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Introduction: Evidence-based Medicine (EbM) was originally developed as a teaching tool for young doctors, but in Germany the last surveys among residents in 2009 and 2011 demonstrated that, across all topics, the largest deficits were seen in the field of EbM. One reason may be a deficit in customised offers for continuing medical education in EbM. In a randomised controlled trial with a wait-control design we investigated a possible gain in knowledge and the acceptance of an online course in EbM for first-year residents., Methods: All first-year residents at the Hospital of the Goethe University in Frankfurt received the offer to voluntarily take part in an online EbM course. The tutored course consisted of five modules according to the five steps of EbM, each module being complemented by practical tasks. The participants were randomised via telephone to the course right away or after a three-month waiting period. The primary endpoint (i.e., knowledge) was tested via two sets of 13 multiple choice questions before and after the course and after 6 and 12 months. The participants were asked to subjectively evaluate the course by using an A-F grading system and to semiquantitatively assess its level of difficulty; they were also asked to evaluate the usefulness of its content in their clinical setting., Results: 114 out of the 120 randomised participants took part. After 3 months the immediate intervention group (n=58) achieved a median of 10 (95 % confidence interval 10 to 11) correct answers following the course, whereas the waiting intervention group only received a median of 4 (95% confidence interval 4 to 5) correct answers after the three month waiting period (p ≤ 0.0001). The median gain in knowledge for both groups throughout the course was 5 correct answers (p ≤ 0.0001), and this proved to remain constant within a twelve month period. Six months after the course, this course was rated as clinically useful by 96.4 % of the participants, and 38.1% stated that they would volunteer again in further teaching activities. The course received a median grade of B., Discussion and Conclusions: A German online EbM course for first-year residents leads to a remarkable and sustainable gain in knowledge, is well marked, and its contents were regarded as clinically relevant. This tutored practical course is applicable to various settings and could provide an important contribution to EbM residency programs., (Copyright © 2012. Published by Elsevier GmbH.)

Background: Conflicts of interest can bias the recommendations of clinical guidelines. In 2010, the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) revised its rules about how conflicts of interest in guidelines should be managed., Methods: All S2 and S3 guidelines in the AWMF database that were created in the years 2009-2011 were independently examined by two reviewers each (TL, MG, SC, BW, LF, SS). Information on conflicts of interest was extracted and descriptively analyzed. The effects of the new AWMF rules were studied with a before-and-after comparison., Results: 60 (20%) of the 297 guidelines studied contained explicit declarations of conflict of interest by their authors. 680 authors (49%) stated that they had financial relationships that constituted a conflict of interest; 86% declared conflicts arising from membership in specialty societies or professional associations. From 2009 to 2011, there was a substantial rise in the frequency of conflict-of-interest declarations in guidelines (8% of 256 guidelines that were created before the AWMF revised its rules in 2010 and 95% of 41 guidelines created afterward). The percentage of persons declaring financial conflicts of interest rose after the new rules were introduced, while the mode of documentation of conflict-of-interest evaluation and of any measures that might have been taken as a result remained unchanged., Conclusion: From 2011 onward, all conflict-of-interest declarations by guideline authors have been published in the AWMF database. There is no current standard for the evaluation and management of conflicts of interest in guideline-creating groups, and this situation urgently needs to be remedied.

The German Agency for Quality in Medicine (ÄZQ) was established as a joint institution of the German Medical Association (BÄK) and the National Association of Statutory Health Insurance Physicians (KBV) in 1995. Starting as a small quality assurance co-ordination unit of the German physicians' national self-governmental bodies, ÄZQ has been developed during the last decade into a centre of excellence for clinical practice guidelines, patient information, patient safety, evidence-based medicine, and knowledge management. The article summarises the institution's acitivities over the period of 15 years with respect to its national projects and international collaboration, being a founding member of the Guidelines International Network. In the future ÄZQ's programme priorities will be in the fields of knowledge transfer and implementation of medical decision aids into the daily work of health-care providers., (© Georg Thieme Verlag KG Stuttgart · New York.)

