILO-based clocking is employed for synchronization and a novel frequency-tracking method that exploits the dynamics of IL in a quadrature ring oscillator to increase the effective locking range. An adaptive body-biasing circuit is designed to maintain the per-bit-energy consumption constant across wide data-rates. The prototype measurements indicate a record-low power consumption of 153fJ/b at 32Gb/s. The receiver sensitivity is measured to be -8.8dBm at 32Gb/s.

Next, on the optical transmitter side, three new techniques will be presented. First one is a differential ring modulator that breaks the optical bandwidth/quality factor trade-off known to limit the speed of high-Q ring modulators. This structure maintains a constant energy in the ring to avoid pattern-dependent power droop. As a first proof of concept, a prototype has been fabricated and measured up to 10Gb/s. The second technique is thermal stabilization of micro-ring resonator modulators through direct measurement of temperature using a monolithic PTAT temperature sensor. The measured temperature is used in a feedback loop to adjust the thermal tuner of the ring. A prototype is fabricated and a closed-loop feedback system is demonstrated to operate at 20Gb/s in the presence of temperature fluctuations. The third technique is a switched-capacitor based pre-emphasis technique designed to extend the inherently low bandwidth of carrier injection micro-ring modulators. A measured prototype of the optical transmitter achieves energy efficiency of 342fJ/bit at 10Gb/s and the wavelength stabilization circuit based on the monolithic PTAT sensor consumes 0.29mW.

Lastly, a first-order frequency synthesizer that is suitable for high-speed on-chip clock generation will be discussed. The proposed design features an architecture combining an LC quadrature VCO, two sample-and-holds, a PI, digital coarse-tuning, and rotational frequency detection for fine-tuning. In addition to an electrical reference clock, as an extra feature, the prototype chip is capable of receiving a low jitter optical reference clock generated by a high-repetition-rate mode-locked laser. The output clock at 8GHz has an integrated RMS jitter of 490fs, peak-to-peak periodic jitter of 2.06ps, and total RMS jitter of 680fs. The reference spurs are measured to be –64.3dB below the carrier frequency. At 8GHz the system consumes 2.49mW from a 1V supply.

Graphene and Semicondutor or Metallic Nanoparticles for Energy Conversion

The purpose of the present PhD thesis is to investigate the properties of innovative nano- materials with respect to the conversion of renewable energies to electrical and chemical energy. The materials have been synthesized and characterized by means of a wide spectrum of morphological, compositional and photophysical techniques, in order to get an insight into the correlation between the properties of each material and the activity towards different energy conversion applications. Two main topics are addressed: in the first part of the thesis the light harvesting in pyrene functionalized silicon nanocrystals has been discussed, suggesting an original approach to suc- cessfully increase the absorption properties of these nanocrystals. The interaction of these nanocrystals was then studied, in order to give a deeper insight on the charge and energy extraction, preparing the way to implement SiNCs as active material in optoelectronic devices and photovoltaic cells. In addition to this, the luminescence of SiNCs has been exploited to increase the efficiency of conventional photovoltaic cells by means of two innovative architectures. Specifically, SiNCs has been used as luminescent downshifting layer in dye sensitized solar cells, and they were shown to be very promising light emitters in luminescent solar concentrators. The second part of the thesis was concerned on the production of hydrogen by platinum nanoparticles coupled to either electro-active or photo-active materials. Within this context, the electrocatalytic activity of platinum nanoparticles supported on exfoliated graphene has been studied, preparing an high-efficiency catalyst and disclosing the role of the exfoliation technique towards the catalytic activity. Furthermore, platinum nanoparticles have been synthesized within photoactive dendrimers, providing the first proof of concept of a dendrimer-based photocatalytic system for the hydrogen production where both sensitizer and catalyst are anchored to a single scaffold.

AUTONOMOUS POWER DISTRIBUTION SYSTEMS

Using robotic systems for many missions that require power distribution can decrease the need for human intervention in such missions significantly. For accomplishing this capability a robotic system capable of autonomous navigation, power systems adaptation, and establishing physical connection needs to be developed. This thesis presents developed path planning and navigation algorithms for an autonomous ground power distribution system. In this work, a survey on existing path planning methods along with two developed algorithms by author is presented. One of these algorithms is a simple path planner suitable for implementation on lab-size platforms. A navigation hierarchy is developed for experimental validation of the path planner and proof of concept for autonomous ground power distribution system in lab environment. The second algorithm is a robust path planner developed for real-size implementation based on lessons learned from lab-size experiments. The simulation results illustrates that the algorithm is efficient and reliable in unknown environments. Future plans for developing intelligent power electronics and integrating them with robotic systems is presented. The ultimate goal is to create a power distribution system capable of regulating power flow at a desired voltage and frequency adaptable to load demands.

