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W1564438703 abstract "a. Definition. Clinical pharmacology is the scientific discipline that involves all aspects of the relationship between drugs and humans. The term ‘clinical pharmacologist’ is also used in the professional sense to refer to those physicians who are specialists in clinical pharmacology. They have undertaken several years of postgraduate training in many aspects of the above relationship involving teaching, research and health care. Such clinical pharmacologists have as their primary goal that of improving patient care, directly or indirectly, by developing better medicines and promoting the safer and more effective use of drugs. b. Aims. This document aims to set the scene for clinical pharmacology in the early part of the 21st century following the concepts of an earlier report by the World Health Organization in 1970 [1]. This document is aimed primarily at decision-makers in a variety of organizations, particularly in governments and their healthcare ministries, in addition to chief executives and board level directors of primary and secondary care systems and directors in pharmaceutical companies. We hope they will realize the great benefits that expertise in clinical pharmacology can bring to the delivery of better healthcare for all populations. c. Clinical care. Clinical pharmacology has developed a number of ways in which the clinical care of patients can be improved. The prime aim is to improve the rational use of drugs (RUD) both for individual patients and for patient populations wherever they may reside. The clinical pharmacologist will be expert in the critical evaluation of new and old therapies, and will use drug utilization studies and pharmacoepidemiological services to help in this task as well as skills such as pharmacogenetics. Clinical pharmacologists have an important role on Drug and Therapeutics Committees where they help the rational introduction and use of new and expensive medicines into the delivery of health care. Clinical pharmacologists will provide, in association with other healthcare staff such as pharmacists, drug information services to a wide variety of prescribers. Specialist services may include therapeutic drug monitoring (TDM), involvement in clinical drug toxicology and pharmacovigilance. Adverse drug reactions (ADRs) still cause many problems for patients, and healthcare systems could do more to prevent these as most of them are predictable through a knowledge of pharmacology. The concept of personalized medicine is one where drug therapy can be based on the pharmacogenetic characteristics of a particular patient. While in its infancy as a discipline, there are now good examples whereby adverse effects can be minimized and drug efficacy enhanced by a knowledge of the genetic make-up of patients. d. Research is a vital part of the training and everyday work of a clinical pharmacologist. The endeavour of a pharmacologist working in the clinical environment is to develop methods and strategies that improve the quality of drug use in individual patients and patient populations. Clinical pharmacological research has always been translational in the sense that the discipline aims to take new scientific data on drugs into rational patient care. Clinical pharmacologists could be even better equipped to undertake ‘translational’ research, especially the design and execution of the early phase of drug studies in humans (Phase 1). Too few contemporary clinical pharmacologists are actively engaged in the design, conduct and improvement of clinical trials. e. Teaching is a vital part of the work of a clinical pharmacologist. Although all doctors and many health care professionals need regular education concerning drugs, perhaps the most important area currently is the training of new prescribers which is primarily new physicians as pharmacists and nurses do comparatively little prescribing when looked at in a worldwide sense. The ability of new young physicians to prescribe safely and effectively has been criticized in recent years and new systems are being developed so that much more attention is paid to these skills in the training of medical students. As assessment drives learning, the assessment systems are being improved, too. Specialist training of clinical pharmacologists is addressed in Addendum II, as there is a worldwide shortage of such specialists. However, the needs, the resources and the regulatory arrangements available in different countries mean that the approach suggested is a general one. f. Pharmaceutical companies have been at the forefront of helping to train clinical pharmacologists. While many of the skills acquired in such companies are useful for the general training of a clinical pharmacologist (e.g. clinical trials), a long-term career in such a company requires a new set of skills for which training is needed. g. Governments need clinical pharmacologists to help deliver the goal of ensuring safe and effective