European Medical Research Councils Research Articles

Clinical characteristics and outcomes of patients with cirrhosis and hepatocellular carcinoma in The Gambia, west Africa: a prospective cohort study

Chronic liver disease is a major cause of premature death in sub-Saharan Africa. Efficacy of antiviral therapy among patients with hepatitis B virus (HBV)-related cirrhosis is not well established in Africa. We described the clinical characteristics and outcomes of patients with cirrhosis and hepatocellular carcinoma in The Gambia and assessed the impact of tenofovir disoproxil fumarate (TDF) on survival of HBV-infected patients with cirrhosis. In this prospective cohort study, we followed up adults who were consecutively diagnosed with cirrhosis or hepatocellular carcinoma between 2012 and 2015 in The Gambia, west Africa. Patients with chronic HBV infection and cirrhosis, without hepatocellular carcinoma, were offered TDF. Primary outcome was overall survival. To determine the effect of TDF on survival, we performed a Cox proportional hazard regression model with inverse probability of treatment weighting (IPTW) based on propensity score. Of 529 patients enrolled in this study, 336 patients (252 with hepatocellular carcinoma and 84 with cirrhosis) were analysed. Patients were predominantly male (253 [75%] men and 83 [25%] women), with a median age of 42 years (IQR 33-55). 276 (84%) of 327 of patients with data were positive for HBV biomarkers, 31 (10%) of 311 were positive for hepatitis C virus antibodies, and 22 (10%) of 223 were positive for hepatitis D virus antibodies. 64% of patients with hepatocellular carcinoma had multifocal tumour, with a median size of 7·5 cm (IQR 5·4-10·8). 173 patients with hepatocellular carcinoma and 70 patients with cirrhosis were included in the survival analysis. Median survival was 1·5 months (95% CI 1·1-2·0) in patients with hepatocellular carcinoma and 17·1 months (11·2-24·0) in patients with cirrhosis (log-rank p<0·0001). In patients with hepatocellular carcinoma, ascites (hazard ratio [HR] 1·78, 95% CI 1·21-2·60), partial or complete portal thrombosis (HR 2·61, 1·58-4·30), and platelet count (HR 1·80, 1·19-2·70) were independent predictive factors of mortality at baseline. In HBV-infected patients with cirrhosis, median turnaround time between cirrhosis diagnosis and TDF initiation was 4·9 months (IQR 3·2-7·3). In IPTW analysis, TDF treatment was associated with improved survival in patients with HBV-related cirrhosis (adjusted HR 0·14, 0·06-0·34; p<0·0001). These results highlight poor survival of patients with cirrhosis or hepatocellular carcinoma as well as the effectiveness of TDF in reducing the premature mortality of patients with cirrhosis and HBV infection. Interventions for early diagnosis and treatment of cirrhosis as well as screening programmes for hepatocellular carcinoma are urgently required in Africa. European Commission and Medical Research Council UK. For the French translation of the abstract see Supplementary Materials section.

Interpretative differences of combined cytogenetic and molecular profiling highlights differences between MRC and ELN classifications of AML

Acute myeloid leukemia (AML) is typically characterized clinically for prognostic purposes using both cytogenetic and molecular characteristics. However, both cytogenetic and molecular risk stratification schemas are varied and few reports have studied correlations between these schemas. We have performed a single institution retrospective review of cytogenetic and molecular classifications of AMLs seen at Penn Medicine between 2013 and 2018. One-hundred fourty-four cases were characterized according to European Leukemia Net (ELN) or Medical Research Council (MRC) criteria for cytogenetics and results compared to molecular profiling. When we analyzed the most common sequencing study results within the risk groupings, negative sequencing studies and FLT3 mutations were common in favorable AMLs, intermediate AMLs had mutations in FLT3, NPM1, DNMT3A and IDH2, while adverse AMLs had a high prevalence of TP53 mutations. We next grouped the genes on the panel by their proteins’ functions and found mutations in signaling pathway genes to be common in favorable AMLs while tumor suppressors were commonly mutated in adverse AMLs. AMLs grouped by the type of chromosomal abnormality present showed that FLT3 mutations were common in AMLs with a trisomy while TP53 mutations were common in AMLs with a monosomy or a deletion. TP53 mutations are especially common in AMLs with a monosomal karyotype and often overlap with 17p loss. Interestingly, although all AMLs with TP53 mutations have a defect in the response to DNA damage, expression of P53 protein before and after irradiation is not consistently predicted by phenotype. Overall, these studies confirm the genetic complexity of AML which does not fall into simple patterns of cooperating mutations.

