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14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis

Fu, Wenyu; Hettinghouse, Aubryanna; Chen, Yujianan; Hu, Wenhuo; Ding, Xiang; Chen, Meng; Ding, Yuanjing; Mundra, Jyoti; Song, Wenhao; Liu, Ronghan; Yi, Young-Su; Attur, Mukundan; Samuels, Jonathan; Strauss, Eric; Leucht, Philipp; Schwarzkopf, Ran; Liu, Chuan-Ju
OBJECTIVES/OBJECTIVE:Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS:Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS:Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS:This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.
PMID: 34226187
ISSN: 1468-2060
CID: 4932152

Component placement accuracy in two generations of handheld robotics-assisted knee arthroplasty

Sicat, Chelsea S; Chow, James C; Kaper, Bertrand; Mitra, Riddhit; Xie, Jing; Schwarzkopf, Ran
INTRODUCTION/BACKGROUND:Total knee arthroplasty (TKA) is the gold standard for treatment of end-stage osteoarthritis. Previous studies have shown that successful outcomes following TKA depend on accurate implant alignment and soft tissue balancing. Robotic-assisted TKA have demonstrated improved accuracy in component placement and have been associated with better outcomes and patient satisfaction. This study aims to report on the execution accuracy of two generations of handheld robotic-assisted surgical systems. METHODS:This was a retrospective analysis of TKA procedures with two sequential generations of the same handheld robotic-assisted surgical system. Intra-operative data captured included pre-operative limb deformity, limb axes, range of motion, kinematic balance, and the resulting plan for component placement in three-dimensional space. Patients were stratified based on their preoperative coronal lower limb mechanical alignment (> 3° varus, < 3° varus, < 3° valgus, and ≥ 3° valgus). Measurements of component placement (overall lower limb alignment, medial and lateral flexion gaps, and tibial and femoral resection depths) were assessed using descriptive statistics. RESULTS:A total of 435 patients were included and stratified based on preoperative lower limb alignment: 229 with ≥ 3° varus, 78 with varus < 3° and 58 with valgus < 3°, and 70 with valgus > 3°. The mean difference between planned and achieved alignment in the lower limb valgus patients was < 1° across all groups. Mean differences between planned and achieved medial flexion gap was higher in the > 3° subgroup in the varus patient cohort ([< 3°]: 1.15 ± 1.92 vs. [> 3°]: 1.90 ± 2.57); this value was higher in the < 3° subgroup for valgus patients ([< 3°]: 1.34 ± 1.83 vs. [> 3°]: 0.956 ± 1.65). Average resection depth ranged from 9.46 to 10.4 mm in the posterior medial femur, 9.25 to 9.95 mm in the posterior lateral femur, 7.45 to 8.79 mm in the distal medial femur, 8.22 to 9.18 mm in the distal lateral femur, 6.70 to 7.07 mm in the medial tibial condyle and 6.40 to 7.19 mm in the lateral tibial condyle. Non-inferiority testing demonstrated the newer generation is non-inferior to the older generation. CONCLUSION/CONCLUSIONS:Robotic-assisted knee replacement using handheld image-free systems is able to maintain accuracy of component placement. Further investigation of patient reported outcomes as well as long-term implant longevity are needed.
PMID: 34304279
ISSN: 1434-3916
CID: 5005782

Botulinum toxin injections as salvage therapy is beneficial for management of patellofemoral pain syndrome

Kesary, Yuval; Singh, Vivek; Frenkel-Rutenberg, Tal; Greenberg, Arie; Dekel, Shmuel; Schwarzkopf, Ran; Snir, Nimrod
PURPOSE/OBJECTIVE:Patellofemoral pain syndrome (PFPS) is a common pathology usually presenting with anterior or retropatellar pain. It is associated with a relative imbalance between the vastus medialis oblique (VMO) and the vastus lateralis (VL) muscles. This can lead to considerable morbidity and reduced quality of life (QOL). This study aims to assess the long-term functional outcome of PFPS treated with VL muscle botulinum toxin A (BoNT-A) injection. MATERIALS AND METHODS/METHODS:A retrospective review was performed on 26 consecutive patients (31 knees) with a mean age of 50.1 years (± 19.7 years) who were treated with BoNT-A injections to the VL muscle followed by physiotherapy between 2008 and 2015. Pre- and post-treatment pain levels (numerical rating scale, NRS), QOL (SF-6D), and functional scores (Kujala and Lysholm questionnaires) were measured. Demographics, physical therapy compliance, previous surgeries, perioperative complications, and patient satisfaction levels were collected. RESULTS:The mean follow-up time was 58.8 ± 36.4 months. There were significant improvements in all the examined domains. The average pain score (NRS) decreased from 7.6 to 3.2 (P < 0.01), and the Kujala, Lysholm, and SF-6D scores improved from 58.9 to 82.7 (P < 0.001), 56.2 to 83.2 (P < 0.001), and 0.6 to 0.8 (P < 0.001), respectively. Similar delta improvement was achieved irrespective of gender, age, compliance to post-treatment physical therapy, or coexisting osteoarthritis. Patients who presented with a worse pre-treatment clinical status achieved greater improvement. Prior to BoNT-A intervention, 16 patients (18 knees) were scheduled for surgery, of whom 12 (75%, 13 knees) did not require further surgical intervention at the last follow-up. CONCLUSIONS:A single intervention of BoNT-A injections to the VL muscle combined with physiotherapy is beneficial for the treatment of patients with persistent PFPS. LEVEL III EVIDENCE/UNASSIGNED:Retrospective cohort study.
PMID: 34715941
ISSN: 2234-0726
CID: 5042912

Conversion total hip arthroplasty for early failure following unstable intertrochanteric hip fracture: what can patients expect?

