Comparing the immune response to a novel intranasal nanoparticle PLGA vaccine and a commercial BPI3V vaccine in dairy calves

peer-reviewedBackground There is a need to improve vaccination against respiratory pathogens in calves by stimulation of local immunity at the site of pathogen entry at an early stage in life. Ideally such a vaccine preparation would not be inhibited by the maternally derived antibodies. Additionally, localized immune response at the site of infection is also crucial to control infection at the site of entry of virus. The present study investigated the response to an intranasal bovine parainfluenza 3 virus (BPI3V) antigen preparation encapsulated in PLGA (poly dl-lactic-co-glycolide) nanoparticles in the presence of pre-existing anti-BPI3V antibodies in young calves and comparing it to a commercially available BPI3V respiratory vaccine. Results There was a significant (P < 0.05) increase in BPI3V-specific IgA in the nasal mucus of the BPI3V nanoparticle vaccine group alone. Following administration of the nanoparticle vaccine an early immune response was induced that continued to grow until the end of study and was not observed in the other treatment groups. Virus specific serum IgG response to both the nanoparticle vaccine and commercial live attenuated vaccine showed a significant (P < 0.05) rise over the period of study. However, the cell mediated immune response observed didn’t show any significant rise in any of the treatment groups. Conclusion Calves administered the intranasal nanoparticle vaccine induced significantly greater mucosal IgA responses, compared to the other treatment groups. This suggests an enhanced, sustained mucosal-based immunological response to the BPI3V nanoparticle vaccine in the face of pre-existing antibodies to BPI3V, which are encouraging and potentially useful characteristics of a candidate vaccine. However, ability of nanoparticle vaccine in eliciting cell mediated immune response needs further investigation. More sustained local mucosal immunity induced by nanoparticle vaccine has obvious potential if it translates into enhanced protective immunity in the face of virus outbreak

Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/principal findingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.ConclusionGiven the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans

Grey and white matter correlates of recent and remote autobiographical memory retrieval:Insights from the dementias

The capacity to remember self-referential past events relies on the integrity of a distributed neural network. Controversy exists, however, regarding the involvement of specific brain structures for the retrieval of recently experienced versus more distant events. Here, we explored how characteristic patterns of atrophy in neurodegenerative disorders differentially disrupt remote versus recent autobiographical memory. Eleven behavioural-variant frontotemporal dementia, 10 semantic dementia, 15 Alzheimer's disease patients and 14 healthy older Controls completed the Autobiographical Interview. All patient groups displayed significant remote memory impairments relative to Controls. Similarly, recent period retrieval was significantly compromised in behavioural-variant frontotemporal dementia and Alzheimer's disease, yet semantic dementia patients scored in line with Controls. Voxel-based morphometry and diffusion tensor imaging analyses, for all participants combined, were conducted to investigate grey and white matter correlates of remote and recent autobiographical memory retrieval. Neural correlates common to both recent and remote time periods were identified, including the hippocampus, medial prefrontal, and frontopolar cortices, and the forceps minor and left hippocampal portion of the cingulum bundle. Regions exclusively implicated in each time period were also identified. The integrity of the anterior temporal cortices was related to the retrieval of remote memories, whereas the posterior cingulate cortex emerged as a structure significantly associated with recent autobiographical memory retrieval. This study represents the first investigation of the grey and white matter correlates of remote and recent autobiographical memory retrieval in neurodegenerative disorders. Our findings demonstrate the importance of core brain structures, including the medial prefrontal cortex and hippocampus, irrespective of time period, and point towards the contribution of discrete regions in mediating successful retrieval of distant versus recently experienced events

Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science

Abstract Background Many interventions found to be effective in health services research studies fail to translate into meaningful patient care outcomes across multiple contexts. Health services researchers recognize the need to evaluate not only summative outcomes but also formative outcomes to assess the extent to which implementation is effective in a specific setting, prolongs sustainability, and promotes dissemination into other settings. Many implementation theories have been published to help promote effective implementation. However, they overlap considerably in the constructs included in individual theories, and a comparison of theories reveals that each is missing important constructs included in other theories. In addition, terminology and definitions are not consistent across theories. We describe the Consolidated Framework For Implementation Research (CFIR) that offers an overarching typology to promote implementation theory development and verification about what works where and why across multiple contexts. Methods We used a snowball sampling approach to identify published theories that were evaluated to identify constructs based on strength of conceptual or empirical support for influence on implementation, consistency in definitions, alignment with our own findings, and potential for measurement. We combined constructs across published theories that had different labels but were redundant or overlapping in definition, and we parsed apart constructs that conflated underlying concepts. Results The CFIR is composed of five major domains: intervention characteristics, outer setting, inner setting, characteristics of the individuals involved, and the process of implementation. Eight constructs were identified related to the intervention (e.g., evidence strength and quality), four constructs were identified related to outer setting (e.g., patient needs and resources), 12 constructs were identified related to inner setting (e.g., culture, leadership engagement), five constructs were identified related to individual characteristics, and eight constructs were identified related to process (e.g., plan, evaluate, and reflect). We present explicit definitions for each construct. Conclusion The CFIR provides a pragmatic structure for approaching complex, interacting, multi-level, and transient states of constructs in the real world by embracing, consolidating, and unifying key constructs from published implementation theories. It can be used to guide formative evaluations and build the implementation knowledge base across multiple studies and settings.http://deepblue.lib.umich.edu/bitstream/2027.42/78272/1/1748-5908-4-50.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/2/1748-5908-4-50-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/3/1748-5908-4-50-S3.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/4/1748-5908-4-50-S4.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/5/1748-5908-4-50.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/6/1748-5908-4-50-S2.PDFPeer Reviewe

Five fathers' experience of an adult son sustaining a cervical spinal cord injury: an Interpretative Phenomenological Analysis

The paper presents an in-depth idiographic study exploring the experience of fathers who have an adult son with a cervical spinal cord injury (SCI). Five participants were recruited and individual semi-structured interviews were conducted. The interviews were transcribed verbatim and analysed using Interpretative Phenomenological Analysis (IPA). Two super-ordinate themes are presented highlighting. Firstly, the ongoing negative impact of their sons’ injury on the participants’ role as fathers’. This comprises the negative impact on emotions with guilt common for failing in their perceived role as a father. The dissonance experienced between wanting to help encourage their sons’ independence. Concern experienced due to their sons altered life trajectory and anxiety because they won’t be alive to protect their son in the future. Secondly, how participants cope and adjust to their son’s SCI are presented. Comprising of how positive thinking, such as focusing on their son surviving the trauma; and the influence of seeing their son cope well affects how participants cope. Also, reflecting on how the injury has changed their life helps participants, to an extent, make sense of the trauma. The results are discussed in relation to the relevant extant literature to give a unique perspective about how SCI impacts their perceived role as fathers and the struggle to cope and adjust to the trauma. Future research investigating the impact of SCI on the family is warranted to better understand the wider implications

Competition and habitat quality influence age and sex distribution in wintering rusty blackbirds.

Bird habitat quality is often inferred from species abundance measures during the breeding and non-breeding season and used for conservation management decisions. However, during the non-breeding season age and sex classes often occupy different habitats which suggest a need for more habitat-specific data. Rusty Blackbird (Euphagus carolinus) is a forested wetland specialist wintering in bottomland hardwood forests in the south-eastern U. S. and belongs to the most steeply declining songbirds in the U.S. Little information is available to support priority birds such as the Rusty Blackbird wintering in this threatened habitat. We assessed age and sex distribution and body condition of Rusty Blackbirds among the three major habitats used by this species in the Lower Mississippi Alluvial Valley and also measured food availability. Overall, pecan groves had the highest biomass mainly driven by the amount of nuts. Invertebrate biomass was highest in forests but contributed only a small percentage to overall biomass. Age and sex classes were unevenly distributed among habitats with adult males primarily occupying pecan groves containing the highest nut biomass, females being found in forests which had the lowest nut biomass and young males primarily staying in forest fragments along creeks which had intermediate nut biomass. Males were in better body condition than females and were in slightly better condition in pecan groves. The results suggest that adult males occupy the highest quality habitat and may competitively exclude the other age and sex classes

