Metformin modulates microbiota and improves blood pressure and cardiac remodeling in a rat model of hypertension.

AIMS: Metformin has been attributed to cardiovascular protection even in the absence of diabetes. Recent observations suggest that metformin influences the gut microbiome. We aimed to investigate the influence of metformin on the gut microbiota and hypertensive target organ damage in hypertensive rats. METHODS: Male double transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR), a model of angiotensin II-dependent hypertension, were treated with metformin (300 mg/kg/day) or vehicle from 4 to 7 weeks of age. We assessed gut microbiome composition and function using shotgun metagenomic sequencing and measured blood pressure via radiotelemetry. Cardiac and renal organ damage and inflammation were evaluated by echocardiography, histology, and flow cytometry. RESULTS: Metformin treatment increased the production of short-chain fatty acids (SCFA) acetate and propionate in feces without altering microbial composition and diversity. It significantly reduced systolic and diastolic blood pressure and improved cardiac function, as measured by end-diastolic volume, E/A, and stroke volume despite increased cardiac hypertrophy. Metformin reduced cardiac inflammation by lowering macrophage infiltration and shifting macrophage subpopulations towards a less inflammatory phenotype. The observed improvements in blood pressure, cardiac function, and inflammation correlated with fecal SCFA levels in dTGR. In vitro, acetate and propionate altered M1-like gene expression in macrophages, reinforcing anti-inflammatory effects. Metformin did not affect hypertensive renal damage or microvascular structure. CONCLUSION: Metformin modulated the gut microbiome, increased SCFA production, and ameliorated blood pressure and cardiac remodeling in dTGR. Our findings confirm the protective effects of metformin in the absence of diabetes, highlighting SCFA as a potential mediators.

Predicting Overall Survival of Glioblastoma Patients Using Deep Learning Classification Based on MRIs.

INTRODUCTION: Glioblastoma (GB) is one of the most aggressive tumors of the brain. Despite intensive treatment, the average overall survival (OS) is 15-18 months. Therefore, it is helpful to be able to assess a patient's OS to tailor treatment more specifically to the course of the disease. Automated analysis of routinely generated MRI sequences (FLAIR, T1, T1CE, and T2) using deep learning-based image classification has the potential to enable accurate OS predictions. METHODS: In this work, a method was developed and evaluated that classifies the OS into three classes - "short", "medium" and "long". For this purpose, the four MRI sequences of a person were corrected using bias-field correction and merged into one image. The pipeline was realized by a bagging model using 5-fold cross-validation and the ResNet50 architecture. RESULTS: The best model was able to achieve an F1-score of 0.51 and an accuracy of 0.67. In addition, this work enabled a largely clear differentiation of the "short" and "long" classes, which offers high clinical significance as decision support. CONCLUSION: Automated analysis of MRI scans using deep learning-based image classification has the potential to enable accurate OS prediction in glioblastomas.

Converting PROMIS®-29 v2.0 profile data to SF-36 physical and mental component summary scores in patients with cardiovascular disorders.

BACKGROUND: Health-related quality of life (HRQL) has become an important outcome parameter in cardiology. The MOS 36-ltem Short-Form Health Survey (SF-36) and the PROMIS-29 are two widely used generic measures providing composite HRQL scores. The domains of the SF-36, a well-established instrument utilized for several decades, can be aggregated to physical (PCS) and mental (MCS) component summary scores. Alternative scoring algorithms for correlated component scores (PCSc and MCSc) have also been suggested. The PROMIS-29 is a newer but increasingly used HRQL measure. Analogous to the SF-36, physical and mental health summary scores can be derived from PROMIS-29 domain scores, based on a correlated factor solution. So far, scores from the PROMIS-29 are not directly comparable to SF-36 results, complicating the aggregation of research findings. Thus, our aim was to provide algorithms to convert PROMIS-29 data to well-established SF-36 component summary scores. METHODS: Data from n = 662 participants of the Berlin Long-term Observation of Vascular Events (BeLOVE) study were used to estimate linear regression models with either PROMIS-29 domain scores or aggregated PROMIS-29 physical/mental health summary scores as predictors and SF-36 physical/mental component summary scores as outcomes. Data from a subsequent assessment point (n = 259) were used to evaluate the agreement between empirical and predicted SF-36 scores. RESULTS: PROMIS-29 domain scores as well as PROMIS-29 health summary scores showed high predictive value for PCS, PCSc, and MCSc (R2 ≥ 70%), and moderate predictive value for MCS (R2 = 57% and R2 = 40%, respectively). After applying the regression coefficients to new data, empirical and predicted SF-36 component summary scores were highly correlated (r > 0.8) for most models. Mean differences between empirical and predicted scores were negligible (|SMD|<0.1). CONCLUSIONS: This study provides easy-to-apply algorithms to convert PROMIS-29 data to well-established SF-36 physical and mental component summary scores in a cardiovascular population. Applied to new data, the agreement between empirical and predicted SF-36 scores was high. However, for SF-36 mental component summary scores, considerably better predictions were found under the correlated (MCSc) than under the original factor model (MCS). Additionally, as a pertinent byproduct, our study confirmed construct validity of the relatively new PROMIS-29 health summary scores in cardiology patients.