Schultz, Blake J; Sicat, Chelsea; Penev, Aleks; Schwarzkopf, Ran; Egol, Kenneth A
PURPOSE/OBJECTIVE:To report surgical outcomes in patients treated with conversion total hip arthroplasty (CTHA) for early failure of cephalomedullary nails (CMNs). METHODS:A retrospective review was conducted of CTHA for treatment of failed CMN within 1 year of initial surgery for intertrochanteric (IT) hip fractures. The cohort was matched 1:5 to patients who underwent elective primary THA (PTHA). Patient demographics, mechanism of CMN failure, surgical outcomes, and complication rates were assessed. RESULTS:22 patients met criteria with a mean time to failure of 145 days. Modes of failure included: lag screw cut-out with superior migration (9, 40.9%), or medialization (8, 36.4%), and aseptic nonunion with implant failure (2, 9.0%) and without implant failure (3, 13.6%). Fourteen of the patients (63.6%) had acetabular-sided damage secondary to lag screw penetration, all in the screw cut-out groups. Patient demographics were similar between cohorts. Compared to PTHA, CTHA patients had increased operative time, blood loss, LOS, and readmission rates. After IMN failure, the operative leg was shorter than the contralateral leg in all cases. CTHA restored leg lengths to <  = 10 mm in 15 (68.1%) of patients, with an average leg length discrepancy after CTHA of 6.7 mm. CTHA patients had increased rates of overall surgical complications and medical complications, specifically anemia (all p < 0.01). Tranexamic acid was used less often in the CTHA group (p < 0.01). Rate of periprosthetic joint infection (PJI), dislocation, and revision were all higher in the CTHA, though did not reach statistical significance. CONCLUSION/CONCLUSIONS:The majority (77.3%) of CMN implant failure for nonunion within 1 year was due to screw cut-out. CTHA is a salvage option for early failed IT hip fracture repair, but expected surgical outcomes are more similar to revision THA than primary THA, with increased risk of readmission, longer surgery and LOS, increased blood loss, and higher complication rates. LEVEL OF EVIDENCE/METHODS:III, Retrospective comparative study.
PMID: 34657163
ISSN: 1434-3916
CID: 5043032

Evaluating Alternate Registration Planes for Imageless, Computer-Assisted Navigation During Total Hip Arthroplasty

Vigdorchik, Jonathan M; Sculco, Peter K; Inglis, Allan E; Schwarzkopf, Ran; Muir, Jeffrey M
BACKGROUND:Imageless computer navigation improves component placement accuracy in total hip arthroplasty (THA), but variations in the registration process are known to impact final accuracy measurements. We sought to evaluate the registration accuracy of an imageless navigation device during THA performed in the lateral decubitus position. METHODS:A prospective, observational study of 94 patients undergoing a primary THA with imageless navigation assistance was conducted. Patient position was registered using 4 planes of reference: the patient's coronal plane (standard method), the long axis of the surgical table (longitudinal plane), the lumbosacral spine (lumbosacral plane), and the plane intersecting the greater trochanter and glenoid fossa (hip-shoulder plane). Navigation measurements of cup position for each plane were compared to measurements from postoperative radiographs. RESULTS:Mean inclination from radiographs (41.5° ± 5.6°) did not differ significantly from inclination using the coronal plane (40.9° ± 3.9°, P = .39), the hip-shoulder plane (42.4° ± 4.7°, P = .26), or the longitudinal plane (41.2° ± 4.3°, P = .66). Inclination measured using the lumbosacral plane (45.8° ± 4.3°) differed significantly from radiographic measurements (P < .0001). Anteversion measured from radiographs (mean: 26.1° ± 5.4°) did not differ significantly from the hip-shoulder plane (26.6° ± 5.2°, P = .50). All other planes differed significantly from radiographs: coronal (22.6° ± 6.8°, P = .001), lumbosacral (32.5° ± 6.4°, P < .0001), and longitudinal (23.7° ± 5.2°, P < .0001). CONCLUSION/CONCLUSIONS:Patient registration using any plane approximating the long axis of the body provided a frame of reference that accurately measured intraoperative cup position. Registration using a plane approximating the hip-shoulder axis, however, provided the most accurate and consistent measurement of acetabular component position.
PMID: 34154856
ISSN: 1532-8406
CID: 4918222

What Is the Optimal Irrigation Solution in the Management of Periprosthetic Hip and Knee Joint Infections?