Publications and new products

Dear Colleagues,The debate on Open Access is still in progress.The objective of the Science Policy Briefing of the European Medical Research Councils (EMRC) of the EuropeanScience Foundation (ESF), is to accelerate the adoption of open access in order to guarantee equitable access toEuropean biomedical research outputs worldwide.

Misconceptions about falling sperm counts and fertility in Europe

The Science Policy Briefing on male reproductive health published by the authoritative European Science Foundation (ESF) in 2010 echoes the views expressed in the famous paper by Carlsen et al., suggesting that mean sperm counts decreased by 50%. The authors are convinced that the male reproductive system in industrialized countries is under attack from environmental chemicals. This may have far-reaching consequences for the reproductive capacity of future generations. Their arguments, however, contain some misconceptions about declining sperm quality and fertility. Although there is reason for concern about the effect of environmental pollution, the authors' pessimism is not justified. The authoritative ESF aims to provide a common platform to advance European research collaboration and explore new directions for research improving the wellbeing of European citizens. To this end, so-called Science Policy Briefings are regularly published. The September 2010 issue is entitled Male Reproductive Health—Its Impact in Relation to Gneral Wellbeing and Low European Fertility Rates.1 The chief executive of ESF and the chairman of the European Medical Research Council write in their foreword: ‘This Science Policy Briefing is the first to highlight this important issue which could have a dramatic impact on future birth rates and demographic changes in industrialised countries'. Apparently, the authors of this Policy Briefing—six renowned experts in the field of toxicology, reproductive biology and environmental pollution—are convinced that the male reproductive system in industrialized countries has been and still is under attack by environmental chemicals. The decline in sperm quality and the increasing prevalence of genito-urinary abnormalities such as testicular cancer, cryptorchidism and hypospadias are part of the so-called ‘testicular dysgenesis syndrome' which has a common environmental aetiology and is caused by in utero exposure to high levels of ‘endocrine disrupting chemicals'. The authors believe that these perturbing exposures may have far-reaching consequences for the reproductive capacity of future generations, the first signs of which are already apparent. To preclude disaster, extensive, international researches followed by preventive actions are mandatory. Surprisingly, this policy briefing on male reproductive health contains some misconceptions and fallacies about declining sperm quality and fertility. Apart from scientific arguments, strong beliefs seem to play a role in the discussion of whether or not male reproductive health is at risk in Europe. The contents and arguments used in the report lean heavily on the work of the corresponding author and his Danish research group. This policy briefing is in fact a concise outline of the views and concepts of their research as published in numerous papers. Hence we use some characteristic passages as the starting-point of the misconceptions discussed. First we will give some background information on reproduction, fecundity and fertility.

Moving forward: putting research into practice

Clinical trials are aimed at acquiring scientific knowledge and evidence to improve patients care. Clinical trials can either be run by industry, as private–public partnership in a collaboration between the pharmaceutical or medical device industry and hospitals or clinics, or it can be so called ‘investigator-driven clinical trials’ instigated by academic researchers. Investigator-driven clinical trials are typically proof-of-concept studies, studies on orphan diseases, comparison of diagnostic or therapeutic interventions, surgical therapies or novel indications for registered drugs. The investigator-driven clinical trials may have a broader scope and a larger potential impact than industry-driven clinical trials. Investigator-driven clinical trials have been under strain in Europe for a multiplicity of reasons. The most important areas to try and strengthen are the improvement of education, training and career structures, and opportunities for scientists involved in patient-orientated clinical research. This was described thoroughly in the Forward Look from the European Medical Research Council (EMRC), European Science Foundation (ESF), in 2009 [101]. The EMRC is the membership organization for all the medical research councils in Europe under the ESF. The Forward Look recommended an increased level of funding for investigator-driven clinical trials, an area where public funding has been sparse. Furthermore, it also recommended an adoption of a risk-based approach to the regulation of investigator-driven clinical trials, to ensure that these trials are carried out with an appropriate number of patients to produce statistically reliable results so that the trials are correctly designed and powered and the procedures for obtaining authorization are streamlined. Aim one is to perform the necessary clinical trials in all research areas, and to perform them with proper design and the necessary funding, infrastructure and trained scientists to perform the trials. The next important step is to implement the research results in clinical practice through so called ‘evidence-based medicine.’ The Forward Look from the EMRC in 2011, titled ‘Implementation of Medical Research in Clinical Practice’ has a series of recommendations regarding the implementation of clinical trials [102]. The Forward Look was developed by dedicated highlevel panels of experts in the field of clinical investigation, who wrote a draft report that was then debated at a Consensus Conference by the Council of Europe in Strasbourg (France) in the autumn of 2010. After a thorough revision of the document, in collaboration with all panel and Consensus Conference participants, the Forward Look was finished, approved by EMRC and launched in May 2011. The Forward Look launched in 2011 has ten recommendations: ■ Strengthen European work, collaboration on, coordination with and funding of systematic reviews of existing evidence, comparative effectiveness research, health technology assessments and clinical practice guidelines;

