Bispidine Chelators for Radiopharmaceutical Applications with Lanthanide, Actinide, and Main Group Metal Ions.

Octadentate and specifically nonadentate ligands with a bispidine scaffold (3,7-diazabicyclo[3.3.1]nonane) are known to be efficiently coordinated to a range of metal ions of interest in radiopharmaceutical chemistry and lead to exceedingly stable and inert complexes. Nonadentate bispidine L2 (with a tridentate bipyridine acetate appended to N3 and a picolinate at N7) has been shown before to be an ideal chelator for 111In3+, 177Lu3+, and 225Ac3+, nuclides of interest for diagnosis and therapy, and a proof-of-principle study with an SSTR2-specific octreotate has shown potential for theranostic applications. We now have extended these studies in two directions. First, we present ligand derivative L3, in which the bipyridine acetate is substituted with terpyridine, a softer donor for metal ions with a preference for more covalency. L3 did not fulfill the hopes because complexation is much less efficient. While for Bi3+ and Pb2+ the ligand is an excellent chelator with properties similar to those of L2, Lu3+ and La3+ show very slow and inefficient complexation with L3 in contrast to L2, and 225Ac3+ is not fully coordinated, even at an increased temperature (92% radiochemical yield at 80 °C, 60 min, [L3] = 10-4 M). These observations have led to a hypothesis for the complexation pathway that is in line with all of the experimental data and supported by a preliminary density functional theory analysis, which is important for the design of further optimized bispidine chelators. Second, the coordination chemistry of L2 has been extended to Bi3+, La3+, and Pb2+, including solid state and solution structural work, complex stabilities, radiolabeling, and radiostability studies. All complexes of this ligand (La3+, Ac3+, Lu3+, Bi3+, In3+, and Pb2+), including nuclides for targeted α therapy (TAT), single-photon emission computed tomography, and positron emission tomography, are formed efficiently under physiological conditions, i.e., suitable for the labeling of delicate biological vectors such as antibodies, and the complexes are very stable and inert. Importantly, for TAT with 225Ac, the daughter nuclides 213Bi and 209Pb also form stable complexes, and this is important for reducing damage to healthy tissue.

[The importance of guidelines in dentistry and dental education]. / Der Stellenwert von Leitlinien in der Zahnheilkunde und in der zahnmedizinischen Ausbildung.

Evidence-based treatment recommendations are gaining importance within the framework of both medical and dental quality management systems. The scientific findings, which have been evaluated critically by expert committees with regard to their methodological quality, are summarized in easy-to-understand guidelines. All guidelines are evaluated qualitatively in accordance with a balance between consensus and evidence during the drafting process regarding their stages of scientific development. The publication of guidelines and the coordination of guideline development has been carried out by the Association of the Scientific Medical Societies in Germany (AWMF) since its foundation in the 1960s. Forty-four dental guidelines are currently available, which are mostly rated at the highest level (S3) of scientific development. Therefore, recommendations for various treatment protocols are defined for both dental staff at university sites or practices and the implementation of these guidelines into the daily clinical routine is desirable. Poor acceptance and adverse resource requirements are major limitations of the establishment of guidelines with regard to the expansion of evidence-based dentistry. However, these limitations might be overcome by the introduction of basic scientific training within dental universities and increased funding of young researchers in order to ensure high treatment quality and economy in dentistry in the future. Guidelines can facilitate education by providing scientifically validated procedural templates to dental students and assisting educators in meeting the requirements of practical skills.

The German Guidelines for the treatment of anxiety disorders: first revision.

