Knowledge representation into Ada parallel processing

The Knowledge Representation into Ada Parallel Processing project is a joint NASA and Air Force funded project to demonstrate the execution of intelligent systems in Ada on the Charles Stark Draper Laboratory fault-tolerant parallel processor (FTPP). Two applications were demonstrated - a portion of the adaptive tactical navigator and a real time controller. Both systems are implemented as Activation Framework Objects on the Activation Framework intelligent scheduling mechanism developed by Worcester Polytechnic Institute. The implementations, results of performance analyses showing speedup due to parallelism and initial efficiency improvements are detailed and further areas for performance improvements are suggested

Advanced information processing system: Input/output system services

The functional requirements and detailed specifications for the Input/Output (I/O) Systems Services of the Advanced Information Processing System (AIPS) are discussed. The introductory section is provided to outline the overall architecture and functional requirements of the AIPS system. Section 1.1 gives a brief overview of the AIPS architecture as well as a detailed description of the AIPS fault tolerant network architecture, while section 1.2 provides an introduction to the AIPS systems software. Sections 2 and 3 describe the functional requirements and design and detailed specifications of the I/O User Interface and Communications Management modules of the I/O System Services, respectively. Section 4 illustrates the use of the I/O System Services, while Section 5 concludes with a summary of results and suggestions for future work in this area

Advanced information processing system: Fault injection study and results

The objective of the AIPS program is to achieve a validated fault tolerant distributed computer system. The goals of the AIPS fault injection study were: (1) to present the fault injection study components addressing the AIPS validation objective; (2) to obtain feedback for fault removal from the design implementation; (3) to obtain statistical data regarding fault detection, isolation, and reconfiguration responses; and (4) to obtain data regarding the effects of faults on system performance. The parameters are described that must be varied to create a comprehensive set of fault injection tests, the subset of test cases selected, the test case measurements, and the test case execution. Both pin level hardware faults using a hardware fault injector and software injected memory mutations were used to test the system. An overview is provided of the hardware fault injector and the associated software used to carry out the experiments. Detailed specifications are given of fault and test results for the I/O Network and the AIPS Fault Tolerant Processor, respectively. The results are summarized and conclusions are given

Advanced information processing system: Inter-computer communication services

The purpose is to document the functional requirements and detailed specifications for the Inter-Computer Communications Services (ICCS) of the Advanced Information Processing System (AIPS). An introductory section is provided to outline the overall architecture and functional requirements of the AIPS and to present an overview of the ICCS. An overview of the AIPS architecture as well as a brief description of the AIPS software is given. The guarantees of the ICCS are provided, and the ICCS is described as a seven-layered International Standards Organization (ISO) Model. The ICCS functional requirements, functional design, and detailed specifications as well as each layer of the ICCS are also described. A summary of results and suggestions for future work are presented

Advanced information processing system: The Army fault tolerant architecture conceptual study. Volume 2: Army fault tolerant architecture design and analysis

Described here is the Army Fault Tolerant Architecture (AFTA) hardware architecture and components and the operating system. The architectural and operational theory of the AFTA Fault Tolerant Data Bus is discussed. The test and maintenance strategy developed for use in fielded AFTA installations is presented. An approach to be used in reducing the probability of AFTA failure due to common mode faults is described. Analytical models for AFTA performance, reliability, availability, life cycle cost, weight, power, and volume are developed. An approach is presented for using VHSIC Hardware Description Language (VHDL) to describe and design AFTA's developmental hardware. A plan is described for verifying and validating key AFTA concepts during the Dem/Val phase. Analytical models and partial mission requirements are used to generate AFTA configurations for the TF/TA/NOE and Ground Vehicle missions

Characterization of an in vitro 3D Human Small Airway Epithelia model for the application of integrated strategies in inhaled drug development

