The Discretionary Function Exception and the Suits in Admiralty Act: A Safe Harbor For Negligence?

This comment will focus on the different circuits\u27 responses to the issue of whether the SIA should be read in light of the discretionary function exception

Implementation evaluation of multiple complex early years interventions: : an evaluation framework and study protocol

Introduction: Implementation evaluations are integral to understanding whether, how and why interventions work. However, unpicking the mechanisms of complex interventions is often challenging in usual service settings where multiple services are delivered concurrently. Furthermore, many locally developed and/or adapted interventions have not undergone any evaluation, thus limiting the evidence base available. Born in Bradford’s Better Start cohort is evaluating the impact of multiple early life interventions being delivered as part of the Big Lottery Fund’s ‘A Better Start’ programme to improve the health and well-being of children living in one of the most socially and ethnically diverse areas of the UK. In this paper, we outline our evaluation framework and protocol for embedding pragmatic implementation evaluation across multiple early years interventions and services. Methods and analysis: The evaluation framework is based on a modified version of The Conceptual Framework for Implementation Fidelity. Using qualitative and quantitative methods, our evaluation framework incorporates semistructured interviews, focus groups, routinely collected data and questionnaires. We will explore factors related to content, delivery and reach of interventions at both individual and wider community levels. Potential moderating factors impacting intervention success such as participants’ satisfaction, strategies to facilitate implementation, quality of delivery and context will also be examined. Interview and focus guides will be based on the Theoretical Domains Framework to further explore the barriers and facilitators of implementation. Descriptive statistics will be employed to analyse the routinely collected quantitative data and thematic analysis will be used to analyse qualitative data. Ethics and dissemination: The Health Research Authority (HRA) has confirmed our implementation evaluations do not require review by an NHS Research Ethics Committee (HRA decision 60/88/81). Findings will be shared widely to aid commissioning decisions and will also be disseminated through peer-reviewed journals, summary reports, conferences and community newsletters

Forced Abstinence from Cocaine Self-Administration is Associated with DNA Methylation Changes in Myelin Genes in the Corpus Callosum: a Preliminary Study

Background: Human cocaine abuse is associated with alterations in white matter integrity revealed upon brain imaging, an observation that is recapitulated in an animal model of continuous cocaine exposure. The mechanism through which cocaine may affect white matter is unknown and the present study tested the hypothesis that cocaine self-administration results in changes in DNA methylation that could result in altered expression of several myelin genes that could contribute to the effects of cocaine on white matter integrity. Methods: In the present study, we examined the impact of forced abstinence from cocaine self-administration on chromatin associated changes in white matter. To this end, rats were trained to self-administer cocaine (0.75 mg/kg/0.1 mL infusion) for 14 days followed by forced abstinence for 1 day (n = 6) or 30 days (n = 6) before sacrifice. Drug-free, sham surgery controls (n = 7) were paired with the experimental groups. Global DNA methylation and DNA methylation at specific CpG sites in the promoter regions ofmyelin basic protein (Mbp), proteolipid protein-1 (Plp1), and SRY-related HMG-box-10 (Sox10) genes were analyzed in DNA extracted from corpus callosum. Results: Significant differences in the overall methylation patterns of the Sox10 promoter region were observed in the corpus callosum of rats at 30 days of forced abstinence from cocaine self-administration relative to sham controls; the −189, −142, −93, and −62 CpG sites were significantly hypomethylated point-wise at this time point. After correction for multiple comparisons, no differences in global methylation or the methylation patterns of Mbp or Plp1 were found. Conclusion: Forced abstinence from cocaine self-administration was associated with differences in DNA methylation at specific CpG sites in the promoter region of the Sox10 gene in corpus callosum. These changes may be related to reductions in normal age related changes in DNA methylation and could be a factor in white matter alterations seen after withdrawal from repeated cocaine self-administration. Further research is warranted examining the effects of cocaine on DNA methylation in white matter

A clinically validated Drosophila S2 based vaccine platform for production of malaria vaccines