Starting in 2019, the 2014 German Guidelines for Anxiety Disorders (Bandelow et al. Eur Arch Psychiatry Clin Neurosci 265:363-373, 2015) have been revised by a consensus group consisting of 35 experts representing the 29 leading German specialist societies and patient self-help organizations. While the first version of the guideline was based on 403 randomized controlled studies (RCTs), 92 additional RCTs have been included in this revision. According to the consensus committee, anxiety disorders should be treated with psychotherapy, pharmacological drugs, or their combination. Cognitive behavioral therapy (CBT) was regarded as the psychological treatment with the highest level of evidence. Psychodynamic therapy (PDT) was recommended when CBT was not effective or unavailable or when PDT was preferred by the patient informed about more effective alternatives. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) are recommended as first-line drugs for anxiety disorders. Medications should be continued for 6-12 months after remission. When either medications or psychotherapy were not effective, treatment should be switched to the other approach or to their combination. For patients non-responsive to standard treatments, a number of alternative strategies have been suggested. An individual treatment plan should consider efficacy, side effects, costs and the preference of the patient. Changes in the revision include recommendations regarding virtual reality exposure therapy, Internet interventions and systemic therapy. The recommendations are not only applicable for Germany but may also be helpful for developing treatment plans in all other countries.

Evaluation of evidence grades in psychiatry and psychotherapy guidelines.

BACKGROUND: Information regarding the distribution of evidence grades in psychiatry and psychotherapy guidelines is lacking. Based on the German evidence- and consensus- based (S3) psychiatry and psychotherapy and the Scottish Intercollegiate Guidelines Network (SIGN) treatment guidelines, we aimed to specify how guideline recommendations are composed and to what extent recommendations are evidence-based. METHODS: Data was collected from all published evidence- and consensus-based S3-classified psychiatry and psychotherapy guidelines. As control conditions, data from German neurology S3-classified guidelines as well as data from recent SIGN guidelines of mental health were extracted. Two investigators reviewed the selected guidelines independently, extracted and analysed the numbers and levels of recommendations. RESULTS: On average, 45.1% of all recommendations are not based on strong scientific evidence in German guidelines of psychiatry and psychotherapy. A related pattern can be confirmed for SIGN guidelines, where the mean average of recommendations with lacking evidence is 33.9%. By contrast, in the German guidelines of neurology the average of such recommendations is 16.5%. A total of 24.5% of all recommendations in the guidelines of psychiatry and psychotherapy are classified as level A recommendations, compared to 31.6% in the field of neurology and 31.1% in the SIGN guidelines. Related patterns were observed for B and 0 level recommendations. CONCLUSION: Guidelines should be practical tools to simplify the decision-making process based on scientific evidence. Up to 45% of all recommendations in the investigated guidelines of psychiatry and psychotherapy are not based on strong scientific evidence. The reasons for this high number remain unclear. Possibly, only a limited number of studies answer clinically relevant questions. Our findings thereby question whether guidelines should include non-evidence-based recommendations to be methodologically stringent and whether specific processes to develop expert-opinion statements must be implemented.

[Update of the German S3 guideline on atraumatic femoral head necrosis in adults]. / Update S3-Leitlinie Atraumatische Femurkopfnekrose des Erwachsenen.

The update of the German S3 guideline on atraumatic femoral head necrosis in adults aims to provide an overview of diagnosis and treatment. All clinical studies, systematic reviews, and meta-analyses published in German or English between 01.05.2013 and 30.04.2017 were included. Of 427 studies, 28 were suitable for analysis. Risk factors are corticosteroids, chemotherapy, kidney transplants, hemoglobinopathies, and alcoholism. Differential diagnoses are for example bone marrow edema, insufficiency fracture, and destructive arthropathy. Radiography should be performed upon clinical suspicion. In patients with normal radiography findings but persistent complaints, magnetic resonance imaging (ARCO classification) is the method of choice. Computed tomography (CT) can be used to confirm/exclude articular surface collapse. A subchondral sclerosis zone >30% in CT indicates a better prognosis. Left untreated, a subchondral fracture will develop within 2 years. The risk of disease development in the opposite side is high during the first 2 years, but unlikely thereafter. In conservative therapy, iloprost and alendronate can be used in a curative approach, the latter for small, primarily medial necrosis. Conservative therapy alone as well as other drug-based and physical approaches are not suitable for treatment. No particular joint-preserving surgery can currently be recommended. Core decompression should be performed in early stages with <30% necrosis. From ARCO stage IIIc or in stage IV, the indication for total hip arthroplasty should be checked. Results after total hip arthroplasty are comparable with those after coxarthrosis, although the revision rate is higher due to the relatively young age of patients. Statements on the effectiveness of cell-based therapies such as expanded stem cells or bone marrow aspirates cannot currently be made.