Assessing the Performance of Deep Learning for Automated Gleason Grading in Prostate Cancer.

Prostate cancer is a dominant health concern calling for advanced diagnostic tools. Utilizing digital pathology and artificial intelligence, this study explores the potential of 11 deep neural network architectures for automated Gleason grading in prostate carcinoma focusing on comparing traditional and recent architectures. A standardized image classification pipeline, based on the AUCMEDI framework, facilitated robust evaluation using an in-house dataset consisting of 34,264 annotated tissue tiles. The results indicated varying sensitivity across architectures, with ConvNeXt demonstrating the strongest performance. Notably, newer architectures achieved superior performance, even though with challenges in differentiating closely related Gleason grades. The ConvNeXt model was capable of learning a balance between complexity and generalizability. Overall, this study lays the groundwork for enhanced Gleason grading systems, potentially improving diagnostic efficiency for prostate cancer.

Towards a FHIR-Based Framework for Analyzing Nursing-Related Data in Smaller Sized Care Facilities.

Data-driven decision making can improve the situation for caregivers and residents in nursing homes. However, smaller facilities often lack the technical and personnel resources required to prepare and analyze data. We introduce a conceptual framework to enable data transformation and analyzation in smaller nursing homes. We deployed a prototype pipeline at a German nursing home, where we demonstrated the feasibility and effectiveness of our approach.

Absence of claudin-3 does not alter intestinal absorption of phosphate in mice.

Intestinal absorption of phosphate is bimodal, consisting of a transcellular pathway and a poorly characterized paracellular mode, even though the latter one contributes to the bulk of absorption under normal dietary conditions. Claudin-3 (Cldn3), a tight junction protein present along the whole intestine in mice, has been proposed to tighten the paracellular pathway for phosphate. The aim of this work was to characterize the phosphate-related phenotype of Cldn3-deficient mice. Cldn3-deficient mice and wildtype littermates were fed standard diet or challenged for 3 days with high dietary phosphate. Feces, urine, blood, intestinal segments and kidneys were collected. Measurements included fecal, urinary, and plasma concentrations of phosphate and calcium, plasma levels of phosphate-regulating hormones, evaluation of trans- and paracellular phosphate transport across jejunum and ileum, and analysis of intestinal phosphate and calcium permeabilities. Fecal and urinary excretion of phosphate as well as its plasma concentration was similar in both genotypes, under standard and high-phosphate diet. However, Cldn3-deficient mice challenged with high dietary phosphate had a reduced urinary calcium excretion and increased plasma levels of calcitriol. Intact FGF23 concentration was also similar in both groups, regardless of the dietary conditions. We found no differences either in intestinal phosphate transport (trans- or paracellular) and phosphate and calcium permeabilities between genotypes. The intestinal expression of claudin-7 remained unaltered in Cldn3-deficient mice. Our data do not provide evidence for a decisive role of Cldn3 for intestinal phosphate absorption and phosphate homeostasis. In addition, our data suggest a novel role of Cldn3 in regulating calcitriol levels.

The Effects of Hypoxia on the Immune-Metabolic Interplay in Liver Cancer.

