Stupnik T.,Univerzitetni Klinicni Center Ljubljana |
Perme M.P.,University of Ljubljana
Statistics in Medicine | Year: 2016
When analyzing time to disease recurrence, we sometimes need to work with data where all the recurrences are recorded, but no information is available on the possible deaths. This may occur when studying diseases of benign nature where patients are only seen at disease recurrences or in poorly-designed registries of benign diseases or medical device implantations without sufficient patient identifiers to obtain their dead/alive status at a later date. When the average time to disease recurrence is long enough in comparison with the expected survival of the patients, statistical analysis of such data can be significantly biased. Under the assumption that the expected survival of an individual is not influenced by the disease itself, general population mortality tables may be used to remove this bias. We show why the intuitive solution of simply imputing the patient's expected survival time does not give unbiased estimates of the usual quantities of interest in survival analysis and further explain that cumulative incidence function analysis does not require additional assumptions on general population mortality. We provide an alternative framework that allows unbiased estimation and introduce two new approaches: an iterative imputation method and a mortality adjusted at risk function. Their properties are carefully studied, with the results supported by simulations and illustrated on a real-world example. © 2016 John Wiley & Sons, Ltd.
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-24-2015 | Award Amount: 18.47M | Year: 2016
The management of febrile patients is one of the most common and important problems facing healthcare providers. Distinction between bacterial infections and trivial viral infection on clinical grounds is unreliable, and as a result innumerable patients worldwide undergo hospitalization, invasive investigation and are treated with antibiotics for presumed bacterial infection when, in fact, they are suffering from self-resolving viral infection. We aim to improve diagnosis and management of febrile patients, by application of sophisticated phenotypic, transcriptomic (genomic, proteomic) and bioinformatic approaches to well characterised large-scale, multi-national patient cohorts already recruited with EU funding. We will identify, and validate promising new discriminators of bacterial and viral infection including transcriptomic and clinical phenotypic markers. The most accurate markers distinguishing bacterial and viral infection will be evaluated in prospective cohorts of patients reflecting the different health care settings across European countries. By linking sophisticated new genomic and proteomic approaches to careful clinical phenotyping, and building on pilot data from our previous studies we will develop a comprehensive management plan for febrile patients which can be rolled out in healthcare systems across Europe.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.2-2 | Award Amount: 7.80M | Year: 2013
Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) represents a major European health care concern with mortality rates between 40-70%. Approximately 70-80% of these patients present with multivessel disease defined as coronary lesions in more than one vessel. The clinician is faced with the decision to either 1) intervene only on the culprit lesion acutely responsible for the initiation of cardiogenic shock, or 2) treat additional lesions considered hemodynamically significant but not acutely triggering the CS cascade as well. Current guidelines recommend percutaneous coronary intervention of all critical lesions. However, due to a lack of randomized trials, these recommendations are solely based on registry data and pathophysiological considerations. Aim of the randomized CULPRIT-SHOCK trial is therefore to compare a) immediate multivessel PCI versus b) culprit lesion only PCI in patients with AMI complicated by CS. A total of 706 CS patients will be randomized in several European countries. The primary endpoint will be 30-day all-cause mortality and/or severe renal failure requiring renal replacement therapy. CULPRIT-SHOCK will therefore determine the optimal percutaneous revascularization strategy in patients with AMI and multivessel disease complicated by CS. In addition, a comprehensive array of efficacy, safety and socio-economic parameters for the chosen population will be assessed. Multiple secondary endpoints and several substudies (microcirculation, biomarkers, angiography) will serve to further understand the presumed differential effects of the 2 treatment arms and to understand the underlying pathophysiology and prognostic markers. From these parameters a multivariable regression model and a risk score for the prediction of clinical prognosis and a cost-effectiveness model in AMI and CS will be developed. Furthermore, CULPRIT-SHOCK will obtain data on CS patients not meeting inclusion criteria by instituting a separate registry.
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-06-2014 | Award Amount: 3.38M | Year: 2015
Despite the fact that iodine deficiency (ID) can easily be prevented by iodine fortification of table salt, industrial salt and cattle food, Europe belongs to the worst regions in terms of access to iodized salt and is seriously ID, resulting in the perpetuation of the single most important, preventable cause of brain damage. European ID is due to significant heterogeneity in prevention and monitoring programs, leading to inappropriate interventions, increased disease burden, health inequities and increased health care costs. Up to 360 Million European citizens are exposed to ID disorders. An effective European monitoring program is a crucial step towards eradication of ID disorders with significant benefits for European citizens and the sustainability of health care systems. The effects of ID in total cause tremendous, preventable costs in health care systems of affected regions. The overall aim of EUthyroid is to evaluate ID prevention and monitoring programs in 24 European countries, to initiate capacity building for harmonized European ID prevention and monitoring programs, and to disseminate project outcomes for supporting measures on national and EU level in order to eradicate ID disorders in Europe. The project will position itself as international hub of current national initiatives in the attempt to coordinate and support existing national activities. EUthyroid will generate the first harmonized data set of ID resulting in the first valid map of iodine status in Europe. With a dedicated dissemination program about the unfavorable health outcomes of ID, EUthyroid will pave the way for a harmonized EU-wide regulation of iodination, a common approach to iodine and outcome monitoring and establish recommendations for scientists on how to monitor IDD prevention programs. The project aims to make Europe a benchmark for ID disorder prevention worldwide.
