A dual-color PAX7 and MYF5 in vivo reporter to investigate muscle stem cell heterogeneity in regeneration and aging.

Increasing evidence suggests that the muscle stem cell (MuSC) pool is heterogeneous. In particular, a rare subset of PAX7-positive MuSCs that has never expressed the myogenic regulatory factor MYF5 displays unique self-renewal and engraftment characteristics. However, the scarcity and limited availability of protein markers make the characterization of these cells challenging. Here, we describe the generation of StemRep reporter mice enabling the monitoring of PAX7 and MYF5 proteins based on equimolar levels of dual nuclear fluorescence. High levels of PAX7 protein and low levels of MYF5 delineate a deeply quiescent MuSC subpopulation with an increased capacity for asymmetric division and distinct dynamics of activation, proliferation, and commitment. Aging primarily reduces the MYF5Low MuSCs and skews the stem cell pool toward MYF5High cells with lower quiescence and self-renewal potential. Altogether, we establish the StemRep model as a versatile tool to study MuSC heterogeneity and broaden our understanding of mechanisms regulating MuSC quiescence and self-renewal in homeostatic, regenerating, and aged muscles.

Denervation alters the secretome of myofibers and thereby affects muscle stem cell lineage progression and functionality.

Skeletal muscle function crucially depends on innervation while repair of skeletal muscle relies on resident muscle stem cells (MuSCs). However, it is poorly understood how innervation affects MuSC properties and thereby regeneration of skeletal muscle. Here, we report that loss of innervation causes precocious activation of MuSCs concomitant with the expression of markers of myogenic differentiation. This aberrant activation of MuSCs after loss of innervation is accompanied by profound alterations on the mRNA and protein level. Combination of muscle injury with loss of innervation results in impaired regeneration of skeletal muscle including shifts in myogenic populations concomitant with delayed maturation of regenerating myofibers. We further demonstrate that loss of innervation leads to alterations in myofibers and their secretome, which then affect MuSC behavior. In particular, we identify an increased secretion of Osteopontin and transforming growth factor beta 1 (Tgfb1) by myofibers isolated from mice which had undergone sciatic nerve transection. The altered secretome results in the upregulation of early activating transcription factors, such as Junb, and their target genes in MuSCs. However, the combination of different secreted factors from myofibers after loss of innervation is required to cause the alterations observed in MuSCs after loss of innervation. These data demonstrate that loss of innervation first affects myofibers causing alterations in their secretome which then affect MuSCs underscoring the importance of proper innervation for MuSC functionality and regeneration of skeletal muscle.

Remodeling of the Cardiac Extracellular Matrix Proteome During Chronological and Pathological Aging.

Impaired extracellular matrix (ECM) remodeling is a hallmark of many chronic inflammatory disorders that can lead to cellular dysfunction, aging, and disease progression. The ECM of the aged heart and its effects on cardiac cells during chronological and pathological aging are poorly understood across species. For this purpose, we first used mass spectrometry-based proteomics to quantitatively characterize age-related remodeling of the left ventricle (LV) of mice and humans during chronological and pathological (Hutchinson-Gilford progeria syndrome (HGPS)) aging. Of the approximately 300 ECM and ECM-associated proteins quantified (named as Matrisome), we identified 13 proteins that were increased during aging, including lactadherin (MFGE8), collagen VI α6 (COL6A6), vitronectin (VTN) and immunoglobulin heavy constant mu (IGHM), whereas fibulin-5 (FBLN5) was decreased in most of the data sets analyzed. We show that lactadherin accumulates with age in large cardiac blood vessels and when immobilized, triggers phosphorylation of several phosphosites of GSK3B, MAPK isoforms 1, 3, and 14, and MTOR kinases in aortic endothelial cells (ECs). In addition, immobilized lactadherin increased the expression of pro-inflammatory markers associated with an aging phenotype. These results extend our knowledge of the LV proteome remodeling induced by chronological and pathological aging in different species (mouse and human). The lactadherin-triggered changes in the proteome and phosphoproteome of ECs suggest a straight link between ECM component remodeling and the aging process of ECs, which may provide an additional layer to prevent cardiac aging.

