Exploring the relationship between metabolism and immune microenvironment in osteosarcoma based on metabolic pathways.

BACKGROUND: Metabolic remodeling and changes in tumor immune microenvironment (TIME) in osteosarcoma are important factors affecting prognosis and treatment. However, the relationship between metabolism and TIME needs to be further explored. METHODS: RNA-Seq data and clinical information of 84 patients with osteosarcoma from the TARGET database and an independent cohort from the GEO database were included in this study. The activity of seven metabolic super-pathways and immune infiltration levels were inferred in osteosarcoma patients. Metabolism-related genes (MRGs) were identified and different metabolic clusters and MRG-related gene clusters were identified using unsupervised clustering. Then the TIME differences between the different clusters were compared. In addition, an MRGs-based risk model was constructed and the role of a key risk gene, ST3GAL4, in osteosarcoma cells was explored using molecular biological experiments. RESULTS: This study revealed four key metabolic pathways in osteosarcoma, with vitamin and cofactor metabolism being the most relevant to prognosis and to TIME. Two metabolic pathway-related clusters (C1 and C2) were identified, with some differences in immune activating cell infiltration between the two clusters, and C2 was more likely to respond to two chemotherapeutic agents than C1. Three MRG-related gene clusters (GC1-3) were also identified, with significant differences in prognosis among the three clusters. GC2 and GC3 had higher immune cell infiltration than GC1. GC3 is most likely to respond to immune checkpoint blockade and to three commonly used clinical drugs. A metabolism-related risk model was developed and validated. The risk model has strong prognostic predictive power and the low-risk group has a higher level of immune infiltration than the high-risk group. Knockdown of ST3GAL4 significantly inhibited proliferation, migration, invasion and glycolysis of osteosarcoma cells and inhibited the M2 polarization of macrophages. CONCLUSION: The metabolism of vitamins and cofactors is an important prognostic regulator of TIME in osteosarcoma, MRG-related gene clusters can well reflect changes in osteosarcoma TIME and predict chemotherapy and immunotherapy response. The metabolism-related risk model may serve as a useful prognostic predictor. ST3GAL4 plays a critical role in the progression, glycolysis, and TIME of osteosarcoma cells.

Patients risk for mortality at 90 days after proximal femur fracture - a retrospective study in a tertiary care hospital.

BACKGROUND: Despite improving the management of proximal femur fractures (PFF) with legal requirements of timing the surgery within 24 h, mortality rates in these patients remain still high. The objective of our study was to analyze potential cofactors which might influence the mortality rate within 90 days after surgery in PFF to avoid adverse events, loss of quality of life and high rates of mortality. METHODS: In this retrospective, single-center study all patients with PFF aged 65 years and older were included. We recorded gender, age, type of fracture, surgery and anesthesia, time, comorbidities and medication as well as complications and mortality rate at 90 days. Separate logistic regression models were used to assess which parameters were associated with patients' mortality. The mortality rate was neither associated with timing, time and type of surgery nor time and type of anesthesia, but with higher age (OR 1.08 per year; 95% CI 1.034-1.128), lower BMI (OR 0.915 per kg/m2; 95% CI 0.857-0.978), higher CCI (OR 1.170 per point; 95% CI 1.018-1.345), dementia (OR 2.805; 95% CI 1.616-4.869), non-surgical complications (OR 2.276; 95% CI 1.269-4.083) and if mobilization was impossible (OR 10.493; 95% CI 3.612-30.479). RESULTS: We analyzed a total of 734 patients (age ≥ 65 years) who had a PFF in 2019 and 2020 and received surgery. 129 patients (17.6%) died until 90 days at an median age of 89.7 years (range 65-101 years). CONCLUSION: The proportion of patients who died until 90 days after surgery is still high. It is less extend influenced by surgical and anaesthesiologic factors than by patient-related factors like age or lower BMI. Physicians should be aware of the importance of avoiding adverse events and the importance of patients' mobilization to reduce mortality and improve patients' outcome.

Epicardial adipose tissue defined by initial polytrauma CT of mechanically ventilated trauma patients: retrospective single-center cohort study to predict short-term outcomes.

PURPOSE: Epicardial adipose tissue (EAT) detected by computed tomography (CT) is associated with morbidity and mortality in patients with COVID-19 and other critical care patient cohorts, whereas their prognostic relevance in trauma patients remains unclear. The present study explored associations with four potential short-term outcomes in trauma patients. METHODS: All consecutive trauma patients requiring emergency tracheal intubation and mechanical ventilation before initial whole-body CT imaging at a level-1 trauma center over a 12-year period (2008-2019) were reanalyzed for this study. EAT was measured semiquantitatively in initial CT and analyzed regarding associations with 24-hour and 30-day mortality using Cox proportional hazard models. In survivors, associations of EAT with intensive care unit length of stay (ICU LOS) and mechanical ventilation duration were analyzed using linear regression analyses. RESULTS: Four hundred fifty-five patients (74.7% male) with a median age of 49 years, and a median injury severity score (ISS) of 26 points were analyzed. In univariable analysis, EAT index was significantly associated with 24-hour and 30-day mortality (p = 0.007, and p = 0.013, respectively). After adjustment for significant predictors age, body mass index, and ISS, no significant associations were confirmed (p = 0.622, and p = 0.903, respectively). In a subanalysis of 353 survivors, EAT index was significantly associated with ICU LOS and mechanical ventilation duration in univariable analyses (p = 0.031, and p = 0.014, respectively), but not in multivariable analyses (p = 0.81 and p = 0.46, respectively). CONCLUSION: EAT index was associated with short-term outcomes in severely injured trauma patients, which not remained significant in multivariable analysis, suggesting that its prognostic capability is limited.

[Measures and Recommendations for Ensuring Adequate Inpatient Care Capacities for Pandemic Management within a Region: Results of a Hybrid Delphi Method]. / Maßnahmen und Empfehlungen für die Sicherstellung adäquater stationärer Versorgungskapazitäten für das Pandemiemanagement innerhalb einer Region ­ Ergebnisse eines hybriden Delphi-Verfahrens.

INTRODUCTION: Since the beginning of the pandemic in spring 2020, inpatient healthcare has been under enormous burden, which is reflected especially in overworked staff, imprecise bed planning and/or data transfer. According to the recommendation of the Science Council, university clinics should play a controlling role in regional healthcare and act in conjunction with surrounding hospitals and practices. METHODS: In September 2021, 31 representatives from 18 university hospitals were invited to a hybrid Delphi study with a total of 4 survey rounds to discuss criteria for effective inpatient care in a pandemic situation, which were extracted from previous expert interviews. Criteria that were classified as very important/relevant by≥75% of the participants in the first round of the survey (consensus definition) were then further summarized in 4 different small groups. In a third Delphi round, all participants came together again to discuss the results of the small group discussions. Subsequently, these were prioritized as Optional ("can"), Desirable ("should") or Necessary ("must") recommendations. RESULTS: Of the invited clinical experts, 21 (67.7%) participated in at least one Delphi round. In an online survey (1st Delphi round), 233 criteria were agreed upon and reduced to 84 criteria for future pandemic management in four thematic small group discussions (2nd Delphi round) and divided into the small groups as follows: "Crisis Management and Crisis Plans" (n=20), "Human Resources Management and Internal Communication" (n=16), "Regional Integration and External Communication" (n=24) and "Capacity Management and Case & Care" (n=24). In the following group discussion (3rd Delphi round), the criteria were further modified and agreed upon by the experts, so that in the end result, there were 23 essential requirements and recommendations for effective inpatient care in a pandemic situation. CONCLUSION: The results draw attention to key demands of clinical representatives, for example, comprehensive digitization, standardization of processes and better (supra) regional networking in order to be able to guarantee needs-based care even under pandemic conditions. The present consensus recommendations can serve as guidelines for future pandemic management in the inpatient care sector.

The impact of acquired coagulation factor XIII deficiency in traumatic bleeding and wound healing.

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60-70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.

"Flexible nature of fixation" in syndesmotic stabilization of the inferior tibiofibular joint affects the radiological reduction outcome.

PURPOSE: Fibular mobility after suture button stabilization (SBS) of inferior tibiofibular joint (syndesmosis) injuries has been described. This effect is called the "flexible nature of fixation (FNF)." In this study, we aimed to quantify FNF in syndesmotic stabilization. METHODS: Postoperative bilateral computed tomography (CT) of ankle fractures with syndesmosis stabilization by SBS or syndesmotic screw (SYS) was retrospectively analyzed. The transverse offset (TO) and vertical offset (VO) were defined by evaluating the drill channels. The reduction outcome was evaluated by the side-to-side difference between the clear space and the anterior tibiofibular distance (antTFD). The calculated anterior tibiofibular distance (cal-antTFD) was calculated by subtracting the TO from the validated antTFD. Subsequently, a reevaluation of the reduction outcomes after SYS or SBS stabilization was performed using cal-antTFD. RESULTS: Sixty patients (44 with SBS and 16 with SYS stabilization) were analyzed. The intra-rater and inter-rater reliabilities for TO and VO were excellent (α > 0.92). SYS stabilization showed lower mean TO (- 0.02 mm; SD 0.14) and VO (0.11 mm; SD, 0.29 mm) than SBS stabilization (TO 1.16 mm, SD 1.4 mm; VO 0.2 mm, SD 0.8 mm; p = 0.001). The rate of malreduction according to cal-antTFD was higher than that of antFTD (p = 0.033). CONCLUSION: The presented method, which evaluates the position of the tibial to the fibular drill channel, allowed the quantification of the "FNF." The often described difference in the dynamic stabilization of SBS compared to the rigid stabilization by SYS could be objectified. Considering cal-antTFD illustrates that FNF potentially reduces the rate of malreduction in SBS stabilization.

Procalcitonin Exerts a Mediator Role in Septic Shock Through the Calcitonin Gene-Related Peptide Receptor.

OBJECTIVES: Clinically, procalcitonin represents the most widely used biomarker of sepsis worldwide with unclear pathophysiologic significance to date. Pharmacologically, procalcitonin was shown to signal through both calcitonin receptor and calcitonin gene-related peptide receptor in vitro, yet the identity of its biologically relevant receptor remains unknown. DESIGN: Prospective randomized animal investigations and in vitro human blood studies. SETTING: Research laboratory of a university hospital. SUBJECTS: C57BL/6J mice and patients with post-traumatic sepsis. INTERVENTIONS: Procalcitonin-deficient mice were used to decipher a potential mediator role in experimental septic shock and identify the relevant receptor for procalcitonin. Cecal ligation and puncture and endotoxemia models were employed to investigate septic shock. Disease progression was evaluated through survival analysis, histology, proteome profiling, gene expression, and flow cytometry. Mechanistic studies were performed with cultured macrophages, dendritic cells, and gamma delta T cells. Main findings were confirmed in serum samples of patients with post-traumatic sepsis. MEASUREMENTS AND MAIN RESULTS: Procalcitonin-deficient mice are protected from septic shock and show decreased pulmonary inflammation. Mechanistically, procalcitonin potentiates proinflammatory cytokine expression in innate immune cells, required for interleukin-17A expression in gamma delta T cells. In patients with post-traumatic sepsis, procalcitonin positively correlates with systemic interleukin-17A levels. In mice with endotoxemia, immunoneutralization of interleukin-17A inhibits the deleterious effect of procalcitonin on disease outcome. Although calcitonin receptor expression is irrelevant for disease progression, the nonpeptide calcitonin gene-related peptide receptor antagonist olcegepant, a prototype of currently introduced antimigraine drugs, inhibits procalcitonin signaling and increases survival time in septic shock. CONCLUSIONS: Our experimental data suggest that procalcitonin exerts a moderate but harmful effect on disease progression in experimental septic shock. In addition, the study points towards the calcitonin gene-related peptide receptor as relevant for procalcitonin signaling and suggests a potential therapeutic application for calcitonin gene-related peptide receptor inhibitors in sepsis, which warrants further clinical investigation.

Synergistic Effects of Forensic Medicine and Traumatology: Comparison of Clinical Diagnosis Autopsy Findings in Trauma-Related Deaths.

