Neutrophil extracellular traps (NETs) consist of decondensed nuclear chromatin that is associated with proteins and are released by neutrophils during an inflammatory response. Released NETs are able to capture pathogens, prevent their dissemination and potentially kill them via antimicrobial peptides and proteins that are associated with the decondensed chromatin. In addition to their antimicrobial functions, NETs have also been shown to exert immunomodulatory effects by activation and differentiation of macrophages, dendritic cells and T cells. However, the effect of NETs on neutrophil functions is poorly understood. Here we report the first comprehensive study regarding the effects of NETs on human primary neutrophils in vitro. NETs were isolated from cultures of PMA-exposed neutrophils. Exposure of neutrophils to isolated NETs resulted in the activation of several neutrophil functions in a concentration-dependent manner. NETs induced exocytosis of granules, the production of reactive oxygen species (ROS) by the NADPH oxidase NOX2, NOX2-dependent NET formation, increased the phagocytosis and killing of microbial pathogens. Furthermore, NETs induced the secretion of the proinflammatory chemokine IL-8 and the B-cell-activating cytokine BAFF. We could show that the NET-induced activation of neutrophils occurs by pathways that involve the phosphorylation of Akt, ERK1/2 and p38. Taken together our results provide further insights into the proinflammatory role of NETs by activating neutrophil effector function and further supports the view that NETs can amplify inflammatory events. On the one hand the amplified functions enhance the antimicrobial defense. On the other hand, NET-amplified neutrophil functions can be involved in the pathophysiology of NET-associated diseases. In addition, NETs can connect the innate and adaptive immune system by inducing the secretion of the B-cell-activating cytokine BAFF.

Background Urinary stone disease is a widespread disease with tremendous impact on those affected and on societies around the globe. Nevertheless, clinical and health care research in this area seem to lag far behind cardiovascular diseases or cancer. This may be due to the lack of an immediate deadly threat from the disease and therefore less public and professional interest. However, the patients suffer from recurring, sometimes intense pain and often must be treated in hospital. Long-term morbidity includes doubled rates of chronic kidney disease and arterial hypertension after at least one stone-related event. Observational studies, more specifically, registries and other electronic data sets have been proposed as a means of filling critical gaps in evidence. We propose a nationwide digital and fully automated registry as part of the German Ministry for Education and Research (BMBF) call for the "establishment of model registries”. Methods RECUR builds on the technical infrastructure of Germany’s Medical Informatics Initiative. Local data integration centres (DIC) of participating medical universities will collect pseudonymized and harmonized data from respective hospital information systems. In addition to their clinical data, participants will provide patient reported outcomes using a mobile patient app. Scientific data exploration includes queries and analysis of federated data from DICs of eleven participating sites. All primary patient data will remain at the participating sites at all times. With comprehensive data from this longitudinal registry, we will be able to describe the disease burden, to determine and validate risk factors, and to evaluate treatments. Implementation and operation of the RECUR registry will be funded by the BMBF for five years. Subsequently, the registry is to be continued by the German Society of Urology without significant costs for study personnel. Discussion The proposed registry will substantially improve the structural and procedural framework for patients with recurrent urolithiasis. This includes advanced diagnostic algorithms and treatment pathways. The registry will help us identify those patients who will most benefit from specific interventions to prevent recurrences. The RECUR study protocol and the registry’s technical architecture including full digitalization and automation of almost all registry-associated proceedings can be transferred to future registries. Trial registration This study is registered at the German Clinical Trial Register (Deutsches Register Klinischer Studien), DRKS-ID DRKS00026923, date of registration January, 11th 2022.

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ZusammenfassungNierensteine werden wie Herz-Kreislauf-Erkrankungen und Diabetes mellitus aufgrund ihrer Häufigkeit zu den Volkskrankheiten gezählt. Erkrankte können durch akute Schmerzen, wiederholte Krankenhausaufenthalte und relevante Folgeerkrankungen belastet sein. Daraus folgen auch erhebliche Kosten, die Gesellschaft und Gesundheitssystem tragen müssen. Die Rezidivrate liegt bei 50%. Mit dem Register für RECurrente URolithiasis (RECUR) sollen bestehenden Evidenzlücken geschlossen werden. Dabei handelt es sich um ein prospektives longitudinales Register, dessen Aufbau und Implementierung vom Bundesministerium für Bildung und Forschung (BMBF) im Rahmen der Förderung „Aufbau modellhafter, patientenbezogener Register für die Versorgungsforschung“ finanziert wird. Es basiert auf der digitalen Infrastruktur der Medizininformatik-Initiative des BMBF. Ziel ist es, möglichst viele Patient*innen der 10 teilnehmenden Kliniken mit mehr als einer Nierenstein-Episode einzuschließen, um neue Erkenntnisse über Risikofaktoren, Diagnose- und Behandlungsalgorithmen zu erhalten. Im Rahmen des RECUR Projekts sollen neben klinischen Routinedaten auch „Patient Reported Outcomes“ von Patienten mit rezidivierenden Nierensteinen erhoben werden. Die Erhebung dieser Daten werden für alle teilnehmenden Standorte in Form von digitalen Fragebögen mithilfe einer Smartphone App durchgeführt und mit den medizinischen Daten aus dem Krankenhausinformationssystemen in pseudonymisierter Form zusammengeführt. Das RECUR-Register hat durch seinen vollständig föderierten, digitalen Ansatz einen modellhaften Charakter. Dieser ermöglicht die Rekrutierung vieler Patient*innen, die Erfassung eines breiten Datenspektrums und dessen Aufbereitung bei gleichzeitig geringem Verwaltungs- und Personalaufwand.