Vaccination with DNA plasmids expressing Gn coupled to C3d or alphavirus replicons expressing Gn protects mice against rift valley fever virus

Background: Rift Valley fever (RVF) is an arthropod-borne viral zoonosis. Rift Valley fever virus (RVFV) is an important biological threat with the potential to spread to new susceptible areas. In addition, it is a potential biowarfare agent. Methodology/Principal Findings: We developed two potential vaccines, DNA plasmids and alphavirus replicons, expressing the Gn glycoprotein of RVFV alone or fused to three copies of complement protein, C3d. Each vaccine was administered to mice in an all DNA, all replicon, or a DNA prime/replicon boost strategy and both the humoral and cellular responses were assessed. DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited high titer neutralizing antibodies that were similar to titers elicited by the live-attenuated MP12 virus. Mice vaccinated with an inactivated form of MP12 did elicit high titer antibodies, but these antibodies were unable to neutralize RVFV infection. However, only vaccine strategies incorporating alphavirus replicons elicited cellular responses to Gn. Both vaccines strategies completely prevented weight loss and morbidity and protected against lethal RVFV challenge. Passive transfer of antisera from vaccinated mice into naïve mice showed that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited antibodies that protected mice as well as sera from mice immunized with MP12. Conclusion/Significance: These results show that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn administered alone or in a DNA prime/replicon boost strategy are effective RVFV vaccines. These vaccine strategies provide safer alternatives to using live-attenuated RVFV vaccines for human use. © 2010 Bhardwaj et al

Immediate Outcome Indicators in Perioperative Care: A Controlled Intervention Study on Quality Improvement in Hospitals in Tanzania.

Outcome assessment is the standard for evaluating the quality of health services worldwide. In this study, outcome has been divided into immediate and final outcome. Aim was to compare an intervention hospital with a Continuous Quality Improvement approach to a control group using benchmark assessments of immediate outcome indicators in surgical care. Results were compared to final outcome indicators. Surgical care quality in six hospitals in Tanzania was assessed from 2006-2011, using the Hospital Performance Assessment Tool. Independent observers assessed structural, process and outcome quality using checklists based on evidence-based guidelines. The number of surgical key procedures over the benchmark of 80% was compared between the intervention hospital and the control group. Results were compared to Case Fatality Rates. In the intervention hospital, in 2006, two of nine key procedures reached the benchmark, one in 2009, and four in 2011. In the control group, one of nine key procedures reached the benchmark in 2006, one in 2009, and none in 2011. Case Fatality Rate for all in-patients in the intervention hospital was 5.5% (n = 12,530) in 2006, 3.5% (n = 21,114) in 2009 and 4.6% (n = 18,840) in 2011. In the control group it was 3.1% (n = 17,827) in 2006, 4.2% (n = 13,632) in 2009 and 3.8% (n = 17,059) in 2011. Results demonstrated that quality assurance improved performance levels in both groups. After the introduction of Continuous Quality Improvement, performance levels improved further in the intervention hospital while quality in the district hospital did not. Immediate outcome indicators appeared to be a better steering tool for quality improvement compared to final outcome indicators. Immediate outcome indicators revealed a need for improvement in pre- and postoperative care. Quality assurance programs based on immediate outcome indicators can be effective if embedded in Continuous Quality Improvement. Nevertheless, final outcome indicators cannot be neglected

Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

Prova tipográfica (In Press)An important question arising from previous observations in vivo is whether glucocorticoids can directly influence neuronal survival in the hippocampus. To this end, a primary postnatal hippocampal culture system containing mature neurons and expressing both glucocorticoid (GR) and mineralocorticoid (MR) receptors was developed. Results show that the GR agonist dexamethasone (DEX) targets neurons (microtubule-associated protein 2-positive cells) for death through apoptosis. GR-mediated cell death was counteracted by the MR agonist aldosterone (ALDO). Antagonism of MR with spironolactone ([7a-(acetylthio)-3-oxo-17a-pregn- 4-ene,21 carbolactone] (SPIRO)) causes a dose-dependent increase in neuronal apoptosis in the absence of DEX, indicating that nanomolar levels of corticosterone present in the culture medium, which are sufficient to activate MR, can mask the apoptotic response to DEX. Indeed, both SPIRO and another MR antagonist, oxprenoate potassium ((7a,17a)-17-Hydroxy-3-oxo-7- propylpregn-4-ene-21-carboxylic acid, potassium salt (RU28318)), accentuated DEX-induced apoptosis. These results demonstrate that GRs can act directly to induce hippocampal neuronal death and that demonstration of their full apoptotic potency depends on abolition of survival-promoting actions mediated by MR

Why a successful task substitution in glaucoma care could not be transferred from a hospital setting to a primary care setting: A qualitative study

Background: Healthcare systems are challenged by a demand that exceeds available resources. One policy to meet this challenge is task substitution-transferring tasks to other professions and settings. Our study aimed to explore stakeholders' perceived feasibility of transferring hospital-based monitoring of stable glaucoma patients to primary care optometrists.Methods: A case study was undertaken in the Rotterdam Eye Hospital (REH) using semi-structured interviews and document reviews. They were inductively analysed using three implementation related theoretical perspectives: sociological theories on professionalism, management theories, and applied political analysis.Results: Currently it is not feasible to use primary care optometrists as substitutes for optometrists and ophthalmic technicians working in a hospital-based gl

Attribution-based motivation treatment efficacy in an online learning environment for students who differ in cognitive elaboration