drug therapy for their populations, whether the clinical pharmacologists are working in hospitals, regulatory agencies or in health technology assessment (HTA). With a few notable exceptions, the discipline of HTA has emerged in the absence of contributions from clinical pharmacology. This needs to change if HTA is to meet its full potential. h. Clinical pharmacologists have a crucial role to play in helping to deliver the WHO agenda of ‘Guidelines for the Development of National Drug Policies’ to which more than 150 countries are now signed up [2]. The policies aim to ensure: the quality, safety and efficacy of medicines equitable access to medicines for all the population the rational/quality use of medicines a viable and responsible local pharmaceutical industry. Clinical pharmacologists could do much more to meet the health needs of those peoples who have in the past been marginalized. They include children, those with rare diseases, and those with conditions that are endemic in the poorest parts of the world. Training of clinical pharmacologists to meet these needs will have to be rather different from that envisaged in 1970 when the first WHO report was published [1]. Some 40 years ago, the World Health Organization brought together a group of experts in clinical pharmacology and therapeutics (CPT) to define the discipline of clinical pharmacology and to outline how it could help to improve the use of drugs in the delivery of health care [1]. In the last four decades, the importance of drug therapy has changed markedly in terms of the potency of the drugs we use, in the number and diversity of drugs that are available, and in the number of diseases that can be treated. In addition, the discipline of molecular biology has had an increasing impact on the development of drugs but solid knowledge about the pharmacological principles that underpin the RUD is just as relevant now as it was in 1970. Since the production of the 1970 report, the cost of developing drugs has risen substantially and the cost of taking a new chemical entity to market can easily be in excess of $US 1000 million (£600 million, €700 million). As a result, newly developed drugs are very expensive making it more difficult for resource poor countries to fund drug therapy for their inhabitants although there are welcome exceptions in the provision by Big Pharma of modern drugs at a very low or no cost (e.g. ivermectin for onchocerciasis). Even resource-rich countries have limitations in financing drug therapy and this has led to new concepts such as the cost-effectiveness of drug therapy and to the discipline of pharmacoeconomics. While clinical pharmacology is learning to face these new problems, we are still dealing with problems in drug therapy that were recognized in the 1970s. We knew then that ADRs were among the more common causes of admission to hospital [3] and this problem has not decreased in importance over the decades largely because little is done about it. In addition, the problem of ADRs is worsened by the increasing use of combination therapies and the higher proportion of elderly patients in the population. We know that ADRs (the formal study of which has now given rise to the discipline of pharmacovigilance) cause some 7% of admissions to hospital and they are also a not uncommon cause of death, particularly in elderly patients [4,5]. Many of these ADRs are predictable and could be prevented if the process of educating prescribers was taken more seriously. Another problem that has not improved significantly over the years since 1970 is the errors made during the prescribing process in spite of the widespread availability of computers and the Internet providing easy access to appropriate information and knowledge [6]. These problems do not only affect resource-rich countries, although the scale of the problem may be less in resource-poor countries. It is clear then the time has come to modernize the original WHO report in the hope that lessons will have been learned and the problems addressed. We hope that WHO itself will do this over the next year or so by a modification of this International Union of Basic and Clinical Pharmacology (IUPHAR) report. After a period of expansion in the last 20 years of the 20th century, clinical pharmacology, as a discipline, declined somewhat in many countries. However, during the last few years, there have been signs both of new growth in and new enthusiasm for the discipline [7], although the importance of clinical pharmacology to pharmaceutical companies has never been in doubt. A recent report on the relationship between the pharmaceutical industry and the National Health Service (NHS) in the United Kingdom has stated that re-building clinical pharmacology as a core discipline in the NHS is of vital importance for the future of health care in the UK and this is likely to be true in many other countries [8]. This document aims to set the scene for clinical pharmacology in the early part of the 21st century using the