[SaxoForN-a transregional primary care research network in Dresden and Frankfurt am Main : Design of a practice-based research infrastructure]. / SaxoForN ­ Transregionales allgemeinmedizinisches Forschungspraxennetz Dresden und Frankfurt am Main : Konzept einer innovativen Forschungspraxeninfrastruktur.

Establishing primary care research networks (PCRNs) makes it easier to conduct clinical trials and health services research in a general-practice setting. Since February 2020, the German Federal Ministry of Education and Research (BMBF) has sponsored the development of six PCRNs and a coordination unit throughout Germany, with the aim of setting up a sustainable outpatient research infrastructure to raise the quantity and quality of primary care.The present article describes the design of a PCRN in Dresden and Frankfurt am Main - SaxoForN - and explains its structure and how it operates. The network is a transregional alliance between the two regional PCRNs named "SaxoN" (Dresden/Saxony) and "ForN" (Frankfurt am Main/Hesse), both of which run transregional and local research projects. For this purpose, joint standards and harmonized structures, for example with respect to the data infrastructure, qualifications, participation, and accreditation, were agreed upon and implemented at both sites.A critical success factor will be whether and to what extent the standards and structures, as well as resource planning, can be designed sustainably enough to permit the PCRNs to carry out high-quality research over the long term. To achieve this, the PCRNs will have to attract new practices and build up lasting relationships with them, qualify the research practices in order to standardize processes as far as possible, and regularly document their basic information and healthcare data.

[Results of a Pilot Study to Assess Quality Indicators in Outpatient Cancer Care]. / Ergebnisse einer Pilotstudie zur Erfassung von Qualitätsindikatoren in der ambulanten onkologischen Versorgung.

AIMS: Indicators of process quality were developed for outpatient oncology care in Germany with the aim to advance quality monitoring and assurance. In this pilot study, data to assess these quality indicators (QI) were gathered and analyzed for the first time. METHODS: Data were retrieved from patient records in oncology practices using an online data tool. Data were collected by practice-internal and in 7 (wave 1), 9 (wave 2) and 7 (wave 3) practices, respectively, by an external documentalist. RESULTS: Altogether, 5,160 patient records from 37 oncology practices were analyzed. The adherence rates varied considerably between QI as well as between practices (0-100%). In summary, adherence rates were higher for QI of basis documentation (81%) than for therapy planning and implementation (72%), holistic care and psychosocial wellbeing (71%) or pain management (63%). CONCLUSION: The ranges and high standard deviations show a high spread of adherence rates of QI. However, except for pain management, 100% fulfilment of QI requirements in some practices suggests that adherence to QI is generally feasible. Data collection for QI is resource intensive (time and personnel). Yet, collecting and examining data for QI provides useful information about areas with potential for improvement. QI can help improve the quality of care in oncology.

Polypharmacy in Older Patients with Multimorbidity: The Agreement Between Patient and General Practitioner-Reported Drugs Observed in a Pilot cRCT.

Polypharmacy (≥5 drugs) increases the risk of discrepancies between patient- and general practitioner (GP)-reported drugs, leading to adverse outcomes. This explorative analysis assesses the agreement between patient- and GP-reported drugs under the influence of a paper-based patient portfolio in a pilot cluster randomized controlled trial (cRCT). Complete data were available for 68 patients aged 65 or older (26 were female), with multimorbidity, polypharmacy, and at least one hospitalization in the past year. Agreement was assessed for drug name and strength level. Differences between the intervention and control group (IG/CG) and comparisons between two time points (six-month interval) stratified according to gender were analyzed using Wilcoxon and Mann-Whitney U tests (α = 5%). To evaluate the reasons for discrepancies, the agreement of active pharmaceutical ingredients (APIs) and anatomical therapeutic chemical (ATC) groups was analyzed. At baseline, the agreement was 72.1% for the IG and 73.9% for the CG. Inclusion of the reported drug strength reduced the agreement in both groups (IG 66.7%, CG 60.0%). Agreement for the IG decreased statistically significantly after six months (-5.4%). ATC groups B, C, and H had the highest agreement, while N, R, and Z had the lowest. Large discrepancies in the drugs reported, due to the APIs and the corresponding ATC group, were observed.

