Virosome-Formulated Plasmodium falciparum AMA-1 & CSP Derived Peptides as Malaria Vaccine: Randomized Phase 1b Trial in Semi-Immune Adults & Children.

Background: This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children.Methods: The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5-9 years) living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal (R) V on day 0 and 90.Results: No serious or severe adverse events (AEs) related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal (R) V group compared to the PEV3B group (p = 0.014). In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal (R) V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal (R) V; RR = 0.50 [95%-CI: 0.29-0.88], p = 0.02).Conclusion: These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.

Short- and long-term changes in chromosomal inversion polymorphism and global warming: Drosophila subobscura from the Balkans

The chromosomal inversion polymorphism of Drosophila subobscura is adaptive to environmental changes. The population of Petnica, Serbia, was chosen to analyze short- and long-term changes in this polymorphism. Short-term changes were studied in the samples collected in May, June, and August of 1995. The inversion polymorphism varied over these months, although various interpretations are possible. To analyze long-term changes, samples obtained in May 1995 and May 2010 were compared. The frequency of the 'cold' adapted inversions (Ast, Jst, Ust, Est, and Ost) decreased and that of the 'warm' adapted inversions (A2, J1, U1+2, and O3+4) increased, from 1995 to 2010. These changes are consistent with the general increase in temperature recorded in Petnica for the same period. Finally, the possible response of chromosomal polymorphism to global warming was analyzed at the regional level (Balkan peninsula). This polymorphism depends on the ecological conditions of the populations, and the changes observed appear to be consistent with global warming expectations. Natural selection seems to be the main mechanism responsible for the evolution of this chromosomal polymorphism.

Short- and long-term changes in chromosomal inversion polymorphism and global warming: Drosophila subobscura from the Balkans

The chromosomal inversion polymorphism of Drosophila subobscura is adaptive to environmental changes. The population of Petnica, Serbia, was chosen to analyze short- and long-term changes in this polymorphism. Short-term changes were studied in the samples collected in May, June, and August of 1995. The inversion polymorphism varied over these months, although various interpretations are possible. To analyze long-term changes, samples obtained in May 1995 and May 2010 were compared. The frequency of the 'cold' adapted inversions (Ast, Jst, Ust, Est, and Ost) decreased and that of the 'warm' adapted inversions (A2, J1, U1+2, and O3+4) increased, from 1995 to 2010. These changes are consistent with the general increase in temperature recorded in Petnica for the same period. Finally, the possible response of chromosomal polymorphism to global warming was analyzed at the regional level (Balkan peninsula). This polymorphism depends on the ecological conditions of the populations, and the changes observed appear to be consistent with global warming expectations. Natural selection seems to be the main mechanism responsible for the evolution of this chromosomal polymorphism.

Ip-10 Is Associated With Il28b Variation And Predicts The First Phase Decline Of Hcv Rna And Outcome Of Therapy In Chronic Hepatitis C

High systemic levels of IP-10 at onset of combination therapy for chronic hepatitis C mirror intrahepatic mRNA levels and predict a slower first phase decline in HCV RNA as well as poor outcome. Recently several genome wide association studies have revealed that single nucleotide polymorphisms (SNPs) on chromosome19 within proximity of IL28B predict spontaneous clearance of HCV infection and as therapeutic outcome among patients infected with HCV genotype 1, with three such SNPs being highly predictive: rs12979860, rs12980275, and rs8099917. In the present study, we correlated genetic variations in these SNPs from 253 Caucasian patients with pretreatment plasma levels of IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO). The favorable genetic variations in all three SNPs (CC, AA, and TT respectively) was significantly associated with lower baseline IP-10 (CC vs. CT/TT at rs12979860: median 189 vs. 258 pg/mL, P=0.02, AA vs. AG/GG at rs12980275: median 189 vs. 258 pg/mL, P=0.01, TT vs. TG/GG at rs8099917: median 224 vs. 288 pg/mL, P=0.04), were significantly less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P=0.01 respectively) and had significantly higher baseline viral load than carriers of the SNP genotypes (6.3 vs. 5.9 log 10 IU/mL, P=0.0012, 6.3 vs. 6.0 log 10 IU/mL, P=0.026, and 6.3 vs. 5.8 log 10 IU/mL, P=0.0003 respectively). Among HCV genotype 1 infected homozygous or heterogeneous carriers of the favorable C, A, and T genotypes, lower baseline IP-10 was significantly associated with greater decline in HCV-RNA day 0-4, which translated into increased rates of achieving SVR among homozygous patients with baseline IP-10 below 150 pg/mL (85%, 75%, and 75% respectively). In a multivariate analysis among genotype 1 infected patients, both baseline IP-10 and the SNPs were significant independent predictors of SVR. Conclusion: Baseline plasma IP-10 is significantly associated with IL28B variations, and augments the predictiveness of the first phase decline in HCV RNA and final treatment outcome.

