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AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with potential antifibrotic effects. Whether AdipoRon can mitigate joint stiffness in a rabbit model of arthrofibrosis is unknown. We examined the efficacy of intravenous (IV) AdipoRon at mitigating contracture in a rabbit model of knee arthrofibrosis. Fifty-six female New Zealand White rabbits were divided into three dosing groups: vehicle (dimethyl sulfoxide, DMSO), 2.5 mg/kg AdipoRon, and 5 mg/kg AdipoRon. AdipoRon, in DMSO, was administered IV preoperatively and for 5 days postoperatively (30 rabbits, Aim 1). AdipoRon was again dosed similarly after Kirschner wire (K-wire) removal at 8 weeks (26 rabbits; Aim 2). The primary outcome of joint passive extension angle (PEA,°) was measured at 8, 10, 12, 16, and 24 weeks following index surgery. At 24 weeks, rabbits were euthanized and limbs were harvested to measure posterior capsular stiffness (N cm/°). In Aim 1, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 16-week (p < 0.05). In Aim 2, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 10-week (p < 0.05). In both aims, no significant differences were observed at later time points. Capsular stiffness was no different in any group. We are the first to report the efficacy of IV AdipoRon in a rabbit model of arthrofibrosis. We identified a significant dose-dependent decrease in joint PEA at early time points; however, no differences were observed between groups at later time points. Clinical Significance: The present investigation provided the first assessment of AdipoRon's efficacy in mitigating knee stiffness in the current gold standard rabbit model of arthrofibrosis. Results of this investigation provided further evidence as to the potential role of AdipoRon as a preventative for arthrofibrosis in large mammals., (© 2024 Orthopaedic Research Society.)

Background: Neurocognitive impairment and quality of life are two important long-term challenges for patients with complex CHD. The impact of re-interventions during adolescence and young adulthood on neurocognition and quality of life is not well understood., Methods: In this prospective longitudinal multi-institutional study, patients 13-30 years old with severe CHD referred for surgical or transcatheter pulmonary valve replacement were enrolled. Clinical characteristics were collected, and executive function and quality of life were assessed prior to the planned pulmonary re-intervention. These results were compared to normative data and were compared between treatment strategies., Results: Among 68 patients enrolled from 2016 to 2020, a nearly equal proportion were referred for surgical and transcatheter pulmonary valve replacement (53% versus 47%). Tetralogy of Fallot was the most common diagnosis (59%) and pulmonary re-intervention indications included stenosis (25%), insufficiency (40%), and mixed disease (35%). There were no substantial differences between patients referred for surgical and transcatheter therapy. Executive functioning deficits were evident in 19-31% of patients and quality of life was universally lower compared to normative sample data. However, measures of executive function and quality of life did not differ between the surgical and transcatheter patients., Conclusion: In this patient group, impairments in neurocognitive function and quality of life are common and can be significant. Given similar baseline characteristics, comparing changes in neurocognitive outcomes and quality of life after surgical versus transcatheter pulmonary valve replacement will offer unique insights into how treatment approaches impact these important long-term patient outcomes.

Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti-fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFβ1-mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFβ1-induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA-seq analysis corroborated the anti-myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle-treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis., (© 2023 Wiley Periodicals LLC.)

Objective: In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age., Methods: Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival., Results: Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; P =0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; P =0.11), percentage predicted peak Vo 2 for age and sex (74±18% [n=91] versus 72±18% [n=84]; P =0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; P =0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; P =0.04) and of catheter interventions (14 versus 10 per 100 patient-years; P =0.01), but had similar rates of other complications., Conclusions: By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo 2 , complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT0245531., Competing Interests: Disclosures None.

Background: Tele-consults provide access to specialized care for a specific question and single point in time. eICU models utilize remote monitoring and ordering but have significant financial burden. We developed a virtual intensive care unit (VICU) for daily input of an intensivist working with local physicians. The purpose was to expand the acute care ability of the critical access hospital (CAH). The study evaluates the impact on the CAH and system., Methods: The CAH developed an ICU team, led by a hospitalist, who staffed the intensive care unit (ICU). The CAH ICU team rounds daily via a secure video link to provide care in consultation with intensivists based at a university, tertiary care center (TC). A retrospective analysis was conducted 6 months before and after implementation (4/2018-3/2019). Fisher's exact test was used to compare pre- and post-intervention with significance at P < .04., Results: After VICU implementation, there were 265 initial daily and 35 follow-up consults. Monthly transfers to a higher level of care decreased from 63 to 57 ( P = .03). Transfers to TC increased from 49.6 to 62.0% ( P = .001). Critical access hospital average monthly census and average monthly inpatient days increased (69 to 130 ( P < .0001) and 158 to 319 ( P < .0001), respectively). Critical access hospital physicians report increased comfort to admit ICU and non-ICU patients due to the program. The total startup cost was $5180. CAH hired 11 providers. There were no unanticipated deaths., Discussion: VICU implementation resulted in new CAH jobs. The CAH experienced increased inpatient census and revenues (ICU and non-ICU) while decreasing patients transferred out of the system.

AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with numerous reported physiological benefits in murine models of human disease, including a proposed reduction in fibrosis. However, AdipoRon has never been investigated in rabbits, which provide a robust model for orthopedic conditions. We examined the safety of intravenous (IV) AdipoRon in New Zealand White (NZW) female rabbits surgically stressed by a procedure that mimics human arthrofibrosis. Fifteen female NZW rabbits were prospectively studied using increasing AdipoRon doses based on established literature. AdipoRon was dissolved in dimethyl sulfoxide (DMSO), diluted in normal saline, and administered IV preoperatively and for 5 subsequent days postoperatively. The primary outcome was overall toxicity to rabbits, whereas secondary outcomes were change in rabbit weights and hemodynamics and defining acid-base characteristics of the drug formulation. Two rabbits expired during preoperative drug administration at 25 mg/kg. Remaining rabbits received preoperative doses of DMSO (vehicle), 2.5, 5, or 10 mg/kg of AdipoRon without complications. On postoperative day 1, one rabbit sustained a tonic-clonic seizure after their second dose of 10 mg/kg AdipoRon. The remaining 12 rabbits (4 in each group) received six serial doses of vehicle, 2.5, or 5 mg/kg of AdipoRon without adverse effects. All formulations of AdipoRon were within safe physiological pH ranges (4-5). We are the first to report the use of IV AdipoRon in a surgically stressed rabbit model of orthopedic disease. AdipoRon doses of 5 mg/kg or less appear to be well-tolerated in female NZW rabbits. Impact statement We provided the first in vivo toxicity assessment and dose optimization of a new antifibrotic experimental medication, AdipoRon, in a surgically stressed rabbit model of knee arthrofibrosis.

Objectives: Virtual reality has emerged as a unique educational modality for medical trainees. However, incorporation of virtual reality curricula into formal training programmes has been limited. We describe a multi-centre effort to develop, implement, and evaluate the efficacy of a virtual reality curriculum for residents participating in paediatric cardiology rotations., Methods: A virtual reality software program ("The Stanford Virtual Heart") was utilised. Users are placed "inside the heart" and explore non-traditional views of cardiac anatomy. Modules for six common congenital heart lesions were developed, including narrative scripts. A prospective case-control study was performed involving three large paediatric residency programmes. From July 2018 to June 2019, trainees participating in an outpatient cardiology rotation completed a 27-question, validated assessment tool. From July 2019 to February 2020, trainees completed the virtual reality curriculum and assessment tool during their cardiology rotation. Qualitative feedback on the virtual reality experience was also gathered. Intervention and control group performances were compared using univariate analyses., Results: There were 80 trainees in the control group and 52 in the intervention group. Trainees in the intervention group achieved higher scores on the assessment (20.4 ± 2.9 versus 18.8 ± 3.8 out of 27 questions answered correctly, p = 0.01). Further analysis showed significant improvement in the intervention group for questions specifically testing visuospatial concepts. In total, 100% of users recommended integration of the programme into the residency curriculum., Conclusions: Virtual reality is an effective and well-received adjunct to clinical curricula for residents participating in paediatric cardiology rotations. Our results support continued virtual reality use and expansion to include other trainees.