M2-like macrophages promote tumor growth and cancer immune evasion. This study used an in vitro model to investigate how hypoxia and tumor metabolism affect macrophage polarization. Liver cancer cells (HepG2 and VX2) and macrophages (THP1) were cultured under hypoxic (0.1% O2) and normoxic (21% O2) conditions with varying glucose levels (2 g/L or 4.5 g/L). Viability assays and extracellular pH (pHe) measurements were conducted over 96 hours. Macrophages were exposed to the tumor-conditioned medium (TCM) from the cancer cells, and polarization was assessed using arginase and nitrite assays. GC-MS-based metabolic profiling quantified TCM meta-bolites and correlated them with M2 polarization. The results showed that pHe in TCMs decreased more under hypoxia than normoxia (p < 0.0001), independent of glucose levels. The arginase assay showed hypoxia significantly induced the M2 polarization of macrophages (control group: p = 0.0120,0.1%VX2-TCM group: p = 0.0149, 0.1%HepG2-TCM group: p < 0.0001, 0.1%VX2-TCMHG group: p = 0.0001, and 0.1%HepG2-TCMHG group: p < 0.0001). TCMs also induced M2 polarization under normoxic conditions, but the strongest M2 polarization occurred when both tumor cells and macrophages were incubated under hypoxia with high glucose levels. Metabolomics revealed that several metabolites, particularly lactate, were correlated with hypoxia and M2 polarization. Under normoxia, elevated 2-amino-butanoic acid (2A-BA) strongly correlated with M2 polarization. These findings suggest that targeting tumor hypoxia could mitigate immune evasion in liver tumors. Lactate drives acidity in hypoxic tumors, while 2A-BA could be a therapeutic target for overcoming immunosuppression in normoxic conditions.

The STOIC2021 COVID-19 AI challenge: Applying reusable training methodologies to private data.

Challenges drive the state-of-the-art of automated medical image analysis. The quantity of public training data that they provide can limit the performance of their solutions. Public access to the training methodology for these solutions remains absent. This study implements the Type Three (T3) challenge format, which allows for training solutions on private data and guarantees reusable training methodologies. With T3, challenge organizers train a codebase provided by the participants on sequestered training data. T3 was implemented in the STOIC2021 challenge, with the goal of predicting from a computed tomography (CT) scan whether subjects had a severe COVID-19 infection, defined as intubation or death within one month. STOIC2021 consisted of a Qualification phase, where participants developed challenge solutions using 2000 publicly available CT scans, and a Final phase, where participants submitted their training methodologies with which solutions were trained on CT scans of 9724 subjects. The organizers successfully trained six of the eight Final phase submissions. The submitted codebases for training and running inference were released publicly. The winning solution obtained an area under the receiver operating characteristic curve for discerning between severe and non-severe COVID-19 of 0.815. The Final phase solutions of all finalists improved upon their Qualification phase solutions.

Morphological changes and their associations with clinical parameters in children with nephropathic cystinosis and chronic kidney disease prior to kidney replacement therapy over 25 years.

BACKGROUND: Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients' clinical and morphological presentation over the past decades have not yet been thoroughly investigated. METHODS: Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016). RESULTS: In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z-score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z-score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients. CONCLUSIONS: Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear.

Clinical Practice Guideline: Microhematuria in Children and Young Adults­Evaluation for the Early Detection of Kidney Disease.

BACKGROUND: Occult blood in the urine, or microhematuria, is a common finding (about 10%) in children and young adults. It is often of brief duration and therefore harmless. In persistent microhematuria, acanthocytes in the urine are a frequently unrecognized early marker of glomerular kidney disease. The purpose of this guideline is to promote the early detection of kidney disease in children and young adults with practical, evidence-based recommendations. METHODS: A systematic search for pertinent publications up to January 2023 was conducted in Pubmed, the Cochrane Database, and Livivo. 474 publications were retrieved, summarized in terms of method and content, and classified by Oxford (2011) evidence level. RESULTS: Approximately 1% of children and young adults have undiagnosed chronic kidney disease. Microhematuria is an early warning sign. A timely nephrological evaluation is indicated if microhematuria persists for 3 to 6 months, if ≥ 5% acanthocytes are detectable in the urine, and if there is also proteinuria, hypertension, or impaired renal function. Ultrasonography of the kidneys and urinary tract is the imaging method of choice; cystoscopy should be avoided. For patients with glomerular microhematuria, molecular genetic testing is recommended. Renal biopsy is recommended in case of florid glomerular diseases, after the determination of various laboratory parameters and clinical findings, including molecular genetic testing especially in children. CONCLUSION: In the absence of a guideline until now, findings have often been incorrectly assessed, leading either to an inadequate work-up or to excessive diagnostics. As a result, in approximately 30% of young patients, valuable opportunities for early treatment to protect the kidneys have been missed.

Favorable Outcome After Single-kidney Transplantation From Small Donors in Children: A Match-controlled CERTAIN Registry Study.

