Academic literature on the topic 'Next Generation Flow'

Includes bibliographical references (leaves 79-80).<br>Next Generation networks will consist of a number of different access networks interconnected to provide ubiquitous access to the global resources available on the Internet. The coverage of these access networks will also overlap, allowing users a choice of access net-works. Increasingly, mobile devices have more than one type of radio access interface built-in. In current mobile devices, a single primary radio interface performs all communications with the service provider. The availability of multiple different radio interfaces proves most beneficial if all these interfaces can connect with the service provider and carry data in collaboration or individually. This means that a control system is needed to route the correct traffic over each different interface, depending on the requirements of that traffic. Having multiple interfaces available provides the opportunity to aggregate two or more interfaces for faster transfer speeds and can provide redundancy. If one interface is expe-riencing high packet loss or no coverage an alternate interface will be available. Multiple interface schemes aim to enable traditional networks to support devices with more than one interface. This is usually achieved by introducing a new agent into the network architecture that acts as the packet redirection point. Incoming packet flows are routed to the different interfaces of the mobile device by this agent according to the traffic types of each packet flow. In this thesis an evaluation platform is developed to investigate whether the possible functionality of a multiple interfaced device provides useful traffic routing options. The evaluation platform consists of three key components evident in schemes from the literature, namely a Corresponding Node, Mobile Node and Router. The Router is emulated with a script-based routing software and configured as the packet redirection point in the evaluation platform. Four test scenarios emulate traffic travelling over two interfaces of a practical mobile node. A mid-flow handover from one interface to the other is investigated to determine that this process can be seamless under certain conditions. Dual Interface Aggregation shows good performance when the limits of each interface are not exceeded. Distinct improvement in combined packet loss of two lossy links carrying duplicate packet streams shows that two interfaces can provide a reliable link in critical situations where both interfaces have poor performance when used separately. Finally, a Bandwidth-on-Demand scenario shows that having two interfaces can allow automatic bandwidth allocation when data-rate is increased beyond the limits of one interface.

Multiple Myeloma (MM) is a Plasma Cells (PCs) malignancy characterized by the uncontrolled proliferation of pathologic PCs in the Bone Marrow (BM) and, sometimes, extra-medullary sites. Myeloma PCs secrete a monoclonal nonfunctional immunoglobulin (M protein) whose accumulation causes the typical clinical symptoms of the disease, such as hypercalcemia, renal impairment, anemia and bone lesions (i.e., CRAB criteria). In the recent years, the introduction of new drugs has improved Patients Free Survival (PFS) and Overall Survival (OS). For instance, Daratumumab (Dara) is an anti-CD38 monoclonal antibody that, binding to the overexpressed CD38 receptor on PCs, may induce death of myeloma cells via several Fc-dependent mechanisms, including Antibody-Dependent Cell-mediated Cytotoxicity (ADCC), Antibody-Dependent Cellular Phagocytosis (ADCP), and Complement-Dependent Cytotoxicity (CDC), and plays an immunomodulatory effect via withdrawal of the CD38-expressing immune suppressor cells. Dara efficacy has been demonstrated in several studies, in combination with other drugs, as induction therapy or for the treatment of relapsed MM patients. However, in many cases MM patients may still relapse or develop resistance to treatment regimens, leading to the necessity of better and higher-sensitive techniques to monitor Minimal Residual Disease (MRD) and discriminate patients at risk for relapsing. In this context, Next Generation Flow (NGF) is a high-standardized and sensitive technique that, in a rapid and low-cost way, permits to monitor MM MRD and obtain a sensitivity of 10-5, necessary to define MRD negativity. Starting from December 2018, a pilot experimental study has been set up at