ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms.

Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMAs) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5- AZA could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in n=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene-expression of the pro-apoptotic factor NOXA in ASXL1 mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.

A Multi-Disciplinary MRI Assessment May Optimize the Evaluation of Chondral Lesions in Acute Ankle Fractures: A Prospective Study.

Chondral lesions (CL) in the ankle following acute fractures are frequently overlooked immediately after the injury or diagnosed at a later stage, leading to persistent symptoms despite successful surgery. The literature presents a wide range of discrepancies in the reported incidence of CLs in acute ankle fractures. The objective of this prospective study is to provide a precise assessment of the occurrence of chondral lesions (CLs) in acute ankle fractures through MRI scans conducted immediately after the trauma and prior to scheduled surgery. Furthermore, the study aims to highlight the disparities in the interpretation of these MRI scans, particularly concerning the size and extent of chondral damage, between radiologists and orthopedic surgeons. Over the period of three years, all patients presenting with an unstable ankle fracture that underwent operative treatment were consecutively included in this single-center prospective study. Preoperative MRIs were obtained for all included patients within 10 days of the trauma and were evaluated by a trauma surgeon and a radiologist specialized in musculoskeletal MRI blinded to each other's results. The location of the lesions was documented, as well as their size and ICRS classification. Correlations and kappa coefficients as well as the p-values were calculated. A total of 65 patients were included, with a mean age of 41 years. The evaluation of the orthopedic surgeon showed CLs in 52.3% of patients. CLs occurred mainly on the tibial articular surface (70.6%). Most talar lesions were located laterally (11.2%). The observed CLs were mainly ICRS grade 4. According to the radiologist, 69.2% of the patients presented with CLs. The most common location was the talar dome (48.9%), especially laterally. Most detected CLs were graded ICRS 3a. The correlation between the two observers was weak/fair regarding the detection and classification of CLs and moderate regarding the size of the detected CLs. To enhance the planning of surgical treatment for ankle chondral lesions (CLs), it may be beneficial to conduct an interdisciplinary preoperative assessment of the performed scans. This collaborative approach can optimize the evaluation of ankle CLs and improve overall treatment strategies.

Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.

Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes.

Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient-individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients' clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

Humanized three-dimensional scaffold xenotransplantation models for myelodysplastic syndromes.

Patient-derived xenograft (PDX) models have emerged as versatile preclinical platforms for investigation of functional pathomechanisms in myelodysplastic syndromes (MDS) and other myeloid neoplasms. However, despite increasingly improved methodology, engraftment efficiencies frequently remain low. Humanized three-dimensional scaffold models (ossicle xenotransplantation models) in immunocompromised mice have recently been found to enable improved engraftment rates of healthy and malignant human hematopoiesis. We therefore interrogated the feasibility of using four different three-dimensional ossicle-based PDX models for application with primary MDS samples. In a fully standardized comparison, we evaluated scaffold materials such as Gelfoam, extracellular matrix (ECM), and human or xenogenous bone substance in comparison to intrafemoral (IF) co-injection of bone marrow (BM)-derived mesenchymal stromal cells (MSCs) and CD34+ hematopoietic stem and progenitor cells (HSPCs). Our study included13 primary MDS patient samples transplanted in parallel according to these five different conditions. Engraftment of MDS samples was assessed by flow cytometry, immunohistological staining, and molecular validation. We determined that three-dimensional ossicle-based methods achieved higher relative rates of engraftment and enabled long-term retrievability of patient-derived MSCs from implanted ossicles. In summary, HSPCs and MSCs derived from MDS BM, which did not significantly engraft in NSG mice after intrafemoral injection, were able to colonize humanized scaffold models. Therefore, these models are promising new xenotransplantation techniques for addressing preclinical and functional questions of the interaction between hematopoiesis and the BM niche in MDS.

Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo.

