[Reference evaluations for estimating prevalence, incidence, and mortality of public health relevant diseases based on routine data]. / Referenzauswertungen für die Schätzung von Prävalenz, Inzidenz und Mortalität Public-Health-relevanter Erkrankungen auf Basis von Routinedaten.

The routine data of all statutorily insured persons according to the Data Transparency Regulation (DaTraV data) represent a promising data source for the recurrent and timely surveillance of non-communicable diseases (NCDs) in Germany. Thereby, it has become apparent that there is a high demand for reference evaluations that enable quick and regularly repeatable analyses on important NCDs. Against this background, ReFern-01 was initiated, a joint project of the Robert Koch Institute (RKI) and the Federal Institute for Drugs and Medical Devices (BfArM). In collaboration with experts from the field of secondary data analysis and healthcare research, reference evaluations for estimating prevalence, incidence, and mortality for important public health-relevant diseases were developed. First, 11 central NCDs were selected by means of an online survey, and initial case definitions were created in conjunction with a literature review. These were then discussed and agreed upon in a virtual workshop. The created reference evaluations (analysis scripts) allow a standardized estimation of the mentioned epidemiological figures, which are comparable over time and regionally. In addition to providing the results, the scripts will be available at the BfArM for further analysis. Provided that remote access to the analysis of the DaTraV data is available in the future, the results of the ReFern project can strengthen the surveillance of NCDs and support public health actors, for example, in the planning and implementation of health promotion and prevention measures at the federal, state, county, and local levels.

[Establishment of the new "Health Data Lab" to provide data for science]. / Aufbau des neuen "Forschungsdatenzentrums Gesundheit" zur Datenbereitstellung für die Wissenschaft.

The analysis of real-world data (RWD) has become increasingly important in health research in recent years. With the BfArM Health Data Lab (HDL), which is currently being set up, researchers will in future be able to gain access to routine data from the statutory health insurance of around 74 million people in Germany. Data from electronic patient records can also be made available for research prospectively. In doing so, the Health Data Lab guarantees the highest data protection and IT security standards. The digital application process, the provision of data in secure processing environments as well as the features supporting the analyses such as catalogues of coding systems, a point-and-click analysis tool and predefined standard analyses increase user-friendliness for researchers. The use of the extensive health data accessible at HDL will open a wide range of future possibilities for improving the health system and the quality of care. This article begins by highlighting the advantages of the HDL and outlining the opportunities that the RWD offers for research in healthcare and for the population. The structure and central aspects of the HDL are explained afterwards. An outlook on the opportunities of linking different data is given. What the application and data usage processes at the HDL will look like is illustrated using the example of fictitious possibilities for analysing long COVID based on the routine data available at the HDL in the future.

Evaluation of the EMPAR study population on the basis of metabolic phenotypes of selected pharmacogenes.

The impact of genetic variability of pharmacogenes as a possible risk factor for adverse drug reactions is elucidated in the EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung/English: influence of metabolic profiles on the safety of drug therapy in routine care) study. EMPAR evaluates possible associations of pharmacogenetically predicted metabolic profiles relevant for the metabolism of frequently prescribed cardiovascular drugs. Based on a German study population of 10,748 participants providing access to healthcare claims data and DNA samples for pharmacogenetic assessment, first analyses were performed and evaluated. The aim of this first evaluation was the characterization of the study population with regard to general parameters such as age, gender, comorbidity, and polypharmacy at baseline (baseline year) as well as important combinations of cardiovascular drugs with relevant genetic variants and predicted metabolic phenotypes. The study was registered in the German Clinical Trials Register (DRKS) on July 6, 2018 (DRKS00013909).

Profiling the physiological pitfalls of anti-hepatitis C direct-acting agents in budding yeast.

Sofosbuvir and Daclatasvir are among the direct-acting antiviral (DAA) medications prescribed for the treatment of chronic hepatitis C (CHC) virus infection as combination therapy with other antiviral medications. DAA-based therapy achieves high cure rates, reaching up to 97% depending on the genotype of the causative hepatitis C virus (HCV). While DAAs have been approved as an efficient and well-tolerated therapy for CHC, emerging concerns about adverse cardiac side effects, higher risk of recurrence and occurrence of hepatocellular carcinoma (HCC) and doubts of genotoxicity have been reported. In our study, we investigated in detail physiological off-targets of DAAs and dissected the effects of these drugs on cellular organelles using budding yeast, a unicellular eukaryotic organism. DAAs were found to disturb the architecture of the endoplasmic reticulum (ER) and the mitochondria, while showing no apparent genotoxicity or DNA damaging effect. Our study provides evidence that DAAs are not associated with genotoxicity and highlights the necessity for adjunctive antioxidant therapy to mitigate the adverse effects of DAAs on ER and mitochondria.

N-Nitrosodimethylamine-Contaminated Valsartan and the Risk of Cancer­A Longitudinal Cohort Study Based on German Health Insurance Data.

