[The Medical Informatics Initiative at a glance-establishing a health research data infrastructure in Germany]. / Die Medizininformatik-Initiative im Überblick ­ Aufbau einer Gesundheitsforschungsdateninfrastruktur in Deutschland.

The Medical Informatics Initiative (MII) funded by the Federal Ministry of Education and Research (BMBF) 2016-2027 is successfully laying the foundations for data-based medicine in Germany. As part of this funding, 51 new professorships, 21 junior research groups, and various new degree programs have been established to strengthen teaching, training, and continuing education in the field of medical informatics and to improve expertise in medical data sciences. A joint decentralized federated research data infrastructure encompassing the entire university medical center and its partners was created in the form of data integration centers (DIC) at all locations and the German Portal for Medical Research Data (FDPG) as a central access point. A modular core dataset (KDS) was defined and implemented for the secondary use of patient treatment data with consistent use of international standards (e.g., FHIR, SNOMED CT, and LOINC). An officially approved nationwide broad consent was introduced as the legal basis. The first data exports and data use projects have been carried out, embedded in an overarching usage policy and standardized contractual regulations. The further development of the MII health research data infrastructures within the cooperative framework of the Network of University Medicine (NUM) offers an excellent starting point for a German contribution to the upcoming European Health Data Space (EHDS), which opens opportunities for Germany as a medical research location.

[NKLZ 2.0: the further development of the National Competence-Based Learning Objectives Catalogue for Dentistry as a basis for the design of the new licensing regulations]. / NKLZ 2.0: Die Weiterentwicklung des Nationalen Kompetenzbasierten Lernzielkatalogs Zahnmedizin als Basis für die Ausgestaltung der neuen Approbationsordnung.

The National Competence-Based Catalogue of Learning Objectives in Dentistry (NKLZ) was adopted in 2015 and defines the learning objectives for dental training in Germany. It specifies which competences students should acquire and serves as a basis for the curricular design of the study programme, examinations and teaching materials. The NKLZ promotes a comprehensive education that includes clinical skills and abilities, professional behaviour and communication skills in addition to specialist knowledge. It contributes to the preparation of future dentists for their profession and standardizes training to ensure quality and comparability.This article describes the background, history, structure and further development of the NKLZ. Currently, the NKLZ is being further developed to version 2.0 in a multi-stage process. Its structure is based on the NKLM 2.0, the National Competence-Based Learning Objectives Catalogue for Medicine. The aim is to comprehensively map the requirements for the dental licensing regulations.An important prerequisite for the official recognition of the NKLZ as a basic guideline for the training of dentists is that it be anchored in a dental licensing regulation that is to be reformed soon. This creates clarity and liability for teachers and students. Such an anchoring also enables better coordination between training objectives and the requirements of professional practice. Since the licensing regulations are modified less frequently, the integration of the NKLZ offers the possibility of updating and adapting the catalogue of learning objectives in a structured and regulated manner. This ensures that training is in line with current standards and developments.

[Private medical education in Germany]. / Medizinische Studienangebote privater Träger in Deutschland.

Through the years, a range of privately funded medical training opportunities has been established in Germany. Only a few of them operate along the German Medical Licensure Act and thus underlie quality assurance regulations in Germany. Most of the courses are a result of German hospitals cooperating with universities from other EU countries. The content of the courses and the examinations underlie the regulations of the university's home country. This article aims to give an overview of the private medical training opportunities offered in Germany and to show differences compared to state funded German medical schools. The authors discuss the opportunities of private medical training as well as its challenges and risks. Basic principles concerning finances and quality assurance of national and international private medical training are provided. Regardless of their mode of financing, the superior goal of the training, according to the German Medical Licensure Act, should always be to enable young doctors to pursue further professional training, so that they can maintain the best possible quality in patient care, research, and medical education.

[Research funding for rare diseases in Germany]. / Forschungsförderung im Bereich seltener Erkrankungen in Deutschland.

There is high need for more research in the field of rare diseases. Not only must the causes and mechanisms of the numerous and often heterogeneous diseases be delineated, but criteria must also be defined for optimal stratification of patients for individualized therapies. In this context, research and innovative diagnostics are linked together more closely than in other fields of medicine. The early stages of disease-oriented research can be performed in individual institutions but, due to low numbers of patients, late translation and transfer into clinics requires multicentric and international collaboration. In Germany research on rare diseases takes place mostly in faculties of medicine at universities. Since the institutional financial support is very low, research grants have substantial significance. The German Research Foundation (DFG) and the Federal Ministry of Education and Research (BMBF) are the main grant agencies for national projects, but foundations and patient advocacy groups also finance research to a certain extent. The ERA-Net "E-Rare" and the programs of the EU target primarily international cross-border projects and patient trials. All of these programs need to be adapted more efficiently to the particular needs of rare disease research. For national and international research projects on rare diseases, sufficient funds are needed but also sustainable interdisciplinary platforms and centers must be established in order to share expert knowledge and to implement complex programs such as proof-of-concept studies in humans.