BACKGROUND: Kidney transplantation (KTx) from small donors is associated with inferior graft survival in registry studies, whereas single-center studies show favorable results. METHODS: We compared 175 pediatric KTx from small donors ≤20 kg (SDKTx) with 170 age-matched recipients from adult donors (ADKTx) from 20 centers within the Cooperative European Paediatric Renal Transplant Initiative registry. Graft survival and estimated glomerular filtration rate (eGFR) were analyzed by Cox regression and mixed models. Detailed data on surgical and medical management were tested for association with graft survival. RESULTS: One-year graft survival was lower after SDKTx compared with ADKTx (90.9% versus 96.5%; odds ratio of graft loss, 2.92; 95% confidence interval [CI], 1.10-7.80; P  = 0.032), but 5-y graft survival was comparable (90.9% versus 92.7%; adjusted hazard ratio of graft loss 1.9; 95% CI, 0.85-4.25; P  = 0.119). SDKTx recipients had an annual eGFR increase of 8.7 ±â€…6.2 mL/min/1.73 m² compared with a decrease of 6.9 ±â€…5.7 mL/min/1.73 m² in ADKTx recipients resulting in a superior 5-y eGFR (80.5 ±â€…25.5 in SDKTx versus 65.7 ±â€…23.1 mL/min/1.73 m² in ADKTx; P  = 0.008). At 3 y posttransplant, eGFR after single SDKTx was lower than after en bloc SDKTx (86.6 ±â€…20.4 versus 104.6 ±â€…35.9; P  = 0.043) but superior to ADKTx (68.1 ±â€…23.9 mL/min/1.73 m²). Single-kidney SDKTx recipients had a lower rate of hypertension at 3 y than ADKTx recipients (40.0% versus 64.7%; P  = 0.008). CONCLUSIONS: Compared with ADKTx, 5-y graft function is superior in SDKTx and graft survival is similar, even when performed as single KTx. Utilizing small donor organs, preferably as single kidneys in experienced centers, is a viable option to increase the donor pool for pediatric recipients.

Claudin-10 Expression and the Gene Expression Pattern of Thick Ascending Limb Cells.

Many genomic, anatomical and functional differences exist between the medullary (MTAL) and the cortical thick ascending limb of the loop of Henle (CTAL), including a higher expression of claudin-10 (CLDN10) in the MTAL than in the CTAL. Therefore, we assessed to what extent the Cldn10 gene expression is a determinant of differential gene expression between MTAL and CTAL. RNAs extracted from CTAL and MTAL microdissected from wild type (WT) and Cldn10 knock out mice (cKO) were analyzed by RNAseq. Differential and enrichment analyses (GSEA) were performed with interactive R Shiny software. Between WT and cKO MTAL, 637 genes were differentially expressed, whereas only 76 were differentially expressed between WT and cKO CTAL. Gene expression patterns and GSEA analyses in all replicates showed that WT MTAL did not cluster with the other replicates; no hierarchical clustering could be found between WT CTAL, cKO CTAL and cKO MTAL. Compared to WT replicates, cKO replicates were enriched in Cldn16, Cldn19, Pth1r, (parathyroid hormone receptor type 1), Casr (calcium sensing receptor) and Vdr (Vitamin D Receptor) mRNA in both the cortex and medulla. Cldn10 is associated with gene expression patterns, including genes specifically involved in divalent cations reabsorption in the TAL.

[Potential Nephrotoxicity of Combination of Vancomycin and Piperacillin-Tazobactam: Recommendations from the AG ABS of the DGPI supported by experts of the GPN]. / Potentielle Nephrotoxizität der Kombinationstherapie von Vancomycin und Piperacillin-Tazobactam: Empfehlungen der AG ABS der DGPI unter Beteiligung von Experten der GPN.

The combination of vancomycin and piperacillin/tazobactam (V+P/T) is used for empirical antibiotic treatment of severe infections, especially in immunocompromised patients and those colonized with multidrug-resistant bacteria. Nephrotoxicity is a frequently observed adverse effect of vancomycin. Its risk can be reduced by therapeutic drug monitoring and adjusted dosing. Piperacillin/tazobactam (P/T) rarely causes interstitial nephritis. The results of retrospective cohort studies in children predominantly show a low, clinically irrelevant, additive nephrotoxicity (defined as an increase in creatinine in the serum) of both substances. Due to the limitations of the existing publications, the ABS working group of the DGPI and experts of the GPN do not recommend against the use of P/T plus vancomycin. Preclinical studies and a prospective study with adult patients, which evaluated different renal function tests as well as clinical outcomes, do not support previous findings of additive nephrotoxicity. Time-restricted use of V+P/T can minimize exposure and the potential risk of nephrotoxicity. Local guidelines, developed in collaboration with the antibiotic stewardship team, should define the indications for empirical and targeted use of P/T and V+P/T. When using combination therapy with V+P/T, kidney function should be monitored through clinical parameters (volume status, balancing, blood pressure) as well as additional laboratory tests such as serum creatinine and cystatin C.