concept of the original WHO report and updating it for IUPHAR. We have gathered a group of distinguished clinical pharmacologists who have written the individual sections which are designed to address the role of clinical pharmacology in health care, research and teaching as well as describing the discipline’s link with industry and governments. We hope that the document will prove useful to many people, perhaps particularly young doctors who are looking to establish themselves in a clinical speciality and who have a particular interest in improving drug therapy and making it safer and more effective as exemplified in the WHO Rational Use of Drugs policy. However, this document is primarily aimed at decision-makers in a variety of organizations, particularly in governments and their healthcare ministries as well as chief executives and board level directors of primary and secondary care organizations and directors in the pharmaceutical industry. We hope they will realize the great benefits that expertise in clinical pharmacology can bring to the delivery of better health care for all populations. Clinical pharmacology is the scientific discipline that involves all aspects of the relationship between drugs and humans. Its breadth includes the development of new drugs, the application of drugs as therapeutic agents, the beneficial and adverse effects of drugs in individuals and society, and the deliberate misuse of drugs. Clinical pharmacology is a science that may be of significant interest to a variety of professions including physicians, pharmacists, nurses and scientists in many different disciplines. The term ‘clinical pharmacologist’ is also used in the professional sense to refer to those physicians who are specialists in clinical pharmacology. They have usually undertaken several years of postgraduate training (see Addendum II) focusing on important aspects of clinical pharmacology including clinical trials theory, drug evaluations, pharmacoepidemiology, pharmacoeconomics, pharmacogenetics, pharmacovigilance and clinical drug toxicology. Such clinical pharmacologists have as their primary goal that of improving patient care, directly or indirectly, by promoting the safer and more effective use of drugs. Clinical pharmacology is both old and young. The practice of drug therapy goes back to ancient times and the discovery of drugs such as quinine, reserpine and artemisinin which were first used as herbal medicines. William Withering’s publication on the use of foxglove in the treatment of heart failure [9] may very well be considered the first scientific account of the discipline but it took 200 years before the pharmacology of digitalis was explored with accurate, clinical pharmacological methods. As a scientific discipline and academic subject, clinical pharmacology is young having originated from the middle of the 20th century. It is difficult to find who first coined the name as opinions differ between countries. Several distinguished pharmacologists active in the middle of the century brought pharmacology and clinical know-how about drugs together and helped to transform drug evaluation from the trial and error state to a scientific discipline. In the Anglo-Saxon literature, Harry Gold at Cornell [9,10] is commonly quoted as the person who first introduced the name clinical pharmacology in the early 1940s. However, in 1914, a textbook was written by Hans Horst Meyer and Rudolf Gottlied in German the title of which was translated as ‘Pharmacology, Clinical and Experimental’. In addition, also in the German literature, Paul Martini, professor of medicine in Bonn, published his monograph in 1932 entitled ‘Methodology of Therapeutic Investigation’ and he is considered by some as the first clinical pharmacologist [11]. According to Shelley and Baur, his contributions escaped the attention of the English-speaking world [11]. In the English literature, there is a long tradition of ‘materia medica’, particularly in Scotland. In 1884, John Mitchell Bruce wrote his textbook entitled ‘Materia Medica and Therapeutics. An Introduction to the Rational Treatment of Disease’ and this, in its 20th edition, became Dilling’s ‘Clinical Pharmacology’. This book was published in 1960, the same year as Desmond Laurence’s textbook entitled ‘Clinical Pharmacology’. There is no doubt that the most vigorous attempts to develop clinical pharmacology as an academic discipline were made in the United States [12,13]. Important landmarks are the first edition of Goodman and Gilman’s ‘The Pharmacological Basics of Therapeutics’ and the successful attempt (1960) by Walter Modell, also at Cornell, to launch the first scientific journal in the subject entitled ‘Clinical Pharmacology and Therapeutics’. In the early 1960s, the United States became the world centre for the training of clinical pharmacologists. The NIH chief James Shannon and his colleagues Bernard B. Brodie and Julius Axelrod introduced biochemical pharmacology as a science and drug measurements in body fluids