Сучасні методи дослідження нелінійних коливань

(ru) Рассмотрены колебания консервативной системы. Предложен метод численного отыскания периода колебаний. Исследуются также колебания в нелинейных системах, рассматривается проблема центра-фокуса, получено численное решение дифференциальных уравнений и построены фазовые траектории. Рассмотрено уравнение Ван дер Поля и методы его исследования.(en) The vibrations of the conservative system are considered. The method of the numeral searching of period of vibrations is offered. Vibrations are also probed in the nonlinear systems, the problem of center-focus is examined, got numeral decision of differential equklizations and phase trajectories are built. Equklization of Van der Paul and methods of his research is considered

Research inventory of child health: A report on roadmaps for the future of child health research in Europe

RICHE was the response to a call under HEALTH-2009-3.3-5, with the title of 'European child health research platform'. The call text asked us to “address the diversity and fragmentation in child health research in Europe in an inclusive multidisciplinary way, identifying existing research programmes in Member States, recent advances and identification of gaps to explore road maps for the future of child health research in Europe”. Project structure A consortium, with a final total of 23 partners, and two associate (i.e. unfunded) partners, responded to this call. We designed a project with a linear structure, where the main focus of activity moved from work on the Inventory, and Indicators and Measurement, in Year 1, to work on Gaps in Year 2, finishing with the preparation of the Roadmap in year 3. The final 6 months (Year 4) were largely dissemination. The Platform, which is instantiated in our website, supported all of the other parts,, and was a focus for communication and dissemination throughout the project. Each workpackage focused on a specific area of work, but each fed into its successors, and all leaders and partners worked closely together. Each group produced a number of technical reports and other outputs. The final output was a Roadmap for future investment in European child health research. This has been widely disseminated, and has fed at Commission level and National level into the Horizon 2020 call preparation process. RICHE Roadmap The RICHE Roadmap is based upon a sound, scientific evidence base, which we had gathered as part of our earlier work. The project prepared an inventory of child health research and of measurements and indicators of child health in Europe (WP1 and WP2) . This was collated using a web platform – which can be found at www.childhealthresearch.eu. In addition to this exercise, a formal study of the gaps in child health research was undertaken by carrying out surveys and interviews of researchers and research users across Europe (WP3). This allowed our initial views on the research gaps to be refined and corrected by an iterative process, involving, both project partners, and the wider scientific community, so seeking grounding and validation for this key phase. These results formed the basis for the RICHE Roadmap. The Roadmap is based on a life-course perspective. It covers the important phases of a child’s development, including maternal health, and pregnancy, through to adolescence and the protective and risk factors, and health services encountered throughout childhood and adolescence as he or she moves towards adulthood. RICHE looked upstream to identify where more work needed to be done to prevent avoidable physical and mental ill-health, disability and death in the population of European children aged 0-18 years. This shows how the many influences and outcomes of children’s health are interrelated; a pattern reflected in the Roadmap. The work necessarily involved a series of value judgements, especially on setting priorities, because there are no objective and unconditionally valid answers to the question “Is there enough research on this topic?”, nor to the question “Is this a topic of significance?”. Nevertheless, the RICHE Roadmap uses an inclusive and transparent process to explain the recommendations it made, and the subjects it chose, making our values, and the reasons for judgements as explicit as possible. The report is organised into broad subject areas, that reflect the key ‘gaps’ in knowledge about children and young people, or about particular aspects of their lifestyle and health. These key areas, and selected findings within each area, are briefly summarised here. Life Course and Lifestyle This section focuses on children as they age, and recognises the importance of continuing to research how factors before conception, during gestation and in the very early years of life can affect present and future health. The challenges that children face as they grow up are also highlighted – these can be created because of policy decisions that fail to take account of children and young people’s lives or because of the pervasive influences of individual circumstances that act ask protective or risk factors for children’s actions. The concept of resilience in childhood is also highlighted, and how research needs to focus on this important and powerful means of improving children’s lives. A key issue, throughout the life course, is mental health and well-being. Fostering well-being in children from birth, and throughout childhood will provide numerous individual and societal benefits. It deserves a greater research focus. Socio-economic and Cultural Factors The socio-economic and cultural environment in which a child is born and grows up has a potent effect on a child’s health and well-being. Inequity and inequalities in health, between and within nations depending on socio-economic circumstances, are known to affect health outcomes. Those in the poorest areas have worse health, and shorter lives than those in the wealthiest areas. Other groups are at risk of marginalisation from health services and from opportunities that can maximise their health. These include migrant children where the question is how best to support their integration into their new societies and communities, while retaining their individual identity; children in the state care system have poor health and social outcomes, so improving these, by focused research is important for the future health of these children; children from minority population groups, in particular those who travel across nations, such as the Roma, need to have focused attention, to ensure that their health outcomes begin to match those of the general European child population. Social and Community Networks The main influences on children and young people are their immediate family and community networks. This extends from the influence of the family as a warm and nurturing environment in which to grow up – and conversely a place of the most profound danger and threat if such a family environment is toxic; to the wider influence of school, and finally the broader community. Becoming engaged and involved in community life is beneficial for the entire population, not just for the children and young people directly involved. It is an aspect of children and young people’s experience that is important for well-being and social inclusion. Environment The term 'environment' covers several different concepts, and the RICHE Roadmap describes the physical, virtual and also the perceived environment – all of which interlink in children’s lives, and have a profound effect on their health and development. These include the physical environment, the virtual (digital) environment, physical safety, including injury prevention, and protection form crime, anti-social behaviour and violence (both as perpetrators and victims). Complex Health Issues The majority of children in Europe are healthy, and ill-health is not a characteristic of this population as it is in, for example, an ageing population. However, there are certain health issues that affect children, and as such can blight an entire lifetime. Our Roadmap does not cover clinical issues, but takes a population perspective. There are certain disorders that have a population-wide effect and are prevalent enough in the child population to warrant particular attention from a public health viewpoint. Four specific areas of concern were identified – overweight and obesity, mental health, sexual and reproductive health, and neuro-developmental disorders. Health Services The main research needs of the health services focuses on the prevention of poor health. Comparing health services across Europe and evaluating the means of conveying health promotion messages are important directions for health research to investigate. Indicators need developing which reflect the effect of preventive actions, particularly among younger children. Vulnerable populations, such as those in deprived communities, need to have health prevention services particularly targeted. There is little systematic evaluation of such interventions, which compromises the development of new interventions and their implementation. Those who do not access services and those who need particular attention can be identified. Public Health Infrastructure Health surveillance is essential so that health needs can be identified and addressed effectively for the benefit of the child population. Yet, many existing sources of data are neither analysed, nor made available in a child-centric way. Children need to be made more visible in the data so that they can have more effective health promotion and health care on a population level. Specific examples include work on autism and morbidity due to injury. Europe also needs to establish proper measures and indicators of children’s health and children’s lives. We cannot act properly without first identifying and measuring the problem. Electronic health records are an emerging technology that has great potential, both for research, and for improved access to care. They need to be developed and investigated further to encourage their use across the European Union. Improving Research Capacity It is necessary to ensure that there are enough resources, both to do research, and to make use of the research findings. To sustain research activity, specialist training for junior child health researchers is needed, as are sufficient resources to maintain a critical mass of researchers and provide attractive career paths for them. Children and young people as subjects of research need to continue to be safeguarded by a consistently ethical framework, and information collected about children needs to be accurate, comprehensive and used intelligently so that interventions and services can be correctly directed. Using the roadmap The roadmap is a complex document, addressed to a number of different stakeholders. One key group are those who make decision bout research finding priorities. We have disseminated the roadmap widely at EU level, to reach into the process of priority setting for Horizon 2020. This has been done thought National Contact Points in each partner country, through relevant NGO's, and by sending copes to and meeting with relevant parts of the European Commission. Readers using the roadmap will most likely use it in two ways, first to make a general case for investment in Child Health Research, and secondly to target that investment, by considering the questions we have identified, and reviewing our justifications for these choices. We do not expect our work to determine future investments in child health, but we are confident that using our work would lead to better decisions overall. Conclusions Our core value is to put children first in our work. We take the rights of the child seriously, and we are conscious that many children do not have the opportunity to exercise the right to health and healthcare that European children they ought to have. The topics in this Roadmap are pragmatic in that they are researchable (within the grasp of presently available research methods and resources) and that are likely to have a significant effect on the lives of European children. This will go a considerable distance in improving the health and well-being of European children who may not have benefited from Europe’s good fortune up until this point. At the very least, the RICHE Roadmap aims to begin a serious conversation across Europe about the need for research to focus on children and how this will ultimately benefit all members of the European population. There is a need for children to become substantially more visible in European society. At present many children’s lives are invisible to health surveillance and to research. Sometimes they are submerged with their families, as in the case of Roma or for children of illegal and undocumented immigrant families. Even in well-documented societies, children’s circumstances are invisible as data are collected from the perspective of economically active adults, or households. Therefore, an overarching recommendation in this road map is the establishment of a European Child Health Observatory with a simple remit to make European Children, and their lives, health and attainment of rights more visible. We also recommend continuing and extending the discussion to the edge of existing child health boundaries, to address topics such as the effects on children’s health of urban design and architecture, fiscal policy (which can affect many health issues), welfare, or health effects of immigration policy. The RICHE Roadmap hopes to point the way in which children can be fully recognised and respected as forming a valuable population and whose health and well-being contributes to the health of our present and future European society