Informational continuity of medication management in transitions of care: Qualitative interviews with stakeholders from the HYPERION-TransCare study.

BACKGROUND: The transition of patients between inpatient and outpatient care can lead to adverse events and medication-related problems due to medication and communication errors, such as medication discontinuation, the frequency of (re-)hospitalizations, and increased morbidity and mortality. Older patients with multimorbidity and polypharmacy are particularly at high risk during transitions of care. Previous research highlighted the need for interventions to improve transitions of care in order to support information continuity, coordination, and communication. The HYPERION-TransCare project aims to improve the continuity of medication management for older patients during transitions of care. METHODS AND FINDINGS: Using a qualitative design, 32 expert interviews were conducted to explore the perspectives of key stakeholders, which included healthcare professionals, patients and one informal caregiver, on transitions of care. Interviews were conducted between October 2020 and January 2021, transcribed verbatim and analyzed using content analysis. We narratively summarized four main topics (stakeholders' tasks, challenges, ideas for solutions and best practice examples, and patient-related factors) and mapped them in a patient journey map. Lacking or incomplete information on patients' medication and health conditions, inappropriate communication and collaboration between healthcare providers within and across settings, and insufficient digital support limit the continuity of medication management. CONCLUSIONS: The study confirms that medication management during transitions of care is a complex process that can be compromised by a variety of factors. Legal requirements and standardized processes are urgently needed to ensure adequate exchange of information and organization of medication management before, during and after hospital admissions. Despite the numerous barriers identified, the findings indicate that involved healthcare professionals from both the inpatient and outpatient care settings have a common understanding.

Implementation and evaluation of a complex intervention to improve information availability at the interface between inpatient and outpatient care in older patients with multimorbidity and polypharmacy (HYPERION-TransCare) - study protocol for a pilot and feasibility cluster-randomized controlled trial in general practice in Germany.

BACKGROUND: Despite attempts to improve the cross-sectoral flow of information, difficulties remain in routine healthcare. The resulting negative impact on continuity of care is often associated with poor health outcomes, especially in older patients. Our intervention aims to increase information availability with respect to medications and health conditions at the interface between inpatient and outpatient care and to contribute towards improving the quality of care in older patients. This pilot study focuses on feasibility and implementability. METHODS: The idea of the complex intervention has been developed in a previous study. This intervention will be tested in a prospective, multicenter, cluster-randomized (via web tool), controlled pilot trial with two parallel study arms (intervention and control group). The pilot study will be conducted in 20 general practices in Hesse and Saxony (Germany) and include 200 patients (≥ 65 years of age with multimorbidity and polypharmacy) recruited by the practices. Practice staff and patients will be blinded. We will use qualitative and quantitative methods to assess the feasibility and implementability of the intervention and the study design in a process evaluation covering topics ranging from expectations to experiences. In addition, the feasibility of proposed outcome parameters for the future definitive trial will be explored. The composite endpoint will include health-related patient outcomes (hospitalization, falls, and mortality using, e.g., the FIMA questionnaire), and we will assess information on medications (SIMS questionnaire), symptoms and side effects of the medication (pro-CTCAE questionnaire), and health literacy (HLQ questionnaire). Data will be collected at study begin (baseline) and after 6 months. Furthermore, the study will include surveys and interviews with patients, general practitioners, and healthcare assistants. DISCUSSION: The intervention was developed using a participatory approach involving stakeholders and patients. It aims to empower general practice teams as they provide patient-centered care and play a key role in the coordination and continuity of care. We aim to encourage patients to adopt an active role in their health care. Overall, we want to increase the availability of health-related information for patients and healthcare providers. The results of the pilot study will be used in the design and implementation of the future definitive trial. TRIAL REGISTRATION: The study was registered in DRKS-German Clinical Trials Register: registration number DRKS00027649 (date: 19 January 2022). Date and version identifier 10.07.2023; Version 1.3.

