Treatment of Angular Deformity and Limb Length Discrepancy With a Retrograde Femur Magnetic Intramedullary Nail: A Fixator-assisted, Blocking Screw Technique

Background: Fixator-assisted nailing techniques that incorporate magnetic internal lengthening nails (MILNs) permit acute deformity correction and then gradual limb lengthening without needing postoperative external fixators. Purposes: We sought to investigate the safety and accuracy of a fixator-assisted, blocking screw technique using retrograde MILNs for the correction of LLD and limb malalignment. Methods: Forty-one patients (13 patients with genu varum and 28 patients with genu valgum) with LLD treated with fixator-assisted, blocking screw retrograde MILN reconstruction were included. Preoperative LLD, mechanical axis deviation, and joint orientation angles were compared with values at the end of treatment, and bone healing indices were calculated. Perioperative complications were tracked. Results: Preoperatively, the mean mechanical lateral distal femoral angle of the varus cohort was 98 ± 12°, whereas the mean lateral distal femoral angle of the valgus cohort was 82±4°. Both cohorts had an average 3-cm LLD. 99% of the planned limb lengthening was achieved. Final LDFAs were 91 ± 6° and 89 ± 4° in the varus and valgus cohorts, respectively, and the limb mechanical axis angles were normalized. 10 patients underwent a total of 21 returns to the operating room. Most commonly, this involved percutaneous injection of bone marrow aspirate concentrate to bone regenerate exhibiting delayed union (6 patients). Conclusions: The use of a retrograde MILN with a fixator-assisted, blocking screw technique is an effective means of acute deformity correction and gradual limb lengthening through minimal incisions. The accuracy of deformity correction relies on intraoperative execution of the appropriate nail start site, osteotomy location, and placement of blocking screws

Leg and Femoral Neck Length Evaluation Using an Anterior Capsule Preservation Technique in Primary Direct Anterior Approach Total Hip Arthroplasty

Background Achieving correct leg and femoral neck lengths remains a challenge during total hip arthroplasty (THA).  Several methods for intraoperative evaluation and restoration of leg length have been proposed, and each has inaccuracies and shortcomings.  Both the supine positioning of a patient on the operating table during the direct anterior approach (DAA) THA and the preservation of the anterior capsule tissue  are simple, readily available, and cost-effective strategies that can lend themselves well as potential solutions to this problem. Technique The joint replacement is performed through a longitudinal incision (capsulotomy) of the anterior hip joint capsule, and release of the capsular insertion from the femoral intertrochanteric line. As trial components of the prosthesis are placed, the position of the released distal capsule in relationship to its original insertion line is an excellent guide to leg length gained, lost, or left unchanged. Methods The radiographs of 80 consecutive primary THAs were reviewed which utilized anterior capsule preservation and direct capsular measurement as a means of assessing change in leg/femoral neck length. Preoperatively, the operative legs were 2.81 +/- 8.5 mm (SD) shorter than the nonoperative leg (range: 17.7 mm longer to 34.1 mm shorter).  Postoperatively, the operative legs were 1.05 +/- 5.64 mm (SD) longer than the nonoperative leg (range: 14.9 mm longer to 13.7 mm shorter). Conclusion The preservation and re-assessment of the native anterior hip capsule in relationship to its point of release on the femur is a simple and effective means of determining leg/femoral neck length during DAA THA

Automatic Hip Fracture Identification and Functional Subclassification with Deep Learning

Purpose: Hip fractures are a common cause of morbidity and mortality. Automatic identification and classification of hip fractures using deep learning may improve outcomes by reducing diagnostic errors and decreasing time to operation. Methods: Hip and pelvic radiographs from 1118 studies were reviewed and 3034 hips were labeled via bounding boxes and classified as normal, displaced femoral neck fracture, nondisplaced femoral neck fracture, intertrochanteric fracture, previous ORIF, or previous arthroplasty. A deep learning-based object detection model was trained to automate the placement of the bounding boxes. A Densely Connected Convolutional Neural Network (DenseNet) was trained on a subset of the bounding box images, and its performance evaluated on a held out test set and by comparison on a 100-image subset to two groups of human observers: fellowship-trained radiologists and orthopaedists, and senior residents in emergency medicine, radiology, and orthopaedics. Results: The binary accuracy for fracture of our model was 93.8% (95% CI, 91.3-95.8%), with sensitivity of 92.7% (95% CI, 88.7-95.6%), and specificity 95.0% (95% CI, 91.5-97.3%). Multiclass classification accuracy was 90.4% (95% CI, 87.4-92.9%). When compared to human observers, our model achieved at least expert-level classification under all conditions. Additionally, when the model was used as an aid, human performance improved, with aided resident performance approximating unaided fellowship-trained expert performance. Conclusions: Our deep learning model identified and classified hip fractures with at least expert-level accuracy, and when used as an aid improved human performance, with aided resident performance approximating that of unaided fellowship-trained attendings.Comment: Presented at Orthopaedic Research Society, Austin, TX, Feb 2, 2019, currently in submission for publicatio

IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer

Antiestrogen resistance in estrogen receptor positive (ER+) breast cancer is associated with increased expression and activity of insulin-like growth factor 1 receptor (IGF1R). Here, a kinome siRNA screen has identified 10 regulators of IGF1R-mediated antiestrogen with clinical significance. These include the tamoxifen resistance suppressors BMPR1B, CDK10, CDK5, EIF2AK1, and MAP2K5, and the tamoxifen resistance inducers CHEK1, PAK2, RPS6KC1, TTK, and TXK. The p21-activated kinase 2, PAK2, is the strongest resistance inducer. Silencing of the tamoxifen resistance inducing genes, particularly PAK2, attenuates IGF1R-mediated resistance to tamoxifen and fulvestrant. High expression of PAK2 in ER+ metastatic breast cancer patients is correlated with unfavorable outcome after first-line tamoxifen monotherapy. Phospho-proteomics has defined PAK2 and the PAK-interacting exchange factors PIXα/β as downstream targets of IGF1R signaling, which are independent from PI3K/ATK and MAPK/ERK pathways. PAK2 and PIXα/β modulate IGF1R signaling-driven cell scattering. Targeting PIXα/β entirely mimics the effect of PAK2 silencing on antiestrogen re-sensitization. These data indicate PAK2/PIX as an effector pathway in IGF1R-mediated antiestrogen resistance

Nano-Stenciled RGD-Gold Patterns That Inhibit Focal Contact Maturation Induce Lamellipodia Formation in Fibroblasts

Cultured fibroblasts adhere to extracellular substrates by means of cell-matrix adhesions that are assembled in a hierarchical way, thereby gaining in protein complexity and size. Here we asked how restricting the size of cell-matrix adhesions affects cell morphology and behavior. Using a nanostencil technique, culture substrates were patterned with gold squares of a width and spacing between 250 nm and 2 µm. The gold was functionalized with RGD peptide as ligand for cellular integrins, and mouse embryo fibroblasts were plated. Limiting the length of cell-matrix adhesions to 500 nm or less disturbed the maturation of vinculin-positive focal complexes into focal contacts and fibrillar adhesions, as indicated by poor recruitment of α5-integrin. We found that on sub-micrometer patterns, fibroblasts spread extensively, but did not polarize. Instead, they formed excessive numbers of lamellipodia and a fine actin meshwork without stress fibers. Moreover, these cells showed aberrant fibronectin fibrillogenesis, and their speed of directed migration was reduced significantly compared to fibroblasts on 2 µm square patterns. Interference with RhoA/ROCK signaling eliminated the pattern-dependent differences in cell morphology. Our results indicate that manipulating the maturation of cell-matrix adhesions by nanopatterned surfaces allows to influence morphology, actin dynamics, migration and ECM assembly of adhering fibroblasts

Protein C Inhibitor—A Novel Antimicrobial Agent

Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their permeabilization. As shown by negative staining electron microscopy, treatment of Escherichia coli or Streptococcus pyogenes bacteria with PCI triggers membrane disruption followed by the efflux of bacterial cytosolic contents and bacterial killing. The antimicrobial activity of PCI is located to the heparin-binding site of the protein and a peptide spanning this region was found to mimic the antimicrobial activity of PCI, without causing lysis or membrane destruction of eukaryotic cells. Finally, we show that platelets can assemble PCI on their surface upon activation. As platelets are recruited to the site of a bacterial infection, these results may explain our finding that PCI levels are increased in tissue biopsies from patients suffering from necrotizing fasciitis caused by S. pyogenes. Taken together, our data describe a new function for PCI in innate immunity

One-Stage Synovectomies Result in Improved Short-Term Outcomes Compared to Two-Stage Synovectomies of Diffuse-Type Tenosynovial Giant Cell Tumor (D-TGCT) of the Knee: A Multicenter, Retrospective, Cohort Study

Diffuse-type tenosynovial giant cell tumors\u27 (D-TGCTs) intra- and extra-articular expansion about the knee often necessitates an anterior and posterior surgical approach to facilitate an extensive synovectomy. There is no consensus on whether two-sided synovectomies should be performed in one or two stages. This retrospective study included 191 D-TGCT patients from nine sarcoma centers worldwide to compare the postoperative short-term outcomes between both treatments. Secondary outcomes were rates of radiological progression and subsequent treatments. Between 2000 and 2020, 117 patients underwent one-stage and 74 patients underwent two-stage synovectomies. The maximum range of motion achieved within one year postoperatively was similar (flexion 123-120°, p = 0.109; extension 0°, p = 0.093). Patients undergoing two-stage synovectomies stayed longer in the hospital (6 vs. 4 days, p \u3c 0.0001). Complications occurred more often after two-stage synovectomies, although this was not statistically different (36% vs. 24%, p = 0.095). Patients treated with two-stage synovectomies exhibited more radiological progression and required subsequent treatments more often than patients treated with one-stage synovectomies (52% vs. 37%, p = 0.036) (54% vs. 34%, p = 0.007). In conclusion, D-TGCT of the knee requiring two-side synovectomies should be treated by one-stage synovectomies if feasible, since patients achieve a similar range of motion, do not have more complications, but stay for a shorter time in the hospital

Systems microscopy approaches to understand cancer cell migration and metastasis

Cell migration is essential in a number of processes, including wound healing, angiogenesis and cancer metastasis. Especially, invasion of cancer cells in the surrounding tissue is a crucial step that requires increased cell motility. Cell migration is a well-orchestrated process that involves the continuous formation and disassembly of matrix adhesions. Those structural anchor points interact with the extra-cellular matrix and also participate in adhesion-dependent signalling. Although these processes are essential for cancer metastasis, little is known about the molecular mechanisms that regulate adhesion dynamics during tumour cell migration. In this review, we provide an overview of recent advanced imaging strategies together with quantitative image analysis that can be implemented to understand the dynamics of matrix adhesions and its molecular components in relation to tumour cell migration. This dynamic cell imaging together with multiparametric image analysis will help in understanding the molecular mechanisms that define cancer cell migration

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016