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Protective Effects of Pertussis Immunoglobulin (P-IGIV) in the Aerosol Challenge Model

Protective Effects of Pertussis Immunoglobulin (P-IGIV) in the Aerosol Challenge Model

The chamber and the nebulizer were enclosed in the BL-2 biosafety hood and certified prior to use to document that airflow barriers were maintained. Uni- formity of the aerosol in the chamber was maintained with the use of two PAPST 900 series AC fans (Newark Supply, Newark, N.J.) and monitored by a laser light source to confirm an even dispersion of the aerosol droplets. Mice were exposed to nebulization for 30 min and removed 30 min after termination of aerosoliza- tion. The completion of the aerosol represented time zero. Mice were removed from the box and returned to their cages. Cages were checked daily for mortality. Establishment of the model. Experiments were designed to examine the phar- macokinetics, dose response, and effect of timing of P-IGIV in the aerosol challenge model. Because P-IGIV is developed for i.v. administration and be- cause intraperitoneal (i.p.) administration is immensely easier in neonatal mice, the basic pharmacology of P-IGIV was studied in uninfected mice, comparing i.v. administration to i.p. administration. We also compared P-IGIV to mouse PHIS and a standard human gamma globulin (HuISG) preparation. Twenty-four-day- old mice were used to approximate the age of mice in the aerosol challenge experiments (17 days old plus 7 days postchallenge). Groups of five mice received P-IGIV at a dose of 1,700 mg/kg in 0.2 ml given either i.p. or i.v. Mice were bled at 1, 3, and 6 h and at 3, 7, and 14 days after administration. Serum half-life and volume of distribution calculations were determined as described above.

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Evaluation of Antihemagglutinin and Antineuraminidase Antibodies as Correlates of Protection in an Influenza A/H1N1 Virus Healthy Human Challenge Model

Evaluation of Antihemagglutinin and Antineuraminidase Antibodies as Correlates of Protection in an Influenza A/H1N1 Virus Healthy Human Challenge Model

IMPORTANCE This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “pro- tective” hemagglutination inhibition (HAI) titer of >1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza.

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Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model

Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model

The authors wish to acknowledge the contribution of all study participants. The authors acknowledge the support of the Wellcome Trust (Wellcome Trust Strategic Translational Award grant no. 092661) in the development of the typhoid human challenge model that was used for this study, and the support of the NIHR Oxford Biomedical Research Centre. Cytokine studies were supported by the Bill & Melinda Gates Foundation: Global Health Vaccine Accelerator Platform grant to the Center for Human Systems Immunology at Stanford (no. OPP1113682). M.M.G. is supported in part by the NIHR Imperial Biomedical Research Centre. In addition, the authors wish to thank the following persons: R. Milward and the Walter Reed Army Institute of Research Pilot BioProduction Facility, who manufactured the GMP challenge lots; the Data Safety Monitoring Committee (D. Lalloo, D. Hill, P. Monk); M. Morgan and the microbiology laboratory at the Oxford University Hospital NHS foundation Trust; M. McClure; M. Raymond; T. Darton; C. Waddington; M. M. Levine; and the University of Maryland for provision of the original S. Typhi Quailes challenge strain. The study was funded by the Bill & Melinda Gates Foundation (no. OPP1126235). The study funders had no role in study design, data collection or analysis.

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Refinement of a Human Challenge Model for Evaluation of Enterotoxigenic Escherichia coli Vaccines

Refinement of a Human Challenge Model for Evaluation of Enterotoxigenic Escherichia coli Vaccines

could be lowered even further with this strain. In addition, it would have been ideal to directly compare these inoculum dose levels in volunteers who were fasted overnight to those with a 90-min fast, in order to establish clearly the role that a longer fast played in this model. This model used a single challenge strain which expresses LT and ST as well as CFA/I. It is unlikely that volunteer studies can be carried out with all combinations of toxin and CFA profiles. However, to facilitate development of vaccines for ETEC it would seem important to be able to demonstrate protection against ETEC diarrhea due to some additional key toxin-CFA combinations. With the ris- ing prevalence and known pathogenicity of ETEC strains ex- pressing ST only and CS6, the development of a relevant ETEC challenge model based on a wild-type strain containing ST with or without CS6 would be advantageous (26). Currently there are no candidate vaccines which are able to induce im- munity to ST, and unless such a vaccine can be developed, vaccines will have to rely on immunity to the colonization factors or other virulence antigens.