the Hematology Unit of Policlinico Le Scotte in Siena, with the aim to evaluate Daratumumab efficacy as a consolidation therapy in 50 MM patients in Very Good Partial Response (VGPR). The MRD of the enrolled MM patients was evaluated by NGF at the time of enrollment, and then at 2 months of treatment, and every 6 months up to 2 years. The aims of my research project are: 1) to confirm that NGF is a high specific technique that permits nowadays to discriminate the MRD status of MM patients after an initial induction treatment; 2) to evaluate Daratumumab efficacy as consolidation therapy, in particular, to determine MRD negativity at time 6 months, which represent the first endpoint of the pilot study; 3) to understand Daratumumab role in controlling the disease and prolonging Overall Survival Rate and Progression-Free Survival of MM patients. A total of 47 MM patients in VGPR have been enrolled up until now. Comparing the response of 39/47 (83%) MM patients who reached the first endpoint of 6 months (mos) of Dara treatment, we observed that 12/39 (31%) achieved MRD negativity, of which 8/12 (67%) were “early responders” and could obtain MRD negative status already at 2 months of treatment, while the other 4/12 (33%) achieved MRD negativity just at 6 months. 29/47 (62%), 19/47 (40%) and 13/47 (28%) patients have been evaluated at the subsequent timepoints of 12, 18 and 24 months respectively, with 2/8 (25%) of the “early responders” patients, negative since 2 mos, persisting in MRD negative status. The high heterogeneity of response we observed needs to be correlated first of all to type of treatment received by MM patients before starting Dara, as the study confirms that undergoing at least one Autologous Stem Cell Transplantation (ASCT) can help patients reducing the pathogenicity of MM and achieving a deeper response with respect to patients not receiving an ASCT; cytogenetic risk correlations, instead, need a larger cohort of patients and/or comparison with other treatment regimens. Lastly, by looking at the percentage of clonal PCs vs normal PCs in those patients who maintain a MRD positive status, we observed a decrease of pathologic MM PCs during Dara treatment, and a tendency to “stabilize” with a low percentage at longer timepoints from Dara treatment, as they could be maintained under control and persist into MM patients without causing relapse. These results demonstrate that Daratumumab is effective as consolidation therapy in MM patients in VGPR, as it induces MRD negativity in some patients and could help “checkmate” pathologic plasma cells, that may persist in MRD positive patients but with a very low tumor burden. Flow MRD negativity should be followed in the next years to better clarify which is the percentage of patients who could be cured or long survivors. The persistence of residual monoclonal plasma cells may be also related to other mechanisms, correlated to immunity of myeloma patients or to the microenvironment, who may help keeping in truck the disease, since myeloma pathogenesis is strictly linked to both reduction of immunity and exploitation of BM microenvironment for the growing of tumor cells. Further future investigations may help elucidate mechanisms underlying responses to therapy in myeloma patients, especially those that are treated with monoclonal antibodies, and find a way to ameliorate remission rate and Progression Free Survival.

Introduzione. Il mieloma multiplo fumante (SMM) occupa una posizione intermedia tra quella che viene solitamente definita una condizione premaligna, la gammapatia monoclonale a significato indeterminato (MGUS) e il mieloma multiplo sintomatico (MM). Il mieloma smoldering ha un carico di malattia maggiore rispetto alla MGUS, ma non mostra danni agli organi né i cosiddetti Myeloma Defining Events (MDE) osservati nei pazienti sintomatici. Nei pazienti affetti da SMM le plasmacellule tumorali circolanti (CTPC) sono state associate ad un aumentato rischio di progressione al mieloma multiplo (MM). Scopo dello studio. L'obiettivo è valutare mediante citometria a flusso-Next Generation Flow (NGF) le caratteristiche delle PC nel midollo osseo (BM), la presenza di CTPC, l'espressione di BCL-2 e PD-L1, correlando i risultati con l'analisi FISH per le alterazioni che configurano la cosiddetta citogenetica a rischio alto e standard [del17p, t (4; 14), gain 1q, t (11; 14), t (14; 16)]. Risultati. Da settembre 2019 a giugno 2022 abbiamo analizzato 28 pazienti (M 20; F 