HERALD (Health Economics using Routine Anonymised Linked Data)

<b>Background</b> Health economic analysis traditionally relies on patient derived questionnaire data, routine datasets, and outcomes data from experimental randomised control trials and other clinical studies, which are generally used as stand-alone datasets. Herein, we outline the potential implications of linking these datasets to give one single joined up data-resource for health economic analysis.<p></p> <b>Method</b> The linkage of individual level data from questionnaires with routinely-captured health care data allows the entire patient journey to be mapped both retrospectively and prospectively. We illustrate this with examples from an Ankylosing Spondylitis (AS) cohort by linking patient reported study dataset with the routinely collected general practitioner (GP) data, inpatient (IP) and outpatient (OP) datasets, and Accident and Emergency department data in Wales. The linked data system allows: (1) retrospective and prospective tracking of patient pathways through multiple healthcare facilities; (2) validation and clarification of patient-reported recall data, complementing the questionnaire/routine data information; (3) obtaining objective measure of the costs of chronic conditions for a longer time horizon, and during the pre-diagnosis period; (4) assessment of health service usage, referral histories, prescribed drugs and co-morbidities; and (5) profiling and stratification of patients relating to disease manifestation, lifestyles, co-morbidities, and associated costs.<p></p> <b>Results</b> Using the GP data system we tracked about 183 AS patients retrospectively and prospectively from the date of questionnaire completion to gather the following information: (a) number of GP events; (b) presence of a GP 'drug' read codes; and (c) the presence of a GP 'diagnostic' read codes. We tracked 236 and 296 AS patients through the OP and IP data systems respectively to count the number of OP visits; and IP admissions and duration. The results are presented under several patient stratification schemes based on disease severity, functions, age, sex, and the onset of disease symptoms.<p></p> <b>Conclusion</b> The linked data system offers unique opportunities for enhanced longitudinal health economic analysis not possible through the use of traditional isolated datasets. Additionally, this data linkage provides important information to improve diagnostic and referral pathways, and thus helps maximise clinical efficiency and efficiency in the use of resources

Ross, Macdonald, and a Theory for the Dynamics and Control of Mosquito-Transmitted Pathogens

Ronald Ross and George Macdonald are credited with developing a mathematical model of mosquito-borne pathogen transmission. A systematic historical review suggests that several mathematicians and scientists contributed to development of the Ross-Macdonald model over a period of 70 years. Ross developed two different mathematical models, Macdonald a third, and various “Ross-Macdonald” mathematical models exist. Ross-Macdonald models are best defined by a consensus set of assumptions. The mathematical model is just one part of a theory for the dynamics and control of mosquito-transmitted pathogens that also includes epidemiological and entomological concepts and metrics for measuring transmission. All the basic elements of the theory had fallen into place by the end of the Global Malaria Eradication Programme (GMEP, 1955–1969) with the concept of vectorial capacity, methods for measuring key components of transmission by mosquitoes, and a quantitative theory of vector control. The Ross-Macdonald theory has since played a central role in development of research on mosquito-borne pathogen transmission and the development of strategies for mosquito-borne disease prevention