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Drivers of Nasopharyngeal Pneumococcal Colonisation: Investigation Using an Experimental Human Challenge Model

Drivers of Nasopharyngeal Pneumococcal Colonisation: Investigation Using an Experimental Human Challenge Model

This thesis focuses on investigating the drivers of nasopharyngeal pneumococcal colonisation. Two studies were conducted, and the clinical aspects of these studies will predominantly be discussed in this thesis. Both studies used the experimental human pneumococcal challenge model to answer research questions which are outlined at the end of the introduction. To form a rationale for these studies, a literature review was conducted on pneumococcal colonisation, transmission of Streptococcus pneumoniae and pneumococcal disease and is presented below along with description of gaps in the literature. Following this introduction, the methods section outlines the broad methods relevant to both studies described in this thesis. Chapter 3 and 4 describe the results of the two studies conducted as part of this MD project. The final chapter (Chapter 5) is a general discussion of the main findings of both studies, a methodological critique of the work conducted and the implications of the findings with an outline of possible future work in this field.

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STAT4 Deficiency Fails To Induce Lung Th2 or Th17 Immunity following Primary or Secondary Respiratory Syncytial Virus (RSV) Challenge but Enhances the Lung RSV-Specific CD8+ T Cell Immune Response to Secondary Challenge

STAT4 Deficiency Fails To Induce Lung Th2 or Th17 Immunity following Primary or Secondary Respiratory Syncytial Virus (RSV) Challenge but Enhances the Lung RSV-Specific CD8+ T Cell Immune Response to Secondary Challenge

Previous studies utilized STAT4 ⫺/⫺ mice to investigate the role of STAT4 in regulating the lung immune response to allergens and viral infection. Using an ovalbumin model of allergic airway in- flammation in STAT4 ⫺/⫺ mice on a BALB/c background, one group showed that STAT4 ⫺/⫺ mice had significantly decreased airway eosinophilia, airway neutrophilia, and airway mucus ex- pression compared to WT mice (41). Another group, using a sim- ilar model, demonstrated that STAT4 ⫺/⫺ mice have decreased airway cellularity and no increase in lung IL-13 expression levels compared to WT mice (44). Using a distinct cockroach antigen model of allergic airway inflammation in BALB/c STAT4 ⫺/⫺ mice, another group showed that STAT4 ⫺/⫺ mice had signifi- cantly decreased peribronchial inflammation and lung IL-5 ex- pression levels, with no increase in lung IL-13 expression levels (43). Finally, using a primary influenza virus challenge model in WT and STAT4 ⫺/⫺ BALB/c mice, another study showed that in- fluenza virus-challenged STAT4 ⫺/⫺ mice did not develop in- creased Th2 immune responses, as quantified by IL-4 expression in the spleen or lungs postchallenge (42). Thus, those previous studies support our conclusions that STAT4, in the context of the FIG 14 Lung protein expression of IFN- ␣ , IFN- ␤ , and IL-27 at early time points following secondary RSV challenge. Shown are lung protein expression levels of IFN- ␣ (A), IFN- ␤ (B), and IL-27 (C) from WT and STAT4 ⫺ / ⫺ mice RSV challenged on days 0 and 42 and harvested at 6, 12, and 24 h post-secondary RSV

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An Approach of Improve Efficiencies through DevOps Adoption

An Approach of Improve Efficiencies through DevOps Adoption

Finding common metrics for both development and operations as well as quality assurance was considered challenging. Traditional metrics such as uptime and the amount of tasks completed in a Scrum sprint, for instance, are still viable but the focus is shifting. The “DevOps” metrics such as lead time, code quality and overall system health can be measured with new kinds of tools. Once the metrics are in place, it may take time for the numbers to be comparable with other applications. According to Pasi Katajainen, there are managers who might be over-enthusiastic with these new metrics. When these metrics are first put in place for an application that has been in development for several years, it is natural for these metrics, such as code quality, to be below average. The challenge is finding the balance between improving the score of the metrics and keeping up a rapid pace in development. Over-emphasizing the metrics can have an adverse effect on the development since a lot of time goes to refactoring code and making the application perform better from a metrics-point of view.