Safety and Mobility Impacts of Winter Weather --Phase 3, SPR RB01-012, 2014

Highway agencies spend millions of dollars to ensure safe and efficient winter travel. However, the effectiveness of winter-weather maintenance practices on safety and mobility are somewhat difficult to quantify. Safety and Mobility Impacts of Winter Weather - Phase 1 investigated opportunities for improving traffic safety on state-maintained roads in Iowa during winter-weather conditions. In Phase 2, three Iowa Department of Transportation (DOT) high-priority sites were evaluated and realistic maintenance and operations mitigation strategies were also identified. In this project, site prioritization techniques for identifying roadway segments with the potential for safety improvements related to winter-weather crashes, were developed through traditional naïve statistical methods by using raw crash data for seven winter seasons and previously developed metrics. Additionally, crash frequency models were developed using integrated crash data for four winter seasons, with the objective of identifying factors that affect crash frequency during winter seasons and screening roadway segments using the empirical Bayes technique. Based on these prioritization techniques, 11 sites were identified and analyzed in conjunction with input from Iowa DOT district maintenance managers and snowplow operators and the Iowa DOT Road Weather Information System (RWIS) coordinator.

Electronic Construction Collaboration System – Final Phase, SPR RB02-008, 2014

This phase of the research project involved two major efforts: (1) Complete the implementation of AEC-Sync (formerly known as Attolist) on the Iowa Falls Arch Bridge project and (2) develop a web-based project management system (WPMS) for projects under $10 million. For the first major effort, AEC-Sync was provided for the Iowa Department of Transportation (DOT) in a software as a service agreement, allowing the Iowa DOT to rapidly implement the solution with modest effort. During the 2010 fiscal year, the research team was able to help with the implementation process for the solution. The research team also collected feedback from the Broadway Viaduct project team members before the start of the project and implementation of the solution. For the 2011 fiscal year, the research team collected the post-project surveys from the Broadway Viaduct project members and compared them to the pre-project survey results. The result of the AEC-Sync implementation in the Broadway Viaduct project was a positive one. The project members were satisfied with the performance of AEC-Sync and how it facilitated document management and transparency. In addition, the research team distributed, collected, and analyzed the pre-project surveys for the Iowa Falls Arch Bridge project. During the 2012 fiscal year, the research team analyzed the post-project surveys for the Iowa Falls Arch Bridge project AEC-Sync implementation and found a positive outcome when compared to the pre-project surveys. The second major effort for this project involved the identification and implementation of a WPMS solution for smaller bridge and highway projects. During the 2011 fiscal year, Microsoft SharePoint was selected to be implemented on these smaller highway projects. In this year, workflows for the shop/working drawings for the smaller highway projects specified in Section 1105 of the Iowa DOT Specifications were developed. These workflows will serve as the guide for the development of the SharePoint pages. In order to implement the Microsoft SharePoint pages, the effort of an integrated team proved to be vital because it brought together the expertise required from researchers, programmers, and webpage developers to develop the SharePoint pages.

3D coronary vessel wall imaging utilizing a local inversion technique with spiral image acquisition.