Chronic heart failure (CHF) is an illness mostly affecting elderly people. In Germany CHF is one of the most common causes of death and at the same time one of the most common diagnosis in inpatient care. Due to the expected increase in life expectancy in the next few years experts predict a further step-up of the incidence. Against this background development of a national guideline on chronic heart failure was prioritised and accordingly the National Disease Management Guideline (NDMG) Chronic Heart Failure was developed by a multi- and interdisciplinary group. The guideline group comprised experts from all relevant scientific medical societies as well as a patient expert. The National Disease Management Guideline (NDMG) on Chronic Heart Failure aims at supporting patients and health care providers with respect to decisions on a specific health care problem by giving recommendations for actions. Recommendations are informed by the best available scientific evidence on this topic.Patients with CHF often suffer from multiple conditions. Due to this fact and the old age patients do have very complex and demanding health care needs. Thus accounting for co-morbidities is paramount in planning and providing health care for theses patients and communication between doctor and patient but also between all health care providers is crucial.Basic treatment strategies in chronic heart failure comprise management of risk factors and prognostic factors as well as appropriate consideration of co-morbidities accompanied by measures empowering patients in establishing a healthy life style and a self-dependant management of their illness.Psycho-social aspects have a very strong influence on patients' acceptance of the disease and their self-management. In addition they have a strong influence on therapy management of the treating physician thus they have to be addressed adequately during the consultation.The National Disease Management Guideline (NDMG) Chronic Heart Failure (CHF) is an interdisciplinary guideline putting particular emphasis on giving recommendations for health care management at the interfaces of the health care system. The NDMG CHF provides a collection of evidence-based and consensus-based recommendations for diagnostics and therapy of patients with CHF. This CPG is meant to improve health care for all affected patients regardless of stage of disease or health care setting. Quality improvement though can only happen when the NDMG CHF is adopted into daily routine. To support implementation a patient version of the guideline was developed. The article compiles the most relevant recommendations and algorithms of the National Disease Management Guideline (NDMG) Chronic Heart Failure (CHF)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Together with an expert committee a structured approach to determining quality indicators for National Disease Management Guidelines has been developed. The key steps of this approach include: introducing guideline authors to the methodology at an early stage of the process of guideline development, pre-selecting recommendations of the guideline which are potentially measurable by means of quality indicators, assessing the potentially measurable quality indicators in written form using five criteria (including their importance for the health care system and clarity of definitions) and approving them in a formal consensus process. For lack of a database these quality indicators must be regarded as preliminary. For the National Disease Management Guideline "Chronic Heart Failure" nine rate-based indicators have been chosen. The indicators correspond to important strong recommendations (grade of recommendation: A) from the fields of diagnosis (two), general therapeutic strategy (two), specific treatment (three), clinical monitoring (one) and co-ordination of care (one). In a second step, the quality indicators have to be validated within a pilot project. The determination and assessment of the potential quality indicators have revealed room for improvement of guideline development. In particular, there is a need for more health care data and for specification of recommendations.

In December 2009, the first version of the German Disease Management Guideline (DM-CPG) for chronic heart failure was completed, including a set of proposed quality indicators for heart failure. This article explores whether proposed indicators can be derived from data collected routinely in general practices. For this purpose, previous experiences and data from the research project CONTENT (CONTinuous morbidity registration Epidemiologic NeTwork) conducted under guidance of the Department of General Medicine and Health Services Research at the University of Heidelberg, Germany, were applied. The availability of numerators and denominators needed for calculating the four quality indicators for diagnosis and pharmacotherapy proposed in the DM-CPG was checked within so-called "routine data" from the existing dataset of the CONTENT project. Within the given context, routine data are defined as data that are periodically transmitted from health care providers to cost units within the health care system. A thorough assessment has revealed that within the given context only one indicator could be deduced from routine data collection. This was the indicator measuring the proportion of patients receiving beta receptor antagonists, compared to all patients with heart failure NYHA class II to IV. Indeed, this single indicator will only be computable if the NYHA grade of heart failure severity and the presence or absence of contraindications to beta receptor antagonist therapy are routinely collected and the data merged into a central database. Against the background of these results it is obvious that a fully developed, transsectoral concept for data collection and data transfer needs to be implemented.

Introduction: Evidence-based medicine (EBM) improves the quality of health care. Courses on how to teach EBM in practice are available, but knowledge does not automatically imply its application in teaching. We aimed to identify and compare barriers and facilitators for teaching EBM in clinical practice in various European countries., Methods: A questionnaire was constructed listing potential barriers and facilitators for EBM teaching in clinical practice. Answers were reported on a 7-point Likert scale ranging from not at all being a barrier to being an insurmountable barrier., Results: The questionnaire was completed by 120 clinical EBM teachers from 11 countries. Lack of time was the strongest barrier for teaching EBM in practice (median 5). Moderate barriers were the lack of requirements for EBM skills and a pyramid hierarchy in health care management structure (median 4). In Germany, Hungary and Poland, reading and understanding articles in English was a higher barrier than in the other countries., Conclusion: Incorporation of teaching EBM in practice faces several barriers to implementation. Teaching EBM in clinical settings is most successful where EBM principles are culturally embedded and form part and parcel of everyday clinical decisions and medical practice.