Impact of Hypermannosylation on the Structure and Functionality of the ER and the Golgi Complex.

Proteins of the secretory pathway undergo glycosylation in the endoplasmic reticulum (ER) and the Golgi apparatus. Altered protein glycosylation can manifest in serious, sometimes fatal malfunctions. We recently showed that mutations in GDP-mannose pyrophosphorylase A (GMPPA) can cause a syndrome characterized by alacrima, achalasia, mental retardation, and myopathic alterations (AAMR syndrome). GMPPA acts as a feedback inhibitor of GDP-mannose pyrophosphorylase B (GMPPB), which provides GDP-mannose as a substrate for protein glycosylation. Loss of GMPPA thus enhances the incorporation of mannose into glycochains of various proteins, including α-dystroglycan (α-DG), a protein that links the extracellular matrix with the cytoskeleton. Here, we further characterized the consequences of loss of GMPPA for the secretory pathway. This includes a fragmentation of the Golgi apparatus, which comes along with a regulation of the abundance of several ER- and Golgi-resident proteins. We further show that the activity of the Golgi-associated endoprotease furin is reduced. Moreover, the fraction of α-DG, which is retained in the ER, is increased. Notably, WT cells cultured at a high mannose concentration display similar changes with increased retention of α-DG, altered structure of the Golgi apparatus, and a decrease in furin activity. In summary, our data underline the importance of a balanced mannose homeostasis for the secretory pathway.

Extracellular matrix: Brick and mortar in the skeletal muscle stem cell niche.

The extracellular matrix (ECM) is an interconnected macromolecular scaffold occupying the space between cells. Amongst other functions, the ECM provides structural support to tissues and serves as a microenvironmental niche that conveys regulatory signals to cells. Cell-matrix adhesions, which link the ECM to the cytoskeleton, are dynamic multi-protein complexes containing surface receptors and intracellular effectors that control various downstream pathways. In skeletal muscle, the most abundant tissue of the body, each individual muscle fiber and its associated muscle stem cells (MuSCs) are surrounded by a layer of ECM referred to as the basal lamina. The core scaffold of the basal lamina consists of self-assembling polymeric laminins and a network of collagens that tether proteoglycans, which provide lateral crosslinking, establish collateral associations with cell surface receptors, and serve as a sink and reservoir for growth factors. Skeletal muscle also contains the fibrillar collagenous interstitial ECM that plays an important role in determining tissue elasticity, connects the basal laminae to each other, and contains matrix secreting mesenchymal fibroblast-like cell types and blood vessels. During skeletal muscle regeneration fibroblast-like cell populations expand and contribute to the transitional fibronectin-rich regenerative matrix that instructs angiogenesis and MuSC function. Here, we provide a comprehensive overview of the role of the skeletal muscle ECM in health and disease and outline its role in orchestrating tissue regeneration and MuSC function.

Visualization of the Skeletal Muscle Stem Cell Niche in Fiber Bundles.

Skeletal muscle stem cells (MuSCs) reside in a complex niche composed of the muscle fiber plasma membrane and the laminin-rich basal lamina surrounded by the microvasculature, as well as different supportive cell types such as fibro-adipogenic progenitors residing in the interstitial extracellular matrix. Within the first few hours after tissue damage, MuSCs undergo cytoskeletal rearrangements and transcriptional changes that prime the cells for activation. Due to their time-consuming nature, enzymatic methods for liberation of single muscle fibers with fully quiescent MuSCs are challenging. Moreover, during enzymatic digestion, important niche components including the microvasculature and the collagenous interstitial matrix are destroyed. Here, we provide a method for the visualization of MuSCs on muscle fibers in their intact niche. Our method relies on mechanical teasing of fiber bundles from fixed skeletal muscles. We demonstrate that teased muscle fiber bundles allow the investigator to capture a representative snapshot of the MuSC niche in skeletal muscle, and outline how stem cell morphology and different microenvironmental components can be visualized. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Isolation of fiber bundles Basic Protocol 2: Immunofluorescence staining of MuSCs on fiber bundles Support Protocol: Preparation of Sylgard dishes.

Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality.

During aging, the regenerative capacity of skeletal muscle decreases due to intrinsic changes in muscle stem cells (MuSCs) and alterations in their niche. Here, we use quantitative mass spectrometry to characterize intrinsic changes in the MuSC proteome and remodeling of the MuSC niche during aging. We generate a network connecting age-affected ligands located in the niche and cell surface receptors on MuSCs. Thereby, we reveal signaling by integrins, Lrp1, Egfr, and Cd44 as the major cell communication axes perturbed through aging. We investigate the effect of Smoc2, a secreted protein that accumulates with aging, primarily originating from fibro-adipogenic progenitors. Increased levels of Smoc2 contribute to the aberrant Integrin beta-1 (Itgb1)/mitogen-activated protein kinase (MAPK) signaling observed during aging, thereby causing impaired MuSC functionality and muscle regeneration. By connecting changes in the proteome of MuSCs to alterations of their niche, our work will enable a better understanding of how MuSCs are affected during aging.

Vascular impulse technology versus elevation for the reduction of swelling of lower extremity joint fractures: results of a prospective randomized controlled study.

AIMS: Complex joint fractures of the lower extremity are often accompanied by soft-tissue swelling and are associated with prolonged hospitalization and soft-tissue complications. The aim of the study was to evaluate the effect of vascular impulse technology (VIT) on soft-tissue conditioning in comparison with conventional elevation. METHODS: A total of 100 patients were included in this prospective, randomized, controlled monocentre study allocated to the three subgroups of dislocated ankle fracture (n = 40), pilon fracture (n = 20), and intra-articular calcaneal fracture (n = 40). Patients were randomized to the two study groups in a 1:1 ratio. The effectiveness of VIT (intervention) compared with elevation (control) was analyzed separately for the whole study population and for the three subgroups. The primary endpoint was the time from admission until operability (in days). RESULTS: The mean length of time until operability was 8.2 days (SD 3.0) in the intervention group and 10.2 days (SD 3.7) in the control group across all three fractures groups combined (p = 0.004). An analysis of the subgroups revealed that a significant reduction in the time to operability was achieved in two of the three: with 8.6 days (SD 2.2) versus 10.6 days (SD 3.6) in ankle fractures (p = 0.043), 9.8 days (SD 4.1) versus 12.5 days (SD 5.1) in pilon fractures (p = 0.205), and 7.0 days (SD 2.6) versus 8.4 days (SD 1.5) in calcaneal fractures (p = 0.043). A lower length of stay (p = 0.007), a reduction in pain (ppreop = 0.05; pdischarge < 0.001) and need for narcotics (ppreop = 0.064; ppostop = 0.072), an increased reduction in swelling (p < 0.001), and a lower revision rate (p = 0.044) could also be seen, and a trend towards fewer complications (p = 0.216) became apparent. CONCLUSION: Compared with elevation, VIT results in a significant reduction in the time to achieve operability in complex joint fractures of the lower limb. Cite this article: Bone Joint J 2021;103-B(4):746-754.

GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation.