Gene-environment interaction in chronic disease: A European Science Foundation Forward Look

Over the last half century, a dramatic increase in the incidence of chronic inflammatory diseases, such as asthma, allergy, and irritable bowel syndrome, has rightfully led to concern about how the modern lifestyle might inappropriately trigger innate physiologic defense mechanisms. Health care research in the Western world is faced with a significant challenge if it is to meet the needs of its populations in the decades ahead. The tools with which we hope to advance our understanding of the intrinsic and extrinsic mechanisms of chronic inflammatory diseases must therefore be adequately exploited and further developed to identify treatment and prevention strategies. There is an urgent need to prioritize resources and identify the most efficient scientific and societal initiatives to be adopted within this area. In this context national collaboration within Europe and beyond to establish state-of-the-art practices with an interdisciplinary perspective and promote an efficient exchange of best practices is essential. Such an approach likely represents the most efficient manner in which strategies for amelioration of the increase of chronic inflammatory diseases in the Western world can be achieved. The present report is based on a Forward Look initiative conducted by the European Medical Research Councils under the European Science Foundation. Experts from industry and academia, as well as relevant interest organizations, have been consulted in the process of conducting this initiative and have, based on this work, developed a set of final recommendations that target academic research, science funders, and policy makers.

Bioethical Principles of Biomedical Research Involving Animals

Bioethical Principles of Biomedical Research Involving Animals

The health of European medical research

The 2001 EU Clinical Trials Directive aimed to harmonize the regulation of medical research, but achieved the opposite. Various attempts are underway to update the directive to make it easier to safely conduct medical research in Europe.

Towards preventive medicine

The sequencing of the human genome was an enormous achievement in more than one sense as both the annotated sequence and the bioinformatics tools developed have become enormously important to biomedical research. In addition, the technological advances made during the project have further promoted the new ‘‐omics’ approach in molecular biology research; it is a global, systematic and comprehensive way of identifying and describing the molecular processes and pathways involved in physiological functions and pathological states. Since the start of the Human Genome Project in 1990, its proponents have pointed out that the knowledge gained could lead to new cures or preventive measures for a wide range of diseases, as well as enormous benefits to general health. A recent white paper by the European Medical Research Council (Strasbourg, France) explicitly encourages the use of new ‐omics technologies, as well as systems biology, nanomedicine, regenerative medicine, and tissue and stem‐cell banking, in order to improve clinical and medical practice (Billig et al , 2007). Currently, the use of functional genomics includes methods to measure gene activity at the transcript level—differential display, expressed sequence tags, serial analysis of gene expression and microarrays—whereas new methods in proteomics help to analyse the protein content and composition of cells and tissues. These rely on instruments capable of the high throughput analysis of biological samples, which themselves generate a large amount of experimental data. This information must, in turn, be processed by powerful information systems and new computational methods to draw meaning from the primary data and generate new knowledge about molecular processes in cells and tissues. These increasingly sensitive, efficient and precise high‐throughput methods and the bioinformatics tools to handle the data, have paved a path on which biologists and clinicians can meet to achieve the ultimate goal: the successful use of these discoveries for …

Editors? highlights

The European Journal of Obstetrics and Gynaecology and Reproductive Biology considers itself to be the forum for clinical and basic scientists in our specialty in Europe. In this context we would like you to be aware of a European organisation where you can find support for your research: the European Science Foundation (www.esf.org) promotes high quality science at a European level. It acts as a catalyst by bringing together leading scientists and funding agencies to debate, plan and implement pan-European initiatives. The Medical Sciences cover such fields as immunology, human genetics and functional genomics, biotechnology, diagnostic and therapeutic medicine, communicable diseases, clinical studies and public health. The Standing Committee, the European Medical Research Council (EMRC), has the overall responsibility for initiating and coordinating scientific activities in those fields and for providing expert advice on issues of science policy. A number of publications are available, which give an insight into activities on the European level. One of the European Clinical Trials has been the investigation “Thromboprophylaxis Using Low molecular weight heparin In Pregnancy (TULIP)”. Activities and results are outlined in detail on the internet. Another group of researchers under the chairmanship of Dr Jacques Sizun came together to conduct “Research on Early Developmental Care for Extremely Premature Babies in Neonatal Intensive Care Units (ECD)”.