Background: Teaching of evidence-based medicine (EBM) has become widespread in medical education. Teaching the teachers (TTT) courses address the increased teaching demand and the need to improve effectiveness of EBM teaching. We conducted a systematic review of assessment tools for EBM TTT courses. To summarise and appraise existing assessment methods for teaching the teachers courses in EBM by a systematic review., Methods: We searched PubMed, BioMed, EmBase, Cochrane and Eric databases without language restrictions and included articles that assessed its participants. Study selection and data extraction were conducted independently by two reviewers., Results: Of 1230 potentially relevant studies, five papers met the selection criteria. There were no specific assessment tools for evaluating effectiveness of EBM TTT courses. Some of the material available might be useful in initiating the development of such an assessment tool., Conclusion: There is a need for the development of educationally sound assessment tools for teaching the teachers courses in EBM, without which it would be impossible to ascertain if such courses have the desired effect.

Aim: To evaluate the educational effectiveness of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduate medical trainees compared to a traditional lecture-based course of equivalent content., Methods: We conducted a cluster randomized controlled trial to compare a clinically integrated e-learning EBM course (intervention) to a lecture-based course (control) among postgraduate trainees at foundation or internship level in seven teaching hospitals in the UK West Midlands region. Knowledge gain among participants was measured with a validated instrument using multiple choice questions. Change in knowledge was compared between groups taking into account the cluster design and adjusted for covariates at baseline using generalized estimating equations (GEE) model., Results: There were seven clusters involving teaching of 237 trainees (122 in the intervention and 115 in the control group). The total number of postgraduate trainees who completed the course was 88 in the intervention group and 72 in the control group. After adjusting for baseline knowledge, there was no difference in the amount of improvement in knowledge of EBM between the two groups. The adjusted post course difference between the intervention group and the control group was only 0.1 scoring points (95% CI -1.2-1.4)., Conclusion: An e-learning course in EBM was as effective in improving knowledge as a standard lecture-based course. The benefits of an e-learning approach need to be considered when planning EBM curricula as it allows standardization of teaching materials and is a potential cost-effective alternative to standard lecture-based teaching.

Within the context of the development of evidence-based oncology guidelines, the Agency for Quality in Medicine undertook evidence reviews for diagnostic imaging procedures. Systematic searches retrieved no randomised controlled trials, but only cohort studies and case series of mostly moderate quality. The identified studies provided only a restricted basis for the guideline recommendations as their validity was limited and only outcomes of diagnostic accuracy were examined. However, decision criteria for recommending diagnostic strategies significantly comprise judgements about required resources and availability of diagnostic imaging procedures. These criteria as well as patient out-comes were mostly implicit and should be explicated in future. In order to increase the relevance of evidence reviews for oncological diagnosis, high quality studies which examine resources and patient-centred outcomes for diagnostic strategies are required., (Copyright © 2010. Published by Elsevier GmbH.)

Gender and diversity have a strong impact on health and illness as evidenced by sex and gender differences in the onset and progression of diseases as well as in diagnosis, therapy, and therapeutic outcome. The number of sex/gender-specific studies in medicine has increased steadily in recent years, indicating sex (biological) and gender (social) differences in numerous diseases. Despite this evidence, however, sex/gender differences are rarely considered in medical practice or in health systems, suggesting a delay in transferring such research into evidence-based medical treatment. Similarly, quality improvement guidelines in medical care do not systematically integrate the sex/gender perspective. Against this backdrop, this paper seeks to enumerate the necessary components of a guideline development and evaluation process that systematically integrates sex/gender differences in addition to providing a sex/gender-based methodological approach. The latter is illustrated by a pilot study in which four international guidelines on depression were selected. The sex/gender appropriateness of these guidelines was analysed using two methods: first, sex/gender-relevant words were counted; and second, relevant sex/gender differences were summarised based on a systematic literature review and then compared with the information given in the guidelines. The findings of the pilot study revealed that although strong evidence exists on sex/gender differences in depression, such research was rarely implemented in the guidelines. Given the scope and potential of guidelines to improve the quality of health care, it is essential that they consider the crucial role of sex/gender differences. To date, sex/gender differences have been insufficiently addressed in guideline development and evaluation when they should be an integral component of the process., (Copyright © 2010. Published by Elsevier GmbH.)