GDP-mannose-pyrophosphorylase-B (GMPPB) facilitates the generation of GDP-mannose, a sugar donor required for glycosylation. GMPPB defects cause muscle disease due to hypoglycosylation of α-dystroglycan (α-DG). Alpha-DG is part of a protein complex, which links the extracellular matrix with the cytoskeleton, thus stabilizing myofibers. Mutations of the catalytically inactive homolog GMPPA cause alacrima, achalasia, and mental retardation syndrome (AAMR syndrome), which also involves muscle weakness. Here, we showed that Gmppa-KO mice recapitulated cognitive and motor deficits. As structural correlates, we found cortical layering defects, progressive neuron loss, and myopathic alterations. Increased GDP-mannose levels in skeletal muscle and in vitro assays identified GMPPA as an allosteric feedback inhibitor of GMPPB. Thus, its disruption enhanced mannose incorporation into glycoproteins, including α-DG in mice and humans. This increased α-DG turnover and thereby lowered α-DG abundance. In mice, dietary mannose restriction beginning after weaning corrected α-DG hyperglycosylation and abundance, normalized skeletal muscle morphology, and prevented neuron degeneration and the development of motor deficits. Cortical layering and cognitive performance, however, were not improved. We thus identified GMPPA defects as the first congenital disorder of glycosylation characterized by α-DG hyperglycosylation, to our knowledge, and we have unraveled underlying disease mechanisms and identified potential dietary treatment options.

Risk Factors for Revision Surgery Following Radial Head Arthroplasty without Cement for Unreconstructible Radial Head Fractures: Minimum 3-Year Follow-up.

BACKGROUND: Revision rates following radial head arthroplasty (RHA) for unreconstructible radial head fractures (RHFs) differ vastly in the literature, and little is known about the risk factors that are associated with revision surgery. The purposes of this study were to assess the revision rate following RHA and to determine the associated risk factors. METHODS: A total of 122 patients (mean age, 50.7 years; range, 18 to 79 years) with 123 RHAs who underwent RHA for unreconstructible RHFs between 1994 and 2014 and were ≥3 years out from surgery were included. Demographic variables, injury and procedure-related characteristics, radiographic findings, complications, and revision procedures were assessed. Cox regression analysis was performed to identify the risk factors that were associated with revision surgery following RHA. RESULTS: The median follow-up for the study cohort was 7.3 years (interquartile range [IQR], 5.1 to 10.1 years). All of the patients had unreconstructible RHFs: Mason-Johnston type-IV injuries were the most prevalent (80 [65%]). One or more associated osseous or ligamentous injuries were seen in 89 elbows (72.4%). The median time to surgery was 7 days (IQR, 3 to 11 days). Implanted prostheses were categorized as rigidly fixed (65 [52.8%]) or loosely fixed (58 [47.2%]). A total of 28 elbows (22.8%) underwent revision surgery at a median of 1.1 years (IQR, 0.3 to 3.8 years), with the majority of elbows (17 [60.7%]) undergoing revision surgery within the first 2 years. The most common reason for revision surgery was painful implant loosening (14 [29.2% of 48 complications]). Univariate Cox regression suggested that Workers' Compensation claims (hazard ratio [HR], 5.48; p < 0.001) and the use of an external fixator (HR, 4.67; p = 0.007) were significantly associated with revision surgery. CONCLUSIONS: Revision rates following RHA for unreconstructible RHFs are high; the most common cause for revision surgery is painful implant loosening. Revision surgeries are predominantly performed within the first 2 years after implantation, and surgeons should be aware that Workers' Compensation claims and the use of an external fixator in management of the elbow injury are associated with revision surgery. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Influence of Body Mass Index and Gender on Stigmatization of Obesity.

BACKGROUND: Stigmatization and discrimination of people with obesity due to their weight are a common problem that may lead to additional weight gain. This study evaluated the influence of different parameters on the stigmatization of obesity. MATERIAL AND METHODS: Participants of six groups (general population, patients with obesity, medical students, physicians, nurses in training and nurses; n = 490) answered the short-form fat phobia scale (FPS) between August 2016 and July 2017. The influence of body mass index (BMI), gender and other factors on total scores and single adjective pairs was analyzed. RESULTS: A total of 490 participants were evaluated. The total mean FPS rating was 3.5 ± 0.6. FPS was significantly lower (more positive) in participants with obesity (3.2 ± 0.7) compared with participants without obesity (3.5 ± 0.5, p < 0.001). Individuals with obesity and diabetes rated the FPS significantly lower (more positive), whereas age and gender did not have a significant influence. Participants with obesity linked obesity more often with good self-control (p < 0.001), being shapely (p = 0.002), industrious (p < 0.001), attractive (p < 0.001), active (p < 0.001), self-sacrificing (p < 0.001) and having more willpower (p < 0.001) than the participants without obesity. Females rated more positive in shapely versus shapeless (p = 0.038) and attractive versus non-attractive (p < 0.001) than males. CONCLUSIONS: The present study shows that stigmatization of obesity is present in medical professionals as well as the general population. People affected by obesity characterized other people with obesity more positively (e.g. attractive or active), whereas people without obesity linked negative characteristics with obesity. Gender had an influence only on single items of FPS but did not affect overall stigmatization of obesity.

