DFG Abschlussbericht zur Projektnummer 250170148

Zusammenfassung: Polytrauma, das gleichzeitige Auftreten schwerer Verletzungen an verschiedenen Körperstellen, führt im Durchschnitt zu einem Verlust von 32 Lebensjahren und ist die Haupttodesursache für Menschen unter 50 Jahren. Überlebende leiden oft langfristig unter Behinderungen, wobei nur etwa die Hälfte nach zwei Jahren wieder arbeitsfähig ist. Frakturen und Trauma-Hämorrhagie (TH) treten häufig gemeinsam auf, wobei unkontrollierter Blutverlust die zweithäufigste Todesursache darstellt. Herausforderungen für PolytraumapatientInnen manifestieren sich in gestörter Frakturheilung aufgrund von Gewebsminderperfusion und einer beeinträchtigten inflammatorischen Frakturheilungs-phase. Besonders relevant ist der Einfluss von Trauma-Hämorrhagie auf die Frakturheilung bei über 70-Jährigen, die oft durch Stürze lange Röhrenknochen brechen. Osteoporose erhöht das Pseudarthroserisiko, was mit erhöhter Morbidität und Mortalität verbunden ist. In der ersten Förderphase wurden die Auswirkungen von schwerem Blutverlust auf die Frakturheilung und die zugrundeliegenden Signalwege untersucht. Ergebnisse zeigten, dass die Frakturheilung nach TH und Fraktur beeinträchtigt war, manifestiert in biomechanischen, histologischen und Signalwegänderungen. In der zweiten Förderphase wurde der Einfluss von Alter und Alkoholintoxikation auf die Frakturheilung und das regenerative Potenzial untersucht. Mäuse wurden in verschiedene Alters- und Behandlungsgruppen aufgeteilt. Fortgeschrittenes Alter führte zu geringerer Knochenmineralisierung und reduzierter Osteoklastenanzahl im Frakturspalt. Ältere Mäuse zeigten erhöhte Anfälligkeit für Organschäden in Leber und Lunge nach Trauma. Alkohol hatte entzündungshemmende Effekte, besonders bei jungen Mäusen, wobei diverse molekulare Mechanismen beeinflusst wurden. Altersabhängige Veränderungen der Immunantwort und verstärkte Entzündungsreaktionen wurden beobachtet. Signalweganalysen zeigten, dass NF-kappaB und Wnt/β-Catenin in Leber und Lunge durch Alkohol beeinflusst wurden. Reduzierte Aktivität von zirkulierenden Neutrophilen nach Alkoholexposition könnte die Heilung beeinträchtigen. Die Ergebnisse bieten Einblicke in die komplexen Wechselwirkungen zwischen Trauma, Hämorrhagie, Alter und Alkohol auf die Frakturheilung, Organregeneration und die zugrundeliegenden Mechanismen auf zellulärer und molekularer Ebene.Summary: Polytrauma, the simultaneous occurrence of severe injuries at different body sites, on average leads to a loss of 32 life years and is the primary cause of death for individuals under 50 years of age. Survivors often suffer long-term disabilities, with only about half being able to return to work after two years. Fractures and trauma-hemorrhage (TH) frequently occur together, with uncontrolled blood loss being the second most common cause of death. Challenges for polytrauma patients manifest in disrupted fracture healing due to tissue hypoperfusion and impaired inflammatory phase of fracture healing. The influence of trauma-hemorrhage on fracture healing is particularly relevant in individuals over 70 years old, who often experience long bone fractures from falls. Osteoporosis increases the risk of pseudarthrosis, associated with higher morbidity and mortality. The project investigates the impact of TH on fracture healing in young and old mice with and without alcohol intoxication. In the first funding phase, the effects of severe blood loss on fracture healing and underlying signaling pathways were examined. Results indicated impaired fracture healing after TH and fracture in male mice, manifested in biomechanical, histological, and signaling changes. In the second funding phase, the influence of age and alcohol intoxication on fracture healing and regenerative potential was explored. Mice were divided into different age and treatment groups. Advanced age led to lower bone mineralization and a reduced number of osteoclasts in the fracture gap. Older mice exhibited increased susceptibility to organ damage in the liver and lungs after trauma. Alcohol had anti-inflammatory effects, especially in young mice, influencing various molecular mechanisms. Age-dependent changes in immune response and heightened inflammatory reactions were observed. Pathway analyses revealed that NF-kappaB and Wnt/β-Catenin in the liver and lungs were influenced by alcohol. Reduced activity of circulating neutrophils and monocytes after alcohol exposure could impact healing. The results provide comprehensive insights into the complex interactions among trauma, hemorrhage, age, and alcohol on fracture healing, organ regeneration, and the underlying mechanisms at the cellular and molecular levels

Comparison of accumulation and distribution of PEGylated and CD-47-functionalized magnetic nanoporous silica nanoparticles in an in vivo mouse model of implant infection

Die zur Verfügung gestellten Rohdaten sind im Rahmen einer tierexperimentellen Studie erhoben (Genehmigungsnummer beim LAVES Nds.: 33.19-42502-04-20/3394) Es handelt sich um histologische Scorewerte, die nach dem im SI des Manuskripts verwendeten Score erhoben wurden und im Excel-Format zur Verfügung gestellt werden. Weiterhin werden mikroskopisch erhobene Messdaten zur Oberflächenanalyse der Implantate im Hinblick auf Partikelanreicherung (Messung der Fluoreszenzsignale in prozentualem Anteil der Gesamtimplantatfläche) ebenfalls im Excel-Format zur Verfügung gestellt. Die Daten wurden im Q3 2023 an der Medizinischen Hochschule Hannover (NIFE) erhoben

Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control

In atopic dermatitis (AD), lesional skin is frequently colonized by Staphylococcus aureus, which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate S. aureus. Therefore, repolarization of macrophages toward the M1 phenotype may foster control of S. aureus. Our data show that the deubiquitinating enzyme cylindromatosis (CYLD) is strongly expressed in macrophages of AD patients and prevents the clearance of S. aureus. Mechanistically, CYLD impaired M1 macrophage polarization by K63-specific deubiquitination of STAT1 and activation of the NF-κB pathway via its interaction with TRAF6, NEMO, and RIPK2. Inhibition of STAT1 and NF-κB, independently, abolished the differences between S. aureus-infected CYLD-deficient and CYLD-competent M1 macrophages. Infection of Cyld-deficient and wild-type mice with S. aureus confirmed the protective CYLD function. Collectively, our study shows that CYLD impairs the control of S. aureus in macrophages of AD patients, identifying CYLD as a potential therapeutic target

Focused attention in late-diagnosed adults with autism spectrum disorder - a matter of reaction time?

This study examined focused attentional profiles in adults with late-diagnosed autism spectrum disorder without intellectual disability and compared them to a matched non-autistic control group (NC) using the Test Battery for Attention Performance (TAP). The study included 37 individuals with ASD and 34 NC. File format: .sav; abbreviations and units in file

Feasibility study of an experimental social space-oriented rehabilitation concept for people with intellectual and/or multiple disabilities: a study protocol