Current 2D black blood coronary vessel wall imaging suffers from a relatively limited coverage of the coronary artery tree. Hence, a 3D approach facilitating more extensive coverage would be desirable. The straightforward combination of a 3D-acquisition technique together with a dual inversion prepulse can decrease the effectiveness of the black blood preparation. To minimize artifacts from insufficiently suppressed blood signal of the nearby blood pools, and to reduce residual respiratory motion artifacts from the chest wall, a novel local inversion technique was implemented. The combination of a nonselective inversion prepulse with a 2D selective local inversion prepulse allowed for suppression of unwanted signal outside a user-defined region of interest. Among 10 subjects evaluated using a 3D-spiral readout, the local inversion pulse effectively suppressed signal from ventricular blood, myocardium, and chest wall tissue in all cases. The coronary vessel wall could be visualized within the entire imaging volume.

Dominant human CD8 T cell clonotypes persist simultaneously as memory and effector cells in memory phase.

The adaptive immune system plays a critical role in protection at the time of secondary infection. It does so through the rapid and robust reactivation of memory T cells which are maintained long-term, in a phenotypically heterogeneous state, following their primary encounter with Ag. Although most HLA-A*0201/influenza matrix protein(58-66)-specific CD8 T cells from healthy donors display characteristics typical of memory T cells, through our extensive phenotypic analysis we have further shown that up to 20% of these cells express neither the IL-7 receptor CD127 nor the costimulatory molecule CD28. In contrast to the majority of CD28(pos) cells, granzyme B and perforin were frequently expressed by the CD28(neg) cells, suggesting that they are effector cells. Indeed, these cells were able to kill target cells, in an Ag-specific manner, directly ex vivo. Thus, our findings demonstrate the remarkable long-term persistence in healthy humans of not only influenza-specific memory cells, but also of effector T cells. We further observed that granzyme B expression in influenza-specific CD8 T cells paralleled levels in the total CD8 T cell population, suggestive of Ag-nonspecific bystander activation. Sequencing of TCR alpha- and beta-chains showed that the TCR repertoire specific for this epitope was dominated by one, or a few, T cell clonotype per healthy donor. Moreover, our sequencing analysis revealed, for the first time in humans, that identical clonotypes can coexist as both memory and effector T cells, thereby supporting the principle of multipotent clonotypic differentiation.

A framework for hybrid simulations of two-phase flow in porous media

Rough a global coarse problem. Although these techniques are usually employed for problems in which the fine-scale processes are described by Darcy's law, they can also be applied to pore-scale simulations and used as a mathematical framework for hybrid methods that couples a Darcy and pore scales. In this work, we consider a pore-scale description of fine-scale processes. The Navier-Stokes equations are numerically solved in the pore geometry to compute the velocity field and obtain generalized permeabilities. In the case of two-phase flow, the dynamics of the phase interface is described by the volume of fluid method with the continuum surface force model. The MsFV method is employed to construct an algorithm that couples a Darcy macro-scale description with a pore-scale description at the fine scale. The hybrid simulations results presented are in good agreement with the fine-scale reference solutions. As the reconstruction of the fine-scale details can be done adaptively, the presented method offers a flexible framework for hybrid modeling.

Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011-40014).

