OrgML - a domain specific language for organisational decision-making

Effective decision-making based on precise understanding of an organisation is critical for modern organisations to stay competitive in a dynamic and uncertain business environment. However, the state-of-the-art technologies that are relevant in this context are not adequate to capture and quantitatively analyse complex organisations. This paper discerns the necessary information for an organisational decision-making from management viewpoint, discusses inadequacy of the existing enterprise modelling and specification techniques, proposes a domain specific language to capture the necessary information in machine processable form, and demonstrates how the collected information can be used for a simulation-based evidence-driven organisational decision-making

Epigenetic Silencing of Host Cell Defense Genes Enhances Intracellular Survival of the Rickettsial Pathogen Anaplasma phagocytophilum

Intracellular bacteria have evolved mechanisms that promote survival within hostile host environments, often resulting in functional dysregulation and disease. Using the Anaplasma phagocytophilum–infected granulocyte model, we establish a link between host chromatin modifications, defense gene transcription and intracellular bacterial infection. Infection of THP-1 cells with A. phagocytophilum led to silencing of host defense gene expression. Histone deacetylase 1 (HDAC1) expression, activity and binding to the defense gene promoters significantly increased during infection, which resulted in decreased histone H3 acetylation in infected cells. HDAC1 overexpression enhanced infection, whereas pharmacologic and siRNA HDAC1 inhibition significantly decreased bacterial load. HDAC2 does not seem to be involved, since HDAC2 silencing by siRNA had no effect on A. phagocytophilum intracellular propagation. These data indicate that HDAC up-regulation and epigenetic silencing of host cell defense genes is required for A. phagocytophilum infection. Bacterial epigenetic regulation of host cell gene transcription could be a general mechanism that enhances intracellular pathogen survival while altering cell function and promoting disease

Comparative field performance and adherence to test results of four malaria rapid diagnostic tests among febrile patients more than five years of age in Blantyre, Malawi

<p>Abstract</p> <p>Background</p> <p>Malaria rapid diagnostics tests (RDTs) can increase availability of laboratory-based diagnosis and improve the overall management of febrile patients in malaria endemic areas. In preparation to scale-up RDTs in health facilities in Malawi, an evaluation of four RDTs to help guide national-level decision-making was conducted.</p> <p>Methods</p> <p>A cross sectional study of four histidine rich-protein-type-2- (HRP2) based RDTs at four health centres in Blantyre, Malawi, was undertaken to evaluate the sensitivity and specificity of RDTs, assess prescriber adherence to RDT test results and explore operational issues regarding RDT implementation. Three RDTs were evaluated in only one health centre each and one RDT was evaluated in two health centres. Light microscopy in a reference laboratory was used as the gold standard.</p> <p>Results</p> <p>A total of 2,576 patients were included in the analysis. All of the RDTs tested had relatively high sensitivity for detecting any parasitaemia [Bioline SD (97%), First response malaria (92%), Paracheck (91%), ICT diagnostics (90%)], but low specificity [Bioline SD (39%), First response malaria (42%), Paracheck (68%), ICT diagnostics (54%)]. Specificity was significantly lower in patients who self-treated with an anti-malarial in the previous two weeks (odds ratio (OR) 0.5; p-value < 0.001), patients 5-15 years old versus patients > 15 years old (OR 0.4, p-value < 0.001) and when the RDT was performed by a community health worker versus a laboratory technician (OR 0.4; p-value < 0.001). Health workers correctly prescribed anti-malarials for patients with positive RDT results, but ignored negative RDT results with 58% of patients with a negative RDT result treated with an anti-malarial.</p> <p>Conclusions</p> <p>The results of this evaluation, combined with other published data and global recommendations, have been used to select RDTs for national scale-up. In addition, the study identified some key issues that need to be further delineated: the low field specificity of RDTs, variable RDT performance by different cadres of health workers and the need for a robust quality assurance system. Close monitoring of RDT scale-up will be needed to ensure that RDTs truly improve malaria case management.</p

Dendritic Cells Exposed to MVA-Based HIV-1 Vaccine Induce Highly Functional HIV-1-Specific CD8+ T Cell Responses in HIV-1-Infected Individuals

Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC) and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B) in human monocyte-derived dendritic cells (MDDC) and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α). MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA) and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B

Novel Structural Components of the Ventral Disc and Lateral Crest in Giardia intestinalis