BACKGROUND: Trauma is the third leading cause of death worldwide after cardiovascular and oncologic diseases. Predominant causes of trauma-related death (TD) are severe traumatic brain injury (sTBI), hemorrhagic shock, and multiple organ failure. An analysis of TD is required in order to review the quality of trauma care and grasp how well the entire trauma network functions, especially for the most severely injured patients. Furthermore, autopsies not only reveal hidden injuries, but also verify clinical assumed causes of death. MATERIAL: During the study period of 3 years, a total of 517 trauma patients were admitted to our supraregional University Centre of Orthopaedics and Traumatology in Dresden. 13.7% (71/517) of the patients died after trauma, and in 25 cases (35.2%), a forensic autopsy was instructed by the federal prosecutor. The medical records, death certificates, and autopsy reports were retrospectively evaluated and the clinical findings matched to autopsy results. RESULTS: The observed mortality rates (13.7%) were 4.2% less than expected by the calculated RISC II probability of survival (mortality rate of 17.9%). The most frequent trauma victims were due to falls >3 m (n = 29), followed by traffic accidents (n = 28). The median ISS was 34, IQR 25, and the median New ISS (NISS) was 50, IQR 32. Locations of death were in emergency department (23.9%), ICU (73.2%), OR and ward (1.4%, respectively). Clinicians classified 47.9% of deaths due to sTBI (n = 34), followed by 9.9% thoracic trauma and multiple organ failure (n = 7), 8.4% multiple trauma (n = 6), and 2.8% hypoxia and exsanguination (n = 2). In 18.3%, cases were unspecific or other causes of death recorded on the death certificates. Evident differences with evident clinical consequences were ascertained in 4% (n = 1) and marginal clinical consequences in 24% (6/25). In 16% (4/25), marginal differences with minor forensic consequences were revealed. CONCLUSIONS: Even in a supraregional trauma center, specialized in multiple trauma management (4.2% survival benefit), room for improvement exists in more than a quarter of all casualties. This underlines the need for higher autopsy rates to uncover missed injuries and to understand the pathomechanism in each trauma fatality. This would also help to uncover potential insufficiencies in clinical routines with regard to diagnostics. The interdisciplinary cooperation of trauma surgeons and forensic pathologists can increase the quality of trauma patient care.

[The Berlin mass casualty hospital triage algorithm : Development, implementation and influence on exercise-based triage results]. / Der Berliner Krankenhaus-Sichtungsalgorithmus für den Massenanfall von Verletzten : Entwicklung, Implementierung und Einfluss auf übungsbasierte Sichtungsergebnisse.

BACKGROUND AND OBJECTIVE: Patient triage has a key function within the scope of the successful management of mass disasters and ensures the correct resource allocation. Analysis of unheralded hospital disaster training in Berlin hospitals revealed triage problems referring the correct classification of patients in the triage categories and relevant overtriaging and undertriaging. Therefore, a triage algorithm tailored to the clinical setting was developed in Berlin and after presentation and discussion within the circle of the representatives for clinical catastrophe protection, the algorithm was introduced as obligatory in 2015. This study was carried out to validate and investigate the effects of the triage algorithm. MATERIAL AND METHODS: This prospective observational study evaluated all unheralded hospital disaster training exercises from 2016/2017 initiated by the senate administration, with 556 roughed persons after implementation of the new triage algorithm and compared the results with disaster training exercises from the years 2010/2011 without a triage algorithm (n = 601). The correct allocation of the prescribed injury patterns to the triage category (T1-3), specificity, sensitivity and positive likelihood ratio of the algorithm are described and group differences were calculated. RESULTS: In 15 unheralded mass disaster drills with 556 actors in 2016-2017 a total of 85% of the category T1 (n = 83/98), 63% of the T2 category (n = 100/159) and 87% of the T3 category (n = 259/299) were correctly recognized. This corresponds to a significantly better triage result of 80% compared to 63% in 2010/2011. Overtriaging and undertriaging also were significantly reduced. The triage algorithm showed a specificity and sensitivity of 97% and 75%, respectively, for T1 (immediately life-threatening), 86%/67% for T2 (severely injured) and 85%/88% for T3 (slightly injured) patients. DISCUSSION: The Berlin hospital triage algorithm was successfully validated. The triage category allocation was significantly improved in all relevant aspects after implementation with a significant reduction of overtriaging and undertriaging.

[Treatment of ankle fractures : Standards, tricks and pitfalls]. / Versorgung der Sprunggelenkfraktur : Standards, Tipps und Fallstricke.

Ankle fractures and associated ligamentous injuries are the most common injuries of a load-bearing joint. There is still no general consensus with respect to the pathomechanism, the treatment indications and surgical techniques. The medium and long-term results are affected by a particularly high risk of posttraumatic arthritis in bimalleolar and trimalleolar fractures and fracture dislocations. There is consensus on the necessity of a thorough preoperative analysis and postoperative control of reduction for which 3D imaging is increasingly generously employed. This detects relevant pathologies, such as bony syndesmotic avulsion and partial impaction of the tibial plafond that may go unnoticed on plain radiographs. Anatomic reconstruction of the ankle mortise, the detection and treatment of syndesmotic instability, reconstruction of the tibial notch and exact placement of the distal fibula into the latter are important prognostic factors.