8) con un'età mediana di 66 anni (40-85). I pazienti sono stati monitorati secondo le attuali linee guida IMWG. Secondo il modello di rischio MAYO 5/28 erano a basso rischio, 17 a rischio intermedio e 6 ad alto rischio di progressione. Attualmente nel sangue periferico non sono state rilevate le CTPC, né allo screening né alle valutazioni successive/ultimo follow-up. I marcatori più espressi a livello midollare erano CD56 (89%), CD27 (92%), CD81 (71%), 2 marcatori erano meno espressi: CD28 (42%), CD117 (28%), CD200 (10%), CD20 (14 %), CD19 e CD45 (3,5%). CD19 era presente solo in 1 paziente di sesso femminile a rischio intermedio che è progredita in mieloma attivo, ora in trattamento, mentre CD45 è stato riscontrato in 1 paziente di sesso femminile a rischio intermedio che ha mantenuto una malattia stabile all'ultimo follow-up. La coesistenza di marcatori che di solito sono reciprocamente esclusi è stata rilevata rispettivamente in 10/28 pazienti (CD27 + CD28 +) e in 3/28 casi (CD27 + CD28 + CD81 + CD117 +). BCL-2 (MFI) era altamente espresso in 11/28 casi (mediana 13,4; ≥ 13,5 nel 33,3%) mentre PD-L1 era positivo in 7/28 casi (25%). Nessuno dei pazienti presentava caratteristiche citogenetiche ad alto rischio. All'ultimo follow-up 4/28 pazienti (2 M; 2 F) hanno avuto una progressione ad MM sintomatico: alla diagnosi 3 erano a rischio intermedio e 1 ad alto rischio, secondo il modello progressivo MAYO. La PFS è stata generalmente influenzata da FLCr (P = 0,0013). Inoltre, una percentuale più alta di plasmacitosi del midollo osseo (&gt; 30%) può avere un impatto negativo sulla PFS con significatività statistica (P = 0,0332). La PFS è stata significativamente influenzata dall'espressione di BCL-2 (P = 0,094): nel gruppo con negatività per BCL-2 la PFS media era 61.778 rispetto alla PFS media di 90 mesi in quelli positivi. La PFS sembra essere influenzata anche dai livelli di PD-L1, anche se senza significatività statistica (P = 0,2986). I pazienti ad alto rischio MAYO sembrano avere una sopravvivenza inferiore, ma non è stata determinata una significatività statistica nelle diverse categorie (P = 0,19). La PFS non è stata influenzata statisticamente dall'entità CM e B2M. Tutti i 28 pazienti sono vivi all'ultimo follow-up. Conclusioni. L'attuale standard di cura in SMM è ancora una stretta sorveglianza clinica, al di fuori di sperimentazioni cliniche. I nostri dati necessitano di ulteriori indagini. Ciò che conferisce una tendenza positiva nella PFS nei pazienti che hanno espresso BCL-2 in eccesso deve essere ulteriormente esplorato. L'espressione diversificata dei marcatori analizzati conferma l'elevata eterogeneità e complessità anche della fase di smoldering del mieloma. Sono in corso ulteriori studi per identificare marcatori genomici, clinici, di laboratorio e/o citometrici più accurati sul PB che ci consentirebbero di assegnare il rischio individuale in modo più preciso.<br>Introduction. Smoldering multiple myeloma (SMM) occupies an intermediate position between what is usually referred to as a pre-malignant condition, monoclonal gammopathy undetermined significance (MGUS) and symptomatic multiple myeloma (MM). SMM has a higher disease burden than MGUS, but does not show end-organ damage or any of the other myeloma-defining events (MDE) observed in MM. In SMM patients tumor circulating plasma cells (CTPC) have been associated with increased risk of progression to Multiple Myeloma (MM). Aim. The aim is to evaluate by next-generation flow (NGF) the characteristics of PCs in bone marrow (BM), the presence of CTPC, the expression of BCL-2 and PD-L1, correlating the results with FISH analysis for del17p, t(4;14), gain 1q, t(11;14), t(14;16). Results. From September 2019 to June, 2022 we analyzed 28 patients (M 20; F 8) with a median age of 66 years (40-85). Patients were monitored according to current IMWG guidelines. According to MAYO risk model 5 were at low risk, 17 at intermediate and 6 at high risk of progression. Currently CPCs were not detected at screening, or at subsequent evaluations/last follow up. The most expressed markers were CD56 (89 %), CD27 (92 %), CD81 (71 %), 2 markers were less expressed: CD28 (42 %), CD117 (28 %), CD200 (10 %), CD20 (14 %), CD19 and CD45 (3,5%). CD19 was present in only 1 female patient at intermediate risk who progressed to active myeloma, now under treatment, while CD45 was found in 1 female patient at intermediate risk who maintained a stable disease at last follow-up. Coexistence