as tools in clinical pharmacology. Several centres of excellence in clinical pharmacology offered training to potential clinical pharmacologists from all parts of the world. The efforts to improve clinical drug evaluation by Louis Lasagna, a pupil of Harry Beecher at John Hopkins Hospital, should be especially recognized [11,12]. In 1966, Lasagna published a brilliant, still valid, account in Science of the present status and future development of clinical pharmacology [12]. The birth of clinical pharmacogenetics can be ascribed to the pioneering contributions of Werner Kalow and A.G. Motulsky [14,15]. Parallel developments occurred in Europe, particularly in the UK, where the strong infrastructure in basic pharmacology and clinical medicine formed an excellent basis for a rapid growth of the discipline. Names that usually are mentioned in this context are Sir John Gaddum, Sir Horace Smirk and Sir Austin Bradford Hill [9]. Chairs in clinical pharmacology were created at the end of the 1960s in Germany, the UK and Sweden, although chairs in Materia Medica had long been established in Scotland. Academic growth of the discipline also took place in France [16]. The IUPHAR took early initiatives to develop clinical pharmacology. A section of clinical pharmacology was formed in the early 1970s and a division in the 1990s. Several IUPHAR executives strongly supported the discipline, particularly the first president Börje Uvnäs in Sweden, but also Sir Arnold Burgen in the UK and Helena Raskowa in Czechoslovakia, who all realized that pharmacology had to reach out to the bedside in order to develop. WHO brought together a Study Group in 1970 [1] to write a report on the scope, organization and training of clinical pharmacology, led by the late Sir Derrick Dunlop (UK), and containing, amongst others, the late professors Louis Lasagna (USA), Franz Gross, (Germany) and Leon Goldberg, (USA). In 1991, WHO Europe put together a booklet and a series of papers in the European Journal of Clinical Pharmacology about the roles of clinical pharmacology in teaching, research and health care [17]. For the first time, the potential usefulness of the discipline for the RUD in primary health care was emphasized. Several Nobel Prize laureates in medicine can be considered as representatives of clinical pharmacological research at its best such as Sir John Vane, Sir James Black, George Hitchings, Gertrude Elion and Arvid Carlsson. They all ‘practised’ clinical pharmacology during their efforts to introduce new pharmacotherapeutic principles into clinical medicine. Modern drug therapy has unquestionably transformed the health of peoples in developed countries over the last 50 years. Conditions such as poliomyelitis, diphtheria and pertussis have largely been eliminated in wealthier nations. Many lethal communicable diseases can be cured by modern antimicrobial agents. And complex surgery, beyond the imagination of our forefathers, can be performed safely and effectively using modern anaesthetic agents. Those with chronic diseases have benefited immeasurably with the emergence of safe and effective treatments for asthma, hypertension and hypercholesterolaemia. Nevertheless, there remains massive unmet clinical need in developing, emerging and developed countries. There is, for example, a pressing need for effective vaccines against HIV/AIDS, malaria and tuberculosis. We have nothing to prevent the inexorable decline in neurological function in people with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease. And, when effective vaccines and treatments have been developed, they are too often unavailable to those in the poorer parts of the world. During most of the second half of the 20th century, research-based pharmaceutical companies were, for practical purposes, the sole source of new medicines. They discovered, developed and delivered products – often with considerable ingenuity – for healthcare systems that were able to afford the costs required to maintain the industry’s infrastructure. People in poorer countries, unable to meet these costs – as well as lacking an appropriate healthcare infrastructure – only rarely benefited. The prospect for satisfying unmet medical need has, in some senses, never been brighter. Advances in molecular techniques offer the promise of identifying drug-sensitive targets that might attenuate or cure many miserable and life-threatening conditions. The massive chemical libraries available to most pharmaceutical companies, coupled with high-throughput screening and combinatorial chemistry, offer unimaginable rewards for us all. In addition, the emergence of an array of biotechnological techniques offers unique approaches to the development of innovative medicines. Yet, despite the promise from the science, the outlook is not favourable. Despite record investment in biomedical research by the public sector and not-for-profit organizations, as well as by pharmaceutical and biopharmaceutical companies, the number of new active molecules