After seven years the National Disease Management Guidelines Programme (German DM-CPG Programme) that was established under the auspices of the German Medical Association, the National Association of Statutory Health Insurance Physicians and the Association of the Scientific Medical Societies in Germany has been widely accepted by both health care professionals and patients. DM-CPGs are available as tools for knowledge and quality management for widespread chronic diseases showing need for improvement in treatment pathways and coordination between health care providers. The main objective of the German DM-CPG Programme is to establish consensus among the medical professions on evidence-based key recommendations covering all sectors of health care provision and facilitating the coordination of care for the individual patient over time and across interfaces. German DM-CPGs provide a conceptual basis for disease management and integrative care aiming at the implementation of best practice recommendations for prevention, acute care, rehabilitation, chronic care and management aspects for high priority health care topics. Thus, representatives of all disciplines, professions and patients concerned with the topic of an individual German DM-CPG are involved in the development process. The methodology of guideline development is in accordance with international standards. However, the improvement of strategies for effective implementation and continuous update remain challenging. Future work will also focus on content-related aspects such as co-morbidity, gender and migration background., (Copyright © 2010. Published by Elsevier GmbH.)

Evidence-based guidelines are important sources of knowledge in everyday clinical practice. In 2005, the German Society for Urology decided to develop a highquality evidence-based guideline for the early detection, diagnosis and treatment of the different clinical manifestations of prostate cancer. The guideline project started in 2005 and involved 75 experts from 10 different medical societies or medical organizations including a patient organization. The guideline was issued in September 2009 and consists of 8 chapters, 170 recommendations, and 42 statements. Due to the broad spectrum of clinical questions covered by the guideline and the high number of participating organizations and authors, the organizers faced several methodological and organizational challenges. This article describes the methods used in the development of the guideline and highlights critical points and challenges in the development process. Strategies to overcome these problems are suggested which might be beneficial in the development of new evidence-based guidelines in the future., (Copyright 2010 S. Karger AG, Basel.)

For seven years the German National Disease Management Guidelines Programme (NDMG Programme) has been supported by its funding bodies: the German Medical Association, the National Association of Statutory Health Insurance Physicians, and the Association of Scientific Medical Societies. The objectives of the NDMG Programme are to develop and to implement comprehensive national clinical guidelines for the management of selected illnesses. Key points of NDMG methodology are the strict adherence to the principles of evidence-based medicine as well as the avoidance of contradictory recommendations by means of neutrally facilitated consensus rounds. Despite the standardised NDMG methodology each guideline has individual structural and content features that make it unique. For example, the complex illness type 2 diabetes is presented in topic- and problem-oriented NDMG modules. For unipolar depression, the NDMG was simultaneously developed as a S3 guideline. Furthermore each NDMG group was faced with its own content-based challenges. For instance, in the case of the NDMG Low-back Pain the guideline group intensely and controversially discussed the definition of unspecific low-back pain. The NDMG Asthma does not solely address adults, but also children and adolescents, and the NDMG Heart Failure for the first time covers other health care relevant aspects such as multimorbidity and psychosocial factors in detail. The following article aims to deliver insight into the diversity of the development of National Disease Management Guidelines and to demonstrate the complexity of guideline development., (Copyright © 2010. Published by Elsevier GmbH.)

Background: Over the past decade, evidence-based medicine (EBM) has gained recognition as a means to improve the quality of health care provision. However, little is known about learning opportunities to acquire EBM-associated skills. The EUebm-Unity partnership explored current educational activities for EBM practice for doctors across Europe., Methods: We surveyed organizations offering postgraduate EBM courses across Europe inquiring about their course programme, teaching content and strategies, and interest in a Europe-wide curriculum in EBM., Results: One hundred and fifty-six organizers in eight European countries reported 403 courses that had started first-time from 1996 to 2006. Despite a steady increase, in absolute terms, the frequency of courses was low and varied from 1 first-time offering of a course per 640 doctors (Spain) to 1 first-time offering per 5600 doctors (Austria) over 10 years. Most adopted the McMaster EBM teaching concept of small group, problem-based learning focussing on interventions, diagnostic tests and guidelines, and included efforts to link EBM to patient care. Teaching staff consisted of doctors from academic and non-academic settings, supported by methodologists. Efforts to formally integrate EBM in postgraduate activities were only partially successful. Most organizations welcomed a standardized European qualification in EBM. A limitation of the survey is the lack of follow-up information about the continuation of courses following the first-time offering., Conclusions: All countries offer some EBM courses with varying teaching intensity. Learning opportunities are insufficient to ensure widespread dissemination of knowledge and skills. Most countries welcome more efforts to develop inexpensive and feasible educational activities at a postgraduate level.

