[Patient safety: current problems and challenges]. / Patientensicherheit ­ aktuelle Probleme und Herausforderungen.

Two decades after "To Err Is Human", the groundbreaking report published by the Institute of Medicine in the US, the German Patient Safety Alliance (Aktionsbündnis Patientensicherheit, APS) has published the "White Paper on Patient Safety". Based on the throughput model of health services research, the paper proposes a revised concept and definition of patient safety that focuses not only on the presence of adverse events (AE), but also on the ability of organizations and systems to adequately prioritize patient safety and implement this sustainably with improvement processes. Accordingly, a concept for measuring patient safety will be developed that no longer only quantitatively records AE, but also focuses on patient safety indicators that describe innovation competence. The epidemiological data will be updated; the rates of approximately 2-4% avoidable AE and 0.1% avoidable deaths among hospital patients appear to be highly conservative estimates. Data from non-representative sources, such as on legal procedures, underestimate frequencies by a factor of 30 ("litigation gap"). The most important obstacles to improving the situation are analyzed and give rise to the recommendation that, instead of one-point interventions (e.g., of a technical nature, such as IT-supported procedures), complex multicomponent interventions should increasingly be used in Germany, combining interventions with different approaches. Interventions at team level and with regard to management structures are focused on here.

[Health services research : Definition, objective, method and perspectives]. / Versorgungsforschung : Definition, Gegenstand, Methodik und Perspektiven.

This overview article highlights the central role of health services research (HSR) for the further development of the healthcare system. As a young scientific discipline in Germany, HSR covers five important elements with different weighting in different definitions, which are elaborated in some detail in this article: patient orientation, results and outcome orientation at the patient and population levels, implementation perspectives and context relation, complex interventions and improvement, multidisciplinarity and multiprofessionalism. One of the fundamental pillars of HRS is related to the insufficient implementation of scientifically proven treatment methods and improvement strategies into routine patient care. Healthcare research is therefore the so-called second translation of clinical trials in the routine daily care (from bedside to practice) after the first translation from bench to bedside. The scientific methods used in HSR clearly extend beyond the spectrum of (clinical) epidemiology. The methodological standards are developed as consensus memoranda of members of the German network of HSR, which serve as orientation points for qualitatively good HSR. Finally, various perspectives for the long-term safeguarding and improvement of the quality of HSR in Germany are proposed.

[Development, Application and Evaluation of a Concept for Safe Patient Identification in Hospital - How can Knowledge Transfer Succeed?] / Entwicklung, Anwendung und Evaluation eines Konzeptes zur sicheren Patientenidentifikation im Krankenhaus ­ Wie kann der Wissenstransfer gelingen?

Aim of the Study: In order to minimise the risk of patient misidentification in clinical settings, the German Coalition for Patient Safety published recommendations for safety patient identification in 2008. The aim of this study was to develop, implement and evaluate a theoretical framework of knowledge transfer. The purpose of the framework was to enhance hospital staff's ability to apply the recommendations for safe patient identification in the daily routine of patient care. Method: A data bank-based research and literature review have been conducted. Research topics were: knowledge transfer, change management and implementation science. Within the application of the concept group interviews were held with hospital staff and the interview material was evaluated using content analysis. On this basis a tailored multifaceted implementation strategy has been developed and applied in 8 hospital wards of 4 hospitals belonging to a communal hospital concern. The evaluation of the developed knowledge transfer concept was conducted 4 weeks after the concept application with a written questionnaire. Results: The developed framework concept of knowledge translation consisted of 4 phases built on top of each other: initiation phase; analysis phase; implementation phase; evaluation phase. The multifaceted implementation strategy included 3 interventions: a poster, a computer-based training and a guideline for team meetings. The survey yielded responses from 56 individuals: 96% declared that they know about the existence of the recommendations for safe patient identification; 86% said that they know about the content of the recommendations; 91% have striven to apply the recommendations in the daily routine of patient care; 71% stated that the recommendations for safe patient identification have become integral part in the daily routine of patient care. To become aware of the recommendations and its content the respondents have used on average 2.3 interventions, however the effect of the CBS was relatively small. Conclusion: The developed theoretical framework concept for knowledge transfer provides a way to integrate the recommendations for safe patient identification in the daily routine of patient care and to counteract risk factors promoting misidentification. Therefore a multifaceted implementation strategy is promising.

[Health services Research Faces New Challenges: Consequences for Definition and Concept]. / Versorgungsforschung vor neuen Herausforderungen: Konsequenzen für Definition und Konzept.

