The advent of modern suture anchor technology has not only revolutionized arthroscopic treatment options for management of complex shoulder pathology, but also engendered a materials science quest to ...identify the ultimate composition and design. What began as an open procedure with transosseous suture fixation has evolved dramatically with the widespread adoption of an arthroscopic, anchor-based technique for rotator cuff repair. Currently, a litany of commercially available “hard” and “soft” anchors are flooding the market, with limited qualitative comparisons to suggest superiority of one type. Ideally, suture anchor design should permit preservation of native glenohumeral bone stock with gradual osseointegration, limit disruption of local tissue homeostasis, and maintain time-zero mechanical strength until soft-tissue healing has occurred. At present, a vented, open-anchor architecture may facilitate better biologic incorporation with increased bony ingrowth through access to marrow elements, although these radiographic advantages have not conferred any clinically meaningful differences for our rotator cuff repair patients. For anchor composition, the jury is still out, and we need to continue to critically evaluate for perianchor cyst formation and longer term remodeling. In fact, the true merits of increased bony ingrowth and limited osteolysis may only be realized at the time of revision rotator cuff repair, during which prior implant position or secondary cystic change may further dictate suture anchor design, size, and placement.
Osteosarcoma (OS) is the most common type of solid bone cancer and remains the second leading cause of cancer-related death for children and young adults. Hypoxia is an element intrinsic to most ...solid-tumor microenvironments, including that of OS, and is associated with resistance to therapy, poor survival, and a malignant phenotype. Cells respond to hypoxia through alterations in gene expression, mediated most notably through the hypoxia-inducible factor (HIF) class of transcription factors. Here we investigate hypoxia-induced changes in the Wnt/β-catenin signaling pathway, a key signaling cascade involved in OS pathogenesis. We show that hypoxia results in increased expression and signaling activation of HIF proteins in human osteosarcoma cells. Wnt/β-catenin signaling is down-regulated by hypoxia in human OS cells, as demonstrated by decreased active β-catenin protein levels and axin2 mRNA expression (p<0.05). This down-regulation appears to rely on both HIF-independent and HIF-dependent mechanisms, with HIF-1α standing out as an important regulator. Finally, we show that hypoxia results in resistance of human OS cells to doxorubicin-mediated toxicity (6-13 fold increase, p<0.01). These hypoxic OS cells can be sensitized to doxorubicin treatment by further inhibition of the Wnt/β-catenin signaling pathway (p<0.05). These data support the conclusion that Wnt/β-catenin signaling is down-regulated in human OS cells under hypoxia and that this signaling alteration may represent a viable target to combat chemoresistant OS subpopulations in a hypoxic niche.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Joint arthroplasty has become increasingly more common in the United States, and it is important to examine the patient-based risk factors and surgical variables associated with hospital ...readmissions. The purpose of this study was to identify stratified rates and risk factors for readmission after upper extremity (shoulder, elbow, and wrist) and lower extremity (hip, knee, and ankle) arthroplasty.
Methods
All patients undergoing upper and lower extremity arthroplasty from 2008–2018 were identified using the National Surgical Quality Improvement Program dataset. Patient demographics, medical comorbidities and surgical characteristics were examined utilizing uni- and multi-variate analysis for significant predictors of 30-days hospital readmission.
Results
A total of 523,523 lower and 25,215 upper extremity arthroplasty patients were included in this study. A number of 22,183 (4.2%) lower and 1072 (4.4%) upper extremity arthroplasty patients were readmitted within 30 days of discharge. Significant risk factors for 30-days readmission after lower extremity arthroplasty included age, Body Mass Index (BMI), operative time, dependent functional status, American Society of Anesthesiologists (ASA) score ≥3, increased length of stay, and various medical comorbidities such as diabetes, tobacco dependency, and chronic obstructive pulmonary disease (COPD). An overweight BMI was associated with a lower odds of 30-days readmission when compared to a normal BMI for lower extremity arthroplasty. Analysis for upper extremity arthroplasty revealed similar findings of significant risk factors for 30-days hospital readmission, although diabetes mellitus was not found to be a significant risk factor.
Conclusion
Nearly one in 25 patients undergoing upper and lower extremity arthroplasty experiences hospital readmission within 30-days of index surgery. There are several modifiable risk factors for 30-days hospital readmission shared by both lower and upper extremity arthroplasty, including tobacco smoking, COPD, and hypertension. Optimization of these medical comorbidities may mitigate the risk short-term readmission following joint arthroplasty procedures and improve overall cost effectiveness of perioperative surgical care.