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Exploring the performance of strategy in two-way interactions : an analysis of annual general meetings from a practice perspective

Exploring the performance of strategy in two-way interactions : an analysis of annual general meetings from a practice perspective

If an audience member begins an interaction by posing a challenge (for example, by laying a charge of wrongdoing), the ensuing two-way interaction would follow the path indicated as Type-A in the emergent model (see Figure x on page x). The first move is made by the audience member as a challenge, and a top manager always first responds with one (or more) of three discursive practices we have identified as re-orienting information, regulating conversation and contextualising actions. The top manager then invariably follows the first response with another discursive practice identified as deliberate self-disclosure. The entire response delivered by the top managers during a turn consists of a pattern that cycles between these two set of practices. If the audience member makes a second move by sustaining the challenge, the top manager then responds by repeating the same pattern of practices as he/she did in the previous turn. The dialogue between the parties continues in this fashion until the audience member yields the floor and concludes the interaction. A new audience member takes up the floor, and the entire cycle repeats itself.

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The manufacturing of human viral challenge agents for use in clinical studies to accelerate the drug development process

The manufacturing of human viral challenge agents for use in clinical studies to accelerate the drug development process

the product during each stage of the process from seed virus collection, pre-production processing, production, through to final fill of the GMP manufactured prod- uct should be conducted. For our challenge viruses, we considered the potential risks from all of the raw materi- als and cell banks/eggs used and possible newly emerg- ing agents at the time of manufacture. Testing included; sterility, microbial enumeration testing, Mycoplasma & Mycobacterium detection tests along with testing for non-specific viral contaminants by in  vitro inocula- tion of indicator cells. Also, we conducted tests for the quantification of reverse transcriptase activity as well as extensive agent-specific molecular testing for a panel of contaminants including known human viruses of both chronic and acute infections as well as the list of other potential pathogen contaminants that were highlighted by the risk assessment.

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Acute Inflammatory Response to Endotoxin Challenge: Model Development, Parameter Estimation, and Treatment Control.

Acute Inflammatory Response to Endotoxin Challenge: Model Development, Parameter Estimation, and Treatment Control.

We successfully derived a reduced 7D model of acute inflammatory response to endotoxin challenge from the 8D model developed in [126]. In addition to reducing the dimension of the state space, the parameter space was also reduce from 46 to 40 parameters. We verified that the solutions of the 7D model demonstrated comparative or better overall performance in predicting the experimental data on inflammatory cytokines while maintaining relevant biological fidelity. The most significant challenge our 7D model faced was not capturing the dynamics of the anti- inflammatory cytokine as well as it consistently did with the pro-inflammatory cytokines. The implementation of an NMPC scheme to derive optimal treatment therapies that can mod- ulate inflammation was successfully conducted. The three therapeutic recalculation time points used in the NMPC scheme all significantly reduced the effects of the inflammation and tissue damage while controlling the states responses. Meanwhile, the “One hour recalculation step” is not biologically feasible since that can lead to too much blood loss in the rats which in turn can result in hypovolemic shock. The in silico simulation done at this recalculation instance only illustrates a theoretical improvement over the other recalculation intervals. A rather conserva- tive but a more practical recalculation step will be to use the same time intervals corresponding to the periods actual data were obtained in the experiment done in [126].

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Designing an Innovation Engine Model and a Software Tool to
Meet Large Organizations Challenges with SMEs Capabilities,
a Pilot Study

Designing an Innovation Engine Model and a Software Tool to Meet Large Organizations Challenges with SMEs Capabilities, a Pilot Study

Innovation is also about the use of new ideas and knowledge in something that will create social, commercial or organizational value (Porter & Kramer, 2011). Innovation can be categorized in open or closed. “Open innovation is a paradigm that assumes that firms can and should use external ideas as well as internal ideas, and internal and external paths to market, as the firms look to advance their technology” (Chesbrough, Vanhaverbeke & West, 2006). Open innovation implies working with associated partners sharing risks and rewards. There is permeability between an organization and its environment, where innovations transfer inward and outward. Open innovation occurs when companies need to solve their needs with the capabilities of other organizations (in-bound innovation: buying or licensing patents or inventions or Intellectual Property (IP)) or when internal inventions are translated outside the company as licensing or spin-offs (outbound innovation) (Busarovs, 2013). Open innovation fosters cost reduction in R&D, customer-centered design and potential for better synergism between organizations (Marais & Schutte, 2009). But, in open innovation collaborations organizations may need to reveal confidential information or intellectual property, and have the challenge to manage innovation internally and externally finding the best partnership (Salter, Criscuolo & Ter Wal, 2014).