Towards a European strategy for controlling antibiotic resistance Nijmegen, Holland August 29–31, 1999

A group of experts met under the auspices of the European Science Foundation, the European Medical Research Council and the European Society of Clinical Microbiology and Infectious Diseases to discuss formulation of a European strategy on the control of antibiotic resistance in Europe. This is a report of the meeting which was used as the basis for a European Commission grant application. The need for a common strategy to make best use of scarce resources was agreed and it was concluded that the first stage (discussed in this article) is to collate existing data on resistance rates, antibiotic consumption, antibiotic stewardship, infection control and molecular typing methods. Consensus reached from analysis of these data can direct us to the most appropriate controlled trials. While it is accepted that there is a widely held perception that the medical profession has been slow to react to the problem of antibiotic resistance, much more work still needs to be carried out before we can recommend, implement and trial definitive control measures. In the meantime, however, all reasonable efforts should be made to reduce antibiotic consumption without compromising patient care, establish cost-effective surveillance systems using existing laboratory generated data, improve hygiene in our hospitals and better define the molecular basis of antibiotic resistance.

Serological screening for coeliac disease: methodological standards and quality control.

To establish methodological standards for serological investigation and screening of coeliac disease, a joint venture has been launched by the European Medical Research Council and the European Society for Paediatric Gastroenterology and Nutrition. Before general screening can be recommended, robust methods and technical standards ought to be introduced. Joint test protocols were defined: an enzyme-linked immunosorbent assay for IgG and IgA gliadin antibodies and an immunofluorescent test for IgA endomysium antibodies. Protocols have now been tested prospectively by one laboratory. Eighty-eight Tuebingen patients were studied (47 coeliac disease on normal diet, 22 coeliac disease on a gluten-free, and 19 disease controls). Single tests did not produce acceptable levels, but combinations of IgA gliadin antibodies and IgA endomysium antibodies showed 98% sensitivity, 100% specificity and 98% predictive efficiency. Only standardized and refereed methods established by ring testing can serve as a reliable basis for serological coeliac screening.

The advisory subgroup in toxicology of the european medical research councils.

The European Medical Research Councils set up an Advisory Group in Toxicology which met from 1975 to 1988. Since encouragement of cross discipline research is still difficult, a resumé is presented of the procedures developed to encourage interdisciplinary research in toxicology in Europe. A programme of grants in toxicology for collaborative research between European countries was begun in 1981 under the auspices of the European Science Foundation. Resulting from the final meeting of AST in Milan, the need for the development of links between epidemiology and molecular aspects of toxicology and for new approaches in eco-toxicology are briefly discussed.

GENE THERAPY IN MAN: Recommendations of European Medical Research Councils

GENE THERAPY IN MAN: Recommendations of European Medical Research Councils

European medical research councils ESF research fellowships in toxicology (PGT): 1986–1987

European medical research councils ESF research fellowships in toxicology (PGT): 1986–1987

Collaboration and mobility in biomedical research: role of the European Medical Research Councils.