Attribution-based motivation treatments can boost performance in competitive achievement settings (Perry and Hamm 2017), yet their efficacy relative to mediating processes and affect-based treatments remains largely unexamined. In a two-semester, pre-post, randomized treatment study (n = 806), attributional retraining (AR) and stress-reduction (SR) treatments were administered in an online learning environment to first-year college students who differed in cognitive elaboration (low, high). Low elaborators who received AR outperformed their SR peers by nearly a letter grade on a class test assessed 5 months post-treatment. Path analysis revealed this AR-performance linkage was mediated by causal attributions, perceived control, and positive and negative achievement emotions in a hypothesized causal sequence. Results advance the literature by showing AR (vs. SR) improved performance indirectly via cognitive and affective process variables specified by Weiner’s (1985a, 2012) attribution theory of motivation and emotion

A Role for Behavior in the Relationships Between Depression and Hostility and Cardiovascular Disease Incidence, Mortality, and All-Cause Mortality: the Prime Study.

BACKGROUND: Behavioral factors are important in disease incidence and mortality and may explain associations between mortality and various psychological traits. PURPOSE: These analyses investigated the impact of behavioral factors on the associations between depression, hostility and cardiovascular disease(CVD) incidence, CVD mortality, and all-cause mortality. METHODS: Data from the PRIME Study (N = 6953 men) were analyzed using Cox proportional hazards models, following adjustment for demographic and biological CVD risk factors, and other psychological traits, including social support. RESULTS: Following initial adjustment, both depression and hostility were significantly associated with both mortality outcomes (smallest SHR = 1.24, p < 0.001). Following adjustment for behavioral factors, all relationships were attenuated both when accounting for and not accounting for other psychological variables. Associations with all-cause mortality remained significant (smallest SHR = 1.14, p = 0.04). Of the behaviors included, the most significant contribution to outcomes was found for smoking, but a role was also found for fruit and vegetable intakes and high alcohol consumption. CONCLUSIONS: These findings demonstrate well-known associations between depression, hostility, and mortality and suggest the potential importance of behaviors in explaining these relationships

Spatiotemporal information transfer pattern differences in motor selection

Analysis of information transfer between variables in brain images is currently a popular topic, e.g. [1]. Such work typically focuses on average information transfer (i.e. transfer entropy [2]), yet the dynamics of transfer from a source to a destination can also be quantified at individual time points using the local transfer entropy (TE) [3]. This local perspective is known to reveal dynamical structure that the average cannot. We present a method to quantify local TE values in time between source and destination regions of variables in brain-imaging data, combining: a. computation of inter-regional transfer between two regions of variables (e.g. voxels) [1], with b. the local perspective of the dynamics of such transfer in time [3]. Transfer is computed over samples from all variables – there is no training in or subset selection of variables to use. We apply this method to a set of fMRI measurements where we could expect to see differences in local information transfer between two conditions at specific time steps. The fMRI data set analyzed (from [4]) contains brain activity recorded from 7 localized regions while 12 subjects (who gave informed written consent) were asked to freely decide whether to pus

Appeals to evidence for the resolution of wicked problems: the origins and mechanisms of evidentiary bias

Wicked policy problems are often said to be characterized by their ‘intractability’, whereby appeals to evidence are unable to provide policy resolution. Advocates for ‘Evidence Based Policy’ (EBP) often lament these situations as representing the misuse of evidence for strategic ends, while critical policy studies authors counter that policy decisions are fundamentally about competing values, with the (blind) embrace of technical evidence depoliticizing political decisions. This paper aims to help resolve these conflicts and, in doing so, consider how to address this particular feature of problem wickedness. Specifically the paper delineates two forms of evidentiary bias that drive intractability, each of which is reflected by contrasting positions in the EBP debates: ‘technical bias’ - referring to invalid uses of evidence; and ‘issue bias’ - referring to how pieces of evidence direct policy agendas to particular concerns. Drawing on the fields of policy studies and cognitive psychology, the paper explores the ways in which competing interests and values manifest in these forms of bias, and shape evidence utilization through different mechanisms. The paper presents a conceptual framework reflecting on how the nature of policy problems in terms of their complexity, contestation, and polarization can help identify the potential origins and mechanisms of evidentiary bias leading to intractability in some wicked policy debates. The discussion reflects on whether being better informed about such mechanisms permit future work that may lead to strategies to mitigate or overcome such intractability in the future

Early chronic kidney disease: diagnosis, management and models of care

Chronic kidney disease (CKD) is prevalent in many countries, and the costs associated with the care of patients with end-stage renal disease (ESRD) are estimated to exceed US$1 trillion globally. The clinical and economic rationale for the design of timely and appropriate health system responses to limit the progression of CKD to ESRD is clear. Clinical care might improve if early-stage CKD with risk of progression to ESRD is differentiated from early-stage CKD that is unlikely to advance. The diagnostic tests that are currently used for CKD exhibit key limitations; therefore, additional research is required to increase awareness of the risk factors for CKD progression. Systems modelling can be used to evaluate the impact of different care models on CKD outcomes and costs. The US Indian Health Service has demonstrated that an integrated, system-wide approach can produce notable benefits on cardiovascular and renal health outcomes. Economic and clinical improvements might, therefore, be possible if CKD is reconceptualized as a part of primary care. This Review discusses which early CKD interventions are appropriate, the optimum time to provide clinical care, and the most suitable model of care to adopt

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis