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.

Anthropometric three-dimensional computed tomography reconstruction measurements of the acetabulum in children/adolescents.

The key element for differentiation between normal anatomical variants and pathological deformities is the prior definition of normal ranges for anthropometric parameters of acetabulum according to each age group. Aim of the present study is to analyze the development of the acetabulum in children/adolescents by accurate anthropometric measurements using 3D-CT scans and determine the variations occurring depending on age, gender and/or side. This retrospective observational study included 85 patients (170 hips) under 15 years of age (0-15) undergoing 1.5mm CT scanning for non-hip related reasons. The measurements were performed by 2 board-certified orthopaedic surgeons. Each year of life represented an age group forming a total of 16 groups. Median number of patients per age group was 12 (range 4-16). The anthropometric parameters included acetabular volume, inclination, version, depth (coronal and axial), width (coronal and axial), Tönnis angle as well as anterior and posterior acetabular sector angles. Mean values, range, standard deviation, p-values, intra- and interrater reliability were calculated. All measurement values correlated significantly with age. Statistically, there was no side or gender related difference. Rapid growth phases were observed at the age of 11-12. The inter- and intrarater reliability was high (range ICC 0.8-0.99, Cronbach alpha 0.86-0.99, Bland-Altman good agreement). The present data provides age- and gender-related normative values as well as growth phases describing acetabular morphology. It should help paediatricians as well as paediatric and orthopaedic surgeons as a tool for early diagnosis of deformity and guidance for possible procedures.

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.

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.

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.

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.

Anthropometry of the proximal femur and femoral head in children/adolescents using three-dimensional computed tomography-based measurements.

PURPOSE: Defining normal anthropometric ranges of proximal femur and femoral head for each age group in children/adolescents is a necessity when differentiating normal anatomical variants from pathological deformities. Aim of this study is to define a set of normal anthropometric parameters based on 3D-CT measurements in normal asymptomatic children/adolescents and analyse the variations arising depending on age, side, and/or gender. METHODS: Morphology of the proximal femur was retrospectively assessed in 170 hips (85 children, < 15 years). Measurements included covered femoral head volume (CFHV), femoral head diameter (FHD), femoral head extrusion index (FHEI), coronal alpha angle (CAA), lateral centre-edge angle (LCEA), anterior (AOS) and posterior head-neck offset (POS) and femoral neck-shaft angle (FNSA). Correlation analyses as well as inter- and intra-rater reliability were performed. RESULTS: CFHV, LCEA, FHD and AOS/POS increased with age and FHEI, CAA, and FNSA decreased with age. None of the measurements correlated with the side. AOS showed a poor correlation with gender. Rapid growth phases were observed at the age of 1, 7 and 11. The inter- and intra-rater reliability was high (range ICC 0.8-0.99 Cronbach alpha 0.86-0.99). CONCLUSION: This data delivers a description of growth phases as well as gender and age-correlated reference values of the proximal femoral morphology that could be used by paediatricians and orthopaedic/paediatric surgeons to early diagnose proximal femur deformities and provide guidance in the planning of possible operations.

[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.

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.

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.

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 during TKA did not affect the accuracy of implant positioning: a randomized clinical trial.

PURPOSE: The accuracy of the identification of anatomical landmarks with versus without tourniquet application and its effect on implant positioning remained unknown. Therefore, the hypothesis of the present study was that tourniquet application did not affect the accuracy of the reconstruction of the mechanical leg alignment, the joint line level, and the patellar height. METHODS: The prospective randomized monocentric trial (Clinical-Trials.gov NCT02475603) included a total of 86 patients scheduled to undergo primary TKA. The patients were allocated to receive TKA with (Group A, n = 43) or without tourniquet (Group B, n = 43). The mechanical leg alignment, the joint line level (modified Kawamura), and the patellar height (Plateau-patella angle, Insall Salvati index, and modified Insall Salvati index) were measured pre- and postoperatively on standardized calibrated digital radiographs. Mean, SEM, median, range, and p value were calculated for each parameter. RESULTS: There was no statistical difference between the groups with regard to demographics, preoperative deformity, implant design, and surgical technique (n.s.). The mechanical leg alignment, the joint line level, and the patellar height revealed, in both groups, similar results pre- and postoperatively (n.s.). CONCLUSION: The mechanical leg alignment, the joint line level, and the patellar height could be accurately reconstructed with and without tourniquet use. With respect to clinically relevant surrogate parameters of implant positioning, TKA can safely be performed without a tourniquet. Available data do not support a routine use of tourniquet during TKA and might justify a change of the clinical pathway. LEVEL OF EVIDENCE: Level I.

Tourniquet-induced ischaemia during total knee arthroplasty results in higher proteolytic activities within vastus medialis cells: a randomized clinical trial.

PURPOSE: Recent data suggest diminished post-operative quadriceps muscle strength after tourniquet application during total knee arthroplasty (TKA). The metabolic effects of the commonly utilized intraoperative tourniquet with consecutive ischaemia on the skeletal muscle cells were unknown. Ubiquitin proteasome system represents one of the main pathways involved in muscle protein breakdown contributing to muscle atrophy. Therefore, the purpose of the present study was to quantify the acute effects of the tourniquet application during TKA on the (1) concentrations of free/conjugated ubiquitin, (2) total ubiquitin-protein ligase activity, (3) proteasome-dependent and (4) proteasome-independent peptidase activities in the cells of vastus medialis. METHODS: The randomized, controlled, monocentric trial included 34 patients scheduled to undergo primary TKA. Each patient was randomly assigned to the tourniquet (n = 17) or non-tourniquet group (n = 17) after receiving a written consent. Muscle biopsies of (5 × 5 × 5 mm) 125 mm3 were obtained from vastus medialis immediately after performing the surgical approach and exactly 60 min later. After preparation of the muscle tissue specimen, the concentrations of the free/conjugated ubiquitin (Ub) were measured by western blot analyses. The ubiquitination was determined as biotinylated Ub incorporated into the sum of the cytosolic proteins and expressed as total ubiquitin-protein ligase activity (tUbPL). The quantification of the proteasome-dependent and proteasome-independent peptidase activities was performed with peptidase assays. RESULTS: Tourniquet application did not influence the concentration of the free/conjugated Ub. There were no differences in tUbPL activities between groups and time points. Tourniquet-induced ischaemia resulted in statistically significant higher proteasome-dependent (caspase-like p = 0.0034; chymotryptic-like p = 0.0013; tryptic-like p = 0.0036) and proteasome-independent (caspase-like p = 0.03; chymotryptic-like p = 0.0001; tryptic-like p = 0.0062) peptidase activities. CONCLUSION: Tourniquet application did not affect the free/conjugated Ub as well as tUbPL significantly, emphasizing the sophisticated regulation of ubiquitination. The proteasome-dependent peptidase activities were significantly upregulated during tourniquet application, suggesting an increase in protein degradation, which in turn might explain the skeletal muscle atrophy occurring after TKA. These findings add further knowledge and should raise the awareness of surgeons about the effects of tourniquet-induced ischaemia at the molecular level. Additional high-quality research may be warranted to examine the short- and long-term clinical significance of the present data. LEVEL OF EVIDENCE: I.

Are joint line changes after primary navigated total knee arthroplasty predictable?

BACKGROUND: Navigation systems have been successful in reducing the outlier of leg alignment after total knee arthroplasty (TKA). Less is known about the restoration of the anatomical joint line with computer-assisted knee replacement. The aim of this study was to determine whether joint line changes <3 or ≥3 mm are predictable with several pre- and intraoperative parameters. METHODS: The study included a total of 180 cases of primary computer-assisted TKA performed using the gap-balancing/tibia-first technique. The final shift of the joint line was calculated using computer verification of proximal tibial and distal femoral cuts. In consideration of the clinical relevance of a 3-mm joint line shift, patients were stratified into two groups: Group I, with joint line change <3 mm, and Group II, with joint line change ≥3 mm. Between groups, variables such as demographics, Kellgren & Lawrence degree of osteoarthritis, preoperative flexion contracture, pre-/intraoperative mechanical leg alignment, flexion/extension gaps, and implant design/sizes were compared statistically. RESULTS: The absolute joint line shift averaged 1.6 ± 1.3 mm (range 0-6 mm). A joint line shift ≥3 mm was observed in 28 cases (15 %). A statistically significant difference between groups was not identified for any of the parameters. Shift of the joint line did not correlate with the analyzed variables. CONCLUSIONS: Joint line was adequately restored when computer navigation was carefully applied as a measuring tool for primary TKA. Knee joint deformity, leg alignment, gap balance, and implant type did not aid in predicting the joint line shift.

Fibula head is a useful landmark to predict the location of posterior cruciate ligament footprint prior to total knee arthroplasty.

