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DigiNet: Optimizing personalized care for patients with stage IV non-small cell lung cancer (NSCLC) through a digitally connected provider network-analysis plan of a prospective multicenter cohort trial.

PURPOSE: The German sector-based healthcare system poses a major challenge to continuous patient monitoring and long-term follow-up, both essential for generating high-quality, longitudinal real-world data. The national Network for Genomic Medicine (nNGM) bridges the inpatient and outpatient care sectors to provide comprehensive molecular diagnostics and personalized treatment for non-small cell lung cancer (NSCLC) patients in Germany. Building on the established nNGM infrastructure, the DigiNet study aims to evaluate the impact of digitally integrated, personalized care on overall survival (OS) and the optimization of treatment pathways, compared to routine care. METHODS: DigiNet is a prospective, controlled, non-randomized multicenter cohort study including patients with stage IV NSCLC in two study regions (East and West) in Germany. The results of molecular diagnostics and clinical information, along with the entire treatment data are documented in a shared database. A board of lung cancer specialists monitors critical events. Patients digitally complete quality of life questionnaires, with results visualized for physicians. To assess the impact of this personalized digital care, a population-based control group will be identified by matching cohorts within the involved cancer registries. The primary endpoint is OS, and secondary endpoints comprise time on first-line treatment and hospitalization rates. Furthermore, a health economic and business economic evaluation will be conducted. Qualitative interviews with patients and physicians will be performed to assess barriers and facilitating factors for implementing the DigiNet intervention. ETHICS: The study protocol was reviewed and approved by the Ethics Committee of the University Hospital of Cologne (21-1521). TRIAL REGISTRATION: NCT05818449, registered retrospectively on December 12, 2022.

Humans

Glomerular hemodynamics and vascular structure in uremia: a network analysis of glomerular path lengths and maximal blood transit times computed for a microvascular model reconstructed from subserial ultrathin sections.

The dimensions of individual capillary segments were determined from a glomerular model constructed on the basis of electron micrographs of subserial ultrathin sections of kidney tissue from a rat made chronically uremic by subtotal nephrectomy. Hemodynamic calculations used computer programs for node pressure analysis and for the determination of path lengths and transit times from afferent to efferent arteriole. The afferent arteriole divided into five primary capillary segments. Three of these carried 84% of the flow through 632 paths, which accounted for 54% of the capillary endothelial area. Their mean path length was 520.97 micron, mean of segment numbers per path 17.66, and mean transit time 0.50 sec. The remaining two capillary segments carried 16% of the flow and led to paths accounting for the remaining 46% of the capillary area. The number of paths from the afferent arteriole through these two segments was 21,244. Mean path length from the initial node through these two segments was 852.18 micron, mean of segment numbers per path 29.62, and mean transit time 20.76 sec. The most striking difference between the two sets of paths was in transit time. This asymmetry would tend to reduce the filtration surface and the Kf (hydraulic conductance x filtering surface area) by causing early filtration pressure equilibrium in much of the capillary network, and suggests an intrinsic glomerular aspect of chronic renal insufficiency.

Animals

Enzyme-Metabolite Network Analysis of Endometrial Cancer-Derived Extracellular Vesicles Through Integrated Proteomics and Metabolomics.

Endometrial cancer (EC) is the most common gynecological malignancy in high-income countries. Extracellular vesicles (EVs) are key mediators of intercellular communication and metabolic reprogramming, but their molecular cargo in EC remains poorly characterized. EVs were isolated from four EC cell lines representing Type I and Type II subtypes (AN3CA, ISHIKAWA, HEC1A, and KLE). Untargeted metabolomics was performed by HILIC-LC-MS/MS, proteomics by data-independent acquisition (DIA) mass spectrometry, and multi-omics integration using MetaboAnalyst and OmicsNet. Metabolomic profiling identified 1463 annotated features and revealed significant differences among EC cell lines (PERMANOVA, p = 0.002). Twenty-eight differentially abundant metabolites, including lactic acid, succinic acid, and uric acid, were identified. Proteomic analysis quantified 8513 proteins with subtype-specific expression patterns. Integrated analysis revealed seven significantly enriched pathways, including glycolysis/gluconeogenesis, central carbon metabolism in cancer, and the pentose phosphate pathway. Increased LDHA abundance in metastatic AN3CA-derived EVs was confirmed by Western blot (p = 0.047). EC-derived EVs display subtype- and metastatic-status-specific metabolo-proteomic signatures, with glycolysis, TCA cycle remodeling, and central carbon metabolism as convergent pathway signatures of molecular reprogramming. These findings establish a multi-omics framework for characterizing EV cargo in EC and identify candidate enzyme-metabolite nodes for future biomarker validation in patient-derived specimens.

Female

Modeling the electrical behavior of anatomically complex neurons using a network analysis program: passive membrane.

We describe the application of a popular and widely available electrical circuit simulation program called SPICE to modeling the electrical behavior of neurons with passive membrane properties and arbitrarily complex dendritic trees. Transient responses may be calculated at any location in the cell model following current, voltage or conductance perturbations at any point. A numbering method is described for binary trees which is helpful in transforming complex dendritic structures into a coded list of short cylindrical dendritic segments suitable for input to SPICE. Individual segments are modeled as isopotential compartments comprised of a parallel resistor and capacitor, representing the transmembrane impedance, in series with one or two core resistors. Synaptic current is modeled by a current source controlled by the local membrane potential and an "alpha-shaped" voltage, thus simulating a conductance change in series with a driving potential. Extensively branched test cell circuits were constructed which satisfied the equivalent cylinder constraints (Rall 1959). These model neurons were perturbed by independent current sources and by synaptic currents. Responses calculated by SPICE are compared with analytical results. With appropriately chosen model parameters, extremely accurate transient calculations may be obtained. Details of the SPICE circuit elements are presented, along with illustrative examples sufficient to allow implementation of passive nerve cell models on a number of common computers. Methods for modeling excitable membrane are presented in the companion paper (Bunow et al. 1985).

Animals

Shunt haemodynamics and extracorporeal dialysis: an electrical resistance network analysis.

A time-dependent resistance model is used to study haemodynamic aspects of haemodialysis treatment. In the first part of the paper one model circuit, consisting of a pressure source, upstream and downstream resistances and a branching resistance, is shown to represent the haemodynamics of any type of arteriovenous fistula (AVF). Simple algebraic relations are derived for the haemodynamic determinants of AVFS, including finger ischaemia and AVF-maturation. The second part of the paper analyses the influences of a two-needle extracorporeal dialysis (ECD) circuit on the systemic vascular haemodynamics. The main result of the analysis is that the ECD-circuit can be considered as virtually independent of the systemic circulation. Consequently the dialysis flow does not depend on systemic vascular determinants and there are no instantaneous changes in the systemic circulation after switching on the ECD circuit. The ECD flow at onset of AVF collapse is shown to be (slightly) larger than the undisturbed AVF flow. Hence, onset of collapse strongly depends on the systemic blood pressure and vascular resistances. It can be used diagnostically to assess AVF capacities. Optimisation of haemodialysis through the ECD circuit is predicted to be inefficient.

Arm