Arthrofibrosis, which is characterized by excessive scar tissue and limited motion, can complicate the daily functioning of patients after total knee arthroplasty (TKA). Molecular hallmarks of arthrofibrosis include pathologic accumulation of myofibroblasts and disproportionate collagen deposition. Epigenetic mechanisms, including posttranslation modification of histones, control gene expression and may regulate fibrotic events. This study assessed the role of the bromodomain and extra-terminal (BET) proteins on myofibroblast differentiation. This group of epigenetic regulators recognize acetylated lysines and are targeted by a class of drugs known as BET inhibitors. RNA-seq analysis revealed robust mRNA expression of three BET members (BRD2, BRD3, and BRD4) while the fourth member (BRDT) is not expressed in primary TKA knee outgrowth fibroblasts. RT-qPCR and western blot analyses revealed that BET inhibition with the small molecule JQ1 impairs TGFβ1-induced expression of ACTA2, a key myofibroblast marker, in primary outgrowth knee fibroblasts. Similarly, JQ1 administration also reduced COL3A1 mRNA levels and collagen deposition as monitored by picrosirius red staining. Interestingly, the inhibitory effects of JQ1 on ACTA2 mRNA and protein expression, as well as COL3A1 expression and collagen deposition, were paralleled by siRNA-mediated depletion of BRD4. Together, these data reveal that BRD4-mediated epigenetic events support TGFβ1-mediated myofibroblast differentiation and collagen deposition as seen in arthrofibrosis. To our knowledge, these are the first studies that assess epigenetic regulators and their downstream events in the context of arthrofibrosis. Future studies may reveal clinical utility for drugs that target epigenetic pathways, specifically BET proteins, in the prevention and treatment of arthrofibrosis., (© 2023 Wiley Periodicals LLC.)

Aims: As has been shown in larger animal models, knee immobilization can lead to arthrofibrotic phenotypes. Our study included 168 C57BL/6J female mice, with 24 serving as controls, and 144 undergoing a knee procedure to induce a contracture without osteoarthritis (OA)., Methods: Experimental knees were immobilized for either four weeks (72 mice) or eight weeks (72 mice), followed by a remobilization period of zero weeks (24 mice), two weeks (24 mice), or four weeks (24 mice) after suture removal. Half of the experimental knees also received an intra-articular injury. Biomechanical data were collected to measure passive extension angle (PEA). Histological data measuring area and thickness of posterior and anterior knee capsules were collected from knee sections., Results: Experimental knees immobilized for four weeks demonstrated mean PEAs of 141°, 72°, and 79° after zero, two, and four weeks of remobilization (n = 6 per group), respectively. Experimental knees demonstrated reduced PEAs after two weeks (p < 0.001) and four weeks (p < 0.0001) of remobilization compared to controls. Following eight weeks of immobilization, experimental knees exhibited mean PEAs of 82°, 73°, and 72° after zero, two, and four weeks of remobilization, respectively. Histological analysis demonstrated no cartilage degeneration. Similar trends in biomechanical and histological properties were observed when intra-articular violation was introduced., Conclusion: This study established a novel mouse model of robust knee contracture without evidence of OA. This was appreciated consistently after eight weeks of immobilization and was irrespective of length of remobilization. As such, this arthrofibrotic model provides opportunities to investigate molecular pathways and therapeutic strategies.Cite this article: Bone Joint Res  2023;12(1):58-71.

Arthrofibrosis following total knee arthroplasty (TKA) is a debilitating condition typically diagnosed based on clinical findings. To gain insight into the histopathologic immune cell microenvironment of arthrofibrosis, we assessed the extent of tissue fibrosis and quantified immune cell populations in specific tissue regions of the posterior capsule. We investigated specimens from three prospectively-collected, matched cohorts, grouped as patients receiving a primary TKA for osteoarthritis, revision TKA for arthrofibrosis, and revision TKA for non-arthrofibrotic, non-infectious reasons. Specimens were evaluated using hematoxylin and eosin staining, picrosirius red staining, immunofluorescence, and immunohistochemistry with Aperio®-based digital image analysis. Increased collagen deposition and increased number of α-SMA/ACTA2 expressing myofibroblasts were present in the arthrofibrosis group compared to the two non-arthrofibrotic groups. CD163 + macrophages were the most abundant immune cell type in any capsular sample with specific enrichment in the synovial tissue. CD163 + macrophages were significantly decreased in the fibrotic tissue region of arthrofibrosis patients compared to the patients with primary TKA, and significantly increased in adipose tissue region of arthrofibrotic specimens compared to non-arthrofibrotic specimens. Synovial CD117 + mast cells were significantly decreased in arthrofibrotic adipose tissue. Together, these findings inform diagnostic and targeted therapeutic strategies by providing insight into the underlying pathogenetic mechanisms of arthrofibrosis., (© 2022. The Author(s).)

Background: The Single Ventricle Reconstruction (SVR) Trial was the first randomized clinical trial of a surgical approach for treatment of congenital heart disease. Infants with hypoplastic left heart syndrome (HLHS) and other single right ventricle (RV) anomalies were randomized to a modified Blalock Taussig Thomas shunt (mBTTS) or a right-ventricular-to-pulmonary-artery shunt (RVPAS) at the time of the Norwood procedure. The aim of the Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type (SVR III) study is to compare early adolescent outcomes including measures of cardiac function, transplant-free survival, and neurodevelopment, between those who received a mBTTS and those who received an RVPAS., Methods: Transplant-free survivors of the SVR cohort were enrolled at 10 to 15 years of age for multifaceted in-person evaluation of cardiac function (cardiac magnetic resonance [CMR], echocardiogram and exercise test) and neurodevelopmental evaluation. Right ventricular ejection fraction measured by CMR served as the primary outcome. Development of arrhythmias, protein losing enteropathy, and other comorbidities were assessed through annual medical history interview. Through the course of SVR III, protocol modifications to engage SVR trial participants were designed to enhance recruitment and retention., Conclusions: Evaluation of long-term outcomes will provide important data to inform decisions about the shunt type placed at the Norwood operation and will improve the understanding of cardiovascular and neurodevelopmental outcomes for early adolescents with HLHS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a complex disease involving increased resistance in the pulmonary arteries and subsequent right ventricular (RV) remodeling. Ventricular-arterial interactions are fundamental to PAH pathophysiology but are rarely captured in computational models. It is important to identify metrics that capture and quantify these interactions to inform our understanding of this disease as well as potentially facilitate patient stratification. Towards this end, we developed and calibrated two multi-scale high-resolution closed-loop computational models using open-source software: a high-resolution arterial model implemented using CRIMSON, and a high-resolution ventricular model implemented using FEniCS. Models were constructed with clinical data including non-invasive imaging and invasive hemodynamic measurements from a cohort of pediatric PAH patients. A contribution of this work is the discussion of inconsistencies in anatomical and hemodynamic data routinely acquired in PAH patients. We proposed and implemented strategies to mitigate these inconsistencies, and subsequently use this data to inform and calibrate computational models of the ventricles and large arteries. Computational models based on adjusted clinical data were calibrated until the simulated results for the high-resolution arterial models matched within 10% of adjusted data consisting of pressure and flow, whereas the high-resolution ventricular models were calibrated until simulation results matched adjusted data of volume and pressure waveforms within 10%. A statistical analysis was performed to correlate numerous data-derived and model-derived metrics with clinically assessed disease severity. Several model-derived metrics were strongly correlated with clinically assessed disease severity, suggesting that computational models may aid in assessing PAH severity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tossas-Betancourt, Li, Shavik, Afton, Beckman, Whiteside, Olive, Lim, Lu, Phelps, Gajarski, Lee, Nordsletten, Grifka, Dorfman, Baek, Lee and Figueroa.)