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PhysIt: A Diagnosis and Troubleshooting Tool for Physiotherapists in Training

PhysIt: A Diagnosis and Troubleshooting Tool for Physiotherapists in Training

Abstract: Many physiotherapy treatments begin with a diagnosis process. The patient describes symptoms, upon which the physiotherapist decides which tests to perform until a final diagnosis is reached. The relationships between the anatomical components are too complex to keep in mind and the possible actions are abundant. A trainee physiotherapist with little experience naively applies multiple tests to reach the root cause of the symptoms, which is a highly inefficient process. This work proposes to assist students in this challenge by presenting three main contributions: (1) A compilation of the neuromuscular system as components of a system in a Model-Based Diagnosis problem; (2) The PhysIt is an AI-based tool that enables an interactive visualization and diagnosis to assist trainee physiotherapists; and (3) An empirical evaluation that comprehends performance analysis and a user study. The performance analysis is based on evaluation of simulated cases and common scenarios taken from anatomy exams. The user study evaluates the efficacy of the system to assist students in the beginning of the clinical studies. The results show that our system significantly decreases the number of candidate diagnoses, without discarding the correct diagnosis, and that students in their clinical studies find PhysIt helpful in the diagnosis process.

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A surprisingly effective out of the box char2char model on the E2E NLG Challenge dataset

A surprisingly effective out of the box char2char model on the E2E NLG Challenge dataset

We train a char2char model on the E2E NLG Challenge data, by exploiting “out-of-the-box” the recently released tf- seq2seq framework, using some of the standard options of this tool. With mini- mal effort, and in particular without delex- icalization, tokenization or lowercasing, the obtained raw predictions, according to a small scale human evaluation, are excel- lent on the linguistic side and quite rea- sonable on the adequacy side, the primary downside being the possible omissions of semantic material. However, in a signifi- cant number of cases (more than 70%), a perfect solution can be found in the top- 20 predictions, indicating promising direc- tions for solving the remaining issues. 1 Introduction

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The challenge of rescheduling nursing staff: Informing the development of a mathematical model decision tool

The challenge of rescheduling nursing staff: Informing the development of a mathematical model decision tool

Applied mathematical optimisation, or intelligent computing, has much potential to assist managers involved in rescheduling (Clark & Walker, 2011), but is as yet largely unrealised (Moz and Pato, 2003, 2004, 2007; Bard and Purnomo, 2006; Kitada et al., 2010; Maenhout and Vanhouke, 2011). In a recent review of the application of mathematical/computational approaches to the challenges associated with rescheduling, few examples of end user involvement - nurse manager decision- making - were evident (Clark et Walker, 2011). Building on that review, we undertook a consultation exercise with ward and senior managers in several NHS trusts (Clark et al., 2013). This brought to the foreground the complexity of rescheduling decision-making, and the urgent imperative to interrogate managers more comprehensively, if such applications were to have operability. This research sought to capture that complexity and managerial intelligence, mapping the typology of decisions and costs associated with rescheduling in an NHS organisation and inform prototype development. It thus contributes to the development of a mathematic model based decision support tool for managers to use to make considered, operationally robust and speedier rescheduling decisions.

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A few hours later loud knocks on the door heralded the arrival of 6 Special branch officers who make it clear that they wanted co-operation otherwise they will use ‘blatant search techniques’. This implied that not only would they turn the place over but that the search would become very obvious to the neighbours. Without the argument of the night before, I might have caved in. Because of it and a silly sense of ‘I told you so’ I calmly suggested that what they were doing infringed academic freedom and was unprecedented. This episode of déjà vu was so well documented in the light of subsequent events, Brian Inglis used it in his book, the Hidden Power. The lesson here is whilst one should never give way to paranoia, it is useful to develop and trust your intuition. Our minds are capable of intuitive leaps which are ours to use even if we can not necessarily rationally explain them and the history of science is full of such episodes. Our challenge is to use hunches as a methodology to conjecture with or refute.

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The contribution of specific class I and II histone deacetylases in the development of anxietyrelated behavior in a mouse model of prenatal immune challenge

The contribution of specific class I and II histone deacetylases in the development of anxietyrelated behavior in a mouse model of prenatal immune challenge

Figure 4. Proposed mechanism of the development of affective disorders in a mouse model of prenatal immune challenge. After administration, poly I:C binds to TLR-3, which activates the maternal immune response. Pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α, are generated and enter the foetal circulation. These cytokines might directly or indirectly (e.g. via the production of oxidative stress and activation of the kynurenine pathway) affect foetal brain development. In addition, immune activation is accompanied by PGE 2 -mediated fever and POM-C -mediated anorexia, both resulting in metabolic deficiencies