The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation

The ability to ensure continuous availability of energy despite highly variable supplies in the environment is a major determinant of the survival of all species. In higher organisms, including mammals, the capacity to efficiently store excess energy as triglycerides in adipocytes, from which stored energy could be rapidly released for use at other sites, was developed. To orchestrate the processes of energy storage and release, highly integrated systems operating on several physiological levels have evolved. The adipocyte is no longer considered a passive bystander, because fat cells actively secrete many members of the cytokine family, such as leptin, tumor necrosis factor-alpha, and interleukin-6, among other cytokine signals, which influence peripheral fuel storage, mobilization, and combustion, as well as energy homeostasis. The existence of a network of adipose tissue signaling pathways, arranged in a hierarchical fashion, constitutes a metabolic repertoire that enables the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess

Biologics registers in RA: methodological aspects, current role and future applications

The beginning of the 21st century saw a biopharmaceutical revolution in the treatment of inflammatory rheumatic diseases, particularly rheumatoid arthritis. The fast-evolving use of biologic therapies highlighted the need to develop registers at national and international levels with the aim of collecting long-term data on patient outcomes. Over the past 15 years, many biologics registers have contributed a wealth of data and provided robust and reliable evidence on the use, effectiveness and safety of these therapies. The unavoidable challenges posed by the continuous introduction of new therapies, particularly with regard to understanding their long-term safety, highlights the importance of learning from experience with established biologic therapies. In this Perspectives article, the role of biologics registers in bridging the evidence gap between efficacy in clinical trials and real-world effectiveness is discussed, with a focus on methodological aspects of registers, their unique features and challenges and their role going forward

Burden of acute otitis media in primary care pediatrics in Italy: A secondary data analysis from the Pedianet database

Background: The incidence of acute otitis media (AOM) vary from country to country. Geographical variations together with differences in study designs, reporting and settings play a role. We assessed the incidence of AOM in Italian children seen by primary care paediatricians (PCPs), and described the methods used to diagnose the disease.Methods: This secondary data analysis from the Pedianet database considered children aged 0 - 6 years between 01/2003 and 12/2007. The AOM episodes were identified and validated by means of patient diaries. Incidence rates/100 person-years (PY) were calculated for total AOM and for single or recurrent AOM.Results: The 92,373 children (52.1% males) were followed up for a total of 227,361 PY: 23,039 (24.9%) presented 38,241 episodes of AOM (94.6% single episodes and 5.4% recurrent episodes). The total incidence rate of AOM in the 5-year period was 16.8 episodes per 100 PY (95% CI: 16.7-16.9), including single AOM (15.9 episodes per 100 PY; 95% CI: 15.7-16.1) and recurrent AOM (0.9 episodes per 100 PY; 95% CI: 0.9-0.9). There was a slight and continuously negative trend decrease over time (annual percent change -4.6%; 95%CI: -5.3, -3.9%). The AOM incidence rate varied with age, peaking in children aged 3 to 4 years (22.2 episodes per 100 PY; 95% CI 21.8-22.7). The vast majority of the AOM episodes (36,842/38,241, 96.3%) were diagnosed using a static otoscope; a pneumatic otoscope was used in only 3.7%.Conclusions: Our data fill a gap in our knowledge of the incidence of AOM in Italy, and indicate that AOM represents a considerable burden for the Italian PCP system. Educational programmes concerning the diagnosis of AOM are needed, as are further studies to monitor the incidence in relation to the introduction of wider pneumococcal conjugate vaccines