In Germany, Health Services Research (HSR) is undergoing rapid and impressive development. Starting from the translation of methods in individual health care (efficacy-effectiveness gap) and the social-scientific description as well as analysis of health care structures and processes, now it is the implementation of complex interventions on the organizational and system level that is the center of interest. This development is mainly triggered by the establishment of the so-called innovation funds by means of legislation in 2015, which has the task to evaluate structural changes and reforms in outpatient and integrated health care. Moreover, benefit and improvement at patient and population level is getting attention. Against this background, in this paper the current definition of HSR is modified so that the term "intervention" is extended to include organizational and system interventions, the focus on population is added to the patient perspective, and the orientation to appropriateness of care and improvement is integrated. Parallel to this, the theoretical throughput model as established by Pfaff in 2003 is updated, including 4 aspects: (1) the input factors of first order (resources of stakeholders) are expanded by complex interventions and active context as input factors of second order, (2) both undergoing modulation during the following throughput, (3) the final outcome is expanded by the population perspective, and (4) feedback loops from output and outcome to input and throughput are established. The "double complexity" of intervention and context as well as their interaction during throughput is the central and most important issue, because the interventions are highly context-sensitive and the complex context is most potent and poorly anticipated at the same time. Improvement science and implementation research represent fields of research from the perspective of improvement and the translation of knowledge and change of attitude, respectively, which are of great importance for HSR. Insofar as HSR is dealing with improvement and translation of complex interventions, the health care politics constitute an important transfer factor itself. Considering that, in the present situation, the political level represents both the main sponsor and the main demander of HSR results, improving methodological standards and further expansion of research structures of HSR are urgently needed.

Bortezomib Treatment can Overcome Glucocorticoid Resistance in Childhood B-cell Precursor Acute Lymphoblastic Leukemia Cell Lines.

BACKGROUND: The response to initial glucocorticoid (gc) treatment is a reliable stratification factor in childhood acute lymphoblastic leukemia (ALL) and may predict the response to multi-agent chemotherapy. In a former study we detected that the valosin-containing protein (VCP, cdc48), a member of the ubiquitin proteasome degradation system (UPS), is altered in gc-resistant leukemic cells suggesting that the associated pathways might be involved in chemotherapy resistance in childhood ALL. METHODS: Human B-cell precursor leukemia cell lines, gc-resistant MHH-cALL-2 and gc-sensitive MHH-cALL-3, were treated with prednisolone and various concentrations of bortezomib. Viability and apoptosis rates were determined. RESULTS: Both cell lines showed a dose-dependent increase in caspase activity after bortezomib single treatment. The gc-sensitive cells showed an additive effect after combined treatment with prednisolone and bortezomib. In contrast, both cell lines showed a reduced viability and enhanced propidium iodide positivity after combined treatment as determined by flow cytometry. Western blot analyses of poly-(ADP-ribose) polymerase 1 (PARP-1) suggested that combined treatment promote necrotic cleavage of PARP-1 in gc-resistant cells. Furthermore, after prednisolone treatment the UPS associated proteins VCP and NFκB-inhibitor IκBα were differentially modulated in gc-resistant cells. CONCLUSIONS: The proteasome inhibitor bortezomib seems to sensitize gc-resistant childhood ALL cells for prednisolone-induced cell death.

Minimal residual disease-based treatment is adequate for relapse-prone childhood acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21: the experience of the ALL-BFM 2000 trial.

BACKGROUND: Recently, the UK CCLG and COG reported that an intrachromosomal amplification of chromosome 21 (iAMP21) in acute lymphoblastic leukemia (ALL) loses its adverse prognostic impact with intensified therapy. PATIENT AND METHODS: We evaluated the prognosis of iAMP21 among patients from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial with 46 of 2 637 (2%) patients iAMP21+. RESULTS: 8-year event-free-survival (EFS, 64 ± 8% vs. 81 ± 1%, p=0.0026) and cumulative incidence of relapse (CIR, 29 ± 8% vs. 14 ± 1%, p=0.008) of the iAMP21 cases were significantly worse compared with non-iAMP21 patients. Within the MRD low-risk group, iAMP21 cases (n=14) had an inferior 8-year EFS (76 ± 12% vs. 92 ± 1%, p=0.0081), but no increased CIR (10 ± 10% vs. 6 ± 1%, p=0.624). Within the MRD intermediate-risk group, iAMP21 cases (n=27) had a worse 8-year EFS (56 ± 11% vs. 78 ± 2%, p=0.0077) and CIR (44 ± 11% vs. 20 ± 2%, p=0.003) with 6/10 relapses occurring after 2 years. CONCLUSIONS: Conclusively, we believe that there is no necessity for enrolling all iAMP21 patients into the high-risk arm of ongoing ALL-BFM trials because MRD low-risk patients have a moderate relapse risk under current therapy. Whether the increased relapse risk in MRD intermediate-risk patients can be avoided by late treatment intensification remains to be answered by the AIEOP-BFM ALL 2009 trial randomly using protracted pegylated L-asparaginase during delayed intensification and early maintenance.

Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria.

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.

Lineage classification of childhood acute lymphoblastic leukemia according to the EGIL recommendations: results of the ALL-BFM 2000 trial.

BACKGROUND: Flow cytometry immunophenotyping (FCM) is an undispensable tool for the diagnosis and for the treatment stratification of childhood acute lymphoblastic leukemia. The correlation of the EGIL-classification with prognostically relevant parameters like age, prednisone response and risk group is analyzed. PATIENTS: Between March 2000 and June 2009 12 patients less than 1 year of age, 1 836 patients with 1 to less than 6 years, 620 patients with 6 to less than 10 years, 615 patients with 10 to less than 15 years and 275 patients with 15 to less than 19 years were analyzed with a comprehensive 4-color antibody panel and classified according to the EGIL recommendations. METHODS: Bone marrow or peripheral blood mononuclear cells were isolated by ficoll gradient centrifugation, washed and stained with fluorochrome-conjugated antigen-specific monoclonal antibodies. Cell preparations were acquired and analyzed on a flow cytometer. RESULTS: Centralized FCM was performed for 2 775 patients (82.6%) with B-cell precursor acute lymphoblastic leukemia, 493 patients (14.7%) with T-cell acute lymphoblastic leukemia and 90 patients (2,7%) with biphenotypic acute leukemia. There was a slight overall predominance of male (56.1%) over female (43.9%) patients. Patients with B-cell precursor ALL had a slightly more favourable outcome with a 10 y pEFS of 78 ± 1.0%, compared to patients with a T-ALL or BAL (biphenotypic acute leukemia) phenotype with a 10 y pEFS of 74 ± 1.8% (n.s.) or 69 ± 9.0% (p<0.009), respectively. CONCLUSIONS: FCM according to the EGIL recommendations not only provides diagnostic lineage determination and subclassification but also enables an initial prognostic orientation before MRD (minimal residual disease)-based risk stratification becomes available.

Prediction of outcome by early response in childhood acute lymphoblastic leukemia.

BACKGROUND: In the ALL-BFM studies for treatment of acute lymphoblastic leukemia, reduction of leukemic blasts in peripheral blood after a one-week prednisone pre-phase - the so-called prednisone response - has been used for risk stratification since the 1980s and has been one of the most relevant factors for identification of high-risk patients. In the trial ALL-BFM 95, early cytomorphological marrow response on day 15 of induction therapy was prospectively evaluated and its prognostic value was analyzed in comparison to the prednisone response and other established prognostic factors. RESULTS: Compared to prednisone response, day 15 marrow response was superior in outcome prediction - yet with differential effect depending on blast lineage. Outcome was poor in T cell leukemia patients with prednisone poor-response independent of day 15 marrow response, whereas among patients with prednisone good-response different risk groups could be identified by day 15 marrow response. In contrast, prednisone response lost prognostic significance in precursor B cell leukemia when stratified by day 15 marrow response. CONCLUSIONS: Selective addition of day 15 marrow response to conventional stratification criteria applied on ALL-BFM 95 may significantly improve risk-adapted treatment delivery. Even though cutting-edge trial risk stratification is meanwhile dominated by minimal residual disease evaluation, an improved conventional risk assessment, as presented here, could be of great importance to countries lacking the technical and/or financial resources associated with the application of minimal residual disease analysis.

Key treatment questions in childhood acute lymphoblastic leukemia: results in 5 consecutive trials performed by the ALL-BFM study group from 1981 to 2000.

Between 1981 and 2000, 6 609 children (<18 years of age) were treated in 5 consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria, and Switzerland. Probability of 10-year event-free survival (survival) improved from 65% (77%) in study ALL-BFM 81-78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: 1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk ALL patients and eliminated in non-high-risk non-T-ALL patients, if it was replaced by high-dose and intrathecal methotrexate; 2) omission of delayed reintensification severely impaired outcome of low-risk patients; 3) 6 months less maintenance therapy caused an increase in systemic relapses; 4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; 5) condensed induction therapy resulted in a significant improvement of outcome; 6) the daunorubicin dose in induction could be safely reduced in low-risk patients; 7) intensification of consolidation/reintensification treatment led to considerable improvement of outcome in high-risk patients.