COLLABORATION AND MOBILITY IN BIOMEDICAL RESEARCH: ROLE OF THE EUROPEAN MEDICAL RESEARCH COUNCILS HENRY DANIELSSON* The European Medical Research Councils (EMRC) were formed in 1971 to constitute a forum for exchange of information among medical research councils and corresponding bodies in Western Europe concerning research policies and research activities. From the start, NIH has taken part in EMRC meetings and activities. Technically, since EMRC is a European organization, NIH has the status of observer. Today, most countries in Western Europe are represented in EMRC. In 1974, the European Science Foundation (ESF) was formed. The members of ESF are research councils and corresponding organizations as well as academies in Western Europe. The main aim of ESF is to promote European collaboration in sciences, but ESF keeps in contact with organizations outside of Western Europe, not only with organizations in the United States. The ESF works, among other things, through standing committees in various disciplines. In 1975, EMRC became the standing committee for medical research. The EMRC is empowered by its statutes to take appropriate initiatives to stimulate international collaboration in medical research. To this end, various working groups, subgroups, or advisory groups have been set up. In principle, these groups have limited mandate periods. The activities of the groups as well as the question of continued mandate are regularly reviewed by EMRC. Over the years, groups have been disbanded , and new groups have been formed. At present, there are groups dealing with human reproduction, mental illness research, technology assessment, and toxicology. The research areas of these groups reflect the policies of EMRC concerning initiatives to further interna- *Professor, Secretary General, Swedish Medical Research Council, Box 6713, S-1 13 85 Stockholm, Sweden.© 1986 by The University of Chicago. AU rights reserved. 0031-5982/86/2932/$01.00 Perspectives in Biology and Medicine, 29, 3, Part 2 · Spring 1986 \ S47 donai collaboration. Medical research is highly international in itself. The results of medical research are mostly published in international journals with worldwide circulation. They are presented and discussed at international workshops, symposia, and congresses. There are a vast number of international associations in practically all disciplines and in many research areas within medicine that regularly arrange congresses, workshops, and training courses. A very important aspect of international collaboration in medical research is the collaboration on specific research projects among researchers or research groups in different countries. Such collaboration is in most cases initiated by the researchers themselves. The volume of this collaboration is not known but is certainly large. It is funded as part of research grants to the individual researchers or research groups from the national research councils. Thus, it is primarily the responsibility of national research councils to provide the necessary means for this type of international collaboration. In my opinion, international organizations have a limited role to play in these cases. I would like to give an example that may illustrate this point. In Scandinavia, there is a Nordic Council with the responsibility to further collaboration between the Nordic countries in every respect, including research. At a meeting of the Nordic prime ministers a few years ago, it was stated that research cooperation between the Nordic countries was too limited and that a fund should be established that would give grants to collaborative projects . It was, ofcourse, not stated, but the fund would in all probability be created by taking resources from the national research councils. With the proposed structure, a primary criterion for obtaining grants from the fund would be that the projects were inter-Nordic. I am afraid that scientific quality would come second. Within the Nordic medical research councils, which were opposed to the proposal, a study was conducted by asking the researchers supported by the councils if they had collaborative projects with researchers in another Scandinavian country. It turned out that there were several hundred projects in which such collaboration was going on. In many instances, the councils were not really aware that such collaboration was going on. Whether the Nordic medical research councils played a role or not for the final decision, I do not know. At any rate, it was decided not to create a special Nordic fund for collaborative research in Scandinavia...

Organization and funding of medical research in 10 European countries

Information on the organization and funding of medical research were obtained by a questionnaire from 10 member countries of the European Medical Research Councils. Responses show that the ratio of medical research expenditure to Gross Domestic Product varied from 0.1 to 0.2 per cent between these countries. In many countries, the largest single source of funds was pharmaceutical industry; its share of the total expenditure varied between one and 58 per cent. Excluding pharmaceutical industry, the contribution of Medical Research Councils (MRCs) varied from 2 to 22 per cent of the remaining expenditure. The present figures, derived directly from the national research organizations, were considerably higher than the respective OECD figures. A great deal of variation between the national MRCs in the distribution of funds by field of research, type of activity, and type of cost was observed. The average cost of a research project varied between 4800–97000 U.S. dollars. The variation is probably explained to a great extent by availability of other sources of funds. All MRCs used peer review in the assessment of research proposals. Criteria for peer review varied much. Only two MRCs mentioned specifically the needs of the society among the criteria. The various medical research organizations are described in detail in this report.

Chemical methods for male fertility control: Expert consultation of the European Medical Research Council Advisory Subgroup on Human Reproduction

The Advisory Subgroup on Human Reproduction of the European Medical Research Council was founded in 1978 in order to coordinate research efforts and facilitate the exchange of information in the field. A conference held by the Subgroup on chemical methods for male fertility control in 1980 is summarized. The conference reviewed current activity in the field of male chemical fertility control, made recommendations for future research topics, and made further recommendations regarding the allocation of research funds in Europe. The following topics were covered: 1) current research being sponsored by WHO; 2) the Chinese program of research on gossypol, a male steroid pill; 3) the need for more basic research into male reproduction; 4) the advantages and disadvantages of male fertility control thorugh steroids; 5) the possibility of an immunological approach to male fertility control; and 6) the possibility that research into male infertility will provide information useful in male fertility control as well.

International coordination of biomedical research.

Recent efforts at international coordination in biomedical research have taken place at two levels. At the level of the working clinician and scientist, European regionalism has become increasingly manifest in such organizations as the European Society for Clinical Investigation, the European Organization for Research into the Treatment of Cancer, the European Molecular Biology Organization and many others. These have developed largely, though not entirely, independently of government funding. At the level of science policy, i.e. of bodies supporting biomedical research mainly from public funds, the major developments have been the Comité de la Recherche Médicale of the European Community and the much wider association of European Medical Research Councils, based on the whole of Western Europe; in October 1975 the latter group became incorporated into the new European Science Foundation as the first Standing Committee of that body. Wider, interregional, cooperation presents greater problems, though there have been some modest successes, and the multinational drive on research into six of the major health problems of the Third World now being proposed by WHO holds further promise for the future.