Applying for, reviewing and funding public health research in Germany and beyond.

Public health research is complex, involves various disciplines, epistemological perspectives and methods, and is rarely conducted in a controlled setting. Often, the added value of a research project lies in its inter- or trans-disciplinary interaction, reflecting the complexity of the research questions at hand. This creates specific challenges when writing and reviewing public health research grant applications. Therefore, the German Research Foundation (DFG), the largest independent research funding organization in Germany, organized a round table to discuss the process of writing, reviewing and funding public health research. The aim was to analyse the challenges of writing, reviewing and granting scientific public health projects and to improve the situation by offering guidance to applicants, reviewers and funding organizations. The DFG round table discussion brought together national and international public health researchers and representatives of funding organizations. Based on their presentations and discussions, a core group of the participants (the authors) wrote a first draft on the challenges of writing and reviewing public health research proposals and on possible solutions. Comments were discussed in the group of authors until consensus was reached. Public health research demands an epistemological openness and the integration of a broad range of specific skills and expertise. Applicants need to explicitly refer to theories as well as to methodological and ethical standards and elaborate on why certain combinations of theories and methods are required. Simultaneously, they must acknowledge and meet the practical and ethical challenges of conducting research in complex real life settings. Reviewers need to make the rationale for their judgments transparent, refer to the corresponding standards and be explicit about any limitations in their expertise towards the review boards. Grant review boards, funding organizations and research ethics committees need to be aware of the specific conditions of public health research, provide adequate guidance to applicants and reviewers, and ensure that processes and the expertise involved adequately reflect the topic under review.

Joint recommendations for a total services account as a factor in simplifying contracts.

The objective of clinical trials is to transfer findings gained from basic research to patients and to result in innovative treatment approaches. Along with basic research, results from clinical trials thus represent a core area of medical advances. As a location for clinical trials, Germany is currently well-positioned and internationally competitive. This is evident in its position as No. 2 in Europe and No. 3 worldwide - behind the US and UK - in clinical trials of pharmaceuticals [1]. Maintaining and further improving this favorable positioning as a location for clinical trials is in the mutual interest of all parties involved in the field of clinical research, patients, trial sites and sponsors of clinical trials. For patients, clinical trials offer opportunities to gain early access to innovative therapy options. In addition to the scientific interest from medical faculties, clinical research is thereby an important aspect for university clinics in Germany as they fulfill their medical care mandate. Their involvement in clinical trials gives physicians the ability to gather experience with new treatment approaches at an early stage and to pass this know-how on to their patients. A location's clinical research is thus an important competitive factor in terms of international comparison as well. Industry likewise benefits from the favorable research infrastructure in Germany, which provides rapid patient recruitment and outstanding quality of results obtained and can thus contribute to the early approval of new drugs. From the perspective of the authors, it is therefore essential that Germany continues to remain competitive as a location for conducting clinical trials, precisely because the number of clinical trials is decreasing overall. Companies themselves are in international competition internally and externally, which often creates a certain pressure on trial preparation and thus on the start of a clinical trial. To ensure that a clinical trial can begin early, it is essential that contracts related to the trial are concluded quickly and simply, including remuneration for participants and full, transparent and comprehensible coverage of content for the business relationship. The swift agreement of key contractual and budgetary aspects is therefore in the interest of everyone involved. Against this backdrop, the German Association of Medical Faculties (MFT), the German Association of Academic Medical Centers (VUD), the Coordination Center for Clinical Studies (KKS-Netzwerk) and the German Association of Research-Based Pharmaceutical Companies (vfa) have held joint discussions regarding an important aspect of the contract negotiations - the cost consideration of clinical trials. As a result of these talks, these organizations have developed and published joint "Recommendations for the preparation of a total services calculation for remuneration related to the conduct of a clinical trial in a trial center" [2], [3]. The parties concerned share the conviction that, against the backdrops described, it would be helpful if the potential contract partners had access to recommendations that offer examples of constantly recurring cost positions in order to more precisely determine remuneration related to the conduct of a clinical trial. This article explains how the "Recommendations for the preparation of a total services calculation for remuneration related to the conduct of a clinical trial in a trial center" [2], [3] were developed and provides an overview of their content.

German Medical Informatics Initiative.

This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. The Medical Informatics Initiative (MII) was launched within the scope of the German Federal Ministry of Education and Research's (BMBF) Medical Informatics Funding Scheme, with the goal of developing infrastructure for the integration of clinical data from patient care and medical research in Germany. Its work is to be performed over the course of a decade (2016-2025) across three funding phases, with the first two concentrating on university hospitals. During the conceptual phase (now concluded), a central supporting project ensured coordination - and laid the ground for standardised solutions for all the initiative's sites and scientific consortia that will enable effective data use and exchange, both for health care as well as research. The conceptual phase focused on the following: a) interoperability, through the consistent use of international standards (from an early stage, i.e. primary IT systems in patient care); b) standardised templates for patient consent and harmonised data protection; and c) standard rules for data use and access (monitoring and safeguarding access to data). On this basis, the initiative aims in the long term to improve medical research (particularly health care research, using data from treatments), to accelerate the transfer of knowledge from research to patient care - and to provide important impetus for the digitalization of medicine in Germany.