[Variations in the epidemiolgy of adverse events: methodology of the Harvard Medical Practice Design]. / Varianz in der Epidemiologie unerwünschter Ereignisse: Methodik des Harvard Medical Practice Design.

The Harvard Medical Practice (HMP) Design is based on a multi-staged retrospective review of inpatient records and is used to assess the frequency of (preventable) adverse events ([P]AE) in large study populations. Up to now HMP studies have been conducted in 9 countries. Results differ largely from 2.9% to 3.7% of patients with AE in the USA up to 16.6% in Australia. In our analysis we systematically compare the methodology of 9 HMP studies published in the English language and discuss possible impacts on reported frequencies. Modifications in HMP studies can be individualised from each stage of planning, conducting, and reporting results. In doing so 2 studies from the USA with lowest rates of AE can be characterised by their context of liability and the absence of screening for nosocomial infections. Studies with a high proportion of AE are marked by an intense training of reviewers. Further conclusions are hindered by divergences in defining periods of observation, by presenting frequencies as cumulative prevalences, and differences in the reporting of study results. As a consequence future HMP studies should go for complete, consistent and transparent coverage. Further research should concentrate on advancing methods for collecting data on (P)AE.

[Patient safety indicators for medication safety (AMTS-PSI): international status, transferability and validation]. / Patientensicherheitsindikatoren zur Arzneimitteltherapiesicherheit (AMTS-PSI): Internationaler Status, Übertragbarkeit und Validierung*

BACKGROUND: The aim of this project was to identify international patient safety indicators used for medication safety (AMTS-PSI), to evaluate the validity by a panel of experts, and to examine the transfer of the international AMTS-PSI to the pharmacotherapy care of the German Health Care System. It was part of the "Agenda for the Improvement of Medication Safety 2008/2009 in Germany" of the German Ministry of Health. METHOD: National and international AMTS-PSI were identified by a systematic review (Set 1). To define patient safety indicators as a subdivision of quality indicators, the indicators were categorised by patient's risk of adverse drug events and the degree of prevention (Set 2). Duplicates of AMTS-PSI were excluded (Set 3). The content validity was determined by the "qualify-instrument" on categories "relevance", "evidence" and "feasibility". This process was based on a double-stage Delphi method. The transferability to the pharmacotherapy care of the German Health Care System of the AMTS-PSI was evaluated (Set 4). RESULTS: 385 AMTS-indicators were identified. The categorisation resulted in a set of 40 AMTS-PSI, 20 AMTS-PSI were excluded. The evaluation of the validity by the "qualify-instrument" and the transferability resulted in a set of 14 for the stationary, ambulant sector. They also were valid for both sectors. CONCLUSION: An AMTS-PSI-set was identified by a systematic review and recognised as valid for transferring it to the pharmacotherapy care of the German Health Care System by the "qualify-instrument". These 14 AMTS-PSI are mainly characterised by their relevance. Before using these indicators in practice, their further operationalisation seems necessary.

Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol.

BACKGROUND: The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. METHODS: Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10-4), and high (≥5∗10-4). RESULTS: The 6-year event-free and overall survival was 73.9% (standard error [SE] = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10-4 had a worse outcome (6-year DFS 61.4% [SE = 12.4], n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% [SE = 6.6], n = 28) or intermediate EOI MRD <5 × 10-4 (6-year DFS 76.4% [SE = 11.3], n = 24; P = 0.02). CONCLUSION: We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.

[Pay for performance (P4P). Long-term effects and perspectives]. / Pay for Performance (P4P). Langfristige Effekte und Anreizwirkungen.

After 10 years of experience and research, a wide array of results on evaluation and long-term effects of pay for performance (P4P) programs have been published. These data do not only give insight into most of the problems of implementation, but also into aspects which, in part, may attenuate the high expectations at the beginning of the discussion. P4P programs exhibit a ceiling effect, some improvements are reversed after incentives are cancelled, and improvements show opportunity costs as absent improvements for indicators, which are not object to financial incentives (in some cases for the same disease). These observations can be explained by the hypothesis that P4P programs have characteristics of fee-for-service reimbursement, if symmetric information is available for insurance and provider. P4P programs are local instruments. While integration of healthcare is considered as an important issue, they should be combined with programs and incentives which foster further vertical and horizontal integration. For Germany, further research in the implementation and effects of P4P programs is necessary.