Background: Mammographic screening alone will miss a certain fraction of malignancies, as evidenced by retrospective reviews of mammograms following a subsequent screening. Mammographic breast density is a marker for increased breast cancer risk and is associated with a higher risk of interval breast cancer, i.e. cancer detected between screening tests. The purpose of this review is to estimate risks and benefits of supplemental breast ultrasound in women with negative mammographic screening with dense breast tissue., Methods: A systematic search and review of studies involving mammography and breast ultrasound for screening of breast cancer was conducted. The search was performed for the period 1/2000-8/2008 within the data source of PubMed, DARE, and Cochrane databases. Inclusion and exclusion criteria were determined prospectively, and the Oxford evidence classification system for diagnostic studies was used for evidence level. The parameters biopsy rate, positive predictive value (PPV) for biopsy, cancer yield for breast ultrasound alone, and carcinoma detection rate by breast density were extracted or constructed., Results: The systematic search identified no randomized controlled trials or systematic reviews, six cohort studies of intermediate level of evidence (3b) were found. Only two of the studies included adequate follow-up of subjects with negative or benign findings. Supplemental breast ultrasound after negative mammographic screening permitted diagnosis of primarily invasive carcinomas in 0.32% of women in breast density type categories 2-4 of the American College of Radiology (ACR); mean tumor size for those identified was 9.9 mm, 90% with negative lymph node status. Most detected cancers occurred in mammographically dense breast ACR types 3 and 4. Biopsy rates were in the range 2.3%-4.7%, with PPV of 8.4-13.7% for those biopsied due to positive ultrasound, or about one third of the PPV of biopsies due to mammography., Limitations: The study populations included wide age ranges, and the application to women age 50-69 years as proposed for mammographic screening could result in less striking benefit. Further validation studies should employ a uniform assessment system such as BI-RADS and report not only PPV, but also negative predictive value, sensitivity and specificity., Conclusion: Supplemental breast ultrasound in the population of women with mammographically dense breast tissue (ACR 3 and 4) permits detection of small, otherwise occult, breast cancers. Potential adverse impacts for women in this intermediate risk group are associated with an increased biopsy rate.

Background: To evaluate the educational effects of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduates compared to a traditional lecture-based course of equivalent content., Methods: We conducted a cluster randomised controlled trial in the Netherlands and the UK involving postgraduate trainees in six obstetrics and gynaecology departments. Outcomes (knowledge gain and change in attitude towards EBM) were compared between the clinically integrated e-learning course (intervention) and the traditional lecture based course (control). We measured change from pre- to post-intervention scores using a validated questionnaire assessing knowledge (primary outcome) and attitudes (secondary outcome)., Results: There were six clusters involving teaching of 61 postgraduate trainees (28 in the intervention and 33 in the control group). The intervention group achieved slightly higher scores for knowledge gain compared to the control, but these results were not statistically significant (difference in knowledge gain: 3.5 points, 95% CI -2.7 to 9.8, p = 0.27). The attitudinal changes were similar for both groups., Conclusion: A clinically integrated e-learning course was at least as effective as a traditional lecture based course and was well accepted. Being less costly than traditional teaching and allowing for more independent learning through materials that can be easily updated, there is a place for incorporating e-learning into postgraduate EBM curricula that offer on-the-job training for just-in-time learning., Trial Registration Number: ACTRN12609000022268.