Evidence for trafficking of PfEMP1 to the surface of P. falciparum-infected erythrocytes via a complex membrane network.

The human malarial parasite Plasmodium falciparum exports virulence determinants, such as the P. falciparum erythrocyte membrane protein 1 (PfEMP1), beyond its own periplasmatic boundaries to the surface of its host erythrocyte. This is remarkable given that erythrocytes lack a secretory pathway. Here we present evidence for a continuous membrane network of parasite origin in the erythrocyte cytoplasm. Co-localizations with antibodies against PfEMP1, PfExp-1, Pf332 and PfSbpl at the light and electron microscopical level indicate that this membrane network is composed of structures that have been previously described as tubovesicular membrane network (TVM), Maurer's clefts and membrane whorls. This membrane network could also be visualized in vivo by vital staining of infected erythrocytes with the fluorescent dye LysoSensor Green DND-153. At sites where the membrane network abuts the erythrocyte plasma membrane we observed small vesicles of 15-25 nm in size, which seem to bud from and/or fuse with the membrane network and the erythrocyte plasma membrane, respectively. On the basis of our data we hypothesize that this membrane network of parasite origin represents a novel secretory organelle that is involved in the trafficking of PfEMP1 across the erythrocyte cytoplasm.

A novel Ca2+-induced Ca2+ release mechanism mediated by neither inositol trisphosphate nor ryanodine receptors.

Members of both major families of intracellular Ca(2+) channels, ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors, are stimulated by substantial increases in cytosolic free Ca(2+) concentration ([Ca(2+)]c). They thereby mediate Ca(2+)-induced Ca(2+) release (CICR), which allows amplification and regenerative propagation of intracellular Ca(2+) signals. In permeabilized hepatocytes, increasing [Ca(2+)]c to 10 microM stimulated release of 30+/-1% of the intracellular stores within 60 s; the EC(50) occurred with a free [Ca(2+)] of 170+/-29 nM. This CICR was abolished at 2 degrees C. The same fraction of the stores was released by CICR before and after depletion of the IP3-sensitive stores, and CICR was not blocked by antagonists of IP3 receptors. Ryanodine, Ruthenium Red and tetracaine affected neither the Ca(2+) content of the stores nor the CICR response. Sr(2+) and Ba(2+) (EC(50)=166 nM and 28 microM respectively) mimicked the effects of increased [Ca(2+)] on the intracellular stores, but Ni(2+) blocked the passive leak of Ca(2+) without blocking CICR. In rapid superfusion experiments, maximal concentrations of IP3 or Ca(2+) stimulated Ca(2+) release within 80 ms. The response to IP3 was complete within 2 s, but CICR continued for tens of seconds despite a slow [half-time (t(1/2))=3.54+/-0.07 s] partial inactivation. CICR reversed rapidly (t(1/2)=529+/-17 ms) and completely when the [Ca(2+)] was reduced. We conclude that hepatocytes express a novel temperature-sensitive, ATP-independent CICR mechanism that is reversibly activated by modest increases in [Ca(2+)], and does not require IP3 or ryanodine receptors or reversal of the sarcoplasmic/endoplasmic-reticulum Ca(2+)-ATPase. This mechanism may both regulate the Ca(2+) content of the intracellular stores of unstimulated cells and allow even small intracellular Ca(2+) signals to be amplified by CICR.

Illumination of the malaria parasite Plasmodium falciparum alters intracellular pH. Implications for live cell imaging.

Live cell fluorescence microscopy has been widely used to study physiological processes in the human malarial parasite Plasmodium falciparum, including pH homeostasis, Ca(2+) signaling and protein targeting. However, the reproducibility of the data is often poor. Controversial statements exist regarding cytosolic and vacuolar baseline pH, as well as regarding the subcellular localization of some of the fluorochromes used. When trying to reproduce published baseline values, we observed an unexpected light sensitivity of P. falciparum, which manifests itself in the form of a strong cytoplasmic acidification. Even short exposure times with moderate to low light intensities caused the parasite cytosol to acidify. We show that this effect arises from the selective disruption of the parasite's acidic food vacuole, brought about by lipid peroxidation initiated by light-induced generation of hydroxyl radicals. Our data suggest that heme serves as a photosensitizer in this process. Our findings have major implications for the use of live cell microscopy in P. falciparum and add a cautionary note to previous studies where live cell fluorometry has been used to determine physiological parameters in P. falciparum.