Arthrofibrosis is characterized by excessive extracellular matrix (ECM) deposition that results in restricted joint motion after total knee arthroplasties (TKAs). Currently, treatment options are limited. Therefore, an in vitro model of knee-related myofibroblastogenesis is valuable to facilitate investigation of the arthrofibrotic process, diagnostic and therapeutic options. In this study, we obtained intraoperative posterior capsule (PC), quadriceps tendon (QT), and suprapatellar pouch (SP) tissues from the knees of four patients undergoing primary TKAs for osteoarthritis. From these tissues, we isolated primary cells by the outgrowth method and subsequently characterized these cells in the absence and presence of the pro-myofibroblastic cytokine, transforming growth factor beta 1 (TGFβ1). Light microscopy of knee outgrowth cells revealed spindle-shaped cells, and immunofluorescence (IF) analysis demonstrated staining for the fibroblast-specific markers TE-7 and vimentin (VIM). These knee outgrowth fibroblasts differentiated readily into myofibroblasts as reflected by enhanced α-smooth muscle actin (ACTA2) mRNA and protein expression and increased mRNA expression of collagen type 1 (COL1A1) and type 3 (COL3A1) with collagenous matrix deposition in the presence of TGFβ1. Outgrowth knee fibroblasts were more sensitive to TGFβ1-mediated myofibroblastogenesis than adipose-derived mesenchymal stromal/stem cells (MSCs). While outgrowth knee fibroblasts isolated from three anatomical regions in four patients exhibited similar gene expression, these cells are distinct from other fibroblastic cell types (i.e., Dupuytren's fibroblasts) as revealed by RNA-sequencing. In conclusion, our study provides an in vitro myofibroblastic model of outgrowth knee fibroblasts derived from patients undergoing primary TKA that can be utilized to study myofibroblastogenesis and assess therapeutic strategies for arthrofibrosis., (© 2022 Wiley Periodicals LLC.)

Background: Patellar complications are a consequential cause of failure of primary total knee arthroplasty (TKA). The purpose of this study was to evaluate the association of demographic and patient factors with the long-term risk of patellar complications as a function of time in a very large cohort of primary TKAs performed with patellar resurfacing., Methods: We identified 27,192 primary TKAs utilizing cemented all-polyethylene patellar components that were performed at a single institution from 1977 through 2015. We evaluated the risk of any aseptic patellar complication and any aseptic patellar reoperation or revision, subanalyzed risks of reoperation or revision for loosening, maltracking/instability, and wear, and evaluated the risk of clinical diagnosis of patellar fracture and clunk/crepitus. The mean age at TKA was 68 years (range, 18 to 99 years); 57% of the patients were female. The mean body mass index (BMI) was 32 kg/m2. The primary diagnosis was osteoarthritis in 83%, and 70% of the TKAs were posterior-stabilized. Median follow-up was 7 years (range, 2 to 40 years). Risk factors for each outcome were evaluated with Cox regression models., Results: Nine hundred and seventy-seven knees with all-polyethylene patellae developed patellar complications. Survivorship free from any aseptic patellar complication was 93.3% at 20 years. Twenty-year survivorship free from any aseptic patellar reoperation was 97.3% and free from any aseptic patellar revision was 97.4%. Fifteen-year survivorship for the same end points for procedures performed from 2000 to 2015 was 95.7%, 99.2% and 99.3% respectively, representing substantial improvements compared with implants placed before 2000. Univariate analysis demonstrated that male sex (hazard ratio [HR], 1.4), an age of <65 years (HR, 1.3), and a BMI of ≥30 kg/m2 (HR, 1.2) were associated with increased risk of patellar complications (all p ≤0.01). Posterior-stabilized designs were associated with fewer patellar reoperations and revisions overall (HR, 0.4 and 0.4; p < 0.001) but higher risk of patellar clunk/crepitus (HR, 14.1; p < 0.001)., Conclusions: The 20-year survivorship free from any aseptic patellar complication in this series of cemented all-polyethylene patellae was 93%. Important risk factors for any aseptic patellar complication were male sex, an age of <65 years, a BMI of ≥30 kg/m2, and a patella implanted before 2000., Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G848)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Experimental analyses of posttraumatic knee arthrofibrosis utilize a rabbit model as a gold standard. However, a rodent model of arthrofibrosis offers many advantages including reduced cost and comparison with other models of organ fibrosis. This study aimed to characterize the biomechanical, histological, and molecular features of a novel posttraumatic model of arthrofibrosis in rats. Forty eight rats were divided into two equal groups. An immobilization procedure was performed on the right hind limbs of experimental rats. One group was immobilized for 4 weeks and the other for 8 weeks. Both groups were remobilized for 4 weeks. Limbs were studied biomechanically via assessment of torque versus degree of extension, histologically via whole knee specimen, and molecularly via gene expression of posterior capsular tissues. Significant differences were observed between experimental and control limbs at 4 N-cm of torque in the 4-week (knee extension: 115° ± 8° vs. 169° ± 17°, respectively; p = 0.007) and 8-week immobilization groups (knee extension: 99° ± 12° vs. 174° ± 9°, respectively; p = 0.008). Histologically, in each group experimental limbs demonstrated increased posterior capsular thickness and total area of tissue when compared to control limbs (p < 0.05). Gene expression values evaluated in each group were comparable. This study presents a novel rat model of arthrofibrosis with severe and persistent knee contractures demonstrated biomechanically and histologically. Statement of clinical significance: Arthrofibrosis is a common complication following contemporary total knee arthroplasties. The proposed model is reproducible, cost-effective, and can be employed for translational investigations studying the pathogenesis of arthrofibrosis and efficacy of neoadjuvant pharmacologic agents., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Aims: Outcomes of current operative treatments for arthrofibrosis after total knee arthroplasty (TKA) are not consistently positive or predictable. Pharmacological in vivo studies have focused mostly on prevention of arthrofibrosis. This study used a rabbit model to evaluate intra-articular (IA) effects of celecoxib in treating contracted knees alone, or in combination with capsular release., Methods: A total of 24 rabbits underwent contracture-forming surgery with knee immobilization followed by remobilization surgery at eight weeks. At remobilization, one cohort underwent capsular release (n = 12), while the other cohort did not (n = 12). Both groups were divided into two subcohorts (n = 6 each) - one receiving IA injections of celecoxib, and the other receiving injections of vehicle solution (injections every day for two weeks after remobilization). Passive extension angle (PEA) was assessed in live rabbits at 10, 16, and 24 weeks, and disarticulated limbs were analyzed for capsular stiffness at 24 weeks., Results: IA celecoxib resulted in greater mean PEA at ten weeks (69.6° (SD 4.6) vs 45.2° (SD 9.6), p = 0.004), 16 weeks (109.8° (SD 24.2) vs 60.9° (SD10.9), p = 0.004), and 24 weeks (101.0° (SD 8.0) vs 66.3° (SD 5.8), p = 0.004). Capsular stiffness was significantly reduced with IA celecoxib (2.72 Newton per cm (N·cm)/° (SD 1.04), p = 0.008), capsular release (2.41 N·cm/° (SD 0.80), p = 0.008), and capsular release combined with IA celecoxib (3.56 N·cm/° (SD 0.99), p = 0.018) relative to IA vehicle (6.09 N·cm/° (SD 1.64))., Conclusion: IA injections of a celecoxib led to significant improvements in passive extension angles, with reduced capsular stiffness, when administered to rabbit knees with established experimental contracture. Celecoxib was superior to surgical release, and the combination of celecoxib and a surgical release did not provide any additional value. Cite this article: Bone Joint Res  2022;11(1):32-39.