Integrative concepts of teaching and learning with close reference to individual work routines are better suited to bring about attitudinal and behavioural modification--apart from a gain in knowledge and skills--than traditional educational approaches. All the same, the vast majority of continuing training courses in Evidence-based Medicine takes place during weekend courses or evening classes, outside the work environment. To counteract this deficit a modular curriculum framework for Evidence-based Medicine was developed within the scope of the European research project EUebm which aims to achieve both a harmonisation of EbM education and training in Europe and a better integration of education and training with everyday clinical practice. The modules of this curriculum are intended to seamlessly fit into our day-to-day clinical work for and with patients and thus facilitate close interaction between the actual clinical work and the learning of EbM techniques and their implementation into our own patients' care. On the basis of a survey conducted among all the project partners in Austria, England, Germany, Hungary, Italy, The Netherlands, Poland, Spain and Switzerland the demand for training and continuing education in EbM in the individual countries was identified. Taking into account the results of this survey as well as previous work such as, for example, the curriculum of the German Network for Evidence-based Medicine or material provided by the Centre for Evidence-based Medicine in Oxford, an Internet-based teaching and learning module on systematic reviews and meta-analyses was developed and tested in five of the participating countries. The test demonstrated that in this way harmonisation of EbM education and training and a better integration of training with our everyday clinical work becomes feasible.

We have identified three novel structures for inhibitors of the poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA and implicated in DNA repair, apoptosis, organ dysfunction or necrosis. 2-[4-(5-Methyl-1H-imidazol-4-yl)-piperidin-1-yl]-4,5-dihydro-imidazo[4,5,1-i,j]quinolin-6-one (BYK49187), 2-(4-pyridin-2-yl-phenyl)-4,5-dihydro-imidazo[4,5,1-i,j]quinolin-6-one (BYK236864), 6-chloro-8-hydroxy-2,3-dimethyl-imidazo-[1,2-alpha]-pyridine (BYK20370), and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC(50) values of 8.36, 7.81, 6.40, and 7.35 (pK(i) 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC(50) values of 7.50, 7.55, 5.71, and 5.38, respectively. BYK49187, BYK236864, and BYK20370 displayed no selectivity for PARP-1/2, whereas BYK204165 displayed 100-fold selectivity for PARP-1. The IC(50) values for inhibition of poly(ADP-ribose) synthesis in human lung epithelial A549 and cervical carcinoma C4I cells as well in rat cardiac myoblast H9c2 cells after PARP activation by H(2)O(2) were highly significantly correlated with those at cell-free PARP-1 (r(2) = 0.89-0.96, P < 0.001) but less with those at PARP-2 (r(2) = 0.78-0.84, P < 0.01). The infarct size caused by coronary artery occlusion and reperfusion in the anesthetized rat was reduced by 22% (P < 0.05) by treatment with BYK49187 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. during 2-h reperfusion), whereas the weaker PARP inhibitors, BYK236864 and BYK20370, were not cardioprotective. In conclusion, the imidazoquinolinone BYK49187 is a potent inhibitor of human PARP-1 activity in cell-free and cellular assays in vitro and reduces myocardial infarct size in vivo. The isoquinolindione BYK204165 was found to be 100-fold more selective for PARP-1. Thus, both compounds might be novel and valuable tools for investigating PARP-1-mediated effects.

Inhibitors of histone deacetylases (HDAC) are currently developed for the treatment of cancer. These include compounds with a sulfur containing head group like depsipeptide, alkylthiols, thiocarboxylates, and trithiocarbonates with a carbonyl group in the alpha-position. In the present investigation, we report on the synthesis and comprehensive SAR analysis of HDAC inhibitors bearing a tri- or dithiocarbonate motif. Such trithiocarbonates are readily accessible from either preformed or in situ prepared alpha-halogenated methylaryl ketones. A HDAC isotype selectivity and a substrate competitive mode-of-action is shown for defined analogues. Exploration of the head group showed the necessity of the dithio-alpha-carbonyl motif for potent HDAC inhibition. Highly potent, substrate competitive HDAC6 selective inhibitors were identified (12ac:IC 50 = 65 nM and K i = 110 nM). Trithiocarbonate analogues with an aminoquinoline-substituted pyridinyl-thienoacetyl cap demonstrate a cytotoxicity profile and potency comparable to that of suberoylanilide hydroxamic acid (SAHA) as an approved cancer drug.

