Applying systems biology to biomedical research and health care: a précising definition of systems medicine

Background: Systems medicine has become a key word in biomedical research. Although it is often referred to as P4-(predictive, preventive, personalized and participatory)-medicine, it still lacks a clear definition and is open to interpretation. This conceptual lack of clarity complicates the scientific and public discourse on chances, risks and limits of Systems Medicine and may lead to unfounded hopes. Against this background, our goal was to develop a sufficiently precise and widely acceptable definition of Systems Medicine. Methods: In a first step, PubMed was searched using the keyword “systems medicine”. A data extraction tabloid was developed putting forward a means/ends-division. Full-texts of articles containing Systems Medicine in title or abstract were screened for definitions. Definitions were extracted; their semantic elements were assigned as either means or ends. To reduce complexity of the resulting list, summary categories were developed inductively. In a second step, we applied six criteria for adequate definitions (necessity, non-circularity, non-redundancy, consistency, non-vagueness, and coherence) to these categories to derive a so-called précising definition of Systems Medicine. Results: We identified 185 articles containing the term Systems Medicine in title or abstract. 67 contained at least one definition of Systems Medicine. In 98 definitions, we found 114 means and 132 ends. From these we derived the précising definition: Systems Medicine is an approach seeking to improve medical research (i.e. the understanding of complex processes occurring in diseases, pathologies and health states as well as innovative approaches to drug discovery) and health care (i.e. prevention, prediction, diagnosis and treatment) through stratification by means of Systems Biology (i.e. data integration, modeling, experimentation and bioinformatics). Our study also revealed the visionary character of Systems Medicine. Conclusions: Our insights, on the one hand, allow for a realistic identification of actual ethical as well as legal issues arising in the context of Systems Medicine and, in consequence, for a realistic debate of questions concerning its matter and (future) handling. On the other hand, they help avoiding unfounded hopes and unrealistic expectations. This especially holds for goals like improving patient participation which are intensely debated in the context of Systems Medicine, however not implied in the concept

Computerized clinical decision system and mobile application with expert support to optimize management of vertigo in primary care: study protocol for a pragmatic cluster-randomized controlled trial

Vertigo and dizziness are amongst the most common symptoms in medicine and often have a major impact on activities of daily life. Although many causes of vertigo and dizziness can easily be recognized, patients often receive inappropriate and ineffective treatment. The reasons for this are various. Because vertigo/dizziness is an interdisciplinary symptom and there is a lack of standardised diagnostic tools, it is easy to lose the overview of the possible differential diagnoses. There is evidence though, that the management of patients with vertigo/dizziness can be optimized using standardized care pathways with digital support. The present study (within the framework of \textquotedblPoiSe-prevention, online feedback, and interdisciplinary therapy of acute vestibular syndromes by e-health\textquotedbl) aims to evaluate the implementation of a program with several interlocking components. The three main components are a computerized clinical decision system, a mobile application, a counselling and interdisciplinary educational program developed by the German Center for Vertigo and Balance Disorders (DSGZ). The study is a cluster-randomized controlled trial with a parallel-group design, as well as a detailed process evaluation. Clusters comprise of primary care physician practices in Bavaria, Germany. In the scope of the study the effectiveness, acceptability and efficiency of the intervention will be evaluated. It is anticipated that the intervention will improve the quality and efficiency of the management of dizzy patients. A higher diagnostic accuracy, optimized treatment, and disease progression monitoring is expected to improve patient-relevant outcomes and reduce health-care costs

