Comparison Of Early And Late Aseptic Baseplate Failure In Primary Reverse Shoulder Arthroplasty With And Without Structural Glenoid Autograft.

INTRODUCTION: Early reverse total shoulder arthroplasty (RTSA) designs demonstrated high glenoid baseplate complication and revision rates. While contemporary designs have reduced the incidence of glenoid baseplate failures, there are reports of elevated failure risks in RTSA with glenoid bone grafting within the first 2 years. This study aims to evaluate the incidence and etiology of aseptic glenoid baseplate failure with a contemporary central screw baseplate. The null hypothesis is that majority of the baseplate failure occurs within the first 2 years and use of glenoid bone grafting does not lead to higher risk of baseplate failure. METHODS: In 2014 - 2019, 753 consecutive patients who underwent primary RSA using the same inlay press-fit humeral stem and monoblock central screw baseplate were retrospectively reviewed. Fracture and septic arthropathy cases were excluded. All patients underwent preoperative radiographic and computed tomography evaluation. If there was significant glenoid erosion (Walch A2, B2, B3, C1, C2, E2, E3, and/or E4 variants), patient-specific structural glenoid bone grafting was performed. All patients underwent standardized radiographic follow-up and failure was strictly defined as any hardware breakage and/or shift in glenoid baseplate position. Failures were defined as "early" if occurring within 2 years and "late" if occurring greater than 2 years after surgery. Comparative analysis was performed to evaluate demographics, glenoid graft use, and graft union rates between the cohorts. RESULTS: There were 23 patients with baseplate failures (23/753, 3.0%) at mean of 23 months. Twenty-two failures (96%) occurred in patients who received structural glenoid bone grafting. Only 1 failure (0.2%) occurred when bone grafting was not indicated (p<0.001). The most common failure pattern was associated with B2 glenoid (16/23, 70%). There were 5 (22%) early failures and 18 (78%) late failures. There were no differences in any patient demographic characteristics between cohorts. All 5 early failures had graft nonunion and 4/5 occurred without trauma. In the 18 late failures , 9/18 (50%) occurred without trauma (p=0.135). Seventeen of these patients had glenoid grafting, of which 9/17 (53%) had graft nonunion. CONCLUSIONS: Contemporary RTSA glenoid baseplate designs have an acceptably low incidence of failure. However, the addition of structural bone graft to correct glenoid wear leads to higher aseptic baseplate failure rate. The majority of these patients suffer failure after the 2-year postoperative mark, highlighting the necessity of longer follow-up. Further analysis is necessary to quantify glenoid characteristics (severity of glenoid erosion, critical size of graft) associated with failure.

Fibroblast Stromal Support Model for Predicting Human Papillomavirus-Associated Cancer Drug Responses.

Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV+OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERα) is overexpressed in HPV+OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV+ specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV+ keratinocytes and HPV+ cancer cells in vitro. Expansion of this work in vivo failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and in vivo therapeutic responses. Our investigations revealed that in vitro co-culture with fibroblasts attenuated HPV+ specific estrogen growth responses. Continuing to monopolize on the HPV+ specific overexpression of ERα, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs in vitro. Utilization of these SERMs in vivo closely resembled the sensitization predicted by our co-culture models. Therefore, the in vitro fibroblast co-culture model better predicts in vivo responses. We propose that utilization of our co-culture in vitro model can accelerate cancer therapeutic drug discovery.

Human Papillomavirus 16 replication converts SAMHD1 into a homologous recombination factor and promotes its recruitment to replicating viral DNA.

We have demonstrated that SAMHD1 (sterile alpha motif and histidine-aspartic domain HD-containing protein 1) is a restriction factor for the HPV16 life cycle. Here we demonstrate that in HPV negative cervical cancer C33a cells and human foreskin keratinocytes immortalized by HPV16 (HFK+HPV16), SAMHD1 is recruited to E1-E2 replicating DNA. Homologous recombination (HR) factors are required for HPV16 replication and viral replication promotes phosphorylation of SAMHD1, which converts it from a dNTPase to an HR factor independent from E6/E7 expression. A SAMHD1 phosphor-mimic (SAMHD1 T592D) reduces E1-E2 mediated DNA replication in C33a cells and has enhanced recruitment to the replicating DNA. In HFK+HPV16 cells SAMHD1 T592D is recruited to the viral DNA and attenuates cellular growth, but does not attenuate growth in isogenic HFK cells immortalized by E6/E7 alone. SAMHD1 T592D also attenuates the development of viral replication foci following keratinocyte differentiation. The results indicated that enhanced SAMHD1 phosphorylation could be therapeutically beneficial in cells with HPV16 replicating genomes. Protein phosphatase 2A (PP2A) can dephosphorylate SAMHD1 and PP2A function can be inhibited by endothall. We demonstrate that endothall reduces E1-E2 replication and promotes SAMHD1 recruitment to E1-E2 replicating DNA, mimicking the SAMHD1 T592D phenotypes. Finally, we demonstrate that in head and neck cancer cell lines with HPV16 episomal genomes endothall attenuates their growth and promotes recruitment of SAMHD1 to the viral genome. The results suggest that targeting cellular phosphatases has therapeutic potential for the treatment of HPV infections and cancers. Importance: Human papillomaviruses are causative agents in around 5% of all human cancers. The development of anti-viral therapeutics depends upon an increased understanding of the viral life cycle. Here we demonstrate that HPV16 replication converts SAMHD1 into an HR factor via phosphorylation. This phosphorylation promotes recruitment of SAMHD1 to viral DNA to assist with replication. A SAMHD1 mutant that mimics phosphorylation is hyper-recruited to viral DNA and attenuates viral replication. Expression of this mutant in HPV16 immortalized cells attenuates the growth of these cells, but not cells immortalized by the viral oncogenes E6/E7 alone. Finally, we demonstrate that the phosphatase inhibitor endothall promotes hyper-recruitment of endogenous SAMHD1 to HPV16 replicating DNA and can attenuate the growth of both HPV16 immortalized human foreskin keratinocytes and HPV16 positive head and neck cancer cell lines. We propose that phosphatase inhibitors represent a novel tool for combating HPV infections and disease.

Arthroscopically Assisted Fixation of Terrible Triad Variant Injuries of the Elbow With Small-Bore Needle Arthroscopy.

The range of diagnostic and therapeutic applications of needle arthroscopy (NA) continue to expand due to advances in image quality and resolution. Minimally invasive techniques can be augmented by the smaller camera size and reduced fluid use made possible by NA. Small-bore arthroscopy presents opportunities for use in smaller joints, such as the elbow, where applications of standard arthroscopic equipment may be limited by small anatomic spaces and fluid extravasation. In this Technical Note, we present our technique for NA-assisted treatment of terrible triad injuries, specifically in the setting of an intact radial head. The technique describes a stepwise approach to arthroscopically aided fixation of the coronoid process, followed by open reconstruction of the lateral collateral ligament complex.