Stem cell aging: The upcoming era of proteins and metabolites.

So far, the investigation of stem cell aging has been primarily carried out at the genomic level to follow transcriptome changes, clonal dominance, epigenetic changes, and, more recently, population heterogeneity by single cell sequencing. Here, we review recent findings in the field of stem cell aging that include failure of proteostasis, the impact of age-related metabolic changes on stem cell differentiation and heterogeneity of stem cell niches. These emerging concepts highlight the need of a paradigm shift to move forward our understanding of stem cell aging to the next level, in particular, the need of investigating cell intrinsic changes in stem cells and their niche by looking in a quantitative manner to proteins and metabolites.

Analyzing Satellite Cell Function During Skeletal Muscle Regeneration by Cardiotoxin Injury and Injection of Self-delivering siRNA In Vivo.

Skeletal muscle possesses an enormous capacity to regenerate after injury. This process is mainly driven by muscle stem cells, also termed satellite cells. Satellite cells are characterized by the expression of the transcription factor Pax7 and their location underneath the basal lamina in the resting skeletal muscle. Upon injury, satellite cells get activated, undergo self-renewal or differentiation to either form new myofibers or to fuse with damaged ones. The functionality of satellite cells in vivo can be investigated using a cardiotoxin based injury model of skeletal muscle. To study the function of one gene during the regeneration of skeletal muscle, transgenic mouse models are mostly used. Here, we present an alternative method to transgenic mice, to investigate the gene function in satellite cells during regeneration, e.g., in cases where transgenic mice are not available. We combine the cardiotoxin mediated injury of a specific skeletal muscle with the injection of a self-delivering siRNA into the regenerating muscle which is then taken up by satellite cells among other cells. Thereby, we provide a method to analyze gene function in satellite cells during regeneration under physiological conditions without the need for transgenic mice.

Adult stem cells at work: regenerating skeletal muscle.

Skeletal muscle regeneration is a finely tuned process involving the activation of various cellular and molecular processes. Satellite cells, the stem cells of skeletal muscle, are indispensable for skeletal muscle regeneration. Their functionality is critically modulated by intrinsic signaling pathways as well as by interactions with the stem cell niche. Here, we discuss the properties of satellite cells, including heterogeneity regarding gene expression and/or their phenotypic traits and the contribution of satellite cells to skeletal muscle regeneration. We also summarize the process of regeneration with a specific emphasis on signaling pathways, cytoskeletal rearrangements, the importance of miRNAs, and the contribution of non-satellite cells such as immune cells, fibro-adipogenic progenitor cells, and PW1-positive/Pax7-negative interstitial cells.

Video Teaching Leads to Improved Attitudes Towards Obesity-a Randomized Study with 949 Participants.

