679 research outputs found

    The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia.

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    Calcitonin receptor-like (CALCRL) is a G-protein-coupled neuropeptide receptor involved in the regulation of blood pressure, angiogenesis, cell proliferation, and apoptosis, and is currently emerging as a novel target for the treatment of migraine. This study characterizes the role of CALCRL in acute myeloid leukemia (AML). We analyzed CALCRL expression in collectively more than 1500 well-characterized AML patients from five international cohorts (AMLCG, HOVON, TCGA, Leucegene, and UKM) and evaluated associations with survival. In the AMLCG analytic cohort, increasing transcript levels of CALCRL were associated with decreasing complete remission rates (71.5%, 53.7%, 49.6% for low, intermediate, high CALCRL expression), 5-year overall (43.1%, 26.2%, 7.1%), and event-free survival (29.9%, 15.8%, 4.7%) (all P < 0.001). CALCRL levels remained associated with all endpoints on multivariable regression analyses. The prognostic impact was confirmed in all validation sets. Genes highly expressed in CALCRLhigh AML were significantly enriched in leukemic stem cell signatures and CALCRL levels were positively linked to the engraftment capacity of primary patient samples in immunocompromised mice. CRISPR- Cas9-mediated knockout of CALCRL significantly impaired colony formation in human myeloid leukemia cell lines. Overall, our study demonstrates that CALCRL predicts outcome beyond existing risk factors and is a potential therapeutic target in AML

    Treatment strategies for scapular spine fractures: a scoping review

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    Fractures of the scapular spine are relatively rare and can occur without (1) or with (2) association to a reverse shoulder arthroplasty (RSA). To date there are only limited data on the topic. The aim of this scoping review was to identify all available literature and report current treatment concepts. A scoping review was conducted by searching PubMed for relevant studies between 2000 and October 2020. All studies were included which gave detailed descriptions of the treatment strategy. A total of 21 studies with 81 patients were included for the analysis. The mean age over all patients was 62 years (range: 24 to 89 years) and 77% of the patients were female. In 19.8% of cases, the fracture occurred after a traumatic fall from standing height. Eighty-six per cent of the patients had an RSA-associated scapular spine fracture (2). These patients were older compared to group (1) (47 ± 19.6 vs. 76 ± 5.6 years, p = 0.0001) and the majority were female (85%). The majority from group (1) underwent operative treatment with plate fixation. Most patients regained full function and range of motion. RSA-associated fractures (2) were mainly treated non-operatively, with moderate clinical outcome. A high rate of nonunions was reported. Scapular spine fractures without RSA are mainly treated operatively with good clinical results. In association with RSA, scapular spine fractures are mainly treated non-operatively and lead to inferior clinical and radiological results. This scenario seems to be problematic and further research is required to sharpen treatment concepts in this group

    Biomechanical Analysis of Coracoid Stability After Coracoplasty:How Low Can You Go?

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    Background: Arthroscopic coracoplasty is a procedure for patients affected by subcoracoid impingement. To date, there is no consensus on how much of the coracoid can be resected with an arthroscopic burr without compromising its stability. Purpose: To determine the maximum amount of the coracoid that can be resected during arthroscopic coracoplasty without leading to coracoid fracture or avulsion of the conjoint tendon during simulated activities of daily living (ADLs). Study Design: Controlled laboratory study. Methods: A biomechanical cadaveric study was performed with 24 shoulders (15 male, 9 female; mean age, 81 ± 7.9 years). Specimens were randomized into 3 treatment groups: group A (native coracoid), group B (3-mm coracoplasty), and group C (5-mm coracoplasty). Coracoid anatomic measurements were documented before and after coracoplasty. The scapula was potted, and a traction force was applied through the conjoint tendon. The stiffness and load to failure (LTF) were determined for each specimen. Results: The mean coracoid thicknesses in groups A through C were 7.2, 7.7, and 7.8 mm, respectively, and the mean LTFs were 428 ± 127, 284 ± 77, and 159 ± 87 N, respectively. Compared with specimens in group A, a significantly lower LTF was seen in specimens in group B (P = .022) and group C (P < .001). Postoperatively, coracoids with a thickness ≥4 mm were able to withstand ADLs. Conclusion: While even a 3-mm coracoplasty caused significant weakening of the coracoid, the individual failure loads were higher than those of the predicted ADLs. A critical value of 4 mm of coracoid thickness should be preserved to ensure the stability of the coracoid process. Clinical Relevance: In correspondence with the findings of this study, careful preoperative planning should be used to measure the maximum reasonable amount of coracoplasty to be performed. A postoperative coracoid thickness of 4 mm should remain

    Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia

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    Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML

    Double Plating for Complex Proximal Humeral Fractures: Clinical and Radiological Outcomes

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    Double plating for proximal humeral fractures (PHF) is an option to increase the primary fixation stability. Clinical data is missing for assessment of clinical and radiological outcome, as well as complications. We retrospectively examined 35 patients with unilateral PHF, who were treated with double plating for PHF between 2013 and 2019. The mean age was 59.5 ± 12 years and the leading fracture type was a varus dislocation (Resch type IV in 55.3%). A head-split was present in 22.9% of the cases. The primary outcome measurement was the radiological neck shaft angle (NSA). The radiological follow-up was 21 ± 16.6 months and the NSA did not differ between the intraoperative and follow-up time point (131.5 ± 6.9° vs. 136.6 ± 13.7°; p = 0.267). The clinical follow-up was 29.5 ± 15.3 months. The Constant-score was 78.5 ± 17 points, the simple-shoulder-test (SST) was 9.3 ± 3.2 points and the subjective shoulder value (SSV) was 78.8 ± 19.5%. The over-all complication rate was 31.4%, and without stiffness 14.3%. An avascular necrosis occurred in two patients (5.7%). In conclusion, this study shows good radiological and functional outcomes after double plating of highly complex proximal humeral fractures, while the complication rate is comparable to the literature. Double plating is a viable option especially for younger patients with complex fractures as a potential alternative to fracture arthroplasty