of markers that are mutually excluded was detected in 10/28 patients (CD27+CD28+) and in 3/28 cases (CD27+CD28+CD81+CD117+) respectively. BCL-2 (MFI) was highly expressed in 11/28 cases (Median 13,4; ≥ 13,5 in 33.3%) while PD-L1 was positive in 7/28 cases (25%). None of the patients had high risk cytogenetic features. At last follow up 4/28 patients (2 M; 2 F) had a progression to multiple myeloma: at diagnosis 3 were at intermediate risk and 1 at high risk, according MAYO progressive model. PFS was in general affected by FLCr (P= 0,0013). Also, an higher percentage of bone marrow plasmacytosis (&gt;30%) can negatively impact on PFS with statistical significance (P = 0,0332). PFS was significantly affected by the expression of BCL-2 (P= 0,094): in the group with BCL-2 negativity mean PFS was 61,778 vs the mean PFS of 90 months in those who were positive. PFS seems to be affected also by PD-L1 levels, even if without statistical significance (P= 0,2986). Patients at high MAYO risk seem to have an inferior survival, but a statistical significance in the different categories was not determined (P= 0,19). PFS was not statistically affected by CM entity and B2M. All 28 patients are alive at last follow up. Conclusions. Current standard of care in SMM is still close surveillance, outside of a clinical trial. Our data need further investigations. What confers a positive trend in PFS in the patients that over expressed BCL-2 needs to be further explored. The diversified expression of analyzed markers confirms the high heterogeneity and complexity of the smoldering phase in MM. Research identifying more accurate genomic, clinical, laboratory and/or cytometric markers on PB that would enable us to assign individual risk more precisely is ongoing.

This thesis is based around examination of three mainstream inhaled drugs Formoterol, Budesonide and Beclomethasone for treatment of asthma and COPD. The areas investigated are these which have been raised in reports and studies, where there are concern, for drug use and assessment of their use. In reporting this work the literature study sets out a brief summary of the background and anatomy and physiology of the respiratory system and then discuses the mechanism of drug deposition in the lung, as well as the methods of studying deposition and pulmonary delivery devices. This section includes the basis of asthma and COPD and its treatment. In addition, a short section is presented on the role of the pharmacist in improving asthma and COPD patient¿s care. Therefore the thesis is divided into 3 parts based around formoterol, budesonide and beclomethasone. In the first case the research determines the in-vitro performance of formoterol and budesonide in combination therapy. In the initial stage a new rapid, robust and sensitive HPLC method was developed and validated for the simultaneous assay of formoterol and the two epimers of budesonide which are pharmacologically active. In the second section, the purpose was to evaluate the aerodynamic characteristics for a combination of formoterol and the two epimers of budesonide at inhalation flow rates of 28.3 and 60 L/min. The aerodynamic characteristics of the emitted dose were measured by an Anderson cascade impactor (ACI) and the next generation cascade impactor (NGI). In all aerodynamic characterisations, the differences between flow rates 28.3 and 60 were statistically significant in formoterol, budesonide R and budesonide S, while the differences between ACI and NGI at 60 were not statistically significant. Spacers are commonly used especially for paediatric and elderly patients. However, there is considerable discussion about their use and operation. In addition, the introduction of the HFAs propellants has led to many changes in the drug formulation characteristics. The purpose of the last section is to examine t h e performance of different types of spacers with different beclomethasone pMDIs. Also, it was to examine the hypothesis of whether the result of a specific spacer with a given drug/ brand name can be extrapolated to other pMDIs or brand names for the same drug. The results show that there are different effects on aerodynamic characterisation and there are significant differences in the amount of drug available for inhalation when different spacers are used as inhalation aids. Thus, the study shows that the result from experiments with a combination of a spacer and a device cannot be extrapolated to other combination.

This thesis is based around examination of three mainstream inhaled drugs Formoterol, Budesonide and Beclomethasone for treatment of asthma and COPD. The areas investigated are these which have been raised in reports and studies, where there are concern, for drug use and assessment of their use. In reporting this work the literature study sets out a brief summary of the background and anatomy and physiology of the respiratory system and then discuses the mechanism of drug deposition in the lung, as well as the methods of studying deposition and pulmonary delivery devices. This section includes the basis of asthma and COPD and its treatment. In addition, a short section is presented on the role of the pharmacist in improving asthma and COPD patient's care. Therefore the thesis is divided into 3 parts based around formoterol, budesonide and beclomethasone. In the first case the research determines the in-vitro performance of formoterol and budesonide in combination therapy. In the initial stage a new rapid, robust and sensitive HPLC method was developed and validated for the simultaneous assay of formoterol and the two epimers of budesonide which are pharmacologically active. In the second section, the purpose was to evaluate the aerodynamic characteristics for a combination of formoterol and the two epimers of budesonide at inhalation flow rates of 28.3 and 60 L/min. The aerodynamic characteristics of the emitted dose were measured by an Anderson cascade impactor (ACI) and the next generation cascade impactor (NGI). In all aerodynamic characterisations, the differences between flow rates 28.3 and 60 were statistically significant in formoterol, budesonide R and budesonide S, while the differences between ACI and NGI at 60 were not statistically significant. Spacers are commonly used especially for paediatric and elderly patients. However, there is considerable discussion about their use and operation. In addition, the introduction of the HFAs propellants has led to many changes in the drug formulation characteristics. The purpose of the last section is to examine t h e performance of different types of spacers with different beclomethasone pMDIs. Also, it was to examine the hypothesis of whether the result of a specific spacer with a given drug/ brand name can be extrapolated to other pMDIs or brand names for the same drug. The results show that there are different effects on aerodynamic characterisation and there are significant differences in the amount of drug available for inhalation when different spacers are used as inhalation aids. Thus, the study shows that the result from experiments with a combination of a spacer and a device cannot be extrapolated to other combination.

Purpose: There is a general consensus that games are effective as learning tools. There is however, a lack of knowledge regarding what makes games effective as a learning tool. The purpose of this study is therefore to answer the question: what are the antecedents of an effective game-based learning environment for the Net generation? The Net generation comprises individuals who prefer to learn using games as a tool. Aim: The aim of this dissertation is to develop a conceptual framework that reflects the antecedents of an effective game-based learning environment for the Net generation. The conceptual framework combines the IS Success Model, and the Task-Technology Fit and Flow theory. Method: The study used a quantitative method. Data was collected using an online instrument. The study used 125 participants from mainly the United Kingdom, United States and South Africa. The model was validated using confirmatory factor analysis and tested using multiple regression analysis. Key Findings: The identified antecedents of effectiveness are Game-Task Fit and Flow, where Flow consists of Clear Goals, Feedback and Concentration. Additionally, the Use factor in the model is replaced by Perceived Usefulness. The Conceptual Framework can be used as an evaluation tool for effective game-based learning environments for the Net generation.