The elderly have conventionally been defined as individuals over the age of 65 and are projected to represent about 21% of the United States (US) population by the year 2030. Distal radius fractures ...(DRF) in particular are one of the most common fractures among elderly patients and their incidence continues to rise in part due to increased activity levels among the elderly, increased life expectancy, rising rates of obesity, changes to dietary habits, and the prevalence of osteoporosis. Although various treatment options exist for these injuries, nonsurgical treatment of distal radius fractures remains a mainstay among elderly patients with mounting evidence of its non-inferiority to surgical fixation in the literature. Here, we summarize the overall approach to nonsurgical treatment of distal radius fractures in the elderly population while examining its supporting data and highlighting potential risks and limitations to it. Keywords: distal radius fracture, osteoporosis, nonsurgical treatment, nonoperative treatment, geriatric trauma, volar locking plate
To use an expected-value decision analysis to determine the optimal treatment decision between repair or a biceps tenodesis (BT) for an isolated type II Superior Labral Anterior Posterior (SLAP) ...injury.
An expected-value decision analysis with sensitivity analysis was performed to systematically quantify the clinical decision. To determine outcome probabilities, a decision tree was constructed (repair vs BT) and a meta-analysis was conducted. To determine outcome utilities, we evaluated 70 patients with a chief complaint of shoulder pain with regard to age, sex, Shoulder Activity Level (SAL) and visual analog scale regarding potential outcome preferences. Statistical fold back analysis calculated optimal treatment. One-way sensitivity analysis determined the effect of changing the reinjury rate on the expected value of a biceps tenodesis.
The overall expected value for biceps tenodesis was 8.66 versus 7.19 for SLAP repair. One-way sensitivity demonstrated that biceps tenodesis was the superior choice if reinjury rates are expected to be less than 28%. Meta-analysis of 23 studies and 908 patients revealed the probability of a well outcome was significantly greater for BT (87.8%; 95% CI 74.9-94.6%, I2=0.0%) than SLAP repair (62.9%; 95% CI 55.9-69.3%, I2=65.9%; p=0.0023). Reinjury with BT was 1.5% (95% CI 0.05% to 33.8%, I2=0.0%) and repair 6.4% (95% CI 4.2%-9.6%, I2=24%) which was not statistically significantly different (p=0.411). 50 participants mean age=25.4 (SD 8.9), male = 76%; overhead athletes = 50% met inclusion criteria. Forty-six percent of participants had a SAL score of ‘high’.
Decision analysis demonstrated that biceps tenodesis is preferred over repair for an isolated type II SLAP tear based on greater expected value of BT versus repair. Meta-analysis demonstrated more frequent favorable outcomes with BT. Surgeons can use this information to tailor discussion with patients..
Aneurysmal bone cyst (ABC) is a benign tumor of bone presenting as a cystic, expansile lesion in both the axial and appendicular skeleton. Axial lesions demand special consideration, because ...treatment-related morbidity can be devastating. In similar lesions, such as giant cell tumor of bone (GCTB), the receptor-activator of nuclear kappaB ligand (RANKL)-receptor-activator of nuclear kappaB (RANK) signaling axis is essential to tumor progression. Although ABC and GCTB are distinct entities, they both contain abundant multinucleated giant cells and are osteolytic characteristically. We hypothesize that ABCs express both RANKL and RANK similarly in a cell-type specific manner, and that targeted RANKL therapy will mitigate ABC tumor progression. Cellular expression of RANKL and RANK was determined in freshly harvested ABC samples using laser confocal microscopy. A consistent cell-type-specific pattern was observed: fibroblastlike stromal cells expressed RANKL strongly whereas monocyte/macrophage precursor and multinucleated giant cells expressed RANK. Relative RANKL expression was determined by quantitative real-time polymerase chain reaction in ABC and GCTB tissue samples; no difference in relative expression was observed ( P > 0.05). In addition, we review the case of a 5-year-old boy with a large, aggressive sacral ABC. After 3 months of targeted RANKL inhibition with denosumab, magnetic resonance imaging demonstrated tumor shrinkage, bone reconstitution, and healing of a pathologic fracture. Ambulation, and bowel and bladder function were restored at 6 months. Denosumab treatment was well tolerated. Post hoc analysis demonstrated strong RANKL expression in the pretreatment tumor sample. These findings demonstrate that RANKL-RANK signal activation is essential to ABC tumor progression. RANKL-targeted therapy may be an effective alternative to surgery in select ABC presentations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Intervertebral disc (IVD) homeostasis is mediated through a combination of micro-environmental and biomechanical factors, all of which are subject to genetic influences. The aim of this study is to ...develop and characterize a genetically tractable, ex vivo organ culture model that can be used to further elucidate mechanisms of intervertebral disc disease. Specifically, we demonstrate that IVD disc explants (1) maintain their native phenotype in prolonged culture, (2) are responsive to exogenous stimuli, and (3) that relevant homeostatic regulatory mechanisms can be modulated through ex-vivo genetic recombination. We present a novel technique for isolation of murine IVD explants with demonstration