Analysis of foot and claw diseases/disorders in Czech Holstein cows

Received: 2018-05-07 | Accepted: 2018-05-14 | Available online: 2018-11-26https://doi.org/10.15414/afz.2018.21.04.194-196Foot and claw diseases/disorders from 24 545 lactations of 10 340 Holstein cows were recorded on 7 farms in the Czech Republic from 1999 to 2018. There were defined a three groups of foot and claw disorders/diseases: diseases of skin (SD), which cover digital, interdigital dermatitis and interdigital phlegmon; then disorders of the claw horn (CH) including ulcers, white line disease, horn fissures, together with double sole and  overall claw diseases (OCD) ingluding all the recorded disorders. The OCD ratio observed during 1th and 305th days of lactation was  52.56% of all evaluated lactations. The observed ratio of SD and CH  were 28.61% and 27.15%, respectively. A foot and claw disorders were defined as 0/1 occurrence per lactation, for the purposes of analyses,. Genetic parameters were estimated using by linear animal models for evaluated traits. Models  included the random additive genetic effect of animal (A), the permanent environmental effect of cow (PE), fixed effects of parity, farm, year and season of calving, and age at calving as discreet variables in classes. The estimated heritability were 13.84%, 12.64% and 9.83%, 8.73% and 9.97%, for OCD, CH, SD, ulcers (U) and for dermatitis digitalis and interdigitalis (DD), respectively. Genetic correlation was 17.66% between SD and CH, whereas traits SD and DD equal high genetic similarity (98.4%). Also correlation between CH and U traits was high (92.62%). The presented results indicate to possibility of selection against foot and claw disorders/diseases for Czech Holstein population. The work was supported by the project QJ1510144 and the institutional support MZE-RO0718 of the Ministry of Agriculture of the Czech Republic.Keywords: cattle, foot and claw disorders, genetic parameters, health traits, uddeReferencesBuch, L. H., A. C. Sørensen, J. Lassen, P. Berg, J. A. Eriksson, J. H. Jakobsen,  M. K. Sørensen (2011) Hygiene-related and feed-related hoof diseases show different patterns of genetic correlations to clinical mastitis and female fertility. J. Dairy Sci., 94, 1540-1551.Chapinal, N., A. Koeck, A. Sewalem, D. F. Kelton, S. Mason, G. Cramer,F. Miglior (2013) Genetic parameters for hoof lesions and their relationship with feet and leg traits in Canadian Holstein cows. J. Dairy Sci., 96, 2596-2604.Egger-Danner, C., O.K. Hansen, K. Stock, J.E. Pryce, J. Cole, N. Gengler, B. Heringstad (2013) Challenges and benefits of health data recording in the context of food chain quality, management and breeding. ICAR Technical Series.Groeneveld, E., M. Kovač, and N. Mielenz (2008) VCE User’s Guide and Reference Manual, Version 6.0. Krpálková, L., M. Štípková & M. Krejčová, 2016. Vliv zdraví paznehtů a úrovně reprodukce na výkonnost a zisk stáda dojnic. Náš chov, 76 (9), 58-63.Krupová, Z., Krupa, E., Michaličková, M., Wolfová, M., Kasarda, R. (2016) Economic values for health and feed efficiency traits of dual-purpose cattle in marginal areas. Journal of Dairy Science, ,. 99,  s. 644-656.Madsen, P. , J. Jensen. 2010. DMU – a package for analysing multivariate mixed models. Version 6, release 5.0., Aarhus University, Foulum, Denmark.Pérez-Cabal, M. A. ,N. Charfeddine, N. (2015) Models for genetic evaluations of claw health traits in Spanish dairy cattle.   J. Dairy Sci., 98 (11), 8186-8194.Sogstad, A. M., T. Fjeldaas, O. Østerås,  K. P. Forshell. (2005) Prevalence of claw lesions in Norwegian dairy cattle housed in tie stalls and free stalls. Prev. Vet. Med., 70, 191-209.van der Spek, D., J.A. van Arendonk, A.A. Vallée, H. Bovenhuis (2013) Genetic parameters for claw disorders and the effect of preselecting cows for trimming. J Dairy Sci., 96 (9), 6070-6078.van der Waaij, E. H., M. Holzhauer, E. Ellen, C. Kamphuis, G.de Jong. (2005) Genetic parameters for claw disorders in Dutch dairy cattle and correlations with conformation traits. J. Dairy Sci., 88, 3672-3678

The Interaction of Asymptotic Giant Branch Stars with the Interstellar Medium

We study the hydrodynamical behavior of the gas expelled by moving Asymptotic Giant Branch Stars interacting with the ISM. Our models follow the wind modulations prescribed by stellar evolution calculations, and we cover a range of expected relative velocities (10 to 100 km/s), ISM densities (between 0.01 and 1 cm-3), and stellar progenitor masses (1 and 3.5 Msun). We show how and when bow-shocks, and cometary-like structures form, and in which regime the shells are subject to instabilities. Finally, we analyze the results of the simulations in terms of the different kinematical stellar populations expected in the Galaxy.Comment: ApJ in press, 42 pages, 12 figures, movies of the simulations will be available in the published electronic version of the pape

The dynamical evolution of the circumstellar gas around low-and intermediate-mass stars I: the AGB