The bone marrow (BM) stroma in myeloid neoplasms is altered and it is hypothesized that this cell compartment may also harbor clonal somatically acquired mutations. By exome sequencing of in vitro expanded mesenchymal stromal cells (MSCs) from n = 98 patients with myelodysplastic syndrome (MDS) and n = 28 healthy controls we show that these cells accumulate recurrent mutations in genes such as ZFX (n = 8/98), RANK (n = 5/98), and others. MDS derived MSCs display higher mutational burdens, increased replicative stress, senescence, inflammatory gene expression, and distinct mutational signatures as compared to healthy MSCs. However, validation experiments in serial culture passages, chronological BM aspirations and backtracking of high confidence mutations by re-sequencing primary sorted MDS MSCs indicate that the discovered mutations are secondary to in vitro expansion but not present in primary BM. Thus, we here report that there is no evidence for clonal mutations in the BM stroma of MDS patients.

Proteins Marking the Sequence of Genotoxic Signaling from Irradiated Mesenchymal Stromal Cells to CD34+ Cells.

Non-targeted effects (NTE) of ionizing radiation may initiate myeloid neoplasms (MN). Here, protein mediators (I) in irradiated human mesenchymal stromal cells (MSC) as the NTE source, (II) in MSC conditioned supernatant and (III) in human bone marrow CD34+ cells undergoing genotoxic NTE were investigated. Healthy sublethal irradiated MSC showed significantly increased levels of reactive oxygen species. These cells responded by increasing intracellular abundance of proteins involved in proteasomal degradation, protein translation, cytoskeleton dynamics, nucleocytoplasmic shuttling, and those with antioxidant activity. Among the increased proteins were THY1 and GNA11/14, which are signaling proteins with hitherto unknown functions in the radiation response and NTE. In the corresponding MSC conditioned medium, the three chaperones GRP78, CALR, and PDIA3 were increased. Together with GPI, these were the only four altered proteins, which were associated with the observed genotoxic NTE. Healthy CD34+ cells cultured in MSC conditioned medium suffered from more than a six-fold increase in γH2AX focal staining, indicative for DNA double-strand breaks, as well as numerical and structural chromosomal aberrations within three days. At this stage, five proteins were altered, among them IQGAP1, HMGB1, and PA2G4, which are involved in malign development. In summary, our data provide novel insights into three sequential steps of genotoxic signaling from irradiated MSC to CD34+ cells, implicating that induced NTE might initiate the development of MN.

Genotoxic Bystander Signals from Irradiated Human Mesenchymal Stromal Cells Mainly Localize in the 10-100 kDa Fraction of Conditioned Medium.

Genotoxic bystander signals released from irradiated human mesenchymal stromal cells (MSC) may induce radiation-induced bystander effects (RIBEs) in human hematopoietic stem and progenitor cells (HSPC), potentially causing leukemic transformation. Although the source of bystander signals is evident, the identification and characterization of these signals is challenging. Here, RIBEs were analyzed in human CD34+ cells cultured in distinct molecular size fractions of medium, conditioned by 2 Gy irradiated human MSC. Specifically, γH2AX foci (as a marker of DNA double-strand breaks) and chromosomal instability were evaluated in CD34+ cells grown in approximate (I) < 10 kDa, (II) 10-100 kDa and (III) > 100 kDa fractions of MSC conditioned medium and un-/fractionated control medium, respectively. Hitherto, significantly increased numbers of γH2AX foci (p = 0.0286) and aberrant metaphases (p = 0.0022) were detected in CD34+ cells grown in the (II) 10-100 kDa fraction (0.67 ± 0.10 γH2AX foci per CD34+ cell ∨ 3.8 ± 0.3 aberrant metaphases per CD34+ cell sample; mean ± SEM) when compared to (I) < 10 kDa (0.19 ± 0.01 ∨ 0.3 ± 0.2) or (III) > 100 kDa fractions (0.23 ± 0.04 ∨ 0.4 ± 0.4) or un-/fractionated control medium (0.12 ± 0.01 ∨ 0.1 ± 0.1). Furthermore, RIBEs disappeared after heat inactivation of medium at 75 °C. Taken together, our data suggest that RIBEs are mainly mediated by the heat-sensitive (II) 10-100 kDa fraction of MSC conditioned medium. We postulate proteins as RIBE mediators and in-depth proteome analyses to identify key bystander signals, which define targets for the development of next-generation anti-leukemic drugs.