Digital participatory workshops with patients and health professionals to develop an intervention for the management of polypharmacy: results from a mixed-methods evaluation and methodological conclusions.

BACKGROUND: In the COVID-19 pandemic, numerous researchers postponed their patient and public involvement (PPI) activities. This was mainly due to assumptions on patients' willingness and skills to participate digitally. In fact, digital PPI workshops differ from in-person meetings as some forms of non-verbal cues and body language may be missing and technical barriers may exist. Within our project HYPERION-TransCare we adapted our PPI workshop series for intervention development to a digital format and assessed whether these digital workshops were feasible for patients, health care professionals and researchers. METHODS: We used a digital meeting tool that included communication via audio, video and chat. Discussions were documented simultaneously on a digital white board. Technical support was provided via phone and chat during the workshops and with a technical introduction workshop in advance. The workshop evaluation encompassed observation protocols, participants' feedback via chat after each workshop on their chance to speak and the usability of the digital tools, and telephone interviews on patients' and health professionals' experiences after the end of the workshop series. RESULTS: Observation protocols showed an active role of moderators in verbally encouraging every participant to get involved. Technical challenges occurred, but were in most cases immediately addressed and solved. Participants median rating of their chance to speak and the usability of the digital tool was "very good". In the evaluation interviews participants reported a change of perspective and mutual understanding as a main benefit from the PPI workshops and described the atmosphere as inclusive and on equal footing. Benefits of the digital format such as overcoming geographical distance, saving time and combining workshop participation with professional or childcare obligations were reported. Technical support was stressed as a pre-condition for getting actively involved in digital PPI. CONCLUSIONS: Digital formats using different didactic and documentation techniques, accompanied by technical support, can foster active patient and public involvement. The advantages of digital PPI formats such as geographical flexibility and saving time for participants as well as the opportunity to prepare and hold workshops in geographically stretched research teams persists beyond the pandemic and may in some cases outweigh the advantages of in-person communication.

Digital patient and public involvement (PPI) activities differ from in-person meetings. For example, some forms of non-verbal cues and body language are limited and technical barriers may exist. Therefore, some research teams were hesitant to switch to a digital PPI format during the COVID-19 pandemic and postponed their PPI activities.In this paper, we aim to describe, how we adapted a PPI workshop series to a digital format, how patients and health care professionals experienced these digital workshops, and which conclusions we have drawn for future digital PPI activities. The workshop evaluation encompassed workshop observation protocols, participants' feedback via chat on their chance to speak and the feasibility of the digital tools, and telephone interviews on participants' experiences.The study results showed that moderators had an active role in verbally encouraging every participant to get involved. Technical challenges occurred, but were in most cases immediately addressed and solved. Most participants rated their chance to speak and the feasibility of the digital format as "very good". They described the atmosphere as inclusive and on equal footing without hierarchy between different stakeholder groups. Participants reported benefits of the digital format such as overcoming geographical distance, saving time and combining workshop participation with professional or childcare obligations. They stressed technical support as a condition for getting actively involved in digital PPI.We conclude that some advantages of digital PPI may persist beyond the pandemic. Therefore, we encourage research teams to discuss the question of digital or in-person PPI with the involved patients and health professionals and decide on a case-by-case basis.

Development of an intervention to improve informational continuity of care in older patients with polypharmacy at the interface between general practice and hospital care: protocol for a participatory qualitative study in Germany.

INTRODUCTION: Older patients with multimorbidity, polypharmacy and related complex care needs represent a growing proportion of the population and a challenge for healthcare systems. Particularly in transitional care (hospital admission and hospital discharge), medical errors, inappropriate treatment, patient concerns and lack of confidence in healthcare are major problems that may arise from a lack of information continuity. The aim of this study is to develop an intervention to improve informational continuity of care at the interface between general practice and hospital care. METHODS AND ANALYSIS: A qualitative approach will be used to develop our participatory intervention. Overall, 32 semistructured interviews with relevant stakeholders will be conducted and analysed. The stakeholders will include healthcare professionals from the outpatient setting (general practitioners, healthcare assistants, ambulatory care nurses) and the inpatient setting (clinical doctors, nurses, pharmacists, clinical information scientists) as well as patients and informal caregivers. At a series of workshops based on the results of the stakeholder analyses, we aim to develop a participatory intervention that will then be implemented in a subsequent pilot study. The same stakeholder groups will be invited for participation in the workshops. ETHICS AND DISSEMINATION: Ethical approval for this study was waived by the Ethics Committee of Goethe University Frankfurt because of the nature of the proposed study. Written informed consent will be obtained from all study participants prior to participation. Results will be tested in a pilot study and disseminated at (inter)national conferences and via publication in peer-reviewed journals. TRIAL REGISTATION NUMBER: Clinical Trials Register: registration number DRKS00027649.

Alternative splicing gives rise to different isoforms of the Neurospora crassa Tob55 protein that vary in their ability to insert beta-barrel proteins into the outer mitochondrial membrane.

Tob55 is the major component of the TOB complex, which is found in the outer membrane of mitochondria. A sheltered knockout of the tob55 gene was developed in Neurospora crassa. When grown under conditions that reduce the levels of the Tob55 protein, the strain exhibited a reduced growth rate and mitochondria isolated from these cells were deficient in their ability to import beta-barrel proteins. Surprisingly, Western blots of wild-type mitochondrial proteins revealed two bands for Tob55 that differed by approximately 4 kDa in their apparent molecular masses. Sequence analysis of cDNAs revealed that the tob55 mRNA is alternatively spliced and encodes three isoforms of the protein, which are predicted to contain 521, 516, or 483 amino acid residues. Mass spectrometry of proteins isolated from purified outer membrane vesicles confirmed the existence of each isoform in mitochondria. Strains that expressed each isoform of the protein individually were constructed. When cells expressing only the longest form of the protein were grown at elevated temperature, their growth rate was reduced and mitochondria isolated from these cells were deficient in their ability to assembly beta-barrel proteins.

[Feedback strategies for routine surveys of quality indicators in outpatient oncology care]. / Feedbackstrategien bei routinemäßigen Erhebungen von Qualitätsindikatoren in der ambulanten onkologischen Versorgung.

OBJECTIVES: The study deals with the efficiency and possible improvements of quality promotion with quality indicators (QI). The goal is to investigate the practical use of feedback from QI surveys in the field of oncology office practices. It captures both the acceptance of results and the independent initiation of search- and improvement strategies. The value of best practice examples is of further interest. METHODS: Within one year, data of six QI of 31 physicians from 24 oncology practices were collected twice and the results were sent back in individual reports including a benchmarking. Practices with particularly good results in individual QI sectors were surveyed in semi-structured telephone interviews about their processes. Based on these results, best practice examples were created and provided to all participating practices to stimulate improvement. Further, two paper-based surveys about the acceptance and handling of results as well as the use of best practice examples were conducted. RESULTS: The practices accepted the reported results as an instrument to assess their own care quality (70 %) and indicated that had been able to identify improvement potentials (75 %). Improvement strategies were developed or planned by approximately every second practice in the respective sectors. The practices were interested in the best practice examples and rated them as helpful (70 %). Many of them indicated that they were already taking up some of the suggestions for improving the organization of their own processes or were planning to do so. CONCLUSION: The extraction of information on QI from patient files is a tedious task for the practices. Both the implementation of the necessary internal measures after receiving the results report as well as the adaptation of external process examples to their own processes is challenging. Nevertheless, oncology practices benefit from the feedback of the results of QI surveys and best practice examples. Thus, QI surveys and the reporting of results can actively encourage quality development.