Drosophila S2 insect cell expression is less known than the extensively used Spodoptera or Trichoplusia ni (Hi-5) insect cell based Baculovirus expression system (BEVS). Nevertheless it has been used in research for almost 40 years. The cell line was derived from late stage Drosophila melanogaster (Fruit fly) embryos by Schneider in the 1970s, who named the cell line Drosophila Schneider line 2 (synonyms: S2, SL2, D.mel. 2). The system has been widely applied to fundamental research, where the availability of the whole genome sequence of Drosophila melanogaster (1, 2) and the S2 cells’ susceptibility to RNA interference methods (3, 4) have enabled genome wide RNAi screening and whole genome expression analysis techniques to be used to great effect. S2 cells have proved to be highly effective for the production of proteins from a great variety of protein classes (5), such as: viral proteins, toxins, membrane proteins, enzyme, etc. Recent publications have also shown the strength of the S2 system in expression of Virus Like Particles (VLPs) (6). ExpreS2ion has developed the ExpreS2, Drosophila S2 platform to achieve improved yields for difficult to express proteins. Furthermore, several technologies have been developed to improve the ease of use of the system, as well as enable fast and efficient screening of multiple constructs. S2 based production processes for two malaria vaccine clinical trails with The Jenner Institute, Oxford University (Rh5 (7,8), blood-stage malaria) and Copenhagen University (VAR2CSA (9) pregnancy associated malaria) have been developed. The placental malaria vaccine is currently in a phase Ia trail in Germany, and a Phase Ib trial in Benin. The blood-stage malaria vaccine is currently in Phase IIa trial and is expecting results by the end of 2018. Several transmission-blocking candidates have been identified over the years with some of the most prominent being pfs48/45, Pfs230C and Pfs25(10). Other vaccine targets focus on blood-stage malaria such as Rh5, PfRIPR and CyrPA. We will present data on the development of a high producing Pfs25 monoclonal cell line and the purification from said cell line,as well as expression data on a range of other malaria vaccine targets. This present the clinically validated ExpreS2 platform as a complete system for a wide range of malaria targeting vaccines. (1) Adams M.D. et al. Science 2000 287:2185-2195 (2) Ashburner M, et al. Genome Res. 2005 Dec;15(12):1661-7 (3) Neumüller RA, et al. Wiley Interdiscip Rev Syst Biol Med. 2011 Jul-Aug; 3(4):471-8 (4) D’Ambrosio M.V. et al. J. Cell Biol. Vol. 191 No. 3 471–478 (5) Schetz J.A. et al. Protein Expression in the Drosophila Schneider 2 Cell System, Current Protocols in Neuroscience, 2004 (6) Yang L. et al. J Virol. 2012, Jul;86(14):7662-76. (7) Wright K.E. et al. Nature, 2014 Nov 20;515(7527):427-30 (8) Hjerrild K.A. et al. Sci Rep. 2016 Jul 26;6:30357 (9) Nielsen M.A. et al. PLoS One. 2015 Sep 1;10(9):e0135406 (10) Chaturvedi N et al. Indian J Med Res. 2016 Jun;143(6):696-71

Health Assessment and Seroepidemiologic Survey of Potential Pathogens in Wild Antillean Manatees (Trichechus manatus manatus)

The Antillean manatee (Trichechus manatus manatus), a subspecies of the West Indian manatee, inhabits fresh, brackish, and warm coastal waters distributed along the eastern border of Central America, the northern coast of South America, and throughout the Wider Caribbean Region. Threatened primarily by human encroachment, poaching, and habitat degradation, Antillean manatees are listed as endangered by the International Union for the Conservation of Nature. The impact of disease on population viability remains unknown in spite of concerns surrounding the species' ability to rebound from a population crash should an epizootic occur. To gain insight on the baseline health of this subspecies, a total of 191 blood samples were collected opportunistically from wild Antillean manatees in Belize between 1997 and 2009. Hematologic and biochemical reference intervals were established, and antibody prevalence to eight pathogens with zoonotic potential was determined. Age was found to be a significant factor of variation in mean blood values, whereas sex, capture site, and season contributed less to overall differences in parameter values. Negative antibody titers were reported for all pathogens surveyed except for Leptospira bratislava, L. canicola, and L. icterohemorrhagiae, Toxoplasma gondii, and morbillivirus. As part of comprehensive health assessment in manatees from Belize, this study will serve as a benchmark aiding in early disease detection and in the discernment of important epidemiologic patterns in the manatees of this region. Additionally, it will provide some of the initial tools to explore the broader application of manatees as sentinel species of nearshore ecosystem health

Meta-analysis of Clear Cell Renal Cell Carcinoma Gene Expression Defines a Variant Subgroup and Identifies Gender Influences on Tumor Biology

Clear cell renal cell carcinoma (ccRCC) displays molecular and histologic heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multigene expression profiles, but it is unclear whether these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histologic descriptions or gender