[Risk factors affecting mortality in patients with hip fractures at a regional trauma center]. / Einflussfaktoren auf die Mortalität bei Patienten mit hüftgelenknahen Frakturen an einem regionalen Traumazentrum.

BACKGROUND: Primary care hospitals and regional trauma centers play an essential role in the treatment of hip fractures. OBJECTIVE: This study investigated the relationship between patient-related parameters and in-hospital mortality as well as complications of hip fractures at a regional trauma center. METHODS: In a retrospective study, data were collected from all patients > 60 years admitted over 2 years to a regional trauma center with a hip fracture. Patient-related parameters included age, sex, fracture location, method of surgical treatment, time of surgery, duration of surgery, length of inpatient stay, blood transfusion, complications, comorbidities, use of anticoagulant medication and need for postoperative intensive care treatment. The relationship between these parameters and hospital mortality as well as complications was investigated. RESULTS: Data were collected from 360 patients undergoing 335 surgeries (f:m 225:110) with a mean age of 83 ± 8 years. The total in-hospital mortality rate was 7.76% (n = 26). Factors increasing in-hospital mortality included: age > 85 years (odds ratio [OR] 5.126; 95% confidence interval [CI] 0.665-39.498; p = 0.1167); male sex (OR 1.85 95%-CI [0.82-4.14]; p = 0.0555); time of surgery > 24 h (OR 1.896 95%-CI [0.661-5.441]; p = 0.2341); ≥ 3 comorbidities (OR 10.61 95%-CI [3.681-27.501]; p < 0.0001); intake of anticoagulants (OR 6.19 95%-CI [2.69-14.24]; p < 0.0001) and postoperative intensive care (OR 5.9 95%-CI [2.56-13.76]; p < 0.0001). CONCLUSION: In the present study a statistically significant influence of the number of comorbidities or Charlson comorbidity index, the intake of anticoagulant drugs and need for postoperative intensive care treatment on the in-hospital mortality of patients with proximal femoral fractures in a regional trauma center was found.

High erythroferrone expression in CD71+ erythroid progenitors predicts superior survival in myelodysplastic syndromes.

Ineffective erythropoiesis and iron overload are common in myelodysplastic syndromes (MDS). Erythroferrone (ERFE) and growth/differentiation factor 15 (GDF15) are two regulators of iron homeostasis produced by erythroid progenitors. Elevated systemic levels of ERFE and GDF15 in MDS are associated with dysregulated iron metabolism and iron overload, which is especially pronounced in MDS with SF3B1 gene mutations. However, the role of ERFE and GDF15 in MDS pathogenesis and their influence on disease progression are largely unknown. Here, we analyzed the expression of ERFE and GDF15 in CD71+ erythroid progenitors of n = 111 MDS patients and assessed their effects on patient survival. The expression of ERFE and GDF15 in MDS was highly aberrant. Unexpectedly, ERFE expression in erythroprogenitors was highly relevant for MDS prognosis and independent of International Prognostic Scoring System (IPSS) stratification. Although ERFE expression was increased in patients with SF3B1 mutations, it predicted overall survival (OS) in both the SF3B1wt and SF3B1mut subgroups. Of note, ERFE overexpression predicted superior OS in the IPSS low/Int-1 subgroup and in patients with normal karyotype. Similar observations were made for GDF15, albeit not reaching statistical significance. In summary, our results revealed a strong association between ERFE expression and MDS outcome, suggesting a possible involvement of ERFE in molecular MDS pathogenesis.

Gene expression analysis of vastus medialis cells after tourniquet-induced ischemia during total knee arthroplasty: a randomized clinical trial.