registered by drug regulatory authorities has fallen dramatically. The costs of bringing a new product to the market are increasing at a rate of 10% per annum, due in part to the failures of products during development, but also to the extended requirements for evidence-based documentation from regulatory authorities (e.g. in elderly patients). Added to this, many of the largest pharmaceutical companies are facing, by 2011, a reduction of 30–40% in turnover as their ‘blockbusters’ come off patent. There have also been spectacular withdrawals of some marketed medicines over the last few years because of safety concerns. As a consequence, drug regulatory authorities have become increasingly risk averse and place ever greater demands on manufacturers to demonstrate the safety of their products before and after marketing. While this may have some benefits for drug safety, these measures are likely to increase the cost of medicines unless they are implemented with considerable care. Moreover, healthcare systems across the world are struggling to meet the apparently high prices that pharmaceutical companies seek to charge for new products that do reach the market. Those responsible for meeting the health needs of the populations they seek to serve are under increasing pressure to provide affordable care. The increasing numbers of elderly and very elderly people (many with long-term chronic diseases requiring multiple drug therapy), the greater availability of effective screening measures (especially in the elderly), and the growing expectations of the public, all mean that resources are constrained. One of the reasons for the rapid emergence of HTA facilities, across Europe and North America, is because of the necessity to look ever more closely at the clinical and cost-effectiveness of therapeutic strategies. Despite this gloomy outlook, a number of relatively recent initiatives suggest that remedial action is being taken: Drug regulatory authorities themselves recognize the need for change if people are to have access to innovative medicines. Both the Food and Drug Administration in the United States [18] and the European Medicines Agency (EMEA) in the EU [19] have published plans for expediting the regulatory process of innovative medicines that are appropriately safe and effective. The process of drug discovery, confined for most of the 20th century to the laboratories of research-based pharmaceutical companies, has become much more pluralistic. In particular, academic scientists working in universities have become ‘drug hunters’ and some have been spectacularly successful. And, whereas 25 years ago, major pharmaceutical companies were unwilling to even contemplate developing products that had not been discovered in their own laboratories, they are now prepared to do so with enthusiasm. Indeed, companies are pursuing truly collaborative projects with academic scientists to the extent that they are allowing access to their chemical libraries. An increasing number of not-for-profit organizations such as the Bill and Melinda Gates Foundation (in Seattle) and the Hereditary Disease Foundation (in New York) are supporting drug discovery and development in co-operation with both academia and pharmaceutical companies. Some major pharmaceutical and biopharmaceutical companies are increasingly recognizing that their traditional models of discovery, development and pricing no longer meet the needs of either patients, healthcare systems or their shareholders [20]. Changes include moving away from seeking ‘blockbusters’; expanding sales to include the emerging markets in Asia; and discussing, with healthcare systems themselves, what future products would bring most value for money. These changes in the global medicines scene require the contributions of appropriately trained clinical pharmacologists if innovative new medicines are to reach those in need: Clinical pharmacologists should be better equipped to undertake ‘translational’ research especially the design and execution of Phase 1 studies. Too few contemporary clinical pharmacologists are actively engaged in the design and conduct of clinical trials. The founding fathers of the discipline (such as Lou Lasagna) made crucial contributions to health care by undertaking clinical trials – often in relatively small patient populations – that characterized a compound’s properties (especially dose–response relationships). With a few notable exceptions, the discipline of HTA has emerged in the absence of contributions from clinical pharmacology. This needs to change if HTA is to meet its full potential. Clinical pharmacologists could do so much more to meet the health needs of those peoples who have in the past been marginalized. They include children, those with rare diseases and those with conditions that are endemic in the poorest parts of the world. Introduction. In the first WHO report on clinical pharmacology in 1970 [1], the section on research emphasized the need for studies that explored the mechanisms