    Good to Excellent Functional Short-Term Outcome and Low Revision Rates Following Primary Anterior Cruciate Ligament Repair Using Suture Augmentation

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    The aim of this study was to evaluate the functional outcome of primary anterior cruciate ligament (ACL) repair using suture augmentation (SA) in 93 consecutive patients (67 female) with a minimum follow-up of 12 months. Patients’ outcomes were determined using International Knee Documentation Committee (IKDC) score, Lysholm score (LS) and Tegner score (TS). Knee-laxity was assessed using the KT-1000 arthrometer. Eighty-eight patients (67 female, mean age 42 years ± standard deviation (SD) 13) were available for follow-up after a mean time of 21 months (range 12–39). Three patients (3%) underwent revision surgery and were excluded from functional analysis. The mean IKDC score was 87.4 ± 11, mean LS was 92.6 ± 11, mean pre-traumatic TS was 6 ± 2 and mean postoperative TS was 6 ± 2, with a mean difference (TSDiff) of 1 ± 1. The interval from injury to surgery had no significant impact on the postoperative IKDC (p = 0.228), LS (p = 0.377) and TSDiff (p = 0.572). Patients’ age (>40 years), BMI (>30) and coexisting ligament or meniscal injuries did not seem to influence postoperative functional results. Primary ACL repair using SA provides good to excellent functional outcomes with a low probability of revision surgery at a minimum of 12 months

    Neutral magic-angle bilayer graphene: Condon instability and chiral resonances

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    We discuss the full optical response of twisted bilayer graphene at the neutrality point close to the magic angle within the continuum model. (i) First, we define the full optical response consistent with the underlying D3D_3 symmetry, yielding the total, magnetic, and chiral response that transform according to the irreducible representations A1A_1, A2A_2, and EE, respectively. Then, we numerically calculate the dissipative and reactive response for twist angles around the magic angle θm\theta_m and comment on the possibility of a Condon instability. (ii) Second, we numerically calculate the full optical response {\it almost at} θm\theta_m. The total response is characterized by three universal plateaus which can be obtained from an analytical calculation. The magnetic and the chiral response, however, is given by corresponding non-universal plateaus depending on the twist angle θ\theta via the dimensionless parameter αθmθ\alpha\sim\theta_m-\theta. (iii) Following the discussion on the large magnetic response, we calculate the plasmonic excitations at the neutrality point inside the optical gap of relaxed twisted bilayer graphene. We find that acoustic plasmons extend over almost the whole optical gap and carry the largest oscillator strength. (iv) Finally, we discuss symmetry relations for the response functions as function of the chemical potential and highlight the consequences of the approximate particle-hole symmetry of the continuum model for twisted bilayer graphene. We then discuss a detailed balance relation where the chiral response at charge neutrality can be understood in terms of electron (hole) transitions for which the initial (final) states are energetically closer to charge neutrality than the final (initial) states.Comment: 17 pages, 7 figure

    Cerclage performance analysis – a biomechanical comparison of different techniques and materials

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    Abstract Background Wire cerclages play a fundamental role in fracture fixation. With an increasing variety of designs being commercially available the question arises which cerclage should be used. This study investigates the biomechanical properties of metallic and non-metallic cerclages and their different application-types. Furthermore, potential influence of muscular interposition between bone and cerclage constructs was tested. Methods Samples of the following four different cerclage types were tested on 3D printed models of human humeri as well as on human cadaveric humeri with and without muscular interposition: Titanium Cable Cerclage (CC), Steel Wire Cerclage (SWC), Suture Tape (ST), Suture Tape Cerclage (STC) with both single- (sSTC) and double-loop application (dSTC). A preinstalled self-locking mechanism secured by the provided tensioner in the STCs being the main difference to the STs. Cyclic loading was performed to 1 kN and then linearly to a maximum load of 3 kN. Statistical analysis was performed using either one-way ANOVA and post-hoc Tukey or Kruskal–Wallis and post-hoc Dunn test depending on normalization of data (p < 0.05). Results Whilst all cerclage options could withstand high loads during failure testing, only within the CC and dSTC group, all samples reached the maximal testing load of 3000 N without any failure. The SWC reached 2977.5 ± 63.6 N, the ST 1970.8 ± 145.9 N, and the sSTC 1617.0 ± 341.6 N on average. Neither muscular interposition nor bone quality showed to have a negative influence on the biomechanical properties of the cerclage constructs, presenting no significant differences. Conclusion All tested cerclage constructs produce reliable stability but differ in their resulting compression forces, in a simplified fracture model. Therefore, non-metallic cerclage alternatives can provide similar stability with less compression and stiffness to metallic cable constructs, but they may offer several advantages and could possibly provide future benefits. Especially, by offering more elasticity without losing overall stability, may offer a biologic benefit. Installing any cerclage constructs should be performed carefully, especially if poor bone quality is present, as the tightening process leads to high forces on the construct