IL-17 Expression in the Time Course of Acute Anti-Thy1 Glomerulonephritis

Background Interleukin-17 (IL-17) is a new pro-inflammatory cytokine involved in immune response and inflammatory disease. The main source of IL-17 is a subset of CD4+ T-helper cells, but is also secreted by non-immune cells. The present study analyzes expression of IL-17 in the time course of acute anti- thy1 glomerulonephritis and the role of IL-17 as a potential link between inflammation and fibrosis. Methods Anti-thy1 glomerulonephritis was induced into male Wistar rats by OX-7 antibody injection. After that, samples were taken on days 1, 5, 10 (matrix expansion phase), 15 and 20 (resolution phase). PBS-injected animals served as controls. Proteinuria and histological matrixes score served as the main markers for disease severity. In in vitro experiments, NRK-52E cells were used. For cytokine expressions, mRNA and protein levels were analyzed by utilizing RT-PCR, in situ hybridization and immunofluorescence. Results Highest IL-17 mRNA-expression (6.50-fold vs. con; p<0.05) was found on day 5 after induction of anti-thy1 glomerulonephritis along the maximum levels of proteinuria (113 ± 13 mg/d; p<0.001), histological glomerular-matrix accumulation (82%; p<0.001) and TGF-β1 (2.2-fold; p<0.05), IL-6 mRNA expression (36-fold; p<0.05). IL-17 protein expression co-localized with the endothelial cell marker PECAM in immunofluorescence. In NRK-52E cells, co-administration of TGF-β1 and IL-6 synergistically up-regulated IL-17 mRNA 4986-fold (p<0.001). Conclusions The pro-inflammatory cytokine IL-17 is up-regulated in endothelial cells during the time course of acute anti-thy1 glomerulonephritis. In vitro, NRK-52E cells secrete IL-17 under pro-fibrotic and pro-inflammatory conditions

Role of Kinesin Heavy Chain in Crumbs Localization along the Rhabdomere Elongation in Drosophila Photoreceptor

BACKGROUND:Crumbs (Crb), a cell polarity gene, has been shown to provide a positional cue for the extension of the apical membrane domain, adherens junction (AJ), and rhabdomere along the growing proximal-distal axis during Drosophila photoreceptor morphogenesis. In developing Drosophila photoreceptors, a stabilized microtubule structure was discovered and its presence was linked to polarity protein localization. It was therefore hypothesized that the microtubules may provide trafficking routes for the polarity proteins during photoreceptor morphogenesis. This study has examined whether Kinesin heavy chain (Khc), a subunit of the microtubule-based motor Kinesin-1, is essential in polarity protein localization in developing photoreceptors. METHODOLOGY/PRINCIPAL FINDINGS:Because a genetic interaction was found between crb and khc, Crb localization was examined in the developing photoreceptors of khc mutants. khc was dispensable during early eye differentiation and development. However, khc mutant photoreceptors showed a range of abnormalities in the apical membrane domain depending on the position along the proximal-distal axis in pupal photoreceptors. The khc mutant showed a progressive mislocalization in the apical domain along the distal-proximal axis during rhabdomere elongation. The khc mutation also led to a similar progressive defect in the stabilized microtubule structures, strongly suggesting that Khc is essential for microtubule structure and Crb localization during distal to proximal rhabdomere elongation in pupal morphogenesis. This role of Khc in apical domain control was further supported by khc's gain-of-function phenotype. Khc overexpression in photoreceptors caused disruption of the apical membrane domain and the stabilized microtubules in the developing photoreceptors. CONCLUSIONS/SIGNIFICANCE:In summary, we examined the role of khc in the regulation of the apical Crb domain in developing photoreceptors. Since the rhabdomeres in developing pupal eyes grow along the distal-proximal axis, these phenotypes suggest that Khc is essential for the microtubule structures and apical membrane domains during the distal-proximal elongation of photoreceptors, but is dispensable for early eye development

ERBB2 in Cat Mammary Neoplasias Disclosed a Positive Correlation between RNA and Protein Low Expression Levels: A Model for erbB-2 Negative Human Breast Cancer

Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%–59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10–15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.POCI/CVT/62940/2004 and by the PhD grants (SFRH/BD/23406/2005 and SFRH/BD/31754/2006, of the Science and Technology Foundation (FCT) from Portugal

Clinical anticancer drug development: targeting the cyclin-dependent kinases

Cell division involves a cyclical biochemical process composed of several step-wise reactions that have to occur once per cell cycle. Dysregulation of cell division is a hallmark of all cancers. Genetic and epigenetic mechanisms frequently result in deranged expression and/or activity of cell-cycle proteins including the cyclins, cyclin-dependent kinases (Cdks), Cdk inhibitors and checkpoint control proteins. The critical nature of these proteins in cell cycling raises hope that targeting them may result in selective cytotoxicity and valuable anticancer activity