PURPOSE: Postoperative quadriceps muscle strength was lowered after tourniquet application during total knee arthroplasty (TKA). Furthermore, tourniquet application results in higher proteolytic activity within vastus medialis cells, without influence on the amount and function of mitochondria. The effects of the commonly utilized intraoperative tourniquet on gene expression within the human skeletal muscle cells are barely examined. The purpose of the present study was to analyze the gene expression within the skeletal muscle cells after tourniquet-induced ischemia to identify differential expressed genes (DEGs) and pathways. METHODS: As part of a randomized, controlled, monocentric trial (Clinical-Trials.gov NCT02475603) 20 patients, scheduled to undergo primary total knee arthroplasty (TKA), were included. Written informed consent was received and the patients were randomly assigned to Group A (TKA with tourniquet) (n = 10) and Group B (TKA without tourniquet) (n = 10). A muscle biopsie of (5 × 5 × 5 mm) 125 mm3 were obtained from the vastus medialis exactly 60 min after performing the surgical approach. After preparation of a muscle homogenate, RNA extraction was performed (RNeasy Plus Universal Mini Kit Qiagen) and RNA integrity (RIN) was determined (Agilent 2100 Bioanalyzer, RNA 6000 Pico Kit). Gene expression profiling was performed using a validated method (GeneChip™ Human Transcriptome Array 2.0; Affymetrix). Statistical analysis (SPSS-Version 24; SAS JMP10 Genomics, Version 6) included the number of significant DEGs (p < 0.05), the number of DEGs with relative difference > 25% and the number of significant pathway (p < 0.05). The serum C-reactive protein (CRP) and the white blood cell (WBC) count were also perioperatively measured. The protocol was approved by our Institutional Ethics Committee (File reference 2012-334N-MA). RESULTS: Tourniquet application resulted in a total of 3555 (13.8%) statistically significant DEGs within vastus medialis cells. 76 DEGs (29 upregulated, 47 downregulated) revealed a relative difference of more than 25%. Statistically significant changes occurred in 59 (25.8%) of 229 analyzed pathways. Furthermore, there was no clinically meaningful difference between the groups with regard to CRP and WBC count. CONCLUSIONS: Tourniquet induced ischemia results in significant changes of the gene expression within cells of vastus medialis including metabolism, genetic information processing and cellular processes. The identified altered expression of genes and pathways might serve as pharmacotherapeutical targets; although further research is needed to clarify the underlying biological processes. CLINICAL RELEVANCE: These findings add further knowledge and should raise the awareness of surgeons about the effects of tourniquet induced ischemia at the gene expression level. Additional high-quality research may be warranted to examine the short and long term clinical significance of the present data. LEVEL OF EVIDENCE: Level I.

Replication stress signaling is a therapeutic target in myelodysplastic syndromes with splicing factor mutations.

Somatic mutations in genes coding for splicing factors, e.g. SF3B1, U2AF1, SRSF2, and others are found in approximately 50% of patients with Myelodysplastic Syndromes (MDS). These mutations have been predicted to frequently occur early in the mutational hierarchy of the disease therefore making them particularly attractive potential therapeutic targets. Recent studies in cell lines engineered to carry splicing factor mutations have revealed a strong association with elevated levels of DNA:RNA intermediates (R-loops) and a dependency on proper ATR function. However, data confirming this hypothesis in a representative cohort of primary MDS patient samples have so far been missing. Using CD34+ cells isolated from MDS patients with and without splicing factor mutations as well as healthy controls we show that splicing factor mutation-associated R-loops lead to elevated levels of replication stress and ATR pathway activation. Moreover, splicing factor mutated CD34+ cells are more susceptible to pharmacological inhibition of ATR resulting in elevated levels of DNA damage, cell cycle blockade, and cell death. This can be enhanced by combination treatment with low-dose splicing modulatory compound Pladienolide B. We further confirm the direct association of R-loops and ATR sensitivity with the presence of a splicing factor mutation using lentiviral overexpression of wild-type and mutant SRSF2 P95H in cord blood CD34+ cells. Collectively, our results from n=53 MDS patients identify replication stress and associated ATR signaling to be critical pathophysiological mechanisms in primary MDS CD34+ cells carrying splicing factor mutations, and provide a preclinical rationale for targeting ATR signaling in these patients.

Incidence of concomitant chondral/osteochondral lesions in acute ankle fractures and their effect on clinical outcome: a systematic review and meta-analysis.