Background: In two recent randomised clinical trials, a meta-analysis and in an effectiveness study analysing routine data from the U.S. Veterans Administration the superiority of the newer atypical drugs over typical antipsychotic drugs, concerning both their efficacy and their side-effect profile, has been questioned., Aims of the Study: To analyse the effectiveness and cost of atypical versus typical antipsychotic treatment for schizophrenia in routine care., Methods: Cohort study using routine care data from a statutory sickness fund with 5.4 million insured in Germany. To be included, patients had to be discharged with a diagnosis of schizophrenia in 2003 and fulfil membership criteria. Main outcome measures were rehospitalisation rates, mean hospital bed days, mean length of stay, cost of inpatient and pharmaceutical care to the sickness fund during follow-up and medication used to treat side-effects., Results: 3121 patients were included into the study. There were no statistically significant differences in the effectiveness of atypical and typical antipsychotics on rehospitalisation during follow-up (rehospitalisation rate ratio 1.07, 95% confidence interval 0.86 to 1.33). However, there were consistent observations of atypical antipsychotics being more effective for severe cases of schizophrenia (14.6% of study population; >61 prior bed days per year in 2000-2002) in the follow-up period, whereas for the other severity strata typical antipsychotics seemed more effective in reducing various rehospitalisation outcomes. Patients treated with atypical antipsychotics received significantly less prescriptions for anticholinergics or tiaprid (relative risk 0.26, 95% confidence interval 0.18 to 0.38)., Discussion: The effectiveness of atypical antipsychotics for schizophrenia on rehospitalisation measures appeared similar to that of typical antipsychotics. With the exception of severe cases, the higher costs for atypical antipsychotics were not offset by savings from reduced inpatient care. Major limitations include the lack of statistical power for subgroup analyses, the lack of clinical severity scale data and of life-course medical history data which both increase the risk of residual confounding by disease severity., Conclusions: This study provides evidence that the effectiveness of atypical and typical antipsychotics measured in terms of hospital readmissions appears to be similar in routine care., Implications for Health Care Provision and Use: From a clinical perspective, this study provides evidence that the effectiveness of atypical and typical antipsychotics measured in terms of hospital readmissions appears to be similar in routine care., Implications for Health Policies: Routine data studies can yield valuable information for policy decision-makers on the costs and the effectiveness of pharmaceuticals in routine care, complementing efficacy data from randomised clinical trials currently used for licensing and reimbursement decisions., Implications for Further Research: The non-significant differences in the effectiveness of atypical compared to typical antipsychotics according to severity of disease should be investigated in a prospective observational study or in a randomised clinical trial.

Due to the highly divided structure of the German health care system, patients are usually cared for within sectors or along sectoral borders and not according to the ideal process of care. Often, as a result of this, individual working steps in health care are carried out parallel to each other in an uncoordinated fashion. The insufficient exchange of information and the lack of coordination of procedures between the involved members of the care process can lead to severe disruptions in the delivery of care. This creates problems like superfluous diagnostic and therapeutical interventions or a higher likelihood of mistakes, for example, when it comes to pharmacological therapy. With improved organization (communication, coordination and cooperation), optimization in the areas of quality and cost effectiveness can be expected. High-quality evidence-based guidelines or clinical pathways developed from evidence-based guidelines define ideal process sequences and requirements for structure, process and outcome quality. Thus, they can play a supporting role in the integration of medical care services in terms of organization and content. Hereby evidence-based quality indicators serve as tools for process supervision. Guideline-based Integrated Care Contracts pose an excellent opportunity for the implementation of guidelines. At the same time, integrated care based on high-quality guidelines can considerably contribute to improving the quality of medical health care.

Background: We developed and evaluated the outcomes of an e-learning course for evidence based medicine (EBM) training in postgraduate medical education in different languages and settings across five European countries., Methods: We measured changes in knowledge and attitudes with well-developed assessment tools before and after administration of the course. The course consisted of five e-learning modules covering acquisition (formulating a question and search of the literature), appraisal, application and implementation of findings from systematic reviews of therapeutic interventions, each with interactive audio-visual learning materials of 15 to 20 minutes duration. The modules were prepared in English, Spanish, German and Hungarian. The course was delivered to 101 students from different specialties in Germany (psychiatrists), Hungary (mixture of specialties), Spain (general medical practitioners), Switzerland (obstetricians-gynaecologists) and the UK (obstetricians-gynaecologists). We analysed changes in scores across modules and countries., Results: On average across all countries, knowledge scores significantly improved from pre- to post-course for all five modules (p < 0.001). The improvements in scores were on average 1.87 points (14% of total score) for module 1, 1.81 points (26% of total score) for module 2, 1.9 points (11% of total score) for module 3, 1.9 points (12% of total score) for module 4 and 1.14 points (14% of total score) for module 5. In the country specific analysis, knowledge gain was not significant for module 4 in Spain, Switzerland and the UK, for module 3 in Spain and Switzerland and for module 2 in Spain. Compared to pre-course assessment, after completing the course participants felt more confident that they can assess research evidence and that the healthcare system in their country should have its own programme of research about clinical effectiveness., Conclusion: E-learning in EBM can be harmonised for effective teaching and learning in different languages, educational settings and clinical specialties, paving the way for development of an international e-EBM course.