of explant viability (CMFDA/propidium iodide staining), disc anatomy (H&E), maintenance of extracellular matrix (ECM) (Alcian Blue staining), and native expression profile (qRT-PCR) as well as ex vivo genetic recombination (mT/mG reporter mice; AdCre) following 14 days of culture in DMEM media containing 10% fetal bovine serum, 1% L-glutamine, and 1% penicillin/streptomycin. IVD explants maintained their micro-anatomic integrity, ECM proteoglycan content, viability, and gene expression profile consistent with a homeostatic drive in culture. Treatment of genetically engineered explants with cre-expressing adenovirus efficaciously induced ex vivo genetic recombination in a variety of genetically engineered mouse models. Exogenous administration of IL-1ß and TGF-ß3 resulted in predicted catabolic and anabolic responses, respectively. Genetic recombination of TGFBR1fl/fl explants resulted in constitutively active TGF-ß signaling that matched that of exogenously administered TGF-ß3. Our results illustrate the utility of the murine intervertebral disc explant to investigate mechanisms of intervertebral disc degeneration.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Osteosarcoma (OS) is the most common type of solid bone cancer, with latent metastasis being a typical mode of disease progression and a major contributor to poor prognosis. For this to occur, cells ...must resist anoikis and be able to recapitulate tumorigenesis in a foreign microenvironment. Finding novel approaches to treat osteosarcoma and target those cell subpopulations that possess the ability to resist anoikis and contribute to metastatic disease is imperative. Here we investigate anchorage-independent (AI) cell growth as a model to better characterize anoikis resistance in human osteosarcoma while using an expression profiling approach to identify and test targetable signaling pathways.
Established human OS cell lines and patient-derived human OS cell isolates were subjected to growth in either adherent or AI conditions using Ultra-Low Attachment plates in identical media conditions. Growth rate was assessed using cell doubling times and chemoresistance was assessed by determining cell viability in response to a serial dilution of either doxorubicin or cisplatin. Gene expression differences were examined using quantitative reverse-transcription PCR and microarray with principal component and pathway analysis. In-vivo OS xenografts were generated by either subcutaneous or intratibial injection of adherent or AI human OS cells into athymic nude mice. Statistical significance was determined using student's t-tests with significance set at α=0.05.
We show that AI growth results in a global gene expression profile change accompanied by significant chemoresistance (up to 75 fold, p<0.05). AI cells demonstrate alteration of key mediators of mesenchymal differentiation (β-catenin, Runx2), stemness (Sox2), proliferation (c-myc, Akt), and epigenetic regulation (HDAC class 1). AI cells were equally tumorigenic as their adherent counterparts, but showed a significantly decreased rate of growth in-vitro and in-vivo (p<0.05). Treatment with the pan-histone deacetylase inhibitor vorinostat and the DNA methyltransferase inhibitor 5-azacytidine mitigated AI growth, while 5-azacytidine sensitized anoikis-resistant cells to doxorubicin (p<0.05).
These data demonstrate remarkable plasticity in anoikis-resistant human osteosarcoma subpopulations accompanied by a rapid development of chemoresistance and altered growth rates mirroring the early stages of latent metastasis. Targeting epigenetic regulation of this process may be a viable therapeutic strategy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary
In this retrospective study, approximately 77% of patients who attended their osteoporosis clinic follow-up appointments following a fragility fracture were started on medical treatment. ...Approximately 82% of those patients were adherent with their treatment, and 1% of patients sustained a secondary fragility fracture while on treatment.
Purpose
To assess the effects of implementation of a fracture liaison service at a tertiary care academic medical center on osteoporosis treatment adherence and secondary fracture rates.
Methods
We retrospectively reviewed over 6000 patients age 50 years or greater during a 5-year time period (2013–2018). Patients were identified as having a fragility fracture on presentation to the emergency department at the Wake Forest Baptist Medical Center and referred to our osteoporosis clinic using the electronic medical record. Data were collected regarding those patients who were recommended treatment, started treatment, maintained adherent to treatment, and those who sustained a secondary fracture.
Results
6178 patients were identified as having a fragility fracture and referred to the osteoporosis clinic. 2631 of these patients successfully had a scheduled outpatient appointment at the osteoporosis clinic, of which 1937 attended their initial appointment and 1840 of these patients were prescribed treatment. Of the 1840 patients who were initially prescribed medication, 1416 (76.96%) initiated their treatment, and 1156 (81.64%) remained adherent to treatment. Fifteen patients (1.05%) on treatment sustained a secondary fracture after initiation of therapy.
Conclusion
Implementation of a fracture liaison service at a tertiary care academic medical center is feasible and is associated with high rates of treatment implementation/adherence and low incidence of secondary fracture.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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