Circulating miRNA expression in extracellular vesicles is associated with specific injuries after multiple trauma and surgical invasiveness.

Introduction: Two trauma treatment principles are Early Total Care (ETC), and Damage Control Orthopedics (DCO). Cellular mechanisms that underlie the connection between treatment type, its systemic effects, and tissue regeneration are not fully known. Therefore, this study aimed to: 1) profile microRNA (miRNA) expression in plasma derived Extracellular Vesicles (EVs) from a porcine multiple trauma model at different timepoints, comparing two surgical treatments; and 2) determine and validate the miRNA's messengerRNA (mRNA) targets. Methods: The porcine multiple trauma model consisted of blunt chest trauma, liver laceration, bilateral femur fractures, and controlled haemorrhagic shock. Two treatment groups were defined, ETC (n=8), and DCO (n=8). Animals were monitored under Intensive Care Unit-standards, blood was sampled at 1.5, 2.5, 24, and 72 hours after trauma, and EVs were harvested from plasma. MiRNAs were analysed using quantitative Polymerase Chain Reaction arrays. MRNA targets were identified in silico and validated in vivo in lung and liver tissue. Results: The arrays showed distinct treatment specific miRNA expression patterns throughout all timepoints, and miRNAs related to the multiple trauma and its individual injuries. EV-packed miRNA expression in the ETC group was more pro-inflammatory, indicating potentially decreased tissue regenerative capacities in the acute post-traumatic phase. In silico target prediction revealed several overlapping mRNA targets among the identified miRNAs, related to inflammation, (pulmonary) fibrosis, and Wnt-signalling. These were, among others, A Disintegrin and Metalloproteinase domain-containing protein 10, Collagen Type 1 Alpha 1 Chain, Catenin Beta Interacting Protein 1, and Signal Transducers and Activators of Transcription 3. Validation of these mRNA targets in the lung showed significant, treatment specific deregulations which matched the expression of their upstream miRNAs. No significant mRNA deregulations were observed in the liver. Discussion: This study showed treatment specific, EV-packed miRNA expression patterns after trauma that correlated with mRNA expressions in the lungs, target organs over distance. A systemic response to the increased surgical trauma in the ETC group was identified, with various miRNAs associated with injuries from the trauma model, and involved in (systemic) inflammation, tissue regeneration. EV-transported miRNAs demonstrated a clear role in multiple trauma, warranting further research into tissue-tissue talk and therapeutic applications of EVs after trauma.

Orthopaedic trauma residency programs: Perspectives from different countries across the world.

The ability to manage the myriad of musculoskeletal conditions successfully requires multiple years of training. Access to and completion of orthopaedic surgical training entails an often grueling, highly regulated path to certification to practice. Although the world is more connected than ever, the question is whether the local certification criteria for medical specialists leads to a generic residency program and a similar training in all countries. This report from eight nations on five continents details the distinctive features of that training, including the number of positions available, the examinations required, the gender distribution of residents, and available possibilities once the residence period is complete. This analysis shows a wide variation in the orthopaedic trauma training program worldwide, with emphasis on different skills per country.

Specific microRNAs are associated with fracture healing phases, patient age and multi-trauma.

Background: Immediately after a fracture occurs, a fracture hematoma (fxH) is formed. This fxH plays an important role in fracture healing and, under normal circumstances, aids in generating an environment in which a wide variety of cells orchestrate processes involved in fracture healing. MicroRNAs (miRNAs) may influence these processes. The aim of this study was therefore to determine the miRNA expression signature of human fxH in normal fracture healing and examine the potential influence of clinical parameters on these expression levels. Methods: fxH was harvested from 61 patients (mean age 52 ± 19; 32♀) during fracture surgery. miRNAs were isolated, transcribed and pooled for qPCR array analysis and validation. Qiagen fibrosis- and inflammation qPCR arrays were used based on an extensive literature study related to fracture healing and osteogenesis. Additionally, miRNA targets were determined. Results: From the array data, a selection of the twenty most regulated miRNAs, 10 up- and 10 down regulated, was validated in the study population. The expression levels of seven out of these twenty miRNAs were correlated to several clinical parameters. The time interval between trauma and surgery showed to influence the expression of three miRNAs, three other miRNAs were expressed in a patient age dependent manner and one miRNA was associated with the severity of trauma. Conclusion: This study portrayed the role and importance of miRNAs in human fxH, linked to key processes in fracture healing. Seven miRNAs showed to be involved in multiple processes that are important in the fracture healing cascade, such as angiogenesis, mineralisation and cellular differentiation. In silico target analysis revealed 260 mRNA targets for 14 out of the 20 validated miRNAs. The Translational Potential of this Article: These data broaden our view on the potential diagnostic and therapeutic implications of miRNAs in fracture healing.

Safety of selective nonoperative management for blunt splenic trauma: the impact of concomitant injuries.