Giardia intestinalis is a ubiquitous parasitic protist that is the causative agent of giardiasis, one of the most common protozoan diarrheal diseases in the world. Giardia trophozoites attach to the intestinal epithelium using a specialized and elaborate microtubule structure, the ventral disc. Surrounding the ventral disc is a less characterized putatively contractile structure, the lateral crest, which forms a continuous perimeter seal with the substrate. A better understanding of ventral disc and lateral crest structure, conformational dynamics, and biogenesis is critical for understanding the mechanism of giardial attachment to the host. To determine the components comprising the ventral disc and lateral crest, we used shotgun proteomics to identify proteins in a preparation of isolated ventral discs. Candidate disc-associated proteins, or DAPs, were GFP-tagged using a ligation-independent high-throughput cloning method. Based on disc localization, we identified eighteen novel DAPs, which more than doubles the number of known disc-associated proteins. Ten of the novel DAPs are associated with the lateral crest or outer edge of the disc, and are the first confirmed components of this structure. Using Fluorescence Recovery After Photobleaching (FRAP) with representative novel DAP::GFP strains we found that the newly identified DAPs tested did not recover after photobleaching and are therefore structural components of the ventral disc or lateral crest. Functional analyses of the novel DAPs will be central toward understanding the mechanism of ventral disc-mediated attachment and the mechanism of disc biogenesis during cell division. Since attachment of Giardia to the intestine via the ventral disc is essential for pathogenesis, it is possible that some proteins comprising the disc could be potential drug targets if their loss or disruption interfered with disc biogenesis or function, preventing attachment

Addressing vulnerability, building resilience:community-based adaptation to vector-borne diseases in the context of global change

Abstract Background The threat of a rapidly changing planet – of coupled social, environmental and climatic change – pose new conceptual and practical challenges in responding to vector-borne diseases. These include non-linear and uncertain spatial-temporal change dynamics associated with climate, animals, land, water, food, settlement, conflict, ecology and human socio-cultural, economic and political-institutional systems. To date, research efforts have been dominated by disease modeling, which has provided limited practical advice to policymakers and practitioners in developing policies and programmes on the ground. Main body In this paper, we provide an alternative biosocial perspective grounded in social science insights, drawing upon concepts of vulnerability, resilience, participation and community-based adaptation. Our analysis was informed by a realist review (provided in the Additional file 2) focused on seven major climate-sensitive vector-borne diseases: malaria, schistosomiasis, dengue, leishmaniasis, sleeping sickness, chagas disease, and rift valley fever. Here, we situate our analysis of existing community-based interventions within the context of global change processes and the wider social science literature. We identify and discuss best practices and conceptual principles that should guide future community-based efforts to mitigate human vulnerability to vector-borne diseases. We argue that more focused attention and investments are needed in meaningful public participation, appropriate technologies, the strengthening of health systems, sustainable development, wider institutional changes and attention to the social determinants of health, including the drivers of co-infection. Conclusion In order to respond effectively to uncertain future scenarios for vector-borne disease in a changing world, more attention needs to be given to building resilient and equitable systems in the present

Factors associated with psychotropic drug use among community-dwelling older persons: A review of empirical studies

BACKGROUND: In the many descriptive studies on prescribed psychotropic drug use by community-dwelling older persons, several sociodemographic and other factors associated with drug use receive inconsistent support. METHOD: Empirical reports with data on at least benzodiazepine or antidepressant drug use in samples of older persons published between 1990 and 2001 (n = 32) were identified from major databases and analyzed to determine which factors are most frequently associated with psychotropic drug use in multivariate analyses. Methodological aspects were also examined. RESULTS: Most reports used probability samples of users and non-users and employed cross-sectional designs. Among variables considered in 5 or more reports, race, proximity to health centers, medical consultations, sleep complaints, and health perception were virtually always associated to drug use. Gender, mental health, and physical health status were associated in about two-thirds of reports. Associations with age, marital status, medication coverage, socioeconomic status, and social support were usually not observed. CONCLUSIONS: The large variety of methods to operationalize drug use, mental health status, and social support probably affected the magnitude of observed relationships. Employing longitudinal designs and distinguishing short-term from long-term use, focusing on samples of drug users exclusively, defining drug use and drug classes more uniformly, and utilizing measures of psychological well-being rather than only of distress, might clarify the nature of observed associations and the direction of causality. Few studies tested specific hypotheses. Most studies focused on individual characteristics of respondents, neglecting the potential contribution of health care professionals to the phenomenon of psychotropic drug use among seniors

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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