Avec les avancées technologiques et la miniaturisation, le réseau d'interconnexions est devenu de plus en plus dense et complexe. Pour les domaines qui utilisent des applications à forts courants, comme l'automobile, les très fortes densités de courant dans les lignes métalliques peuvent conduire à des phénomènes comme l'électromigration, le voltage drop ou encore les surcharges électriques. La conception des circuits doit donc être réalisée en prenant en compte ces contraintes et en adaptant la largeur des lignes aux courants. Ce travail de thèse a eu comme objectif de développer des solutions pour la prise en compte des contraintes en courant lors de la phase de routage de blocs analogiques fort courants. Après une présentation des phénomènes impliqués et de l'état de l'art, une approche algorithmique pour l'aide au routage est introduite. Une méthode de caractérisation du courant est définie, un algorithme exhaustif de routage est présenté, puis utilisé pour effectuer des recherches de critères d'une bonne topologie. Deux algorithmes sont ensuite étudiés et comparés, un algorithme glouton, servant de référence, et un « Divide &amp; Conquer » original. Il présente une amélioration d'environ 10% pour l'aire, et presque 27% en temps CPU par rapport à l'algorithme glouton. La section suivante s'intéresse à la correction du current crowding, avec une méthode basée sur un ensemble de modèles mathématiques. Enfin, un flot basé sur les solutions développées durant la thèse est présenté et validé<br>In deep submicron VLSI circuits, excessive current density in interconnects is a major concern for analog high current application. If current over maximum density is not effectively mitigated, this can lead to phenomena like electromigration, voltage drop and electrical overload. It is a hot topic of interest in modern circuits due to the decrease of metal track sizes while high currents are necessary in automotive or mobile applications. This thesis had as goal to develop solutions for the consideration of the constraints in the current phase of routing analog blocks strong currents. After a presentation of the phenomena and the state of the art, an algorithmic approach to current driven net generation is introduced. A method to characterize the current is defined. Then an exhaustive routing algorithm is presented and used to search criteria for a good topology. Next, two algorithms are studied and compared, first a greedy algorithm, used as a reference, and a "Divide &amp; Conquer" original algorithm. It shows results improved on average by about 10% for area and almost 27% for CPU time compared with existing solution. The next section focuses on current crowding correction, with a method based on a set of mathematical models. Finally, a conception flow based on the developed solutions is introduced and validated

Data Centers (DCs) have become an intrinsic element of emerging technologies such as big data, artificial intelligence, cloud services; all of which entails interconnected and sophisticated computing and storage resources. Recent studies of conventional data center networks (DCNs) revealed two key challenges: a biased distribution of inter-rack traffic and unidentified flow classes: delay sensitive mice flows (MFs) and throughput-hungry elephant flows (EFs). Unfortunately, existing DCN topologies support only uniform distribution of capacities, provide limited bandwidth flexibilities and lacks of efficient flow classification mechanism. Fortunately, wireless DCs can leverage wireless communication emerging technologies, such as multi-terabit free-space optic (FSO), to provide flexible and reconfigurable DCN topologies. It is worth noting that indoor FSO links are less vulnerable to outdoor FSO channel impairments. Consequently, indoor FSO links are more robust and can offer high bandwidths with long stability, which can further be enhanced with wavelength division multiplexing (WDM) methods. In this thesis, we alleviate the bandwidth inefficiency by FSO links that have the desired agility by allocating the transmission powers to adapt link capacity for dynamically changing traffic conditions, and to reduce the maintenance costs and overhead. While routing the two classes along the same path causes unpleasant consequences, the DC researchers proposed traffic management solutions to treat them separately. However, the solutions either suffer from packet reordering and high queuing delay, or lack of accurate visibility and estimation on end-to-end path status. Alternatively, we leverage WDM to design elastic network topologies (i.e., part of the wavelengths are assigned to route MFs and the remaining for EFs). Since bandwidth demands can be lower than available capacity of WDM channels, we use traffic grooming to aggregate multiple flows into a larger flow and to enhance the link utilization. On the other hand, to reap the benefits of the proposed WDM isolated topology, an accurate and fast EF detection mechanism is necessary. Accordingly, we propose a scheme that uses TCP communication behavior and collect indicative packets for its flow classification algorithm, it demonstrates perfect flow classification accuracy, and is in order of magnitudes faster than existing solutions with low communication and computation overhead.