Introduction The United Nations underlines the participation in all domains of daily living for people with intellectual and/or multiple disabilities in the Disability Rights Convention, which also includes medical services. In line with this, the German Federal Participation Act has further developed the relevant disability policy at the national level. This also implies access to comprehensive medical care. In 2015, Germany created a legal basis for the establishment of medical centres for adults with intellectual and/or multiple disabilities in order to ensure basic medical care for these patients. However, the medical centres cannot provide complex rehabilitation. Mobile rehabilitation can be another tool to address the underuse of medical rehabilitation for people with intellectual and/or multiple disabilities. Mobile rehabilitation refers to rehabilitation services provided in a patient's home or local community, rather than in a traditional inpatient or outpatient rehabilitation facility. The advantages of mobile rehabilitation are its accessibility for patients with mobility problems, the comfort of a familiar environment, which can reduce stress, and the fact that rehabilitation can be tailored to the patient's living conditions and daily routine. In Germany, mobile rehabilitation is currently only available in the field of geriatrics.Within the framework of the feasibility study 'Social space-oriented individualised medical rehabilitation for people with intellectual and/or multiple disabilities (SIMRE),' a social space-oriented rehabilitation concept was developed to close the rehabilitation gap for people with intellectual and/or multiple disabilities. It is funded by the German Federal Ministry of Health. This study protocol describes the procedure of this feasibility study. Methods This study is a prospective mixed methods feasibility study. The rehabilitation concept combines outpatient and home-based rehabilitation, medical, and therapeutic care for people with intellectual and/or multiple disabilities. Analysis The primary target criteria are the feasibility and acceptance of the concept by participants, relatives, carers and the rehabilitation staff. Guided interviews with participants and their relatives and/or carers will be analysed using the content-structuring analysis according to Kuckartz. Quantitative analysis will include a cost-benefit analysis to provide information on the economic feasibility of the rehabilitation concept. Changes in individual participation, quality of life and rehabilitation goals will be assessed using a before-and-after comparison with questionnaires. The frequency and type of rehabilitation procedures used will be evaluated quantitatively.The trial was prospectively registered in the German Clinical Trials Register on 17 August 2023. (https://www.drks.de/DRKS00032493). Ethics and dissemination Ethical approval was granted by the Ethics Committee of Hannover Medical School (reference number: 10985_BO_S_2023).1. Publication: The results of the project will be made available to the public through open access publications. We plan to develop a treatment guideline for the treatment concept based on clinical experience.2. Widespread implementation: If the project is continued and adequately staffed, the rehabilitative care concept could be implemented nationwide, and the University Hospital could be available as a reference clinic. Trial registration number German Clinical Trials Register (reference number: DRKS00032493)

Severe soft tissue injuries in multiple trauma patients-a challenge we can meet? A matched-pair analysis from the TraumaRegisterDGU®

Introduction Despite tremendous clinical efforts over the past few decades, the treatment of severely injured patients remains still challenging. Concomitant soft tissue injuries represent a particular challenge, as they can lead to complications at any time of trauma care, hold a high risk of infection and often require multiple surgical interventions and interdisciplinary collaboration. Methods This retrospective, multicentric study used the TraumaRegister DGU® to examine the effect of open fractures and severe soft tissue injuries on outcome of multiple trauma patients. Primary admitted multiple trauma patients at the age of 16 to 70 years, treated from 2010 to 2021, were included. A Matched pair analysis was performed for better comparability of trauma patients with and without open fractures and/or severe soft tissue injuries. Results After applying the matching criteria, 5,795 pairs were created and analyzed. The group with sustained soft tissue injuries/open fractures was found to have a higher ISS ([mean ± SD] 22.1 ± 10.4 vs. 20.6 ± 10.2, p < 0.001). Endotracheal tube insertion (27.7% vs. 30.4%, p = 0.003), catecholamine administration (6.0% vs. 8.4%, p < 0.001) and cardio-pulmonary resuscitation (1.6% vs. 2.1%, p = 0.027) were more frequent in the group with sustained soft tissue injury. Both groups were equally frequent admitted to the intensive care unit (ICU) and length of stay (LOS) at the ICU (median (quartiles) 3 (1-9) versus 3 (1-9)) did not differ significantly. However, total LOS at the hospital was longer for the group with sustained soft tissue injury (median (quartiles) 18 (11-29) versus 17 (10-27)). Sepsis occurred more often in patients with soft tissue injury (4.3% vs. 5.2%, p = 0.034). There was no significant difference in prevalence of multi organ failure, 24 h-mortality (2.1% vs. 2.5%, p = 0.151) and overall-mortality (3.6% vs. 3.9%, p = 0.329) between both groups. Conclusion Due to database analysis and revision of guidelines, the treatment of severely injured patients has steadily improved in recent years. Patients with severe soft tissue injuries/open fractures required more medical interventions and length of stay at the hospital was longer. In this study, we were able to show that although concomitant severe soft tissue injuries required more ICU interventions and led to a longer length of stay, 24-h and all-cause mortality were not significantly increased