Aims: Varus-valgus constrained (VVC) devices are typically used in revision settings, often with stems to mitigate the risk of aseptic loosening. However, in at least one system, the VVC insert is compatible with the primary posterior-stabilized (PS) femoral component, which may be an option in complex primary situations. We sought to determine the implant survivorship, radiological and clinical outcomes, and complications when this VVC insert was coupled with a PS femur without stems in complex primary total knee arthroplasties (TKAs)., Methods: Through our institution's total joint registry, we identified 113 primary TKAs (103 patients) performed between 2007 and 2017 in which a VVC insert was coupled with a standard cemented PS femur without stems. Mean age was 68 years (SD 10), mean BMI was 32 kg/m 2 (SD 7), and 59 patients (50%) were male. Mean follow-up was four years (2 to 10)., Results: The five-year survivorship free from aseptic loosening was 100%. The five-year survivorship free from any revision was 99%, with the only revision performed for infection. The five-year survivorship free from reoperation was 93%. The most common reoperation was treatment for infection (n = 4; 4%), followed by manipulation under anaesthesia (MUA; n = 2; 2%). Survivorship free from any complication at five years was 90%, with superficial wound infection as the most frequent (n = 4; 4%). At most recent follow-up, two TKAs had non-progressive radiolucent lines about both the tibial and femoral components. Knee Society Scores improved from 53 preoperatively to 88 at latest follow-up (p < 0.001)., Conclusion: For complex primary TKA in occasional situations, coupling a VVC insert with a standard PS femur without stems proved reliable and durable at five years. Longer-term follow-up is required before recommending this technique more broadly. Cite this article: Bone Jt Open  2021;2(11):921-925.

Background: Two-stage exchange arthroplasty with high-dose antibiotic-loaded bone cement spacer and intravenous (IV) antibiotics is the most common method of managing infected total hip arthroplasties. However, the contemporary incidence, risk factors, and outcomes of acute kidney injuries (AKIs) in this cohort are unknown., Methods: We identified 227 patients treated with 256 antibiotic-loaded bone cement spacers after resection of an infected primary total hip arthroplasty between 2000 and 2017. Mean age was 65 years, mean body mass index was 30 mg/kg 2 , 55% were men, and 16% had pre-existing chronic kidney disease (CKD). Spacers were in situ for a mean of 15 weeks, concomitantly associated with IV or oral antibiotics for a mean of 6 weeks. AKI was defined as a creatinine ≥1.5X baseline or ≥0.3 mg/dL. Mean follow-up was 8 years., Results: AKI occurred in 13 patients without pre-existing CKD (7%) vs 10 patients with CKD (28%; OR 5; P = .0001). None required acute dialysis. Postoperative fluid depletion (β = 0.31; P = .0001), ICU requirement (β = 0.40; P = .0001), and acute atrial fibrillation (β = 0.43; P = .0001) were independent predictors for AKI in patients without pre-existing CKD. Duration of in situ spacer, mean antibiotic dose in cement, use of amphotericin B, and type of IV antibiotics were not significant risk factors. At last follow-up, 8 AKIs progressed to CKD, with one receiving dialysis 7 years later., Conclusion: AKIs occurred in 7% of patients with normal renal function, with 5-fold greater risk in those with CKD, and 4% did develop CKD. Importantly, causes of acute renal blood flow impairment were independent predictors for AKI., Level of Evidence: Level III, comparative study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: The prevalence of ipsilateral total hip arthroplasty (THA) and total knee arthroplasty (TKA) is rising in concert with life expectancy, putting more patients at risk for interprosthetic femur fractures (IPFFs). Our study aimed to assess treatment methodologies, implant survivorship, and IPFF clinical outcomes., Methods: A total of 76 patients treated for an IPFF from February 1985 to April 2018 were reviewed. Prior to fracture, at the hip/knee sites respectively, 46 femora had primary/primary, 21 had revision/primary, three had primary/revision, and six had revision/revision components. Mean age and BMI were 74 years (33 to 99) and 30 kg/m 2 (21 to 46), respectively. Mean follow-up after fracture treatment was seven years (2 to 24)., Results: Overall, 59 fractures were classified as Vancouver C (Unified Classification System (UCS) D), 17 were Vancouver B (UCS B). In total, 57 patients (75%) were treated with open reduction and internal fixation (ORIF); three developed nonunion, three developed periprosthetic joint infection, and two developed aseptic loosening. In all, 18 patients (24%) underwent revision arthroplasty including 13 revision THAs, four distal femoral arthroplasties (DFAs), and one revision TKA: of these, one patient developed aseptic loosening and two developed nonunion. Survivorship free from any reoperation was 82% (95% confidence interval (CI) 66.9% to 90.6%) and 77% (95% CI 49.4% to 90.7%) in the ORIF and revision groups at two years, respectively. ORIF patients who went on to union tended to have stemmed knee components and greater mean interprosthetic distance (IPD = 189 mm (SD 73.6) vs 163 mm (SD 36.7); p = 0.546) than nonunited fractures. Patients who went on to nonunion in the revision arthroplasty group had higher medullary diameter: cortical width ratio (2.5 (SD 1.7) vs 1.3 (SD 0.3); p = 0.008) and lower IPD (36 mm (SD 30.6) vs 214 mm (SD 32.1); p < 0.001). At latest follow-up, 95% of patients (n = 72) were ambulatory., Conclusion: Interprosthetic femur fractures are technically and biologically challenging cases. Individualized approaches to internal fixation versus revision arthroplasty led to an 81% (95% CI 68.3% to 88.6%) survivorship free from reoperation at two years with 95% of patients ambulatory. Continued improvements in management are warranted. Cite this article: Bone Joint J  2021;103-B(7 Supple B):122-128.

Arthrofibrosis is characterized by excessive extracellular matrix deposition in patients with total knee arthroplasties (TKAs) and causes undesirable joint stiffness. The pathogenesis of arthrofibrosis remains elusive and currently there are no diagnostic biomarkers for the pathological formation of this connective tissue. Fibrotic soft tissues are known to have elevated levels of plasminogen activator inhibitor-1 (PAI-1) (encoded by SERPINE1 ), a secreted serine protease inhibitor that moderates extracellular matrix remodeling and tissue homeostasis. The 4G/5G insertion/deletion (rs1799889) is a well-known SERPINE1 polymorphism that directly modulates PAI-1 levels. Homozygous 4G/4G allele carriers typically have higher PAI-1 levels and may predispose patients to soft tissue fibrosis (e.g., liver, lung, and kidney). Here, we examined the genetic contribution of the SERPINE1 rs1799889 polymorphism to musculoskeletal fibrosis in arthrofibrotic (n = 100) and non-arthrofibrotic (n = 100) patients using Sanger Sequencing. Statistical analyses revealed that the allele frequencies of the SERPINE1 rs1799889 polymorphism are similar in arthrofibrotic and non-arthrofibrotic patient cohorts. Because the fibrosis related SERPINE1 rs1799889 polymorphism is independent of arthrofibrosis susceptibility in TKA patients, the possibility arises that fibrosis of joint connective tissues may involve unique genetic determinants distinct from those linked to classical soft tissue fibrosis., Competing Interests: Competing interests Mark E. Morrey’s disclosures include Tenex. Joaquin Sanchez-Sotelo’s disclosures include ASES, Elsevier, Exactech, JSES, Oxford University Press, Stryker, Wright Medical Technology, Precision OS, PSI. Daniel J. Berry’s disclosures include Bodycad, DePuy, Elsevier, IHS, JBJS Am, Mayo Clinic Board of Governors, Wolters Kluwer Health - Lippincott Williams & Wilkins, OREF, CCJR. Matthew P. Abdel’s disclosures include AAOS Board of Directors, Springer, Stryker. No other authors have conflicts of interest to disclosure.