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“My Way of Telling a Story”: Persona based Grounded Story Generation

“My Way of Telling a Story”: Persona based Grounded Story Generation

We present an example of the story generated by each of the models proposed in Figure 1. This example belongs to persona in cluster C3. The words corresponding to this cluster are highlighted with blue color in the persona conditioned gen- eration of the stories. The main observation is that all of the five sentences in the story contain a word relevant to happiness for each of the MPP, LEPC and LEPD models. SEPC and SEPD mod- els capture these happiness features in only two and one sentences respectively. The glocal model does not cater explicitly to the personality while our proposed models attempt to capture the per- sona tone in generation. This is observed in the fourth generated sentence in the sequence by each of our proposed models. While the glocal model uses the word ‘silly’, our models capture the tone and generate ‘excited’ and ‘great’. Similarly for the fifth sentence, MPP, LEPC and LEPD gener- ate ‘happy’, ‘surprised’ and ‘happy’ respectively.

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The Galleria mellonella Infection Model Does Not Accurately Differentiate between Hypervirulent and Classical Klebsiella pneumoniae

The Galleria mellonella Infection Model Does Not Accurately Differentiate between Hypervirulent and Classical Klebsiella pneumoniae

IMPORTANCE Hypervirulent Klebsiella pneumoniae (hvKp) is of increasing concern because it can infect individuals in community and health care settings and because such infections are becoming difficult to treat. Identification of hvKp is important for patient care and to track its global spread. The genetic definition of hvKp, which can be used for its identification and the development of diagnostic tests, has not been optimized. Determination of possession of 4 of 5 genes that are present on the hvKp-specific virulence plasmid is highly accurate for identifying hvKp. However, an ongoing issue is whether strains that possess only some of these markers are still hypervirulent. The Galleria mellonella model and, less commonly, the murine infec- tion model have been used to assess the virulence of these ambiguously identifiable strains. This report demonstrates that the murine model but not the G. mellonella model accurately identifies suspected hvKp strains. This information is critical for the development of diagnostics for patient care and for future research studies.

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A  Challenge  Obfuscation  Method  for  Thwarting  Model  Building  Attacks  on  PUFs

A Challenge Obfuscation Method for Thwarting Model Building Attacks on PUFs

Abstract. Physical Unclonable Functions (PUFs), as novel lightweight hardware security primitives, provide a higher level security with lower power and area overhead in comparison with traditional cryptographic solutions. However, it has been demonstrated that PUFs are vulnerable to model building attacks, especially those using linear additive func- tions such as Arbiter PUF (APUF) and k-sum PUF as building units. Nevertheless, both APUFs and k-sum PUFs are highly desirable secu- rity primitives, especially for authentication, because they are capable of producing a huge number of challenge response pairs (CRPs) and can be easily integrated into silicon. In this paper, we actually rely on the demonstrated vulnerability of PUFs to model building attacks as well as the relative ease with which this can be achieved to develop a new parameter-based authentication protocol based on obfuscating challenges sent to PUFs and their subsequent recovery. We show, using statistical analysis and model building attacks using published approaches, that constructing a model using machine learning techniques are infeasible when our proposed method is employed. Finally, we also demonstrate that our challenge obfuscation and recovery method can be successfully used for secure key exchange between two parties.

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Simulation of climate, ice sheets and CO 2evolution during the last four glacial cycles with an Earth system model of intermediate complexity

Simulation of climate, ice sheets and CO 2evolution during the last four glacial cycles with an Earth system model of intermediate complexity

A1 Modifications of terrestrial carbon cycle model The old version of the CLIMBER-2 carbon cycle model de- scribed in Brovkin et al. (2002) considers two vegetation types – trees and grass. Each of the two vegetation types has four carbon pools – leaves, stems, and fast and slow soil carbon. Each of these four pools occupies the same frac- tion of grid cell as the respective vegetation type. Crichton et al. (2014) in their version of permafrost carbon implementa- tion in CLIMBER-2 have not changed the pool structure but modified turnover time, assuming that it is increasing under permafrost conditions. In the new version of the carbon cycle model which we use in the present work, we have introduced three new carbon pools: boreal peat, permafrost, and carbon buried under ice sheets. The fractions of land covered by grass and trees are computed in the vegetation model follow- ing Brovkin et al. (1997), the fraction of land covered by ice sheets is computed by the ice sheet model and the fraction of permafrost f pm for the temperature range − 5 ◦ C < T ts < 5 ◦ C

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