Methods to study microbial adhesion on abiotic surfaces

Microbial biofilms are a matrix of cells and exopolymeric substances attached to a wet and solid surface and are commonly associated to several problems, such as biofouling and corrosion in industries and infectious diseases in urinary catheters and prosthesis. However, these cells may have several benefits in distinct applications, such as wastewater treatment processes, microbial fuel cells for energy production and biosensors. As microbial adhesion is a key step on biofilm formation, it is very important to understand and characterize microbial adhesion to a surface. This study presents an overview of predictive and experimental methods used for the study of bacterial adhesion. Evaluation of surface physicochemical properties have a limited capacity in describing the complex adhesion process. Regarding the experimental methods, there is no standard method or platform available for the study of microbial adhesion and a wide variety of methods, such as colony forming units counting and microscopy techniques, can be applied for quantification and characterization of the adhesion process.This work was financially supported by: Project UID/EQU/00511/2013-LEPABE, by the FCT/MEC with national funds and co-funded by FEDER in the scope of the P2020 Partnership Agreement; Project NORTE-07-0124-FEDER-000025 - RL2_Environment&Health, by FEDER funds through Programa Operacional Factores de Competitividade-COMPETE, by the Programa Operacional do Norte (ON2) program and by national funds through FCT - Fundacao para a Ciencia e a Tecnologia; European Research Project SusClean (Contract number FP7-KBBE-2011-5, project number: 287514), Scholarships SFRH/BD/52624/2014, SFRH/BD/88799/2012 and SFRH/BD/103810/2014

Chemical genetics strategies for identification of molecular targets

Chemical genetics is an emerging field that can be used to study the interactions of chemical compounds, including natural products, with proteins. Usually, the identification of molecular targets is the starting point for studying a drug’s mechanism of action and this has been a crucial step in understanding many biological processes. While a great variety of target identification methods have been developed over the last several years, there are still many bioactive compounds whose target proteins have not yet been revealed because no routine protocols can be adopted. This review contains information concerning the most relevant principles of chemical genetics with special emphasis on the different genomic and proteomic approaches used in forward chemical genetics to identify the molecular targets of the bioactive compounds, the advantages and disadvantages of each and a detailed list of successful examples of molecular targets identified with these approaches

The 13th Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-IV Survey Mapping Nearby Galaxies at Apache Point Observatory

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) began observations in July 2014. It pursues three core programs: APOGEE-2,MaNGA, and eBOSS. In addition, eBOSS contains two major subprograms: TDSS and SPIDERS. This paper describes the first data release from SDSS-IV, Data Release 13 (DR13), which contains new data, reanalysis of existing data sets and, like all SDSS data releases, is inclusive of previously released data. DR13 makes publicly available 1390 spatially resolved integral field unit observations of nearby galaxies from MaNGA,the first data released from this survey. It includes new observations from eBOSS, completing SEQUELS. In addition to targeting galaxies and quasars, SEQUELS also targeted variability-selected objects from TDSS and X-ray selected objects from SPIDERS. DR13 includes new reductions ofthe SDSS-III BOSS data, improving the spectrophotometric calibration and redshift classification. DR13 releases new reductions of the APOGEE-1data from SDSS-III, with abundances of elements not previously included and improved stellar parameters for dwarf stars and cooler stars. For the SDSS imaging data, DR13 provides new, more robust and precise photometric calibrations. Several value-added catalogs are being released in tandem with DR13, in particular target catalogs relevant for eBOSS, TDSS, and SPIDERS, and an updated red-clump catalog for APOGEE.This paper describes the location and format of the data now publicly available, as well as providing references to the important technical papers that describe the targeting, observing, and data reduction. The SDSS website, http://www.sdss.org, provides links to the data, tutorials and examples of data access, and extensive documentation of the reduction and analysis procedures. DR13 is the first of a scheduled set that will contain new data and analyses from the planned ~6-year operations of SDSS-IV.PostprintPeer reviewe

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700