Background: Amongst patients with CHD, the time of transition to adulthood is associated with lapses in care leading to significant morbidity. The purpose of this study was to identify differences in perceptions between parents and teens in regard to transition readiness., Methods: Responses were collected from 175 teen-parent pairs via the validated CHD Transition Readiness survey and an information request checklist. The survey was distributed via an electronic tablet at a routine clinic visit., Results: Parents reported a perceived knowledge gap of 29.2% (the percentage of survey items in which a parent believes their teen does not know), compared to teens self-reporting an average of 25.9% of survey items in which they feel deficient (p = 0.01). Agreement was lowest for long-term medical needs, physical activities allowed, insurance, and education. In regard to self-management behaviours, agreement between parent and teen was slight to moderate (weighted κ statistic = 0.18 to 0.51). For self-efficacy, agreement ranged from slight to fair (weighted κ = 0.16 to 0.28). Teens were more likely to request information than their parents (79% versus 65% requesting at least one item) particularly in regard to pregnancy/contraception and insurance., Conclusion: Parents and teens differ in several key perceptions regarding knowledge, behaviours, and feelings related to the management of heart disease. Specifically, parents perceive a higher knowledge deficit, teens perceive higher self-efficacy, and parents and teens agree that self-management is low.

Background: Two-stage exchange arthroplasty with a high-dose antibiotic-loaded bone cement (ALBC) spacer and intravenous or oral antibiotics is the most common method of managing a periprosthetic joint infection (PJI) after a total knee arthroplasty (TKA). However, little is known about the contemporary incidence, the risk factors, and the outcomes of acute kidney injuries (AKIs) in this cohort., Methods: We identified 424 patients who had been treated with 455 ALBC spacers after resection of a PJI following a primary TKA from 2000 to 2017. The mean age at resection was 67 years, the mean body mass index (BMI) was 33 kg/m2, 47% of the patients were women, and 15% had preexisting chronic kidney disease (CKD). The spacers (87% nonarticulating) contained a mean of 8 g of vancomycin and 9 g of an aminoglycoside per construct (in situ for a mean of 11 weeks). Eighty-six spacers also had amphotericin B (mean, 412 mg). All of the patients were concomitantly treated with systemic antibiotics for a mean of 6 weeks. An AKI was defined as a creatinine level of ≥1.5 times the baseline or an increase of ≥0.3 mg/dL within any 48-hour period. The mean follow-up was 6 years (range, 2 to 17 years)., Results: Fifty-four AKIs occurred in 52 (14%) of the 359 patients without preexisting CKD versus 32 AKIs in 29 (45%) of the 65 patients with CKD (odds ratio [OR], 5; p = 0.0001); none required acute dialysis. Overall, when the vancomycin concentration or aminoglycoside concentration was >3.6 g/batch of cement, the risk of AKI increased (OR, 1.9 and 1.8, respectively; p = 0.02 for both). Hypertension (β = 0.17; p = 0.002), perioperative hypovolemia (β = 0.28; p = 0.0001), and acute atrial fibrillation (β = 0.13; p = 0.009) were independent predictors for AKI in patients without preexisting CKD. At the last follow-up, 8 patients who had sustained an AKI had progressed to CKD, 4 of whom received dialysis., Conclusions: In our study, the largest series to date that we are aware of regarding this issue, AKI occurred in 14% of patients with normal renal function at baseline, and 2% developed CKD after undergoing a 2-stage exchange arthroplasty for a PJI after TKA. However, the risk of AKI was fivefold greater in those with preexisting CKD. The causes of acute renal blood flow impairment were independent predictors for AKI., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The authors indicated that no external funding was received for any aspect of this work. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work; “yes” to indicate that the author had a patent and/or copyright, planned, pending, or issued, broadly relevant to this work; and “yes” to indicate that the author had other relationships or activities that could be perceived to influence, or have the potential to influence, what was written in this work (http://links.lww.com/JBJS/G370)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Debate remains regarding the utility of mechanical axis alignment as a predictor of durability after total knee arthroplasty (TKA). Our study aimed to assess the effects of coronal alignment on implant durability, clinical outcomes, and radiographic results with a single fixed-bearing TKA design. All patients undergoing primary cemented TKA of a single design (Stryker Triathlon) from 2005-2007 with >10 years of follow-up and available pre-operative and post-operative hip-knee-ankle radiographs were included ( n = 89). Radiographs were measured to determine coronal alignment and assessed for loosening. Mean preoperative mechanical axis alignment was -6° ± 6.7° (varus, range, -16°-23°), while mean post-operative alignment was -1° ± 2.7° (varus, range, -3°-15°). The aligned group was defined as knees with a post-operative mechanical axis of 0° ± 3° ( n = 73) and the outlier group as those outside this range ( n = 16). No patients underwent revision. Ten-year survivorship free from any reoperation was 99% and 100% in the aligned and outlier groups, respectively ( p = 0.64). Knee Society scores improved significantly in both groups ( p < 0.001) and did not differ at final follow-up ( p = 0.15). No knees demonstrated radiographic evidence of loosening. Post-operative mechanical axis alignment within 3° of neutral was not associated with improved implant durability, clinical outcomes, or radiographic results at 10 years following primary TKA.

(1) Background: Arthrofibrosis is a common cause of patient debility and dissatisfaction after total knee arthroplasty (TKA). The diversity of molecular pathways involved in arthrofibrosis disease progression suggest that effective treatments for arthrofibrosis may require a multimodal approach to counter the complex cellular mechanisms that direct disease pathogenesis. In this study, we leveraged RNA-seq data to define genes that are suppressed in arthrofibrosis patients and identified adiponectin ( ADIPOQ ) as a potential candidate. We hypothesized that signaling pathways activated by ADIPOQ and the cognate receptors ADIPOR1 and ADIPOR2 may prevent fibrosis-related events that contribute to arthrofibrosis. (2) Methods: Therefore, ADIPOR1 and ADIPOR2 were analyzed in a TGFβ1 inducible cell model for human myofibroblastogenesis by both loss- and gain-of-function experiments. (3) Results: Treatment with AdipoRon, which is a small molecule agonist of ADIPOR1 and ADIPOR2, decreased expression of collagens ( COL1A1 , COL3A1 , and COL6A1 ) and the myofibroblast marker smooth muscle α-actin (ACTA2) at both mRNA and protein levels in basal and TGFβ1-induced cells. (4) Conclusions: Thus, ADIPOR1 and ADIPOR2 represent potential drug targets that may attenuate the pathogenesis of arthrofibrosis by suppressing TGFβ-dependent induction of myofibroblasts. These findings also suggest that AdipoRon therapy may reduce the development of arthrofibrosis by mediating anti-fibrotic effects in joint capsular tissues.