Validation and reliability of a guideline appraisal mini-checklist for daily practice use.

BACKGROUND: The use of comprehensive instruments for guideline appraisal is time-consuming and requires highly qualified personnel. Since practicing physicians are generally busy, the rapid-assessment Mini-Checklist (MiChe) tool was developed to help them evaluate the quality and utility of guidelines quickly. The aim of this study was to validate the MiChe in comparison to the AGREE II instrument and to determine its reliability as a tool for guideline appraisal. METHODS: Ten guidelines that are relevant to general practice and had been evaluated by 2 independent reviewers using AGREE II were assessed by 12 GPs using the MiChe. The strength of the correlation between average MiChe ratings and AGREE II total scores was estimated using Pearson's correlation coefficient. Inter-rater reliability for MiChe overall quality ratings and endorsements was determined using intra-class correlations (ICC) and Kendall's W for ordinal recommendations. To determine the GPs' satisfaction with the MiChe, mean scores for the ratings on five questions were computed using a six-point Likert scale. RESULTS: The study showed a high level of agreement between MiChe and AGREE II in the quality rating of guidelines (Pearson's r = 0.872; P < 0.001). Inter-rater-reliability for overall MiChe ratings (ICC = 0.755; P < 0.001) and endorsements (Kendall's W = 0.73; P < 0.001) were high. The mean time required for guideline assessment was less than 15 min und user satisfaction was generally high. CONCLUSIONS: The MiChe performed well in comparison to AGREE II and is suitable for the rapid evaluation of guideline quality and utility in practice. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00007480.

Guidelines International Network: Principles for Disclosure of Interests and Management of Conflicts in Guidelines.

Conflicts of interest (COIs) have been defined by the American Thoracic Society as "a divergence between an individual's private interests and his or her professional obligations such that an independent observer might reasonably question whether the individual's professional actions or decisions are motivated by personal gain, such as direct financial, academic advancement, clinical revenue streams, or community standing." In the context of guideline development, the concerns are not simply about identifying and disclosing direct financial or indirect COIs. Despite this recognition, the management of COIs in guidelines is often unsatisfactory. In response to requests from its international membership and informed by existing syntheses of the evidence and policies of international organizations, the Guidelines International Network Board of Trustees developed guidance on the disclosure of interests and management of COIs. Current approaches are relatively similar throughout the guideline development community, with an increasing recognition of the importance of disclosing and managing indirect COIs. Although there are differences in detail among the approaches, the similarities allow for the formulation of 9 core principles for managing COIs. In formulating these principles, the Guidelines International Network Board of Trustees recognizes that COIs cannot be totally avoided when panel members are being chosen for certain guidelines or in certain settings; thus, the important issue is the management of COIs in a fair, judicious, transparent manner.

The GIN-McMaster guideline tool extension for the integration of quality improvement and quality assurance in guidelines: a description of the methods for its development.

BACKGROUND AND OBJECTIVES: Our objective was to develop an extension of the widely used GIN-McMaster Guideline Development Checklist and Tool for the integration of quality assurance and improvement (QAI) schemes with guideline development. METHODS: We used a mixed-methods approach incorporating evidence from a systematic review, an expert workshop and a survey of experts to iteratively create an extension of the checklist for QAI through three rounds of feedback. As a part of this process, we also refined criteria of a good guideline-based quality indicator. RESULTS: We developed a 40-item checklist extension addressing steps for the integration of QAI into guideline development across the existing 18 topics and created one new topic specific to QAI. The steps span from 'organization, budget, planning and training', to updating of QAI and guideline implementation. CONCLUSION: The tool supports integration of QAI schemes with guideline development initiatives and it will be used in the forthcoming integrated European Commission Initiative on Colorectal Cancer. Future work should evaluate this extension and QAI items requiring additional support for guideline developers and links to QAI schemes.

Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and adolescents. Immunomodulatory drugs are used frequently in its treatment. Using the nominal group technique (NGT) and Delphi method, we created a multidisciplinary, evidence- and consensus-based treatment guideline for JIA based on a systematic literature analysis and three consensus conferences. Conferences were headed by a professional moderator and were attended by representatives who had been nominated by their scientific societies or organizations. 15 statements regarding drug therapy, symptomatic and surgical management were generated. It is recommended that initially JIA is treated with NSAID followed by local glucocorticoids and/or methotrexate if unresponsive. Complementing literature evidence with long-standing experience of caregivers allows creating guidelines that may potentially improve the quality of care for children and adolescents with JIA.

A memorandum of understanding has facilitated guideline development involving collaborating groups.

OBJECTIVE: Collaboration between groups can facilitate the development of high-quality guidelines. While collaboration is often desirable, misunderstandings can occur. One method to minimize misunderstandings is the pre-specification of terms of engagement in a memorandum of understanding (MOU). This study considered when an MOU may be most helpful, and which key elements should be included. STUDY DESIGN AND SETTING: An international panel of representatives from guideline groups was convened. A literature review to identify publications and other documents relevant to the establishment of MOUs between two or more guideline groups, supplemented by available source documents, was used to inform development of a draft MOU resource. This was iteratively refined until consensus was achieved. RESULTS: The level of detail in an MOU may vary based on institutional preferences and the particular collaboration. Elements within an MOU include those pertaining to: (1) scope and purpose; (2) leadership and team; (3) methods and commitment; (4) review and endorsement; and (5) publication and dissemination. CONCLUSION: Since groups may have different expectations regarding how a collaboration will unfold, an MOU may mitigate preventable misunderstandings. The result may be a higher likelihood of producing a guideline without disruption and delay.

[Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline enterprise]. / Guidelines 2.0: Systematische Entwicklung einer umfassenden Checkliste für eine vertrauenswürdige Leitlinienentwicklung.

BACKGROUND: Although several tools to evaluate the credibility of health care guidelines exist, guidance on practical steps for developing guidelines is lacking. We systematically compiled a comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item. METHODS: We searched data sources, including manuals of international guideline developers, literature on guidelines for guidelines (with a focus on methodology reports from international and national agencies, and professional societies) and recent articles providing systematic guidance. We reviewed these sources in duplicate, extracted items for the checklist using a sensitive approach and developed overarching topics relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions and suggestions for items to be added. RESULTS: We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers. The topics and included items cover all stages of the guideline enterprise, from the planning and formulation of guidelines, to their implementation and evaluation. The final checklist includes links to training materials as well as resources with suggested methodology for applying the items. INTERPRETATION: The checklist will serve as a resource for guideline developers. Consideration of items on the checklist will support the development, implementation and evaluation of guidelines. We will use crowdsourcing to revise the checklist and keep it up to date.

International experiences in the development and implementation of guideline-based quality indicators: a qualitative study.

OBJECTIVES: Evidence-based clinical guidelines play an important role in healthcare and can be a valuable source for quality indicators (QIs). However, the link between guidelines and QI is often neglected and methodological standards for the development of guideline-based QI are still lacking. The aim of this qualitative study was to get insights into experiences of international authors with developing and implementing guideline-based QI. SETTING: We conducted semistructured interviews via phone or skype (September 2017-February 2018) with guideline authors developing guideline-based QI. PARTICIPANTS: 15 interview participants from eight organisations in six European and North American countries. METHODS: Organisations were selected using purposive sampling with a maximum variation of healthcare settings. From each organisation a clinician and a methodologist were asked to participate. An interview guide was developed based on the QI development steps according to the 'Reporting standards for guideline-based performance measures' by the Guidelines International Network. Interviews were analysed using qualitative content analysis with deductive and inductive categories. RESULTS: Interviewees deemed a programmatic approach, involvement of representative stakeholders with clinical and methodological knowledge and the connection to existing quality improvement strategies important factors for developing QI parallel to or after guideline development. Methodological training of the developing team and a shared understanding of the QI purpose were further seen conducive. Patient participation and direct patient relevance were inconsistently considered important, whereas a strong evidence base was seen essential. To assess measurement characteristics interviewees favoured piloting, but often missed implementation. Lack of measurability is still experienced a serious limitation, especially for qualitative aspects and individualised care. CONCLUSION: Our results suggest that developing guideline-based QI can succeed either parallel to or following the guideline process with careful planning and instruction. Strategic partnerships seem key for implementation. Patient participation and relevance, measurement of qualitative aspects and piloting are areas for further development. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS00013006).