We have investigated the dynamical interaction of low- and-intermediate mass stars (from 1 to 5 Msun) with their interstellar medium (ISM). In this first paper, we examine the structures generated by the stellar winds during the Asymptotic Giant Branch (AGB) phase, using a numerical code and the wind history predicted by stellar evolution. The influence of the external ISM is also taken into account. We find that the wind variations associated with the thermal pulses lead to the formation of transient shells with an average lifetime of 20,000 yr, and consequently do not remain recorded in the density or velocity structure of the gas. The formation of shells that survive at the end of the AGB occurs via two main processes: shocks between the shells formed by two consecutive enhancements of the mass-loss or via continuous accumulation of the material ejected by the star in the interaction region with the ISM. Our models show that the mass of the circumstellar envelope increases appreciably due to the ISM material swept up by the wind (up to 70 % for the 1 Msun stellar model). We also point out the importance of the ISM on the deceleration and compression of the external shells. According to our simulations, large regions (up to 2.5 pc) of neutral gas surrounding the molecular envelopes of AGB stars are expected. These large regions of gas are formed from the mass-loss experienced by the star during the AGB evolution.Comment: 43 pages, 15 figures. Accepted for publication in the Astrophysical Journa

Development of a Sandwich ELISA to Measure Exposure to Occupational Cow Hair Allergens

Background: Cow hair and dander are important inducers of occupational allergies in cattle-exposed farmers. To estimate allergen exposure in farming environments, a sensitive enzyme immunoassay was developed to measure cow hair allergens. Methods: A sandwich ELISA was developed using polyclonal rabbit antibodies against a mixture of hair extracts from different cattle breeds. To assess the specificity of the assay, extracts from other mammalian epithelia, mites, molds and grains were tested. To validate the new assay, cow hair allergens were measured in passive airborne dust samples from the stables and homes of farmers. Dust was collected with electrostatic dust fall collectors (EDCs). Results: The sandwich ELISA was found to be very sensitive (detection limit: 0.1 ng/ml) and highly reproducible, demonstrating intra-and interassay coefficients of variation of 4 and 10%, respectively. The assay showed no reactivity with mites, molds and grains, but some cross-reactivity with other mammalian epithelia, with the strongest reaction with goat. Using EDCs for dust sampling, high concentrations of bovine allergens were measured in cow stables (4,760-559,400 mu g/m(2)). In addition, bovine allergens were detected in all areas of cattle farmer dwellings. A large variation was found between individual samples (0.3-900 mu g/m(2)) and significantly higher values were discovered in changing rooms. Conclusion: The ELISA developed for the detection of cow hair proteins is a useful tool for allergen quantification in occupational and home environments. Based on its low detection limit, this test is sensitive enough to detect allergens in passive airborne dust. Copyright (C) 2011 S. Karger AG, Base

Diffusion-based structural connectivity patterns of multiple sclerosis phenotypes

BACKGROUND: We aimed to describe the severity of the changes in brain diffusion-based connectivity as multiple sclerosis (MS) progresses and the microstructural characteristics of these networks that are associated with distinct MS phenotypes. METHODS: Clinical information and brain MRIs were collected from 221 healthy individuals and 823 people with MS at 8 MAGNIMS centres. The patients were divided into four clinical phenotypes: clinically isolated syndrome, relapsing-remitting, secondary progressive and primary progressive. Advanced tractography methods were used to obtain connectivity matrices. Then, differences in whole-brain and nodal graph-derived measures, and in the fractional anisotropy of connections between groups were analysed. Support vector machine algorithms were used to classify groups. RESULTS: Clinically isolated syndrome and relapsing-remitting patients shared similar network changes relative to controls. However, most global and local network properties differed in secondary progressive patients compared with the other groups, with lower fractional anisotropy in most connections. Primary progressive participants had fewer differences in global and local graph measures compared with clinically isolated syndrome and relapsing-remitting patients, and reductions in fractional anisotropy were only evident for a few connections. The accuracy of support vector machine to discriminate patients from healthy controls based on connection was 81%, and ranged between 64% and 74% in distinguishing among the clinical phenotypes. CONCLUSIONS: In conclusion, brain connectivity is disrupted in MS and has differential patterns according to the phenotype. Secondary progressive is associated with more widespread changes in connectivity. Additionally, classification tasks can distinguish between MS types, with subcortical connections being the most important factor