The dense formation of abnormal scar tissue after total knee arthroplasty results in arthrofibrosis, an unfortunate sequela of inflammation. The purpose of this study was to use a validated rabbit model to assess the effects on surgically-induced knee joint contractures of two combined pharmacological interventions: celecoxib (CXB) loaded on an implanted collagen membrane, and subcutaneously (SQ) injected ketotifen. Thirty rabbits were randomly divided into five groups. The first group received no intervention after the index surgery. The remaining four groups underwent intra-articular implantation of collagen membranes loaded with or without CXB at the time of the index surgery; two of which were also treated with SQ ketotifen. Biomechanical joint contracture data were collected at 8, 10, 16, and 24 weeks. At the time of necropsy (24 weeks), posterior capsule tissue was collected for messenger RNA and histopathologic analyses. At 24 weeks, there was a statistically significant increase in passive extension among rabbits in all groups treated with CXB and/or ketotifen compared to those in the contracture control group. There was a statistically significant decrease in COL3A1, COL6A1, and ACTA2 gene expression in the treatment groups compared to the contracture control group (P < .001). Histopathologic data also demonstrated a trend towards decreased fibrous tissue density in the CXB membrane group compared to the vehicle membrane group. The present data suggest that intra-articular placement of a treated collagen membrane blunts the severity of contracture development in a rabbit model of arthrofibrosis, and that ketotifen and CXB may independently contribute to the prevention of arthrofibrosis. Statement of clinical significance: Current literature has demonstrated that arthrofibrosis may affect up to 5% of primary total knee arthroplasty patients. For that reason, novel pharmacologic prophylaxis and treatment modalities are critical to mitigating reoperations and revisions while improving the quality of life for patients with this debilitating condition., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Aims: Arthrofibrosis is a relatively common complication after joint injuries and surgery, particularly in the knee. The present study used a previously described and validated rabbit model to assess the biomechanical, histopathological, and molecular effects of the mast cell stabilizer ketotifen on surgically induced knee joint contractures in female rabbits., Methods: A group of 12 skeletally mature rabbits were randomly divided into two groups. One group received subcutaneous (SQ) saline, and a second group received SQ ketotifen injections. Biomechanical data were collected at eight, ten, 16, and 24 weeks. At the time of necropsy, posterior capsule tissue was collected for histopathological and gene expression analyses (messenger RNA (mRNA) and protein)., Results: At the 24-week timepoint, there was a statistically significant increase in passive extension among rabbits treated with ketotifen compared to those treated with saline (p = 0.03). However, no difference in capsular stiffness was detected. Histopathological data failed to demonstrate a decrease in the density of fibrous tissue or a decrease in α-smooth muscle actin (α-SMA) staining with ketotifen treatment. In contrast, tryptase and α-SMA protein expression in the ketotifen group were decreased when compared to saline controls (p = 0.007 and p = 0.01, respectively). Furthermore, there was a significant decrease in α-SMA ( ACTA2 ) gene expression in the ketotifen group compared to the control group (p < 0.001)., Conclusion: Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis., (© 2020 Author(s) et al.)

Arthrofibrosis is an abnormal histopathologic response, is debilitating for patients, and poses a substantial unsolved clinical challenge. This study characterizes molecular biomarkers and regulatory pathways associated with arthrofibrosis by comparing fibrotic and non-fibrotic human knee tissue. The fibrotic group encompasses 4 patients undergoing a revision total knee arthroplasty (TKA) for arthrofibrosis (RTKA-A) while the non-fibrotic group includes 4 patients undergoing primary TKA for osteoarthritis (PTKA) and 4 patients undergoing revision TKA for non-arthrofibrotic and non-infectious etiologies (RTKA-NA). RNA-sequencing of posterior capsule specimens revealed differences in gene expression between each patient group by hierarchical clustering, principal component analysis, and correlation analyses. Multiple differentially expressed genes (DEGs) were defined in RTKA-A versus PTKA patients (i.e., 2059 up-regulated and 1795 down-regulated genes) and RTKA-A versus RTKA-NA patients (i.e., 3255 up-regulated and 3683 down-regulated genes). Our findings define molecular and pathological markers of arthrofibrosis, as well as novel potential targets for risk profiling, early diagnosis and pharmacological treatment of patients., Competing Interests: Declaration of Competing Interest Mark E. Morrey's disclosures include Tenex. Joaquin Sanchez-Sotelo's disclosures include Acumed LLC, AAOS, ASES, Elsevier, Exactech Inc., JOOT, JOSEA, JOSES, Oxford University Press, Stryker, Wright Medical Technology. Daniel J. Berry's disclosures include Bodycad, DePuy, Elsevier, IHS, Hip and Knee Society, JBJS, Mayo Clinic Board of Governors, Wolters Kluwer Health - Lippincott Williams & Wilkins. Matthew P. Abdel's disclosures include AAHKS, ICJR, BJJ, MOS, Springer, and Stryker. No other authors have conflicts of interest to disclosure., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Protein detection techniques such as western blotting and ELISA rely on housekeeping proteins as standards for sample normalization. However, clinical or animal tissue specimens are heterogeneous due to presence of contaminating cell types and tissues (e.g., blood vessels and muscle) or cellular decay during tissue storage and isolation which may compromise protein integrity. This biological heterogeneity may invalidate the assumption that housekeeping proteins are invariable across various specimens. This study provides data that advocate for protein standardization based on total protein staining in rabbit posterior capsular tissues. We compared the classical normalization markers glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-tubulin (TUBB) with other proteins that have low variation in expression (i.e., FTL, FTH1, EEF1A1, TPT1) based on RNAseq data for human posterior capsular tissues. Histological examination revealed a high degree of qualitative variation in microscopic images of capsular tissue specimens. This variation is reflected by significant differences in specific protein signals for all housekeeping proteins as detected by western blot analysis. However, total protein staining, which combines the intensity of multiple gel electrophoretic bands, normalizes natural biological variation observed for individual housekeeping proteins and permits assessment of protein integrity. Therefore, we propose that normalization based on total protein staining increases accuracy of protein quantification of heterogeneous tissue specimen samples., Competing Interests: Conflict of Interest: No benefits in any form have been received or will be received by any authors from a commercial party related directly or indirectly to the subject of this article.

Objectives: To examine changes in transition readiness (knowledge, self-efficacy, self-management) over time and explore factors associated with transition readiness, including psychosocial quality of life (QOL) and health service utilization in teens/young adults with congenital heart disease., Study Design: In a multicenter prospective cohort study, 356 patients, age 14-27 years, completed transition readiness and QOL assessments at routine cardiology visits at baseline and 1-year follow-up., Results: Median patient age was 19.8 years at 1.03 years (IQR 0.98-1.24) following baseline transition readiness assessment. Average knowledge deficit scores decreased at follow-up (P < .0001) and self-efficacy scores increased (P < .0001). Self-management scores increased (P < .0001), but remained low (mean 57.7, 100-point scale). Information was requested by 73% of patients at baseline and was associated with greater increase in knowledge at follow-up (P = .005). Increased knowledge (P = .003) and perceived self-efficacy (P = .01) were associated with improved psychosocial QOL, but not health service utilization at follow-up. Patients who preferred face-to-face information from healthcare providers (47%) vs other information sources were more likely to request information (P < .0001). In patients <18 years old, greater agreement between teen and parental perception of teen's knowledge was associated with greater increase in patient knowledge (P = .02) and self-efficacy (P = .003)., Conclusion: Transition readiness assessment demonstrated improved knowledge, self-efficacy, and self-management at 1-year follow-up in teens/young adults with congenital heart disease. Improved knowledge and self-efficacy were associated with improved psychosocial QOL. Self-management remained low. Supplemental media for conveying information and greater involvement of parents may be needed to optimize transition readiness., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Hemochromatosis can result in metabolic bone pathology (due to excessive iron absorption) and degenerative joint disease, leading to total joint arthroplasties. The aim of this study is to analyze the survivorship, complications, radiographic results, and clinical outcomes of patients with hemochromatosis who received either a total hip arthroplasty (THA) or a total knee arthroplasty (TKA)., Methods: We identified 34 lower extremity arthroplasties in 29 patients with hemochromatosis performed between 2000 and 2016. There were 17 primary THAs in 15 patients and 17 primary TKAs in 14 patients. Mean age at arthroplasty was 63 years with 76% being male. The mean body mass index was 28 kg/m 2 . Mean follow-up was 5 years., Results: The survivorship free from any revision for THAs was 94% at 10 years. One patient was revised for aseptic loosening of the femoral stem at 6 months. In THA patients, no infections, no other complications, and no radiographic evidence of aseptic loosening were identified. Harris Hip Scores improved from a mean of 55 preoperatively to 94 postoperatively (P < .001). The survivorship free from any revision for TKAs was 100% at 10 years. Two patients (12%) developed acquired idiopathic stiffness postoperatively; no infections were identified. There was no radiographic evidence of aseptic loosening in any TKA. Knee Society Scores improved from a mean of 61 preoperatively to 94 postoperatively (P < .001)., Conclusion: This study found excellent survivorship, significant improvements in clinical outcomes, and a very low complication profile for both THA and TKA in patients with hemochromatosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Varus-valgus constrained (VVC) implants are often used during revision total knee arthroplasty (TKA) to gain coronal plane stability. However, the increased mechanical torque applied to the bone-cement interface theoretically increases the risk of aseptic loosening. We assessed mid-term survivorship, complications, and clinical outcomes of a fixed-bearing VVC device in revision TKAs., Methods: A total of 416 consecutive revision TKAs (398 patients) were performed at our institution using a single fixed-bearing VVC TKA from 2007 to 2015. Mean age was 64 years (33 to 88) with 50% male (199). Index revision TKA diagnoses were: instability (n = 122, 29%), aseptic loosening (n = 105, 25%), and prosthetic joint infection (PJI) (n = 97, 23%). All devices were cemented on the epiphyseal surfaces. Femoral stems were used in 97% (n = 402) of cases, tibial stems in 95% (n = 394) of cases; all were cemented. In total, 93% (n = 389) of cases required a stemmed femoral and tibial component. Femoral cones were used in 29%, and tibial cones in 40%. Survivorship was assessed via competing risk analysis; clinical outcomes were determined using Knee Society Scores (KSSs) and range of movement (ROM). Mean follow-up was four years (2 to 10)., Results: The five-year cumulative incidence of subsequent revision for aseptic loosening and instability were 2% (95% confidence interval (CI) 0.2 to 3, number at risk = 154) and 4% (95% CI 2 to 6, number at risk = 153), respectively. The five-year cumulative incidence of any subsequent revision was 14% (95% CI 10 to 18, number at risk = 150). Reasons for subsequent revision included PJI (n = 23, of whom 12 had previous PJI), instability (n = 13), and aseptic loosening (n = 11). The use of this implant without stems was found to be a significant risk factor for subsequent revision (hazard ratio (HR) 7.58 (95% CI 3.98 to 16.03); p = 0.007). KSS improved from 46 preoperatively to 81 at latest follow-up (p < 0.001). ROM improved from 96° prerevision to 108° at latest follow-up (p = 0.016)., Conclusion: The cumulative incidence of subsequent revision for aseptic loosening and instability was very low at five years with this fixed-bearing VVC implant in revision TKAs. Routine use of cemented and stemmed components with targeted use of metaphyseal cones likely contributed to this low rate of aseptic loosening. Cite this article: Bone Joint J 2020;102-B(4):458-462.