A BACKING DEVICE BASED ON AN EMBEDDED STIFFENER AND RETRACTABLE INSERTION TOOL FOR THIN-FILM COCHLEAR ARRAYS

Intracochlear trauma from surgical insertion of bulky electrode arrays and inadequate pitch perception are areas of concern with current hand-assembled commercial cochlear implants. Parylene thin-film arrays with higher electrode densities and lower profiles are a potential solution, but lack rigidity and hence depend on manually fabricated permanently attached polyethylene terephthalate (PET) tubing based bulky backing devices. As a solution, we investigated a new backing device with two sub-systems. The first sub-system is a thin poly(lactic acid) (PLA) stiffener that will be embedded in the parylene array. The second sub-system is an attaching and detaching mechanism, utilizing a poly(N-vinylpyrrolidone)-block-poly(d,l-lactide) (PVP-b-PDLLA) copolymer-based biodegradable and water soluble adhesive, that will help to retract the PET insertion tool after implantation. As a proof-of-concept of sub-system one, a microfabrication process for patterning PLA stiffeners embedded in parylene has been developed. Conventional hotembossing, mechanical micromachining, and standard cleanroom processes were integrated for patterning fully released and discrete stiffeners coated with parylene. The released embedded stiffeners were thermoformed to demonstrate that imparting perimodiolar shapes to stiffener-embedded arrays will be possible. The developed process when integrated with the array fabrication process will allow fabrication of stiffener-embedded arrays in a single process. As a proof-of-concept of sub-system two, the feasibility of the attaching and detaching mechanism was demonstrated by adhering 1x and 1.5x scale PET tube-based insertion tools and PLA stiffeners embedded in parylene using the copolymer adhesive. The attached devices survived qualitative adhesion tests, thermoforming, and flexing. The viability of the detaching mechanism was tested by aging the assemblies in-vitro in phosphate buffer solution. The average detachment times, 2.6 minutes and 10 minutes for 1x and 1.5x scale devices respectively, were found to be clinically relevant with respect to the reported array insertion times during surgical implantation. Eventually, the stiffener-embedded arrays would not need to be permanently attached to current insertion tools which are left behind after implantation and congest the cochlear scala tympani chamber. Finally, a simulation-based approach for accelerated failure analysis of PLA stiffeners and characterization of PVP-b-PDLLA copolymer adhesive has been explored. The residual functional life of embedded PLA stiffeners exposed to body-fluid and thereby subjected to degradation and erosion has been estimated by simulating PLA stiffeners with different parylene coating failure types and different PLA types for a given parylene coating failure type. For characterizing the PVP-b-PDLLA copolymer adhesive, several formulations of the copolymer adhesive were simulated and compared based on the insertion tool detachment times that were predicted from the dissolution, degradation, and erosion behavior of the simulated adhesive formulations. Results indicate that the simulation-based approaches could be used to reduce the total number of time consuming and expensive in-vitro tests that must be conducted.

Il sistema Trauma Tracker - individuazione e analisi di parametri vitali acquisiti da monitor multiparametrico.

Lo scopo della presente tesi è lo studio e la progettazione di un sistema Hands-Free applicato in ambito Healthcare, volto ad aiutare il personale sanitario nello svolgimento delle mansioni lavorative. Il progetto, denominato Trauma Tracker, ha avuto origine grazie alla collaborazione con medici ed infermieri dell'ospedale Maurizio Bufalini di Cesena. In particolare, il sistema in prodotto si prende carico della compilazione del report finale contenente tutte le operazioni svolte sui pazienti nell'ambito del Pronto Soccorso, riducendo così notevolmente le possibilità di errori dovuti a fattori umani. Durante le fasi di sviluppo e progettazione sono state aggiunte ulteriori funzionalità al sistema, fino a farlo diventare vero e proprio oggetto incantato, in grado di esibire proprietà finora inimmaginabili in questo campo di applicazione. Trauma Tracker, almeno in queste prime fasi, non si propone come uno strumento immediatamente utilizzabile sul campo e pronto ad affiancare i medici, poiché necessiterebbe subito di qualità come robustezza ed affidabilità a livelli estremamente elevati. Per questo motivo il progetto è stato trattato come un "Proof of Concept", ossia un prototipo che ha lo scopo di dimostrare la fattibilità di tale sistema nella realtà, e di verificarne l'utilità una volta applicato in uno scenario concreto. L'argomento trattato ha quindi una grande importanza, poiché getta le basi di una tecnologia che un giorno potrà aiutare medici ed infermieri a svolgere al meglio l'impegnativo compito di salvare vite. In questa tesi, è stato approfondito in particolare il sottosistema utilizzato per il riconoscimento dei parametri vitali dal monitor multi-parametrico posto nei diversi reparti ospedalieri. Esso ha richiesto lunghe fasi di implementazione e collaudo per ottenere dei risultati soddisfacenti, che alla fine sono stati raggiunti.