of action of drugs and identified their pharmacokinetics in humans. Improvement of the early studies of new drugs in humans and conventional therapeutic trials were also prioritized. Research in clinical pharmacology has now taken new paths and this satisfies many principles of translational medicine defined as taking scientific data on drugs into rational patient care. However, we should be aware that not all research into drugs falls within the remit of translational medicine. The endeavour of a pharmacologist working in a clinical environment is to develop methods and strategies that improve the quality of drug use in individual patients and patient populations. Research in drug evaluation, drug utilization, pharmacovigilance and pharmacoepidemiology – areas that were only superficially mentioned in the 1970 document – is now the priority. All these research areas have great potential for supporting healthcare personnel in their RUD. Rational use of drugs implies that drugs should be chosen according to efficacy, ADRs and cost as potentially equally important parameters. Research in clinical pharmacology therefore also includes studies that elicit new data about drugs in use such as new indications and treatment of neglected patient populations (children, elderly). It also includes research into ADRs, pharmacogenetics and drug interactions. Research in clinical pharmacology is usually interdisciplinary and hence often carried out in collaboration with other professions: pharmacists, drug analytical chemists, molecular biologists, statisticians, computer specialists as well as clinical researchers from other medical specialities. Pharmacokinetic, pharmacodynamic and pharmacogenetic studies in human volunteers. This research should lead to a fundamental understanding of the mechanisms involved in the actions of the drugs on the organism or the actions of the organism on the drugs. The research is particularly focused on intra- and interindividual differences in pharmacokinetics and pharmacodynamics, an area in which clinical pharmacologists have made important contributions in the past. The mechanisms in such variability usually involve inherited individualities in the genes encoding drug targets, drug transporters and drug metabolizing enzymes. The perspective of the research should not only be in understanding the molecular mechanisms but also in designing genotyping or phenotyping tests, which may be applied to forecast drug response and to differentiate between genetic and non-genetic modifiers of the outcome of drug treatment. In vivo research is often combined with experimental studies in vitro and in silico (see glossary). The research aims to identify the routes of metabolism and excretion of drugs. There are two separate approaches in pharmacokinetic research, one based on several drug measurements over a fixed time schedule in a few subjects and the other being based on sparse measurements in each subject of a large population of individuals (population pharmacokinetics). Such data may help to identify subpopulations with impaired or enhanced elimination capacity. The population approach can also be applied to pharmacokinetic–pharmacodynamic evaluation. Clinical drug evaluation and clinical trial Phases I–III. Important research areas are to improve the methods used to evaluate drugs in humans. The first examination of the effects of a new drug in humans (Phase I) is done with great care and in great detail, few subjects being tested. These Phase I studies are often done by clinical pharmacologists working in industry or in specialized clinical trial units. When the time comes to examine the effect of the drug in patients with the disease to be treated (e.g. hypertension), again small numbers of patients will be studied in detail (Phase II studies). The training that clinical pharmacologists undergo gives them the skills to do such studies. The randomized controlled trial (RCT) or its extension to meta-analysis or systematic reviews of several RCTs is considered to be the gold standard for documenting the efficacy of drugs. The RCT has advantages but also disadvantages, and other methods for the evaluation of clinical interventions are needed [21]. Clinical pharmacologists have been the pioneers in introducing the RCT and in particular in introducing the placebo as control. The RCT is now mastered by clinical intervention researchers in practically all medical specialities and is no longer solely the province of clinical pharmacologists. The RCT is a method with which all clinical pharmacologists should be familiar as it still forms the basis of most drug evaluations. One area in which clinical pharmacologists could make a difference is the detection of relatively frequent ADRs that are predictable and understandable on the" @default.
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W1564438703 title "Clinical Pharmacology in Research, Teaching and Health Care" @default.
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