Arthrofibrosis is a common complication following total knee arthroplasty caused by pathologic fibroblast activation and excessive collagen deposition around a synovial joint leading to debilitating loss of motion. Treatment options are limited because the pathologic mechanisms remain to be characterized. Dysregulation of the inflammatory cascade may lead to communication between myofibroblasts and immune cells triggering tissue metaplasia, and excessive collagen deposition described clinically as arthrofibrosis. We explored the novel use of celecoxib (selective cyclooxygenase-2 [COX-2] inhibitor) to disrupt the downstream effects of the post-traumatic inflammatory cascade and inhibit scar tissue formation in a validated rabbit model of arthrofibrosis combined with new parameters for quantifying the stiffness of the posterior capsule. Biomechanical and molecular analyses, of contracted rabbit knee posterior capsule tissue after COX-2 inhibition revealed increased maximal passive extension and down-regulation of collagen messenger RNA compared with controls. Histopathologic examination suggested a trend of decreased quantities of dense fibrous connective tissue with COX-2 inhibition. These data may suggest that inhibiting the inflammatory cascade could potentially reduce pathologic myofibroblast activation, thereby reducing scar tissue formation and increasing the range of motion in arthrofibrotic joints. Implementing a multi-modal pharmacologic approach may simultaneously target numerous cellular components contributing to the complex process of arthrofibrogenesis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2609-2620, 2019., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Total hip arthroplasty (THA) alleviates hip pain and improves joint function. Current implant design permits long-term survivorship of THAs, but certain metal-on-metal (MoM) articulations can portend catastrophic failure due to adverse local tissue reactions (ALTR). Here, we identified biological and molecular differences between periacetabular synovial tissues of patients with MoM THA failure undergoing revision THA compared to patients undergoing primary THA for routine osteoarthritis (OA). Analysis of tissue biopsies by RNA-sequencing (RNA-seq) revealed that MoM patient samples exhibit significantly increased expression of immune response genes but decreased expression of genes related to extracellular matrix (ECM) remodeling. Thus, interplay between local tissue inflammation and ECM degradation may account for the pathology and compromised clinical outcomes in select patients with MoM implants. We conclude that adverse responses of host tissues to implant materials result in transcriptomic modifications in patients with MoM implants that permit consideration of strategies that could mitigate ECM damage., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: We previously reported common knowledge deficits and lack of transition readiness in 13- 25-year-olds with congenital or acquired heart disease. The aims of this study were to re-evaluate transition readiness in this cohort at follow-up and to examine the relationship between changes in transition readiness and quality of life (QOL)., Study Design: In this prospective cohort study, patients completed the Transition Readiness Assessment and the Pediatric Quality of Life Inventory using an e-tablet, web-based format at a routine follow-up visit. Changes from initial to follow-up scores were evaluated., Results: Sixty-five percent of patients (106 of 164) completed follow-up assessments at a median age of 18.7 years (IQR, 16.5-21.2 years) at a median follow-up of 1 year. The average perceived knowledge deficit score (percent of items with no knowledge) at follow-up was 18.0 ± 15.2%, which decreased from 24.7 ± 16.5% (P < .0001). On a 100-point scale, the mean score for self-efficacy increased from 71.4 ± 17.0 to 76.7 ± 18.2 (P = .0004) and for self-management increased from 47.9 ± 18.4 to 52.0 ± 20.7 (P = .004). Although physical QOL did not change, the mean psychosocial QOL score increased significantly (P = .02). A decrease in the knowledge deficit score at follow-up was significantly associated with an increased psychosocial QOL score (P = .03). An increase in the self-efficacy score was associated with an increase in psychosocial QOL score (P = .04), especially social QOL (P = .02)., Conclusions: Although deficits in knowledge and self-management skills persist, transition readiness assessment and recognition of deficits can improve transition readiness with improved psychosocial QOL., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Stiffness is a common reason for suboptimal clinical outcomes after primary total knee arthroplasty (pTKA). There is a lack of consensus regarding its definition, which is often conflated with its histopathologic subcategory-i.e., arthrofibrosis. There is value in refining the definition of acquired idiopathic stiffness in an effort to select for patients with arthrofibrosis. We conducted a systematic review and meta-analysis to establish a consensus definition of acquired idiopathic stiffness, determine its prevalence after pTKA, and identify potential risk factors for its development., Methods: MEDLINE, Embase, Cochrane Controlled Register of Trials (CENTRAL), and Scopus databases were searched from 2002 to 2017. Studies that included patients with stiffness after pTKA were screened with strict inclusion and exclusion criteria to isolate the subset of patients with acquired idiopathic stiffness unrelated to known extrinsic or surgical causes. Three authors independently assessed study eligibility and risk of bias and collected data. Outcomes of interest were then analyzed according to age, sex, and body mass index (BMI)., Results: In the 35 included studies (48,873 pTKAs), the mean patient age was 66 years. In 63% of the studies, stiffness was defined as a range of motion of <90° or a flexion contracture of >5° at 6 to 12 weeks postoperatively. The prevalence of acquired idiopathic stiffness after pTKA was 4%, and this did not differ according to age (4%, I = 95%, among patients <65 years old and 5%, I = 96%, among those ≥65 years old; p = 0.238). The prevalence of acquired idiopathic stiffness was significantly lower in males (1%, I = 85%) than females (3%, I = 95%) (p < 0.0001) as well as in patients with a BMI of <30 kg/m (2%, I = 94%) compared with those with a BMI of ≥30 kg/m (5%, I = 97%) (p = 0.027)., Conclusions: Contemporary literature supports the following definition for acquired idiopathic stiffness: a range of motion of <90° persisting for >12 weeks after pTKA in patients in the absence of complicating factors including preexisting stiffness. The mean prevalence of acquired idiopathic stiffness after pTKA was 4%; females and obese patients were at increased risk., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background: Some prior reports of total knee arthroplasty after high tibial osteotomy have shown high rates of aseptic loosening. As such, the goal of this study was to analyze the outcomes of contemporary total knee arthroplasty after high tibial osteotomy, with particular emphasis on survivorship free from aseptic loosening, any revision, and any reoperation; complications; radiographic results; and clinical outcomes., Methods: We retrospectively reviewed 207 patients who underwent 231 total knee arthroplasties using cemented prostheses after high tibial osteotomy from 2000 to 2012 through our total joint registry: 87% were after a closing-wedge osteotomy and 13% were after an opening-wedge osteotomy. The mean follow-up from total knee arthroplasty was 8 years. At the time of the total knee arthroplasty, the mean age was 64 years and the mean body mass index was 31 kg/m. The majority of total knee arthroplasties had a posterior-stabilized design (93%), and 4% had a varus-valgus constraint design. Tibial stems were utilized in 8% of cases. Bivariate and multivariate Cox regression analyses were utilized to analyze risk factors for poorer survival., Results: At 10 years, survivorship free from aseptic loosening was 97%, survivorship free from any revision was 90%, and survivorship free from any reoperation was 85%. Fifteen patients (15 total knee arthroplasties [6%]) underwent aseptic revision, most commonly for instability (3%), aseptic loosening (2%), and periprosthetic fracture (1%). On bivariate analysis, patient age of <60 years was a significant risk factor for poorer revision-free survival (hazard ratio, 2.9; p = 0.02); on multivariate analysis, younger age was the only significant risk factor for revision (p = 0.04). There were 14 complications (6%), the most common being a manipulation under anesthesia in 9 cases (4%). No unrevised total knee arthroplasties had definitive radiographic evidence of loosening. Knee Society scores improved from a mean preoperative score of 59 points to a mean postoperative score of 93 points (p < 0.001)., Conclusions: Contemporary total knee arthroplasty with a cemented prosthesis after high tibial osteotomy demonstrated excellent long-term durability, with 10-year survivorship free from aseptic loosening of 97%. There was reliable improvement in clinical outcomes, but perfect knee balance was sometimes challenging, as reflected by a 4% prevalence of manipulation under anesthesia and a 3% prevalence of revision for instability., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Trauma, surgery, and other inflammatory conditions can lead to debilitating joint contractures. Adjunct pharmacologic modalities may permit clinical prevention and treatment of recalcitrant joint contractures. We investigated the therapeutic potential of rosiglitazone by intra-articular delivery via oligo[poly(ethylene glycol)fumarate] (OPF) hydrogels in an established rabbit model of arthrofibrosis. OPF hydrogels loaded with rosiglitazone were characterized for drug elution properties upon soaking in minimum essential media (MEM) with 10% fetal bovine serum and measurements of drug concentrations via High Performance Liquid Chromatography (HPLC). Drug-loaded scaffolds were surgically implanted into 24 skeletally mature female New Zealand White rabbits that were divided into equal groups receiving OPF hydrogels loaded with rosiglitazone (1.67 mg), or vehicle control (10 µl DMSO). After 8 weeks of joint immobilization, rabbits were allowed unrestricted cage activity for 16 weeks. Contracture angles of rabbit limbs treated with rosiglitazone showed statistically significant improvements in flexion compared to control animals (mean angles, respectively, 64.4° vs. 53.3°, p < 0.03). At time of sacrifice (week 24), animals in the rosiglitazone group continued to exhibit less joint contracture than controls (119.0° vs. 99.5°, p = 0.014). The intra-articular delivery of rosiglitazone using implanted OPF hydrogels decreases flexion contractures in a rabbit model of arthrofibrosis without causing adverse effects (e.g., gross inflammation or arthritis). Statement of Clinical Significance: Post-traumatic joint contractures are common and debilitating, with limited available treatment options. Pharmacologic interventions can potentially prevent and treat such contractures. This study is translational in that a commercially approved medication has been repurposed through a novel delivery device. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2949-2955, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Objectives: To evaluate transition readiness, including perceived knowledge deficits, self-efficacy, and self-management behaviors, in 13- to 25-year-olds with congenital heart disease or heart transplant and to examine the relationships between transition readiness assessment, information seeking behavior, and quality of life (QOL)., Study Design: In this cross-sectional study, patients (n = 164) completed the Transition Readiness Assessment and the Pediatric Quality of Life Inventory using an e-tablet, web-based format at a routine clinic visit., Results: Median patient age was 18.1 years (range 13.0-25.5). Average perceived knowledge deficit score (% of items with no knowledge) was 25.7% (range 0%-75%). On a 100-point scale, the mean score was 72.0 ± 17.2 for self-efficacy and 49.7 ± 17.5 for self-management. Knowledge deficits were negatively correlated with self-efficacy (r = -0.45, P < .0001) and self-management (r = -0.36, P < .0001). Overall, 66% of patients requested information (73% ≥ 18 years old). Higher psychosocial QOL scores were correlated with lower knowledge deficit scores (r = -0.21, P = .01) and higher perceived self-efficacy scores (r = 0.41, P < .0001)., Conclusions: Transition knowledge deficits are common and associated with decreased self-efficacy and self-management skills in adolescents and young adults with heart disease. Greater transition knowledge and perceived self-efficacy are associated with better psychosocial QOL. Routine assessment of transition readiness is recommended to facilitate recognition of deficits and interventions to promote successful transition outcomes., (Copyright © 2015 Elsevier Inc. All rights reserved.)