PURPOSE: The hypothesis of our study is that a routine tibial cut during cruciate retaining TKA may result in a partial or a total removal of the PCL footprint. Therefore providing a reliable landmark is essential to estimate the probability of PCL damage with a tibial cut and to enable the surgeon to decide pre-operatively whether a cruciate retaining implant design is suitable. METHODS: In a case series of 175 cruciate retaining TKA, the routinely made standing postoperative AP-view radiographs were evaluated to determine the distance between fibula head and tibial cutting plane. In a second case series knee MRI of 223 subjects were consecutively used to measure the vertical distance between tibial attachment of PCL and fibula head. The probability of partial or total PCL damage was calculated for different vertical distances between tibial cut and fibula head. RESULTS: The vertical distance between the tibial cut and the most proximal point of the fibula head averaged 6.1 mm ±4.8 mm. The mean vertical distance from fibula head to proximal and to distal PCL footprint revealed to be 11.4 mm ±3.7 mm and 5.4 mm ±2.9 mm, respectively. The location of the insertion was not significantly different between subgroups such as age (<50 or >50 years), gender and side. Based on our results 11 (7%) knees were considered at high risk of an entire PCL removal after implantation of a cruciate retaining TKA design. CONCLUSIONS: Currently available routine tibial preparation techniques result in partial or total posterior cruciate ligament detachment. Fibula head as a landmark aids to predict the PCL location and to estimate its disruption pre- and postoperatively on AP-view radiographs.

Titanium induces pro-inflammatory and tissue-destructive responses in primary human macrophages.

Implants and medical devices are efficient and practical therapeutic solutions for a multitude of pathologies. Titanium and titanium alloys are used in orthopedics, dentistry, and cardiology. Despite very good mechanical properties, and corrosion resistance titanium implants can fail due to inflammatory or tissue-degradation related complications. Macrophages are major immune cells that control acceptance of failure of the implant. In this study, for the first time, we have performed a systematic analysis of the response of differentially activated human macrophages (M(Control), M(IFNγ) and M(IL-4)) to the polished and porous titanium surfaces in order to identify the detrimental effect of titanium leading to the tissue destruction and chronic inflammation. Transcriptome analysis revealed that the highest number of differences between titanium and control settings are found in M(IL-4) that model healing type of macrophages. RT-qPCR analysis confirmed that both polished and porous titanium affected expression of cytokines, chitinases/chitinase-like proteins and matrix metalloproteinases. Titanium-induced release and activation of MMP7 by macrophages was enhanced by fibroblasts in both juxtacrine and paracrine cell interaction models. Production of titanium-induced MMPs and cytokines associated with chronic inflammation were independent of the presence of Staphylococcus aureus. MMP7, one of the most pronounced tissue-destroying factor and chitinase-like protein YKL-40 were expressed in CD68+ macrophages in peri-implant tissues of patients with orthopedic implants. In summary, we demonstrated that titanium induces pro-inflammatory and tissue-destructing responses mainly in healing macrophages, and the detrimental effects of titanium surfaces on implant-adjacent macrophages are independent on the bacterial contamination.

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.

Anthropometric measurements of the pediatric hip using CT-based simulated anteroposterior radiographs of the pelvis.

Normal anatomical variants and pathological deformities of the pediatric hip can only be differentiated after a prior definition of normal ranges for anthropometric parameters with increasing age. Aim of the present study was to provide reliable reference values of the pediatric hip morphometry, using computed tomography (CT)-based rotation-corrected summation images of the pelvis that simulate the widely available plain radiograph-based measurements, but offer the higher precision of the CT technique. This retrospective study included 85 patients (170 hips) under 15 years of age (0-15). The measured anthropometric parameters included femur head extrusion index, lateral center-edge angle, acetabular inclination, Tönnis angle, and femoral neck-shaft angle. Mean values, range, SD, P values, intra-rater, and inter-rater reliability were calculated. All measurements correlated with age. None of the measurements correlated with gender or side. Rapid growth phases were noted in all measurements at the age of 12 (14 in males and 11 in females). The inter-rater and intra-rater reliability was high (range inter/intraclass correlation coefficient 0.926-0.998 Cronbach's alpha 0.986-0.998). The present work provides age- and gender-related normative values of the classically used hip measurements as well as growth phases describing pediatric hip morphology in a broad age range. A discrepancy was noted between the values measured in the current study and the classical X-ray-based reference values in the literature especially for the Tönnis angle and LCEA values. This suggests that the rotation and inclination correction in the CT-based techniques might have the advantage of compensating for a possible overestimation in the conventional X-ray-based methods.