BACKGROUND: Obesity is a rising social and economic burden. Patients with obesity often suffer from stigmatization and discrimination. Underrecognition of obesity as a disease could be a contributing factor. The present study aimed to compare attitudes towards obesity with other chronic diseases and to evaluate the recognition of need of professional treatment. METHODS: Nine hundred and forty-nine participants (subgroups: general population, patients with obesity, nurses in training, nurses, medical students, physicians) were randomized to video teaching on obesity and control. Questionnaires on the burden and influence of obesity on daily life compared to other chronic diseases and the fat phobia scale (FPS) were answered. RESULTS: Burden of obesity was rated low (4.2 ± 1.3; rank 9 of 11) compared to other diseases. Bowel cancer (5.5 ± 0.9) had the highest and caries the lowest (2.7 ± 1.4) estimated impact. Females (p = 0.011) and older people (p < 0.001) rated burden of obesity high whereas general population (p < 0.001) and control (p < 0.001) rated it low. Females (p = 0.001) and people with higher BMI (p = 0.004) rated the influence of obesity on daily life high; the general population (p < 0.001; reference physicians) and the control group (p < 0.001) rated it low. FPS was lowest in patients with obesity (3.2 ± 0.7) and highest in the general population (3.6 ± 0.4) and medical students (3.6 ± 0.5; p < 0.001; compared to physicians). CONCLUSIONS: Obesity is underestimated as a disease compared to other chronic diseases and attitudes towards obesity are rather negative in comparison. Video teaching showed positive effects so a focus in medical education and public campaigns should aim to improve prevention and treatment of obesity.

Isolation and Culture of Individual Myofibers and Their Adjacent Muscle Stem Cells from Aged and Adult Skeletal Muscle.

The isolation and culture of single floating myofibers with their adjacent muscle stem cells allow the analysis and comparison of muscle stem cells from aged and young mice. This method has the advantage that muscle stem cells are cultured on the myofiber, thereby culturing them in conditions as close to their endogenous niche as possible. Here we describe the isolation, culture, transfection with siRNA, and subsequent immunostaining for muscle stem cells on their adjacent myofibers from aged and young mice.

Tablets for Image Review and Communication in Daily Routine of Orthopedic Surgeons-An Evaluation Study.

Medical images are essential in modern traumatology and orthopedic surgery. Access to images is often cumbersome due to a limited number of workstations. Moreover, due to the tremendous increase of data, the time to review or to communicate images has also become limited. One approach to overcome these problems is to make use of modern mobile devices, like tablet computers, to facilitate image access and associated workflows. Ten orthopedic surgeons were equipped with an Apple iPad mini 2 and specialized viewing software for medical images. The surgeons were able to send images from a workstation onto the tablets or to search for patient images directly. The software enabled the physicians to share images, annotated key slices, and messages instantly with their colleagues. The surgeons carried the tablets within or in the periphery of the hospital. The participants evaluated the software by means of daily questionnaires. Data was collected for a period of 9 months. Nearly 25 images were viewed in total by the surgeons per day. The tablet viewer was used for accessing approximately 30% of these images. On average, the surgeons were asked 1.7 times per day by a colleague for a second opinion. They used the tablets in approximately 29% of these cases. Furthermore, the mean time for accessing images was significantly lower using mobile software compared to conventional methods. Tablet computers can play a vital role for image access and communication in the daily routine of an orthopedic surgeon. Mobile image access is an important aspect for surgeons, especially in larger facilities, to facilitate and accelerate the clinical workflows.

Choice of futility boundaries for group sequential designs with two endpoints.

BACKGROUND: In clinical trials, the opportunity for an early stop during an interim analysis (either for efficacy or for futility) may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. For example, when including two primary endpoints in the confirmatory analysis, the power of the trial depends on the effects of both endpoints and on their correlation. Assessing the feasibility of such a trial is therefore difficult, as the number of parameter assumptions to be correctly specified is large. For this reason, so-called 'group sequential designs' are of particular importance in this setting. Whereas the choice of adequate boundaries to stop a trial early for efficacy has been broadly discussed in the literature, the choice of optimal futility boundaries has not been investigated so far, although this may have serious consequences with respect to performance characteristics. METHODS: In this work, we propose a general method to construct 'optimal' futility boundaries according to predefined criteria. Further, we present three different group sequential designs for two endpoints applying these futility boundaries. Our methods are illustrated by a real clinical trial example and by Monte-Carlo simulations. RESULTS: By construction, the provided method of choosing futility boundaries maximizes the probability to correctly stop in case of small or opposite effects while limiting the power loss and the probability of stopping the study 'wrongly'. Our results clearly demonstrate the benefit of using such 'optimal' futility boundaries, especially compared to futility boundaries commonly applied in practice. CONCLUSIONS: As the properties of futility boundaries are often not considered in practice and unfavorably chosen futility boundaries may imply bad properties of the study design, we recommend assessing the performance of these boundaries according to the criteria proposed in here.