Drug Inhalation is one of the most effective administration routes; in fact, first pass metabolism is bypassed, rapid action onset is enabled and drug doses can be kept relatively low compared to other administration routes. The most recent 3D in vitro models allow to mimic some of the pulmonary tissue functionalities. These models reproduce the air-liquid interface, with beating cilia and mucus production, since different types of cells are present. Therefore, these models could be possibly applied to multi-disciplinary investigations following liquid, dry powder or aerosol treatment. In this thesis, an integrated strategy is proposed, with the aim to increase the rate of success in the drug candidate selection phase. Ideally, safety data should be integrated with early pharmacokinetics (PK) and efficacy indications in order to increase chances to select the candidate with the highest safety margins. With this ambitious objective in mind, a human-based 3D model were evaluated as model for the toxicity assessment and drug permeability evaluation. In particular, a commercially available 3D respiratory model SmallAir\u2122 has been qualified for: a) sensibility and specificity in the evaluation of lung toxicity potential of new compounds; b) permeability to test drug transport through tissues for formulation screening purposes; c) quantitative cytokine secretion on cell supernatant; d) cilia beating and muco-ciliary clearance evaluation by image analysis. These tests performed on a human tissue could provide more reliable results also because all tests were performed in the same model and this could be helpful in data integration. This approach could allow to fill gaps in drug discovery for human-relevant screening of new chemical entities (NCEs), best formulation selection, including physiochemical equivalence evaluation generic drug development. In vitro and in silico data can be helpful in predicting PK and toxicity profiles prior to preclinical and clinical studies. This allows to respect the 3Rs principle of replacement, reduction and refinement of in vivo studies. The proposed integrated testing strategy (ITS) has the potential to reduce the attrition in drug development, to optimize the inhaled formulation, to screen compounds for candidate selection and to reduce in vivo studies.For the toxicity tests, well-known respiratory toxic compound were tested both in the SmallAir\u2122 model and in the A549 cell line model. On the basis of results, the SmallAir\u2122 model seemed to be less sensitive than A549, probably due to the 3D structure physiological features. Cilia beating and mucus production can indeed protect the cells from the toxic effect miming the in vivo response. For the permeability study, well-known inhalation compounds with very different permeability values were evaluated both in SmallAir\u2122 model and in the standard Caco2 cell model. For low and high permeable compounds results obtained were comparable in the two test considered systems. The most evident difference was observed with medium permeable compounds, suggesting that the SmallAir\u2122 model should express different efflux pumps on their surface form the standard Caco2 cell model. The SmallAir\u2122 model was also evaluated as in vitro model for the inflammatory mediators assessment. The treatment with TGF-\u3b2 allowed to confirm the activation of the signalling via Smad2 while, inconclusive results were obtained with regards to cytokines and ROS release following Bleomycin treatment. The SmallAir\u2122 model was finally evaluated as in vitro model for the assessment of the Muco-ciliary Clearance (MCC). Results obtained in this project, showed that the SmallAir\u2122 can be a promising model to assess the MCC in vitro after treatment with compound acting on ATP release and Cystic fibrosis transmembrane conductance Inhibitor-172 (CFTR172inh). More test considering different compound, study design and end points has to be conducted, in order to identify a human relevant in vitro lung model to be applied in many fields of analysis

Advanced information processing system: The Army fault tolerant architecture conceptual study. Volume 1: Army fault tolerant architecture overview

Digital computing systems needed for Army programs such as the Computer-Aided Low Altitude Helicopter Flight Program and the Armored Systems Modernization (ASM) vehicles may be characterized by high computational throughput and input/output bandwidth, hard real-time response, high reliability and availability, and maintainability, testability, and producibility requirements. In addition, such a system should be affordable to produce, procure, maintain, and upgrade. To address these needs, the Army Fault Tolerant Architecture (AFTA) is being designed and constructed under a three-year program comprised of a conceptual study, detailed design and fabrication, and demonstration and validation phases. Described here are the results of the conceptual study phase of the AFTA development. Given here is an introduction to the AFTA program, its objectives, and key elements of its technical approach. A format is designed for representing mission requirements in a manner suitable for first order AFTA sizing and analysis, followed by a discussion of the current state of mission requirements acquisition for the targeted Army missions. An overview is given of AFTA's architectural theory of operation

Development and Validation of a New Prognostic System for Patients with Hepatocellular Carcinoma

BACKGROUND: Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. METHODS AND FINDINGS: Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26-106 mo) and 39 mo for Taiwanese patients (interquartile range, 12-61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score 64 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2-3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4-5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score's prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups. CONCLUSIONS: The ITA.LI.CA prognostic system includes both a tumor staging-stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)-and a prognostic score-integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations

Years of life that could be saved from prevention of hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour 65 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost