Osteoporosis and cement usage in total hip arthroplasty.

PURPOSE: Cement usage in total hip arthroplasty (THA) is increasingly common. However, osteoporosis-related fracture risk in cemented vs uncemented THA patients is poorly characterized. We aim to analyze the usage of metabolic bone care and osteoporosis fracture risk in cemented vs uncemented THA patients using FRAX and radiographic bone measurements. METHODS: Chart review on 250 THA patients was performed retrospectively. Demographics, FRAX scores, hip radiograph measurements, osteoporosis diagnosis, treatment and screening were compared between cemented and uncemented THA patients. Logistic regression model was used to analyze factors influencing cement usage. RESULTS: Cemented THA patients have significantly higher osteoporosis-related fracture risk as measured by FRAX major (20% vs 13%) and FRAX hip (8% vs 5%). There is no significant difference in osteoporosis treatment, vitamin D / calcium supplementation, or metabolic bone disease screening based on patients' cement status. Female sex and rheumatoid arthritis status significantly predict cement usage, but FRAX scores do not predict cement usage. Additionally, 50% (10/20) of patients with Dorr C classification were uncemented. CONCLUSION: Although some patients undergoing THA with high osteoporosis-related fracture risk were identified and cemented, some risk factors including poor proximal femur shape (by Dorr classification) and poor bone quality (as measured by FRAX score) were potentially overlooked. Cemented patients had an increased risk for fractures but did not receive appropriately increased osteoporosis screening or treatment. LEVEL OF EVIDENCE: III.

Long-Term Patient Outcomes for Treatment of Difficult Osteochondral Lesions of the Talus with Particulated Juvenile Allograft Cartilage Implantation ± Calcaneal Autograft: A Cohort Study.

BACKGROUND: Osteochondral lesions of the talus (OCLT) are common injuries that can be difficult to treat. To date, long-term patient reported outcome measures (PROMs) of patients with particulated juvenile allograft cartilage implantation with or without calcaneal autograft have not been compared. METHODS: Thirteen patients with difficult to treat OCLTs underwent arthroscopic-assisted implantation of particulated juvenile allograft cartilage (DeNovo NT®) with or without autogenous calcaneal bone grafting by a single surgeon. Calcaneal bone graft use was determined by lesion size > 150 mm2 and/or deeper than 5 mm. Patients were evaluated using physical examination, patient interviews, and PROMs. RESULTS: When comparing patients in regards to calcaneal bone graft implantation, no difference in age, BMI, pre-operative PROMs, or follow-up was noted, however, calcaneal bone graft patients did have a significantly larger lesion size (188.5 ± 50.9 vs. 118.7 ± 29.4 mm2 respectively; p value = 0.027). VAS and FAAM ADL scores during final follow-up improvement did not significantly differ between cohorts. The FAAM Sports score improved significantly more for the DeNovo alone group compared to the bone graft cohort (p value = 0.032). The AOFAS score improvement did not differ between cohorts (p value = 0.944), however, the SF-36 PCS improved significantly more for the DeNovo alone group compared to the bone graft cohort (p value = 0.038). No intraoperative/perioperative complications were observed with calcaneal bone grafting. CONCLUSION: While patients followed over the course of ~ 8 years after implantation of particulated juvenile allograft cartilage (DeNovo NT®) with/without autogenous calcaneal bone graft had positive post-operative PROMs, patients without calcaneal bone graft had significantly greater improvement in functional outcome scores. Whether these differences are due to graft incorporation or larger lesion size is unclear. LEVEL OF EVIDENCE: III, retrospective cohort study.

Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis.

BACKGROUND: Retinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression. Previous work indicated that Rbbp4 cooperates with the Rb tumor suppressor to block cell cycle entry. Here, we use genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival. RESULTS: Rbbp4 is upregulated across the spectrum of human embryonal and glial brain cancers. Transgenic rescue of rbbp4 mutant embryos shows Rbbp4 is essential for zebrafish neurogenesis. Rbbp4 loss leads to apoptosis and γ-H2AX in the developing brain that is suppressed by tp53 knockdown or maternal zygotic deletion. Mutant retinal neural precursors accumulate in M phase and fail to initiate G0 gene expression. rbbp4; rb1 mutants show an additive effect on the number of M phase cells. In rbbp4 mutants, Tp53 acetylation is detected; however, Rbbp4 overexpression did not rescue DNA damage-induced apoptosis. CONCLUSION: Rbbp4 is necessary for neural progenitor cell cycle progression and initiation of G0 independent of Rb. Tp53-dependent apoptosis in the absence of Rbpb4 correlates with Tp53 acetylation. Together these results suggest that Rbbp4 is required for cell cycle exit and contributes to neural progenitor survival through the regulation of Tp53 acetylation.

A Systematic Review of Lower-Body Kinematic and Strength Factors Associated With Pitch Velocity in Adult Baseball Pitchers.

CONTEXT: Ball velocity for baseball pitchers is influenced by a multitude of factors along the kinetic chain. While a vast amount of data currently exist exploring lower-extremity kinematic and strength factors in baseball pitchers, no previous study has systematically reviewed the available literature. OBJECTIVE: The aim of this systematic review was to perform a comprehensive assessment of the available literature investigating the association between lower-extremity kinematic and strength parameters and pitch velocity in adult pitchers. EVIDENCE ACQUISITION: Cross-sectional studies that investigated the association between lower-body kinematic and strength factors and ball velocity in adult pitchers were selected. A methodological index for nonrandomized studies checklist was used to evaluate the quality of all included studies. EVIDENCE SYNTHESIS: Seventeen studies met the inclusion criteria comprising a total of 909 pitchers (65%, professional, 33% college, and 3% recreational). The most studied elements were hip strength and stride length. The mean methodological index for nonrandomized studies score was 11.75 of 16 (range = 10-14). Pitch velocity was found to be influenced by several lower-body kinematic and strength factors including the following: (1) hip range of motion and strength of muscles around the hip and pelvis, (2) alterations in stride length, (3) alterations in lead knee flexion/extension, and (4) several pelvic and trunk spatial relationships throughout the throwing phase. CONCLUSIONS: Based on this review, we conclude that hip strength is a well-established predictor of increased pitch velocity in adult pitchers. Further studies in adult pitchers are needed to elucidate the effect of stride length on pitch velocity given mixed results across multiple studies. This study can provide a basis for trainers and coaches to consider the importance of lower-extremity muscle strengthening as a means by which adult pitchers can improve pitching performance.

Fracture Risk Assessment Tool Scores and Radiographical Bone Measurements in Total Hip Arthroplasty Patients.

BACKGROUND: Osteoporosis is a major risk factor for periprosthetic fractures (PPFx) in total hip arthroplasty (THA) patients but is not routinely screened for in this population. Given the availability of hip x-rays and preoperative screenings, Fracture Risk Assessment Tool (FRAX) scores and radiographic bone measurements are potentially promising, novel risk stratification tools. This study aims to characterize FRAX scores and radiographic bone measurements in THA and PPFx patients. METHODS: A retrospective chart review for demographic variables and FRAX scores was performed on 250 THA and 40 PPFx patients. Radiographic bone measurements including cortical thicknesses (both antero-posterior [AP] and lateral), canal to calcar ratio, canal flare index, and Dorr classifications were obtained from preoperative x-rays. Correlation between FRAX scores and radiographic bone measurements was investigated with linear regressions. FRAX scores and radiographic bone measurements were compared between the THA and PPFx patients. Multivariate logistic regressions were used to identify factors predicting PPFx. RESULTS: FRAX scores were significantly correlated with both AP (P < .001) and lateral (P = .007) cortical thicknesses. Compared to THA patients, those with PPFx had significantly higher FRAX scores (P = .003) and lower AP cortical thickness (P = .005). Multivariate logistic regressions demonstrated that FRAX major osteoporotic fracture risk score and AP cortical thickness were independent predictors of PPFx (P = .001 and .024, respectively). CONCLUSION: Cortical thicknesses are good proxy measurements of osteoporosis-related fracture risk in THA patients. In addition, both major and AP cortical thickness indices are promising tools for identifying patients who are at a high risk of PPFx in the THA population.

A Comparison of Throwing Arm Kinetics and Ball Velocity in High School Pitchers With Overall Fast and Overall Slow Cumulative Joint and Segment Velocities.

BACKGROUND: Individual maximum joint and segment angular velocities have shown positive associations with throwing arm kinetics and ball velocity in baseball pitchers. PURPOSE: To observe how cumulative maximum joint and segment angular velocities, irrespective of sequence, affect ball velocity and throwing arm kinetics in high school pitchers. STUDY DESIGN: Descriptive laboratory study. METHODS: High school (n = 55) pitchers threw 8 to 12 fastball pitches while being evaluated with 3-dimensional motion capture (480 Hz). Maximum joint and segment angular velocities (lead knee extension, pelvis rotation, trunk rotation, shoulder internal rotation, and forearm pronation) were calculated for each pitcher. Pitchers were classified as overall fast, overall slow, or high velocity for each joint or segment velocity subcategory, or as population, with any pitcher eligible to be included in multiple subcategories. Kinematic and kinetic parameters were compared among the various subgroups using t tests with post hoc regressions and multivariable regression models created to predict throwing arm kinetics and ball velocity, respectively. RESULTS: The lead knee extension and pelvis rotation velocity subgroups achieved significantly higher normalized elbow varus torque (P = .016) and elbow flexion torque (P = .018) compared with population, with equivalent ball velocity (P = .118). For every 1-SD increase in maximum pelvis rotation velocity (87 deg/s), the normalized elbow distractive force increased by 4.7% body weight (BW) (B = 0.054; ß = 0.290; P = .013). The overall fast group was older (mean ± standard deviation, 16.9 ± 1.4 vs 15.4 ± 0.9 years; P = .007), had 8.9-mph faster ball velocity (32.7 ± 3.1 vs 28.7 ± 2.3 m/s; P = .002), and had significantly higher shoulder internal rotation torque (63.1 ± 17.4 vs 43.6 ± 12.0 Nm; P = .005), elbow varus torque (61.8 ± 16.4 vs 41.6 ± 11.4 Nm; P = .002), and elbow flexion torque (46.4 ± 12.0 vs 29.5 ± 6.8 Nm; P < .001) compared with the overall slow group. A multiregression model for ball velocity based on maximum joint and segment angular velocities and anthropometrics predicted 53.0% of variance. CONCLUSION: High school pitchers with higher maximum joint and segment velocities, irrespective of sequence, demonstrated older age and faster ball velocity at the cost of increased throwing shoulder and elbow kinetics. CLINICAL RELEVANCE: Pitchers and coaching staff should consider this trade-off between faster ball velocity and increasing throwing arm kinetics, an established risk factor for elbow injury.

Osteoid Osteomas of the Talus: A Case Report of Four Patients.

Osteoid osteomas are benign bone tumors that are commonly found in the cortical segments of long bone but can occasionally occur in the talus of the foot. They typically present in younger males and are characterized by lesions with a vascularized nidus surrounded by sclerotic bone. Plain radiographs can often miss the diagnosis, requiring further imaging with computed tomography (CT) or magnetic resonance imaging (MRI). Lesions often lead to a significant inflammatory response resulting in an impaired range of motion and nocturnal pain. Conservative management with non-steroidal anti-inflammatory medications and a walking boot is considered first-line therapy, with failure to respond being an indication for surgical intervention. Surgical treatment traditionally consisted of en bloc resection but has been replaced by CT-guided radio-frequency ablation (RFA) when conservative management has failed. Four cases of osteoid osteoma of the talus are presented which all went on to RFA after conservative management failed. The patients' non-specific symptomatology and unremarkable findings on plain radiographs led to further evaluation using MRI or CT, which aided in the diagnosis. Following imaging, RFA was performed which resulted in 100% relief of pain and symptoms in all four patients and a return to full activity without limitations. Osteoid osteomas of the talus present unique challenges due to the non-specific symptoms and complex surrounding anatomy that accompanies this condition. Management should include the use of CT for localization and RFA of the lesion, which we have shown leads to complete resolution of symptoms and return to normal daily activities.

Early outcomes of the Exactech Vantage fixed-bearing total ankle replacement.

Aims: The Vantage Total Ankle System is a fourth-generation low-profile fixed-bearing implant that has been available since 2016. We aimed to describe our early experience with this implant. Methods: This is a single-centre retrospective review of patients who underwent primary total ankle arthroplasty (TAA) with a Vantage implant between November 2017 and February 2020, with a minimum of two years' follow-up. Four surgeons contributed patients. The primary outcome was reoperation and revision rate of the Vantage implant at two years. Secondary outcomes included radiological alignment, peri-implant complications, and pre- and postoperative patient-reported outcomes. Results: There were 168 patients (171 ankles) included with a mean follow-up of 2.81 years (2 to 4.6) and mean age of 63.0 years (SD 9.4). Of the ten ankles with implant failure (5.8%), six had loosening of the tibial component. In the remaining four failed implants, one was due to periprosthetic joint infection (PJI), one was due to loosening of the talar component, and two were due to loosening of both the tibial and talar components. Seven patients underwent reoperation: irrigation and debridement for superficial infection (n = 4); bone grafting for cysts (n = 2); and open reduction internal fixation (n = 1). Asymptomatic peri-implant lucency/subsidence occurred in 20.1% of ankles, with the majority involving the tibial component (n = 25). There were statistically significant improvements in PROMs in all domains. Conclusion: Short-term results of this implant demonstrate early survival comparable to the reported survivorship of similar low-profile, non-stemmed implants. Radiological lucency occurred more commonly at the tibial component, and revisions occurred primarily due to loosening of the tibial component. Further research is needed to evaluate longer-term survivorship.

A Primer Genetic Toolkit for Exploring Mitochondrial Biology and Disease Using Zebrafish.

Mitochondria are a dynamic eukaryotic innovation that play diverse roles in biology and disease. The mitochondrial genome is remarkably conserved in all vertebrates, encoding the same 37-gene set and overall genomic structure, ranging from 16,596 base pairs (bp) in the teleost zebrafish (Danio rerio) to 16,569 bp in humans. Mitochondrial disorders are amongst the most prevalent inherited diseases, affecting roughly 1 in every 5000 individuals. Currently, few effective treatments exist for those with mitochondrial ailments, representing a major unmet patient need. Mitochondrial dysfunction is also a common component of a wide variety of other human illnesses, ranging from neurodegenerative disorders such as Huntington's disease and Parkinson's disease to autoimmune illnesses such as multiple sclerosis and rheumatoid arthritis. The electron transport chain (ETC) component of mitochondria is critical for mitochondrial biology and defects can lead to many mitochondrial disease symptoms. Here, we present a publicly available collection of genetic mutants created in highly conserved, nuclear-encoded mitochondrial genes in Danio rerio. The zebrafish system represents a potentially powerful new opportunity for the study of mitochondrial biology and disease due to the large number of orthologous genes shared with humans and the many advanced features of this model system, from genetics to imaging. This collection includes 15 mutant lines in 13 different genes created through locus-specific gene editing to induce frameshift or splice acceptor mutations, leading to predicted protein truncation during translation. Additionally, included are 11 lines created by the random insertion of the gene-breaking transposon (GBT) protein trap cassette. All these targeted mutant alleles truncate conserved domains of genes critical to the proper function of the ETC or genes that have been implicated in human mitochondrial disease. This collection is designed to accelerate the use of zebrafish to study many different aspects of mitochondrial function to widen our understanding of their role in biology and human disease.

Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the lrpprc locus. Here, we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

Building the vertebrate codex using the gene breaking protein trap library.

One key bottleneck in understanding the human genome is the relative under-characterization of 90% of protein coding regions. We report a collection of 1200 transgenic zebrafish strains made with the gene-break transposon (GBT) protein trap to simultaneously report and reversibly knockdown the tagged genes. Protein trap-associated mRFP expression shows previously undocumented expression of 35% and 90% of cloned genes at 2 and 4 days post-fertilization, respectively. Further, investigated alleles regularly show 99% gene-specific mRNA knockdown. Homozygous GBT animals in ryr1b, fras1, tnnt2a, edar and hmcn1 phenocopied established mutants. 204 cloned lines trapped diverse proteins, including 64 orthologs of human disease-associated genes with 40 as potential new disease models. Severely reduced skeletal muscle Ca2+ transients in GBT ryr1b homozygous animals validated the ability to explore molecular mechanisms of genetic diseases. This GBT system facilitates novel functional genome annotation towards understanding cellular and molecular underpinnings of vertebrate biology and human disease.

The human genome counts over 20,000 genes, which can be turned on and off to create the proteins required for most of life processes. Once produced, proteins need move to specific locations in the cell, where they are able to perform their jobs. Despite striking scientific advances, 90% of human genes are still under-studied; where the proteins they code for go, and what they do remains unknown. Zebrafish share many genes with humans, but they are much easier to manipulate genetically. Here, Ichino et al. used various methods in zebrafish to create a detailed 'catalogue' of previously poorly understood genes, focusing on where the proteins they coded for ended up and the biological processes they were involved with. First, a genetic tool called gene-breaking transposons (GBTs) was used to create over 1,200 strains of genetically altered fish in which a specific protein was both tagged with a luminescent marker and unable to perform its role. Further analysis of 204 of these strains revealed new insight into the role of each protein, with many having unexpected roles and localisations. For example, in one zebrafish strain, the affected gene was similar to a human gene which, when inactivated, causes severe muscle weakness. These fish swam abnormally slowly and also had muscle problems, suggesting that the GBT fish strains could 'model' the human disease. This work sheds new light on the role of many previously poorly understood genes. In the future, similar collections of GBT fish strains could help researchers to study both normal human biology and disease. They could especially be useful in cases where the genes responsible for certain conditions are still difficult to identify.