Comparing the cumulative live birth rate of cleavage-stage versus blastocyst-stage embryo transfers between IVF cycles:a study protocol for a multicentre randomised controlled superiority trial (the ToF trial)

Introduction In vitro fertilisation (IVF) has evolved as an intervention of choice to help couples with infertility to conceive. In the last decade, a strategy change in the day of embryo transfer has been developed. Many IVF centres choose nowadays to transfer at later stages of embryo development, for example, transferring embryos at blastocyst stage instead of cleavage stage. However, it still is not known which embryo transfer policy in IVF is more efficient in terms of cumulative live birth rate (cLBR), following a fresh and the subsequent frozen-thawed transfers after one oocyte retrieval. Furthermore, studies reporting on obstetric and neonatal outcomes from both transfer policies are limited. Methods and analysis We have set up a multicentre randomised superiority trial in the Netherlands, named the Three or Fivetrial. We plan to include 1200 women with an indication for IVF with at least four embryos available on day 2 after the oocyte retrieval. Women are randomly allocated to either (1) control group: embryo transfer on day 3 and cryopreservation of supernumerary good-quality embryos on day 3 or 4, or (2) intervention group: embryo transfer on day 5 and cryopreservation of supernumerary good-quality embryos on day 5 or 6. The primary outcome is the cLBR per oocyte retrieval. Secondary outcomes include LBR following fresh transfer, multiple pregnancy rate and time until pregnancy leading a live birth. We will also assess the obstetric and neonatal outcomes, costs and patients' treatment burden. Ethics and dissemination The study protocol has been approved by the Central Committee on Research involving Human Subjects in the Netherlands in June 2018 (CCMO NL 64060.000.18). The results of this trial will be submitted for publication in international peer-reviewed and in open access journals. Trial registration number Netherlands Trial Register (NL 6857)

Phosphodiesterase 3B Is Localized in Caveolae and Smooth ER in Mouse Hepatocytes and Is Important in the Regulation of Glucose and Lipid Metabolism

Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction processes mediated by cAMP and cGMP. One PDE family member, PDE3B, plays an important role in the regulation of a variety of metabolic processes such as lipolysis and insulin secretion. In this study, the cellular localization and the role of PDE3B in the regulation of triglyceride, cholesterol and glucose metabolism in hepatocytes were investigated. PDE3B was identified in caveolae, specific regions in the plasma membrane, and smooth endoplasmic reticulum. In caveolin-1 knock out mice, which lack caveolae, the amount of PDE3B protein and activity were reduced indicating a role of caveolin-1/caveolae in the stabilization of enzyme protein. Hepatocytes from PDE3B knock out mice displayed increased glucose, triglyceride and cholesterol levels, which was associated with increased expression of gluconeogenic and lipogenic genes/enzymes including, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein 1c and hydroxyl-3-methylglutaryl coenzyme A reductase. In conclusion, hepatocyte PDE3B is localized in caveolae and smooth endoplasmic reticulum and plays important roles in the regulation of glucose, triglyceride and cholesterol metabolism. Dysregulation of PDE3B could have a role in the development of fatty liver, a condition highly relevant in the context of type 2 diabetes

Antimicrobial Activity and Genetic Profile of Enteroccoci Isolated from Hoopoes Uropygial Gland

Symbiotic microorganisms may be directly transferred from parents to offspring or acquired from a particular environment that animals may be able to select. If benefits for hosts vary among microbial strains, natural selection may favour hosts holding the most beneficial one. Enterococci symbionts living in the hoopoe (Upupa epops) uropygial gland are able to synthesise bacteriocins (antimicrobial peptides that inhibit the growth of competitor bacteria). We explored variability in genetic profile (through RAPD-PCR analyses) and antimicrobial properties (by performing antagonistic tests against ten bacterial indicator strains) of the different isolates obtained from the uropygial glands of hoopoe females and nestlings. We found that the genetic profile of bacterial isolates was related to antimicrobial activity, as well as to individual host identity and the nest from which samples were obtained. This association suggest that variation in the inhibitory capacity of Enterococci symbionts should be under selection.This work was financed by Ministerio de Ciencia e Innovación (Spanish National Government) and FEDER founds (projects CGL2010-19233-C03-01, and CGL2010-19233-C03-03), and Junta de Andalucía (P09-RNM-4557)