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe

Solving unsolved rare neurological diseases-a Solve-RD viewpoint.

Funder: Durch Princess Beatrix Muscle Fund Durch Speeren voor Spieren Muscle FundFunder: University of Tübingen Medical Faculty PATE programFunder: European Reference Network for Rare Neurological Diseases | 739510Funder: European Joint Program on Rare Diseases (EJP-RD COFUND-EJP) | 44140962

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

NordChild - Hälsa och välfärd bland barn och ungdom i de nordiska länderna

The NordChild study is a cross-sectional postal study among children aged 2-17 years from the five Nordic countries; Denmark, Finland, Iceland, Norway and Sweden. A random sample stratified for age and gender was drawn in all the Nordic countries. The total population included 10213 individuals in 1984, 10317 in 1996 and 7715 in 2011.NordChild-studien är en tvärsnittsstudie av barn mellan 2-17 år från de fem Nordiska länderna; Danmark, Finland, Island, Norge och Sverige. Data samlades in via postenkät. Ett randomiserat urval baserat på ålder och kön har gjorts i alla de nordiska länderna. Den totala populationen inkluderade 10213 individer år 1984, 10317 individer år 1996 och 7715 individer år 2011. Variablerna i datafilen bygger på de frågor som förekom i enkäterna alla undersökningsår