Urinary Acidification Does Not Explain the Absence of Nephrocalcinosis in a Mouse Model of Familial Hypomagnesaemia with Hypercalciuria and Nephrocalcinosis (FHHNC).

Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice.

Sodium as an Important Regulator of Immunometabolism.

Salt sensitivity concerns blood pressure alterations after a change in salt intake (sodium chloride). The heart is a pump, and vessels are tubes; sodium can affect both. A high salt intake increases cardiac output, promotes vascular dysfunction and capillary rarefaction, and chronically leads to increased systemic vascular resistance. More recent findings suggest that sodium also acts as an important second messenger regulating energy metabolism and cellular functions. Besides endothelial cells and fibroblasts, sodium also affects innate and adaptive immunometabolism, immune cell function, and influences certain microbes and microbiota-derived metabolites. We propose the idea that the definition of salt sensitivity should be expanded beyond high blood pressure to cellular and molecular salt sensitivity.

Erectile dysfunction: role of computed tomography cavernosography in the diagnosis and treatment planning of venous leak.

BACKGROUND: Venous leak appears to be the most common cause of vasculogenic erectile dysfunction (ED), which can be treated with venous embolization. Traditionally, conventional cavernosography was used for the diagnosis and treatment planning of venous leak. Recently, computed tomography (CT) cavernosography was introduced as a novel cross-sectional imaging method proposed to be advantageous over conventional cavernosography. We created a novel management algorithm for diagnosing venous leak including CT cavernosography as an imaging modality. In order to provide a broader basis for our management algorithm, a systematic literature review was conducted. MAIN BODY: In this article we systematically review relevant literature on using CT cavernosography for the diagnosis and treatment planning in ED patients with venous leak following the PRISMA selection process. Nine full-text articles were included in the review and assigned a level of evidence grade (all grade II). Two studies (2/9) compared the results of conventional cavernosography with those of CT cavernosography which was superior for site-specific venous leak identification (19.4% vs. 100%, respectively). CT cavernosography is a more detailed imaging method that is faster to perform, exposes the patient to less radiation, and requires less contrast material. In one study (1/9), CT cavernosography was used for diagnostic purposes only. Eight studies (8/9) cover both, diagnostic imaging and treatment planning including embolization (1/9) and sclerotherapy (2/9) of venous leak in patients with venogenic ED. Three studies (3/9) describe anatomical venous leak classifications that were established based on CT cavernosography findings for accurate mapping of superficial and/or deep venous leak and identification of mixed or more complex forms of venous leak present in up to 84% of patients. In addition to treatment planning, one study (1/9) used CT cavernosography also for follow-up imaging post treatment. CONCLUSION: CT cavernosography is superior to conventional cavernosography for diagnosis and treatment planning in patients with ED caused by venous leak (grade II levels of evidence). Consequently, CT cavernosography should be included in management algorithms for ED patients with suspected venous leak.

Enhancing Interoperability and Harmonisation of Nuclear Medicine Image Data and Associated Clinical Data.

Nuclear imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) in combination with computed tomography (CT) are established imaging modalities in clinical practice, particularly for oncological problems. Due to a multitude of manufacturers, different measurement protocols, local demographic or clinical workflow variations as well as various available reconstruction and analysis software, very heterogeneous datasets are generated. This review article examines the current state of interoperability and harmonisation of image data and related clinical data in the field of nuclear medicine. Various approaches and standards to improve data compatibility and integration are discussed. These include, for example, structured clinical history, standardisation of image acquisition and reconstruction as well as standardised preparation of image data for evaluation. Approaches to improve data acquisition, storage and analysis will be presented. Furthermore, approaches are presented to prepare the datasets in such a way that they become usable for projects applying artificial intelligence (AI) (machine learning, deep learning, etc.). This review article concludes with an outlook on future developments and trends related to AI in nuclear medicine, including a brief research of commercial solutions.

Protocol of the Berlin Long-term Observation of Vascular Events (BeLOVE): a prospective cohort study with deep phenotyping and long-term follow up of cardiovascular high-risk patients.

INTRODUCTION: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations. METHODS AND ANALYSIS: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes. ETHICS AND DISSEMINATION: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations. STUDY REGISTRATION: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021.