BACKGROUND: N-Nitrosodimethylamine (NDMA), classified as a probable human carcinogen, has been found as a contaminant in the antihypertensive drug valsartan. Potentially carcinogenic effects associated with the consumption of NDMAcontaminated valsartan have not yet been analyzed in large-scale cohort studies. We therefore carried out the study reported here to explore the association between NDMA-contaminated valsartan and the risk of cancer. METHODS: This cohort study was based on longitudinal routine data obtained from a large German statutory health insurance provider serving approximately 25 million insurees. The cohort comprised patients who had filled a prescription for valsartan in the period 2012-2017. The endpoint was an incident diagnosis of cancer. Hazard ratios (HR) for cancer in general and for certain specific types of cancer were calculated by means of Cox regression models with time-dependent variables and adjustment for potential confounders. RESULTS: A total of 780 871 persons who had filled a prescription for valsartan between 2012 and 2017 were included in the study. There was no association between exposure to NDMA-contaminated valsartan and the overall risk of cancer. A statistically significant association was found, however, between exposure to NDMA-contaminated valsartan and hepatic cancer (adjusted HR 1.16; 95% confidence interval [1.03; 1.31]). CONCLUSION: These findings suggest that the consumption of NDMA-contaminated valsartan is associated with a slightly increased risk of hepatic cancer; no association was found with the risk of cancer overall. Close observation of the potential long-term effects of NDMA-contaminated valsartan seems advisable.

Using gradient boosting with stability selection on health insurance claims data to identify disease trajectories in chronic obstructive pulmonary disease.

OBJECTIVE: We propose a data-driven method to detect temporal patterns of disease progression in high-dimensional claims data based on gradient boosting with stability selection. MATERIALS AND METHODS: We identified patients with chronic obstructive pulmonary disease in a German health insurance claims database with 6.5 million individuals and divided them into a group of patients with the highest disease severity and a group of control patients with lower severity. We then used gradient boosting with stability selection to determine variables correlating with a chronic obstructive pulmonary disease diagnosis of highest severity and subsequently model the temporal progression of the disease using the selected variables. RESULTS: We identified a network of 20 diagnoses (e.g. respiratory failure), medications (e.g. anticholinergic drugs) and procedures associated with a subsequent chronic obstructive pulmonary disease diagnosis of highest severity. Furthermore, the network successfully captured temporal patterns, such as disease progressions from lower to higher severity grades. DISCUSSION: The temporal trajectories identified by our data-driven approach are compatible with existing knowledge about chronic obstructive pulmonary disease showing that the method can reliably select relevant variables in a high-dimensional context. CONCLUSION: We provide a generalizable approach for the automatic detection of disease trajectories in claims data. This could help to diagnose diseases early, identify unknown risk factors and optimize treatment plans.

One cysteine is enough: A monothiol Grx can functionally replace all cytosolic Trx and dithiol Grx.

Glutaredoxins are small proteins of the thioredoxin superfamily that are present throughout life. Most glutaredoxins fall into two major subfamilies. Class I glutaredoxins are glutathione-dependent thiol-disulfide oxidoreductases whilst class II glutaredoxins coordinate Fe-S clusters. Class I glutaredoxins are typically dithiol enzymes with two active-site cysteine residues, however, some enzymatically active monothiol glutaredoxins are also known. Whilst both monothiol and dithiol class I glutaredoxins mediate protein deglutathionylation, it is widely claimed that only dithiol glutaredoxins are competent to reduce protein disulfide bonds. In this study, using a combination of yeast 'viability rescue', growth, and redox-sensitive GFP-based assays, we show that two different monothiol class I glutaredoxins can each facilitate the reduction of protein disulfide bonds in ribonucleotide reductase, methionine sulfoxide reductase and roGFP2. Our observations thus challenge the generalization of the dithiol mechanism for glutaredoxin catalysis and raise the question of why most class I glutaredoxins have two active-site cysteine residues.

Tom70 enhances mitochondrial preprotein import efficiency by binding to internal targeting sequences.

The biogenesis of mitochondria depends on the import of hundreds of preproteins. N-terminal matrix-targeting signals (MTSs) direct preproteins to the surface receptors Tom20, Tom22, and Tom70. In this study, we show that many preproteins contain additional internal MTS-like signals (iMTS-Ls) in their mature region that share the characteristic properties of presequences. These features allow the in silico prediction of iMTS-Ls. Using Atp1 as model substrate, we show that iMTS-Ls mediate the binding to Tom70 and have the potential to target the protein to mitochondria if they are presented at its N terminus. The import of preproteins with high iMTS-L content is significantly impaired in the absence of Tom70, whereas preproteins with low iMTS-L scores are less dependent on Tom70. We propose a stepping stone model according to which the Tom70-mediated interaction with internal binding sites improves the import competence of preproteins and increases the efficiency of their translocation into the mitochondrial matrix.

Life-threatening disseminated tuberculosis as a complication of TNF-α blockade in an adolescent.

Life-threatening disseminated tuberculosis developed in a 17-year-old girl who was treated with the TNF-α blocker adalimumab for refractory SAPHO syndrome. The patient presented to the emergency department with dyspnea and somnolence and within 2 h developed the clinical picture of a septic shock. In addition to this unusual presentation, she showed a complicated course with increasing cerebral granuloma formation in spite of adequate antimycobacterial treatment. Immune reconstitution after discontinuation of TNF blockade may contribute to this "paradoxical reaction." Possible implications for screening, diagnosis, and treatment of tuberculosis in children and adolescents receiving anti-TNF treatment are discussed.