BACKGROUND: Nonoperative management for blunt splenic injury is the preferred treatment. To improve the outcome of selective nonoperative therapy, the current challenge is to identify factors that predict failure. Little is known about the impact of concomitant injury on outcome. Our study has two goals. First, to determine whether concomitant injury affects the safety of selective nonoperative treatment. Secondly we aimed to identify factors that can predict failure. METHODS: From our prospective trauma registry we selected all nonoperatively treated adult patients with blunt splenic trauma admitted between 01.01.2000 and 12.21.2013. All concurrent injuries with an AIS ≥ 2 were scored. We grouped and compared patients sustaining solitary splenic injuries and patients with concomitant injuries. To identify specific factors that predict failure we used a multivariable regression analysis. RESULTS: A total of 79 patients were included. Failure of nonoperative therapy (n = 11) and complications only occurred in patients sustaining concomitant injury. Furthermore, ICU-stay as well as hospitalization time were significantly prolonged in the presence of associated injury (4 versus 13 days,p < 0.05). Mortality was not seen. Multivariable analysis revealed the presence of a femur fracture and higher age as predictors of failure. CONCLUSIONS: Nonoperative management for hemodynamically normal patients with blunt splenic injury is feasible and safe, even in the presence of concurrent (non-hollow organ) injuries or a contrast blush on CT. However, associated injuries are related to prolonged intensive care unit- and hospital stay, complications, and failure of nonoperative management. Specifically, higher age and the presence of a femur fracture are predictors of failure.

COMplex Fracture Orthopedic Rehabilitation (COMFORT) - Real-time visual biofeedback on weight bearing versus standard training methods in the treatment of proximal femur fractures in the elderly: study protocol for a multicenter randomized controlled trial.

BACKGROUND: Proximal femur fractures are a common injury after low energy trauma in the elderly. Most rehabilitation programs are based on restoring mobility and early resumption of weight-bearing. However, therapy compliance is low in patients following lower extremity fractures. Moreover, little is known about the relevance of gait parameters and how to steer the rehabilitation after proximal femur fractures in the elderly. Therefore, the aim of this prospective, randomized controlled trial is to gain insight in gait parameters and evaluate if real-time visual biofeedback can improve therapy compliance after proximal femur fractures in the elderly. METHODS: This is a two-arm, parallel-design, prospective, randomized controlled trial. Inclusion criteria are age ≥ 60 years, a proximal femur fracture following low energy trauma, and unrestricted-weight bearing. Exclusion criteria are cognitive impairment and limited mobility before trauma. Participants are randomized into either the control group, which receives care as usual, or the intervention group, which receives real-time visual biofeedback about weight-bearing during gait in addition to care as usual. Spatiotemporal gait parameters will be measured in 94 participants per group during a 30-m walk with an ambulatory biofeedback system (SensiStep). The progress of rehabilitation will be evaluated by the primary outcome parameters maximum peak load and step duration in relation to the discharge date. Secondary outcome parameters include other spatiotemporal gait parameters in relation to discharge date. Furthermore, the gait parameters will be related to three validated clinical tests: Elderly Mobility Scale; Functional Ambulation Categories; and Visual Analogue Scale. The primary hypothesis is that participants in the intervention group will show improved and faster rehabilitation compared to the control group. DISCUSSION: The first aim of this multicenter trial is to investigate the normal gait patterns after proximal femur fractures in the elderly. The use of biofeedback systems during rehabilitation after proximal femur fractures in the elderly is promising; therefore, the second aim is to investigate the effect of real-time visual biofeedback on gait after proximal femur fractures in the elderly. This could lead to improved outcome. In addition, analysis of the population may indicate characteristics of subgroups that benefit from feedback, making a differentiated approach in rehabilitation strategy possible. TRIAL REGISTRATION: TrialRegister.nl, NTR6794 . Registered on 31 October 2017.

Non-operative management for penetrating splenic trauma: how far can we go to save splenic function?

BACKGROUND: Selective non-operative management (NOM) for the treatment of blunt splenic trauma is safe. Currently, the feasibility of selective NOM for penetrating splenic injury (PSI) is unclear. Unfortunately, little is known about the success rate of spleen-preserving surgical procedures. The aim of this study was to investigate the outcome of selective NOM for penetrating splenic injuries. METHODS: A dual-centre study is performed in two level-one trauma centres. All identified patients treated for PSI were identified. Patients were grouped based on the treatment they received. Group one consisted of splenectomised patients, the second group included patients treated by a spleen-preserving surgical intervention, and group three included those patients who were treated by NOM. RESULTS: A total of 118 patients with a median age of 27 and a median ISS of 25 (interquartile range (IQR) 16-34) were included. Ninety-six patients required operative intervention, of whom 45 underwent a total splenectomy and 51 underwent spleen-preserving surgical procedures. Furthermore, 22 patients (12 stab wounds and 10 gunshot wounds) were treated by NOM. There were several anticipated significant differences in the baseline encountered. The median hospitalization time was 8 (5-12) days, with no significant differences between the groups. The splenectomy group had significantly more intensive care unit (ICU) days (2(0-6) vs. 0(0-1)) and ventilation days (1(0-3) vs. 0(0-0)) compared to the NOM group. Mortality was only noted in the splenectomy group. CONCLUSIONS: Spleen-preserving surgical therapy for PSI is a feasible treatment modality and is not associated with increased mortality. Moreover, a select group of patients can be treated without any surgical intervention at all.