INTRODUCTION: Despite successful osteosynthesis, some patients report residual symptoms after ankle fractures. One of the reasons behind the postoperative complaints might be traumatic concomitant chondral lesions (CL) and/or osteochondral lesions (OCL) within the ankle joint. The study aims to systematically review the incidence of CL and/or OCL in ankle fractures and to assess their effect on the clinical outcome. MATERIALS AND METHODS: This work was conducted according to PRISMA checklists. A systematic literature search was performed using following keywords: "Ankle Fractures" OR "Trimalleolar Fracture" OR "Bimalleolar Fracture" OR "Maisonneuve fracture" OR "Malleolus Fracture" AND "Cartilage" OR "Cartilage Diseases" OR "Cartilage, Articular" OR "chondral" up to March 2020. The identified articles were analysed to determine the incidence of CL and/or OCL. Included studies in the meta-analysis assessed possible cartilage damage through arthroscopy or MRI immediately after traumatic ankle fractures and described the postoperative clinical outcome. RESULTS: The search identified a total of 111 publications; 19 described the incidence of CL and/or OCL after ankle fractures; six met the criteria to be included in the meta-analysis: five (n = 293) diagnosed CL and/or OCL through arthroscopy during ORIF and one study (n = 153) used preoperative MRI. The clinical outcome was evaluated in four studies (n = 177) using AOFAS score and in two (n = 269) using FAOS score. The mean incidence of arthroscopically detected CL and/or OCL was 65 ± 21% [95% CI 53.9 to 76.72]. The cumulative meta-analysis sample size comprised a total of 400 Patients (170 with and 230 without CL and/or OCL) available for a mean follow-up of 23.9 ± 11.5 months [95% CI 11.79 to 36.07]. The average age was 44.3 ± 5.5 years [95% CI 38.57 to 50.13]. The meta-analysis revealed a mean AOFAS score of 91.2 ± 4.8 [95% CI 83.53 to 98.93] with versus 94.4 ± 4.7 [95% CI 86.81 to 102.07] without CL and/or OCL (p = 0.15) and a mean FAOS score of 73.2 ± 11.31 [95% CI - 28.44 to 174.85] with versus 79.0 ± 18.4 [95% CI - 86.77 to 244.87] without CL and/or OCL (p = 0.18). CONCLUSIONS: CL and/or OCL appear very frequently after ankle fractures. A tendency towards a favourable short- to mid-term clinical outcome was noticed in ankle fractures without CL and/or OCL, however without reaching statistical significance. LEVEL OF EVIDENCE: Level I.

Influence of the Tourniquet on Pain and Function in Total Knee Arthroplasty: a Systematic Review and Meta-Analysis. / Einfluss der Blutsperre auf die postoperative Schmerzintensität und Funktion nach der Implantation von Knietotalendoprothesen: eine systematische Übersichtsarbeit und Metaanalyse.

BACKGROUND: The use of the tourniquet in total knee arthroplasty is still a subject of controversial discussion. Previous studies mainly focus on parameters like blood loss and operation time. The aim of this systematic review is to evaluate the postoperative outcome involving parameters such as pain intensity, analgesic consumption, knee function and complication rate with and without tourniquet use, to find a recommendation for future application in total knee arthroplasty. MATERIAL AND METHODS: This review is based on the PRISMA Checklists. A systematic research was performed in PubMed using the key words "tourniquet", "total knee arthroplasty", "TKA" and "knee endoprosthesis" up to and including January 2018. The initial search revealed 686 Papers which were extracted by the parameters intensity of pain, analgesic consumption, function (range of motion, Hospital for Special Surgery Score, Knee Society Score) and complications (deep vein thrombosis, surgical side infection, pulmonary embolism). The program Review Manager Version 5.3 was used for statistical analysis. A significance level of p < 0,05 was defined. RESULTS: 18 studies were included in this review with 1279 total knee arthroplasties overall (646 with the use of tourniquet and 633 without). The analysis shows a significant lower pain intensity until the fifth postoperative day (p = 0,03) and also after one to three months (p = 0,04) without using the tourniquet. Range of motion is significantly higher in two to three days postoperatively (p < 0,00 001) when the surgery was performed without tourniquet. Knee Society Score shows no difference between the two groups. A deep vein thrombosis appears significantly more often when using a tourniquet (p = 0,04). There was no higher occurrence in pulmonary embolism and surgical side infections. CONCLUSION: The use of a pneumatic tourniquet in total knee arthroplasty affects especially the early postoperative pain and functional recovery.