Depressive disorders rank among the most frequent causes of consultation and diseases in health care. Although they are treatable, there is further need to optimize diagnostics and therapy, despite sizable progress in recent years. The implementation of evidence- and consensus-based guidelines is an appropriate measure to improve care for depressive patients. An evidence-based guideline for depression is currently being developed for Germany. In order to ensure its acceptance and a wide dissemination, this guideline will be adopted in consensus by all relevant health care providers in this field. According to this, it is a future challenge to anchor guideline-based diagnostics and treatment in routine care.

Background: Over the last years key stake holders in the healthcare sector have increasingly recognised evidence based medicine (EBM) as a means to improving the quality of healthcare. However, there is considerable uncertainty about the best way to disseminate basic knowledge of EBM. As a result, huge variation in EBM educational provision, setting, duration, intensity, content, and teaching methodology exists across Europe and worldwide. Most courses for health care professionals are delivered outside the work context ('stand alone') and lack adaptation to the specific needs for EBM at the learners' workplace. Courses with modern 'adaptive' EBM teaching that employ principles of effective continuing education might fill that gap. We aimed to develop a course for post-graduate education which is clinically integrated and allows maximum flexibility for teachers and learners., Methods: A group of experienced EBM teachers, clinical epidemiologists, clinicians and educationalists from institutions from eight European countries participated. We used an established methodology of curriculum development to design a clinically integrated EBM course with substantial components of e-learning. An independent European steering committee provided input into the process., Results: We defined explicit learning objectives about knowledge, skills, attitudes and behaviour for the five steps of EBM. A handbook guides facilitator and learner through five modules with clinical and e-learning components. Focussed activities and targeted assignments round off the learning process, after which each module is formally assessed., Conclusion: The course is learner-centred, problem-based, integrated with activities in the workplace and flexible. When successfully implemented, the course is designed to provide just-in-time learning through on-the-job-training, with the potential for teaching and learning to directly impact on practice.

Inhibition of histone deacetylases class I/II enzymes is a new, promising approach for cancer therapy. In the present study, we disclose a new structural class of HDAC inhibitors with the trithiocarbonate motif. A clear structure-activity-relationship was obtained for the cap-linker motif and the putative Zn(2+) complexing head group. Selected analogs display potent inhibition of HDAC enzymatic activity and a cellular potency comparable to that of suberoylanilide hydroxamic acid (SAHA), recently approved for treatment of patients with advanced cutaneous T-cell lymphoma.

The Programme for National Disease Management Guidelines (German DM-CPG Programme) was established in 2002 by the German Medical Association (umbrella organisation of the German Chambers of Physicians) and joined by the Association of the Scientific Medical Societies (AWMF)--umbrella organisation of more than 150 professional societies--and by the National Association of Statutory Health Insurance Physicians (NASHIP) in 2003. The programme provides a conceptual basis for disease management, focussing on high priority healthcare topics and aiming at the implementation of best practice recommendations for prevention, acute care, rehabilitation and chronic care. It is organised by the German Agency for Quality in Medicine, a founding member of the Guidelines International Network G-I-N. The main objective of the German DM-CPG Programme is to establish consensus among the medical professions on evidence-based key recommendations covering all sectors of healthcare provision and facilitating the coordination of care for the individual patient through time and across interfaces. Within the last year DM-CPGs have been published for asthma, COPD, type 2 diabetes and coronary heart disease. In addition, experts from national patient self-help groups have been developing patient guidance based upon the recommendations for healthcare providers. The article describes background, methods and tools of the DM-CPG programme using the DM-CPG Method Report 2007.

Expensive drugs are good value for money if they are effective and safe, and if they have a better cost-effectiveness ratio than the standard therapy. In this article, an overview of commonly used methods, sources and functions of health economic evaluation is presented and illustrated using clinical examples to facilitate interpretation of the health economic information.