Agency: European Commission | Branch: FP7 | Program: CSA-SA | Phase: HEALTH-2007-4.1-4 | Award Amount: 560.14K | Year: 2008
There are two objectives for this project, firstly to clarify the expectations and needs of children and their families who have participated or who might participate in clinical trials for new drugs in Europe. Secondly, to identify methods by which the expectations and needs can be translated into empowering and motivating participants in future clinical trails research. This will be achieved in three stages. The partners will be from different areas involving patients, clinicians, regulators, and researchers (industrial and academic) on a broad basis in order to cover a broad spectrum of diseases. Stage 1) The project will construct a basis for coordination and harmonization. This will involve a literature search and a preliminary workshop. We will build a web site for communication within the project and with a wider audience. Stage 2) We will ground our diverse experience and knowledge through benchmarking good practice case studies, and collecting opinions from patients organisations in Europe. The results will be presented at an expert harmonization workshop composed of all partners of the project. This workshop will identify the operating procedures needed to encourage empowerment and increase motivation for participation in clinical trials. Stage 3) The results of the project will be presented in a series of European conferences. This will ensure that the impact on clinical practice will be facilitated. This will help to improve translational research which depends upon the clinical trial process being undertaken with large enough populations to ensure safety of new products. Greater participation in clinical trials research will result in more valid and reliable products available for children as envisaged by the EC 1901/2006 Paediatric Regulation. In addition it will make European health businesses more competitive and will improve the global health in Europe.
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-15-2014 | Award Amount: 6.00M | Year: 2015
Stem Cell therapy in IschEmic Non-treatable Cardiac diseasE (SCIENCE) With more than 17 million deaths worldwide each year, ischemic heart disease (IHD) caused by coronary artery disease is the most common cause of death and a major cause of hospital admissions in industrialised countries. IHD caused over four million deaths in Europe in the year 2012 constituting 47% of all deaths. Today IHD is the main cause of death among women throughout Europe and the main cause of death among men in all but six European countries. Conventional therapies have reduced mortality of IHD significantly, but have left an increasing number of patients with chronic IHD and/or heart failure without further treatment options. An increasing morbidity rate of this nature in an ageing population is a huge burden for society. The overall aim of the SCIENCE project is to implement an effective stem cell-based therapy with allogeneic adipose derived stromal cells to improve myocardial function in patients with ischemic heart disease and heart failure. This goal will be achieved by conducting a multicentre clinical trial in a strong consortium of experienced international scientists and experts as well as significant representatives of the biomedical industry within translational medicine and a close collaboration with relevant authorities. The consortium will ensure feasibility of treatment by simplifying and rationalising cell production and distribution using state-of-the art manufacturing technology that makes cell therapy a realistic option for clinical practise. The consortium expects the SCIENCE project to pave the way for future approval of this treatment by national authorities throughout Europe as the standard form of care for patients with ischemic heart disease and heart failure. This concept will establish a new platform for growth and consolidation of innovative small and medium-size companies within stem cell research and development. Such a platform will ease implementati
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.1-7 | Award Amount: 4.11M | Year: 2008
This project aims at improving drug delivery to cancer cells by developing targeted radiotherapy with alpha-emitting radionuclides. Alpha particles emitted by radionuclides have short tracks (about 100 microns) in body tissues. As a result, they should be most appropriate to treat small-size tumours and isolated cancer cells. This project proposes the development of improved vectors and targeting technology based on specific targeting agents (recombinant antibody fragments and synthetic peptides), pretargeting approaches and nano-colloids especially designed to deliver alpha-emitting radionuclides to cancer cells after local or systemic administration. The concept of in situ generator, that allows the use of longer half-life parents of alpha-emitting radionuclides will be developed. Several approaches to prevent the release of radionuclides after parent isotope disintegration, including encapsulation in nano-colloids, are proposed. Improved targeting methods will be tested in animal models of small-size tumours and associated dosimetry (including micro-dosimetry) and toxicity studies will be performed. The final goal of the project will be to propose one or several new products for targeted delivery of alpha-emitting radionuclides for clinical development.