Outcome Measures to Evaluate Upper and Lower Extremity: Which Scores are Valid? / Scores zur Nachuntersuchung von Behandlungsergebnissen: Welche sind valide?

OBJECTIVE: In orthopaedics and trauma surgery scores are frequently used to assess treatment outcomes. The purpose of the review is to create an overview analysing the content of validity studies of frequently utilized scores for upper and lower extremity. METHODS: Commonly used outcome measures to assess clinical outcome of upper (n = 19) and lower (n = 22) extremity were included. For each of the scores a comprehensive search in several databases (Medline, PubMed, google scholar) were performed to identify validation studies. The COSMIN-Checklist (COSMIN: Consensus-based Standards for the selection of health Measurement Instruments) introduced by Mokkink et al. were used to analyse systematically the methodological quality of the validation studies. RESULTS: Validity, objectivity and reliability were not routinely considered and addressed in validation studies. The score related validation studies did not include all defined criteria of the COSMIN-Checklist. Six scores of the upper extremity and four scores of the lower extremity are not adequately validated. The best validated scores of the upper extremity is Oxford Shoulder Score (OSS) and for the lower extremity Hip Disabilities and Osteoarthritis Outcome Score (HOOS) as well as Western Ontario and McMaster Universities Score (WOMAC). CONCLUSION: There is no gold standard for the content-comprehension of validation studies due to the structure of the original study. The more criteria were tested the more informative and significant the outcome measure is. However some scores, such as Neer and Castaing Score, that lack validation are still being successfully used in research and clinical practice. The present review provides an overview of frequently used score in orthopaedics and trauma surgery and their grade of validity.

No effect of tourniquet in primary total knee arthroplasty on muscle strength, functional outcome, patient satisfaction and health status: a randomized clinical trial.

PURPOSE: Tourniquet use during primary total knee arthroplasty (TKA) may negatively impact the early postoperative functional recovery due to molecular effects of ischaemia. The hypothesis of the present study was that primary TKA without a tourniquet positively influences the postoperative muscle strength, functional outcome, patient satisfaction and health status. METHODS: The monocentric, randomized, controlled trial included a total of 99 patients scheduled to undergo primary TKA (ClinicalTrials.gov NCT02475603). The patients were randomly assigned to the tourniquet (n = 50) or non-tourniquet (n = 49) group after receiving a written informed consent. As primary outcome parameter, the functional outcome, patient expectation/satisfaction and the health status were assessed preoperatively, 6 weeks, 6 months postoperatively using Oxford knee score, WOMAC score, Mancuso score, EQ-5D index, EQ-VAS, anxiety score, depression score, hospital anxiety and depression scale, respectively. Additionally, a rope pulley isokinetic system (Moflex, Recotec/Bernina, Switzerland) was applied to quantify the muscle strength preoperatively, 1 week, 6 weeks and 6 months postoperatively. RESULTS: No difference in any of the outcome parameters could be observed between the groups at all time points after TKA (n.s.). Also the isokinetic muscle strength of the knee joint as quantified by concentric/eccentric peak force (N), workload (J), total workload (J) and power (W) did not reveal statistically significant differences between the groups and time points. However, in both groups improved results were found with respect to the functional outcome, patient satisfaction, health status and isokinetic muscle strength up to 6 months postoperatively. CONCLUSIONS: The application of the tourniquet did not affect the isokinetic muscle strength, the functional outcome, the patient satisfaction and the health status following primary TKA. However, with and without tourniquet use, the level of the knee functionality, the patient satisfaction as well as the health status improved significantly. LEVEL OF EVIDENCE: I.