Vascular Impulse Technology versus elevation in the treatment of posttraumatic swelling of extremity fractures: study protocol for a randomized controlled trial.

BACKGROUND: Fractures of the extremities are often complicated by a variable degree of swelling secondary to hemorrhage and soft tissue injury. Patients typically require up to 7 days of inpatient bed rest and elevation to reduce swelling to an acceptable level for operative treatment with internal fixation. Alternatively, an intermittent pneumatic compression device, such as the Vascular Impulse Technology (VIT) system, can be used at the injured extremity to reduce the posttraumatic swelling. The VIT system consists of a pneumatic compressor that intermittently rapidly inflates a bladder positioned under the arch of the hand or the foot, which results in compression of the venous hand or foot plexus. That intermittent compression induces an increased venous velocity and aims to reduce the soft tissue swelling of the affected extremity. METHODS/DESIGN: The VIT study is a prospective, monocenter, randomized controlled trial to compare the VIT system with elevation in the treatment of posttraumatic swelling in the case of a fracture of the upper and lower extremity. This study will include 280 patients with fractures of the upper and the lower extremity with nine different injury types. For each of the nine injury types a separate randomization to the two intervention groups (VIT group or control group) will be performed. The primary outcome parameter is the time taken for the swelling to resolve sufficiently to permit surgery. A separate analysis for each of the nine injury types will be performed. DISCUSSION: In the proposed study, the effectiveness of the VIT system in the treatment of posttraumatic swelling of upper and lower extremity fractures will be evaluated. TRIAL REGISTRATION: German Clinical Trial Register, No. DRKS00010510 . Registered on 17 July 2016.

Interobserver and intraobserver agreement of ligamentous injuries on conventional MRI after simple elbow dislocation.

BACKGROUND: The primary objective of this study was to assess the interobserver and intraobserver agreement on ligamentous injuries on conventional magnetic resonance imaging (MRI) in acute simple elbow dislocation. The secondary objectives were to determine the interobserver agreement on the assessment of joint congruity, joint effusion, loose bodies and chondral lesions on conventional MRI. METHODS: Conventional MRIs (1.5 Tesla, elbow specific surface coil) of 30 patients (40.7 years; range 14-72) with simple elbow dislocations were evaluated by four blinded examiners. An analysis of the interobserver agreement of all raters and for several subgroups (radiologists, orthopaedics, experienced, non-experienced) was performed. The examiners assessed the integrity (intact, partial tear, complete tear) of the lateral collateral ligament (LCL), medial collateral ligament (MCL), extensor and flexor tendons, as well as the presence of joint congruity, joint effusion, loose bodies and chondral lesions. Agreement strength, correlation and proportion of exact agreement were determined for interobserver agreement, and intraobserver agreement analyses. RESULTS: Interobserver agreement of all examiners was fair to moderate for collateral ligaments (LCL: 0.441, MCL: 0.275). Exact agreement of all raters was found in 33.3% for the LCL and in 26.7% for the MCL. The both experienced examiners showed highest agreement strength for the LCL (0.619) and the radiologists showed highest agreement strength for the MCL (0.627), the proportion of exact agreement was 60.0% in both categories. A high proportion of exact agreement regarding joint congruity (90%), joint effusion (100%), loose bodies (96.7%) and chondral lesion (80%) was found among the radiologists. The evaluation of the intraobserver agreement revealed slight to substantial agreement (0.227 to 0.718) for the collateral ligaments. CONCLUSIONS: This study shows difficulties in the evaluation of ligaments by conventional MRI technique as demonstrated by a weak inter- and intraobserver agreement. This should be the basis to develop new MRI quality standards with special focus on coronal oblique reconstructions to improve the evaluation of ligament injuries after simple elbow dislocations.