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2013.2.2.1-1 | Award Amount: 7.03M | Year: 2013
Traumatic brain injury (TBI) is among the leading causes of death and disability and the main cause of death among the under-45s. Most patients with moderate to severe TBI are admitted to intensive care units (ICUs) The PROSAFE ICU network was recently established in 6 European countries through EU funding (PHEA 2007331), and has continued to collect high-quality data beyond the grant duration. In 2011, 225 ICUs had joined PROSAFE, recruiting a total of 73,163 patients, 2,694 of whom were admitted for TBI. Hence the network can expect to enrol 7-9,000 moderate to severe TBI patients in 4 years. The PROSAFE consortium has already focused attention on TBI and has just started collecting additional information on this condition in order to develop a prognostic model to identify centres of excellence in TBI management Aims of proposal are to consolidate the existing network in order to better describe the epidemiology of moderate-severe TBI in 7 countries (Greece has now joined the consortium); build a prognostic model based on short- and long-term outcome measures; identify most effective clinical interventions for optimally treating TBI patients, and recognize the determinants of optimal vs suboptimal performance All TBI-CDEs endorsed by InTBIR will be collected, along with other items needed to develop a sensible prognostic model, permitting the consortium to join forces with international collaborative initiatives in the field Availing of the coordinating institutes biobank and consolidated expertise in biochemical and genetic biomarkers, the aim is to identify prognostic markers and underlying genetic factors influencing response to treatment and final outcome The PROSAFE consortium is thus in a position to guarantee superior quality data collection in 7 countries and ensure it continues beyond the life of the project. These conditions are essential if the consortium is to contribute to Europe playing a key role in the success of the InTBIR initiative
Mlakar U.,Univerzitetni klinicni center Ljubljana
Zdravniski Vestnik | Year: 2012
Background: Retrospective analyses of unselected patients with acute myeloid leukaemia (AML), treated at individual centres, provide an estimate of treatment success in real world, in contrast to artificially designed conditions in clinical trials. We analysed the treatment outcome of adult patients with AML at the University Medical Centre of Ljubljana over the last four years. Results: From year 2008 to 2011, 222 patients with AML were treated at our centre. Out of the 222 treated patients, 19 patients had acute promyelocytic leukaemia (APL) and they received a combination of tretinoin and anthracycline based chemotherapy. Four patients died in the period of induction therapy, while the remaining patients reached molecular remission, which still lasts. In the group of 203 non-APL patients, 129 patients (of these 76 younger and 53 older than 59 years) received intensive chemotherapy. Non-intensive treatment was given to 74 patients. The intensive treatment included daunorubicin-cytarabine- based induction therapy (DA3+10). In 22 % of younger patients the time from diagnosis to the beginning of intensive treatment lasted more than 5 days. The percentage of early deaths (less than 33 days after the beginning of treatment) was 12 % for younger, and 19 % for older patients. The remission rate was 67 % in younger and 47 % in older patients. The estimated medianof overall survival was 13 months and relapsefree survival was 12.5 months. Three-year survival rate was 31 %. Allogeneic stem-cell transplantation was performed in 36 patients; in 10 of these patients transplantation was induction treatment. Remission was achieved in a half of the patients,8 patients died and of these only 2 survived more than a year. Allogeneic stem cell transplantation was a part of consolidation treatment in 26 patients. In four cases AML relapsed and 10 patients died (38 %). Relapse of the disease was the cause of death in two cases only.Conclusions: The remission rate in our study is comparable with the reports of several randomized trials. For survival analysis, if we are critical, the duration of follow-up in our study might be too short. Suggested measures for the improvement of treatment outcome are: once a diagnosis of APL is suspected, treatment with tretinoin (and blood products) should be started immediately, in younger patients with AML the time from diagnosis to treatment initiation should be under 5 days, patient-specific and leukaemia-associated factors should be analysed carefully before the treatment decisions, especially in older patients.
Univerzitetni Klinicni Center Ljubljana | Date: 2015-02-03
The present invention relates to the field of immunological methods, more precisely to the field of detection methods for antibodies against double-stranded DNA (dsDNA) for diagnostics of chronic autoimmune diseases, such as systemic lupus erythematosus (SLE). The fluorometric immunoassay method for detection of anti-dsDNA solves the technical problem of designing a method for detection of the aforesaid antibodies, which would be faster, cheaper and less toxic as the standard Farr-RIA method, but would have the same diagnostic specificity (which is 100%) and improved diagnostic sensitivity (for 3%). Detection of anti-dsDNA is based on detection of fluorescence in two fractions of samples, in the supernatant and in the sample with a precipitate, which contains immune complexes composed of added dsDNA and anti-dsDNA present in the patients serum, wherein the detected fluorescence is a consequence of binding fluorescent dyes with dsDNA bound in the complexes or with free dsDNA. The method according to the invention allows obtaining reliable results, fast sample analysis and results availability to the attending physician, use of human and environmentally safe chemicals and lowering of costs in comparison to the standard Farr-RIA method.