Characterization of the insertase for ß-barrel proteins of the outer mitochondrial membrane.

The TOB-SAM complex is an essential component of the mitochondrial outer membrane that mediates the insertion of ß-barrel precursor proteins into the membrane. We report here its isolation and determine its size, composition, and structural organization. The complex from Neurospora crassa was composed of Tob55-Sam50, Tob38-Sam35, and Tob37-Sam37 in a stoichiometry of 1:1:1 and had a molecular mass of 140 kD. A very minor fraction of the purified complex was associated with one Mdm10 protein. Using molecular homology modeling for Tob55 and cryoelectron microscopy reconstructions of the TOB complex, we present a model of the TOB-SAM complex that integrates biochemical and structural data. We discuss our results and the structural model in the context of a possible mechanism of the TOB insertase.

Roles of the Mdm10, Tom7, Mdm12, and Mmm1 proteins in the assembly of mitochondrial outer membrane proteins in Neurospora crassa.

The Mdm10, Mdm12, and Mmm1 proteins have been implicated in several mitochondrial functions including mitochondrial distribution and morphology, assembly of beta-barrel proteins such as Tom40 and porin, association of mitochondria and endoplasmic reticulum, and maintaining lipid composition of mitochondrial membranes. Here we show that loss of any of these three proteins in Neurospora crassa results in the formation of large mitochondrial tubules and reduces the assembly of porin and Tom40 into the outer membrane. We have also investigated the relationship of Mdm10 and Tom7 in the biogenesis of beta-barrel proteins. Previous work showed that mitochondria lacking Tom7 assemble Tom40 more efficiently, and porin less efficiently, than wild-type mitochondria. Analysis of mdm10 and tom7 single and double mutants, has demonstrated that the effects of the two mutations are additive. Loss of Tom7 partially compensates for the decrease in Tom40 assembly resulting from loss of Mdm10, whereas porin assembly is more severely reduced in the double mutant than in either single mutant. The additive effects observed in the double mutant suggest that different steps in beta-barrel assembly are affected in the individual mutants. Many aspects of Tom7 and Mdm10 function in N. crassa are different from those of their homologues in Saccharomyces cerevisiae.

Emergence of resistance to protease inhibitor amprenavir in human immunodeficiency virus type 1-infected patients: selection of four alternative viral protease genotypes and influence of viral susceptibility to coadministered reverse transcriptase nucleoside inhibitors.

Previous data have indicated that the development of resistance to amprenavir, an inhibitor of the human immunodeficiency virus type 1 protease, is associated with the substitution of valine for isoleucine at residue 50 (I50V) in the viral protease. We present further findings from retrospective genotypic and phenotypic analyses of plasma samples from protease inhibitor-naïve and nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients who experienced virological failure while participating in a clinical trial where they had been randomized to receive either amprenavir or indinavir in combination with NRTIs. Paired baseline and on-therapy isolates from 31 of 48 (65%) amprenavir-treated patients analyzed demonstrated the selection of protease mutations. These mutations fell into four distinct categories, characterized by the presence of either I50V, I54L/I54M, I84V, or V32I+I47V and often included accessory mutations, commonly M46I/L. The I50V and I84V genotypes displayed the greatest reductions in susceptibility to amprenavir, although each of the amprenavir-selected genotypes conferred little or no cross-resistance to other protease inhibitors. There was a significant association, for both amprenavir and indinavir, between preexisting baseline resistance to NRTIs subsequently received during the study and development of protease mutations (P = 0.014 and P = 0.031, respectively). Our data provide a comprehensive analysis of the mechanisms by which amprenavir resistance develops during clinical use and present evidence that resistance to concomitant agents in the treatment regimen predisposes to the development of mutations associated with protease inhibitor resistance and treatment failure.