Usefulness of slice encoding for metal artifact correction (SEMAC) technique for reducing metal artifacts after total knee arthroplasty.

PURPOSE: To evaluate the usefulness of a novel MRI sequence strategy in the assessment of the periprosthetic anatomical structures after primary total knee arthroplasty. METHODS: Two MR sequences were retrospectively compared for the imaging of 15 patients with implanted cruciate-retaining/fixed-bearing TKAs (DePuy, PFC Sigma): a slice encoding sequence for metal artifact correction (SEMAC) and a standard sequence. Images were acquired on a 1.5-T system. The degree of artifact reduction was assessed using several qualitative (Likert-type scale) (artifact size, distorsion, blur, image quality, periprosthetic bone, posterior cruciate ligament, lateral collateral ligament, medial collateral ligament, patella tendon, popliteal vessels) and quantitative (artifact volume, Insall-Salvati index, length of patella/tendon, prosthesis dimensions) parameters by blinded reads performed by four investigators. The SEMAC sequences were statistically compared with the standard sequence using Wilcoxon test. Additionally, the intraclass correlation coefficient (ICC) for interobserver agreement was calculated. RESULTS: Higher levels of blurring were found with SEMAC compared to standard sequences (p < 0.001). All other qualitative parameters improved significantly with the application of SEMAC. In comparison with conventional sequences, the artifact volume was reduced by 59% utilizing SEMAC. Thus, the artifact reduction improved the precision of measurements such as Insall-Salvati index and length of patella/tendon (p < 0.001). The dimension of the tibial component (Ti alloy/polyethylene) revealed accurate values with both MRI sequences. A sufficient interobserver agreement among all readers was found with SEMAC, qualitatively ICC 0.9 (range 0.8-1) as well as quantitatively ICC 0.95 (range 0.92-0.98). CONCLUSIONS: SEMAC effectively reduces artifacts caused by metallic implants after total knee arthroplasty relative to standard imaging. This allows for an improved assessment of periprosthetic anatomical structures. This might enable an improved detectability of postoperative complications in the future. LEVEL OF EVIDENCE: Diagnostic Study Level III.

Tourniquet application does not affect the periprosthetic bone cement penetration in total knee arthroplasty.

PURPOSE: Poor scientific evidence exists on the issue of tourniquet application during total knee arthroplasty (TKA). It has been suggested that tourniquet application might improve interdigitation of the cement into the periprosthetic bones due to relatively dry surgical field. The hypothesis of the present study was that tourniquet use did not affect the periprosthetic bone cement penetration. METHODS: The single-centre, randomized, controlled trial included 86 patients undergoing primary TKA (Clinical-Trials.gov NCT02475603). All patients meeting the inclusion criteria were randomly assigned to the tourniquet (n = 43) or non-tourniquet (n = 43) group after obtaining a written informed consent. The cumulative bone cement penetration was radiologically measured in AP (seven zones) and lateral views (three zones) as defined by Knee Society Scoring System. Further parameters such as perioperative blood loss, soft tissue swelling, pain level/analgesic consumption, operative time, length of hospital stay (LOS) and complication rate were statistically compared between the groups. RESULTS: The cumulative bone cement penetration averaged 28.5 ± 1.7 mm in tourniquet versus 26.6 ± 1.6 mm in non-tourniquet groups (n.s.). The mean intraoperative blood loss was 250 ml higher in the non-tourniquet group (p = 0.0001). Patient-reported pre- to 6th-day post-operative reduction of the pain level was significantly higher in the non-tourniquet group (p = 0.003). The Morphine Equivalent Dose was higher in the Tourniquet group at discharge day (p = 0.02). Parameters such as total blood loss, soft tissue swelling, surgical time, LOS, and complication rates revealed similar results between the groups. CONCLUSIONS: Tourniquet application did not influence the bone cement penetration significantly. Even though the intraoperative blood loss was reduced, the total blood loss was not affected significantly by tourniquet use. There was a tendency of higher post-operative pain and opioid analgesic requirement in the tourniquet group. LEVEL OF EVIDENCE: I.