[Memorandum III: Methods for Health Services Research (Part 2)]. / Memorandum III: Methoden für die Versorgungsforschung (Teil 2)*

The methodical quality of health services research studies is often subject to criticism. Common standards in the field of health services research have been lacking so far. Hence, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] decided to contribute to an improvement of this situation. The DNVF e. V. has already published part 1 of the Memorandum III"Methods for Health Services Research" for the 3 subject areas "Epidemiological Methods for Health Services Research", "Methods for Organisational Health Services Research" and "Methods for Quality of Life Research". The herewith published Part 2 of the Memorandum extends the spectrum by describing the methodological principles and minimum standards of "Methods of Health Economic Evaluations" and "Registries for Health Services Research". On 30 (th) August 2010, the member societies, mentioned as authors, approved this second part of the Memorandum III. 2 in-depth publications focussing on the 2 mentioned topics will be published in the next issues of this journal. This memorandum is intended for health services researchers who are planning, conducting and publishing studies as well as for reviewers who evaluate research proposals and publications on health services research studies. In accord with the expected advances in knowledge in health services research, it is planned to update the 2 parts of Memorandum III at appropriate intervals and to publish further parts from the huge spectrum of methods relevant to this field in the near future. Thus, the Memorandum has to be considered as work in progress.

[Methods of health economic evaluation for health services research]. / Methoden der gesundheitsökonomischen Evaluation in der Versorgungsforschung.

On August 30, 2010, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] approved the Memorandum III "Methods for Health Services Research", supported by the member societies mentioned as authors and published in this Journal [Gesundheitswesen 2010; 72: 739-748]. The present paper focuses on methodological issues of economic evaluation of health care technologies. It complements the Memorandum III "Methods for Health Services Research", part 2. First, general methodological principles of the economic evaluations of health care technologies are outlined. In order to adequately reflect costs and outcomes of health care interventions in the routine health care, data from different sources are required (e. g., comparative efficacy or effectiveness studies, registers, administrative data, etc.). Therefore, various data sources, which might be used for economic evaluations, are presented, and their strengths and limitations are stated. Finally, the need for methodological advancement with regard to data collection and analysis and issues pertaining to communication and dissemination of results of health economic evaluations are discussed.

[Memorandum III: "Methods for Health Services Research" (Part 1)]. / Memorandum III: Methoden für die Versorgungsforschung (Teil I).

The methodical quality of health services research studies is often subject to criticism. Common standards in the field of health services research have been lacking so far. Hence, the German Network Health Services Research [Deutsches Netzwerk Versorgungsforschung e.V. (DNVF e.V.)] decided to contribute to improve this situation. On 1 July 2009, the DNVF e.V. approved the Memorandum III "Methods for Health Services Research", supported by the member societies mentioned as authors. For the three subject areas "Epidemiological Methods for Health Services Research", "Methods for Organisational Health Services Research" and "Methods for Quality of Life Research", this Memorandum describes the methodological principles and minimum standards which should be adhered to when conducting and publishing health services research studies. Three in-depth publications focussing on the three mentioned topics will be published in the next issues of this journal. This memorandum is intended for health services researchers who are planning, conducting and publishing studies as well as for reviewers who evaluate research proposals and publications on health services research studies. In accord with the expected advances in knowledge in health services research, it is planned to update the Memorandum III (part 1) at appropriate intervals and to publish part 2 in the near future. Thus, the Memorandum has to be considered as work in progress.

[Clean Hands Campaign. No chance for hospital infections!]. / "AKTION Saubere Hände". Keine Chance den Krankenhausinfektionen!

There are approximately 500,000 hospital acquired infections per year in Germany of which about 20-30% (100,000-150,000) could be prevented. Hospital acquired infections are associated with increased mortality and prolonged hospital stay. Based on approximately 4 additional days of hospital stay, nosocomial infections cause additional 2 million hospital days per year. In other words, 6 hospitals each with 1,000 beds would be caring solely for patients with nosocomial infections for 1 year in Germany. Experts agree that careful hand hygiene is the single most effective measure to prevent transmission of pathogens. The rate of nosocomial infections can be reduced by improved compliance of hand hygiene as demonstrated in the literature. The ''AKTION Saubere Hände'' (Clean Hands Campaign) is a national campaign by the National Reference Centre for the Surveillance of Nosocomial Infections, the Society for Quality Management in the Health System and the Action Alliance Patient Safety aimed at the sustained improvement of hand hygiene behaviour in German hospitals.