PURPOSE: To assess the feasibility and activity of radio-chemotherapy with mitomycin C (MMC) and cisplatin (CDDP) in locally advanced squamous cell anal carcinoma with reference to radiotherapy (RT) combined with MMC and fluorouracil (5-FU). PATIENTS AND METHODS: Patients with measurable disease >4 cmN0 or N+ received RT (36Gy+2 week gap+23.4Gy) with either MMC/CDDP or MMC/5-FU (MMC 10mg/m(2) d1 of each sequence; 5-FU 200mg/m(2)/day c.i.v. daily; CDDP 25mg/m(2) weekly). Forty patients/arm were needed to exclude a RECIST objective response rate (ORR), 8 weeks after treatment, of <75% (Fleming 1, alpha=10%, beta=10%). RESULTS: The ORR was 79.5% (31/39) (lower bound confidence interval [CI]: 68.8%) with MMC/5-FU versus 91.9% (34/ 37) (lower bound CI: 82.8%) with MMC/CDDP. In the MMC/5-FU group, two patients (5.1%) discontinued treatment due to toxicity versus 11 (29.7%) in the MMC/CDDP group. Nine grade 3 haematological events occurred with MMC/CDDP versus none with 5-FU/MMC. The rate of other toxicities did not differ. There was no toxic death. Thirty-one patients in the MMC/5-FU arm (79.5%) and 18 in the MMC/CDDP arm (48.6%) were fully compliant with the protocol treatment (p=0.005). CONCLUSIONS: Radio-chemotherapy with MMC/CDDP seems promising as only MMC/CDDP demonstrated enough activity (RECIST ORR >75%) to be tested further in phase III trials; MMC/5-FU did not. MMC/CDDP also had an overall acceptable toxicity profile.

Evaluation des Nationalen Krebsbekämpfungsprogrammes, Phase I, 1999. Studie 2: Inventar der vorhandenen Datenquellen und Indikatoren

[Table des matières] 1. Allgemeine Schlussforschungen und Empfehlungen. 2. Einleitung. 3. Methodik. 4. Ergebnisse. 4.1. Zentrale Datenquellen : Kontinuierliche und periodische Erhabungen, Mortalitätsstatistik, Spitalstatistik, Vereinigung Schweizerischer Krebsregister, Schweizerische Gesundheitsbefragung, Trendstudie zum Konsum von Alkohol, Tabak, Medikamenten und illegalen Drogen SFA, SChülerbefragung SFA, Warenkorb BFS, Schweizer Haushalt-Panel, Traditioneller Haushaltspanel IHA-GfM, Pharmaabsatzzahlen IHA-GfM, Sonnenexposition und Sonnenschutz, Indikatoren für den Tabakkonsum in der Schweiz, Statistische Erhebungen und Schätzungen über Landwirtschaft und Ernährung, Participants' Report SIAK, Trial guide SAKK, Guidelines, Berufskrankheiten SUVA, Krebstelefon SKL. 4.2. Weitere Datenquellen : Kontinuierliche und periodische Erhebungen, Statistik der verteilten Broschüren SKL, Jahresbericht von im Bereich Krebs tätigen Institutionen, Invalidenversicherung BSV, Andere Statistiken des BSV, Konkordat der Schweizerischen Krankenversicherer, Nestlé-Studie. 4.3. Zentrale Einzelerhebungen : Frauen und Krebs, Vorstudie für eine nationale Kampagne zur Früherfassung des kolorektalen Karzinoms, Ausmass und Intensität von Krebsschmerzen in der Schweiz. 4.4. Weitere Einzelerhebungen : IUMSP : die Gesundheit Jugendlicher in der Schweiz, Stillhäufigkeit und Stilldauer in der Schweiz 1994, Kohortenstudie Alkohol- und Drogenkonsum SFA. 4.5. Abgeschlossene Erhebungen : Krebsvorsorge, MONICA-Studie und Basler Ernährungsstudie. 5. Schlussfolgerungen und Empfehlungen : Zusammenfassende Schlussfolgerungen und Empfehlungen. 6. Anhang. 6.1. Zentrale Datenquellen im Uberblick : Globalkonzept, Brustkrebsprogramm, Lungenkrebsprogramm, Hautkrebsprogramm, Darmkrebsprogramm. 6.2. Zieltabelle : formulierte Ziele des nationalen Krebsbekämpfungsprogramms. 6.3. Abkürzungen.

Fast Approximation of Nonlinearities for improving inversion algorithms of PNL mixtures and Wiener systems

This paper proposes a very fast method for blindly approximating a nonlinear mapping which transforms a sum of random variables. The estimation is surprisingly good even when the basic assumption is not satisfied.We use the method for providing a good initialization for inverting post-nonlinear mixtures and Wiener systems. Experiments show that the algorithm speed is strongly improved and the asymptotic performance is preserved with a very low extra computational cost.