[The G-BA innovation fund's project "Avenue-Pal" - analysis and improvement of cross-sectoral and cross-departmental interface and relocation management in palliative care]. / Das G-BA-Innovationsfonds-Projekt "Avenue-Pal" : Analyse und Verbesserung des sektor- und bereichsübergreifenden Schnittstellen- und Verlegungsmanagements in der Palliativversorgung.

BACKGROUND: About 80% of all people in Germany die in inpatient care. Around every fifth person in inpatient care is relocated to another care area in the last phase of their life. That is more than 150,000 people being relocated, often without indication. 13 risk factors were identified for these non-indicated relocations. METHOD: With the support of the AWMF, two regionally effective guidelines were developed and implemented in a maximum care hospital and a care facility. A palliative consultation service has been established in the university hospital. Comprehensive personnel and organizational development was carried out in the care facility. Different collaborations with relevant regional partners of both model institutions were systematically expanded. RESULTS AND CONCLUSIONS: The relocations could be significantly reduced despite the short duration of the project. This was also possible through the establishment of decision-making aids and digital implementation support. The results of the accompanying ethical and social research justify the procedure: There is an increase in the satisfaction of relatives and employees.

[Methodological Standard for the Development of Quality Indicators within Clinical Practice Guidelines - Results of a structured consensus process]. / Methodischer Standard für die Entwicklung von Qualitätsindikatoren im Rahmen von S3-Leitlinien ­ Ergebnisse einer strukturierten Konsensfindung.

BACKGROUND: Recommendations of evidence- and formally consensus-based clinical practice guidelines (CPGs) represent a valuable source of quality indicators (QIs). Nevertheless, a standardized methodological procedure for developing QIs in the context of CPGs does not yet exist in Germany for all CPGs. For this reason, a methodological standard for the guideline-based development of QIs (QI Standard) was developed based on a structured consensus process involving multiple key stakeholders. METHODS: The proposed content of the QI Standard was derived from evidence, drawing upon results of reviews and qualitative studies, and considered German manuals for guideline-based QI development of two guideline programs. A multi-perspective consensus panel, broadly representing key stakeholders from the German healthcare system with expertise in CPGs and/or quality management, was nominated to vote on recommendations for guideline-based development of QIs. The iterative, structured consensus process included a two-stage online survey based on the Delphi method ("preliminary voting") and a moderated final stakeholder conference where all those recommendations were definitely included in the QI Standard that received approval of more than 75 % (consensus criterion) of the consensus panel. RESULTS: Based on the agreed QI Standard, the QI development process starts with a criteria-based selection of "potential" QIs which - in case of adoption - are published in CPGs as "preliminary" QIs and can achieve the status "final" after successful testing. The QI Standard is composed of a total of 30 recommendations, which are allocated to six areas: A) preparatory work steps for the guideline-based recommendation of QIs, B) QI development group and cooperation with the CPG group, C) development of potential QIs, D) critical appraisal of potential QIs, E) formal adoption and publication as well as F) piloting/testing of preliminary QIs and conversion into final QIs. DISCUSSION: Before the QI Standard can be recommended for implementation in future CPGs, it should have been successfully tested in selected German CPG projects. In addition to methodological requirements for the QI development, it must be ensured that guideline groups have adequate resources for the implementation of the QI Standard. CONCLUSION: By using the QI Standard, scientifically sound and healthcare-relevant QIs can be expected.

Development of the interdisciplinary evidence-based s3 guideline for the diagnosis and treatment of prostate cancer: methodological challenges and solutions.

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.