Siddiqi, Ahmed; Abdo, Zuhdi E; Rossman, Stephen R; Kelly, Michael A; Piuzzi, Nicolas S; Higuera, Carlos A; Schwarzkopf, Ran; Springer, Bryan D; Chen, Antonia F; Parvizi, Javad
BACKGROUND:Thorough irrigation and debridement using an irrigation solution is a well-established treatment for both acute and chronic periprosthetic joint infections (PJIs). In the absence of concrete data, identifying the optimal irrigation agent and protocol remains challenging. METHODS:A thorough review of the current literature on the various forms of irrigations and their additives was performed to evaluate the efficacy and limitations of each solution as pertaining to pathogen eradication in the treatment of PJI. As there is an overall paucity of high-quality literature comparing irrigation additives to each other and to any control, no meta-analyses could be performed. The literature was therefore summarized in this review article to give readers concise information on current irrigation options and their known risks and benefits. RESULTS:Antiseptic solutions include povidone-iodine, chlorhexidine gluconate, acetic acid, hydrogen peroxide, sodium hypochlorite, hypochlorous acid, and preformulated commercially available combination solutions. The current literature suggests that intraoperative use of antiseptic irrigants may play a role in treating PJI, but definitive clinical studies comparing antiseptic to no antiseptic irrigation are lacking. Furthermore, no clinical head-to-head comparisons of different antiseptic irrigants have identified an optimal irrigation solution. CONCLUSION/CONCLUSIONS:Further high-quality studies on the optimal irrigation additive and protocol for the management of PJI are warranted to guide future evidence-based decisions.
PMID: 34127346
ISSN: 1532-8406
CID: 4936732

Inpatient Opioid Consumption Variability following Total Knee Arthroplasty: Analysis of 4,038 Procedures

Roof, Mackenzie A; Sullivan, Connor W; Feng, James E; Anoushiravani, Afshin A; Waren, Daniel; Friedlander, Scott; Lajam, Claudette M; Schwarzkopf, Ran; Slover, James D
This study examined an early iteration of an inpatient opioid administration-reporting tool, which standardized patient opioid consumption as an average daily morphine milligram equivalence per surgical encounter (MME/day/encounter) among total knee arthroplasty (TKA) recipients. The objective was to assess the variability of inpatient opioid administration rates among surgeons after implementation of a multimodal opioid sparing pain protocol. We queried the electronic medical record at our institution for patients undergoing elective primary TKA between January 1, 2016 and June 30, 2018. Patient demographics, inpatient and surgical factors, and inpatient opioid administration were retrieved. Opioid consumption was converted into average MME for each postoperative day. These MME/day/encounter values were used to determine mean and variance of opioids prescribed by individual surgeons. A secondary analysis of regional inpatient opioid consumption was determined by patient zip codes. In total, 23 surgeons performed 4,038 primary TKA. The institutional average opioid dose was 46.24 ± 0.75 MME/day/encounter. Average intersurgeon (IS) opioid prescribing ranged from 17.67 to 59.15 MME/day/encounter. Intrasurgeon variability ranged between ± 1.01 and ± 7.51 MME/day/encounter. After adjusting for patient factors, the average institutional MME/day/encounter was 38.43 ± 0.42, with average IS variability ranging from 18.29 to 42.84 MME/day/encounter, and intrasurgeon variability ranging between ± 1.05 and ± 2.82 MME/day/encounter. Our results suggest that there is intrainstitutional variability in opioid administration following primary TKA even after controlling for potential patient risk factors. TKA candidates may benefit from the implementation of a more rigid standardization of multimodal pain management protocols that can control pain while minimizing the opioid burden. This is a level of evidence III, retrospective observational analysis.
PMID: 32311746
ISSN: 1938-2480
CID: 4396892

Factors Affecting Range of Motion After Revision Total Knee Arthroplasty

Lygrisse, Katherine A; Roof, Mackenzie A; Sharan, Mohamad; Teo, Greg; Long, William J; Schwarzkopf, Ran
BACKGROUND:Range of motion (ROM) after revision total knee arthroplasty (RTKA) is an important clinical outcome, as decreased ROM can lead to patient dissatisfaction and diminished mobility. This study sought to determine the effect of type of revision, implant constraint level, and reason for revision has on RTKA ROM. METHODS:A retrospective review of 832 RTKA cases from 2011 to 2019 was conducted at a single, urban academic institution. Patients who underwent aseptic RTKA and had preoperative and 1-year postoperative ROM in their chart were included. The ΔROM was calculated by subtracting the preoperative ROM from the 1-year postoperative ROM. ROM was compared between tibial polyethylene liner-only revisions (liner) and all other revision types (component) and based on reason for revision. Subanalysis was performed within the liner and component revision cohorts to determine the effect of reason for revision and implant constraint level on ROM. RESULTS:In total, 290 patients qualified. Forty-two patients had liner revisions (14.5%) and 248 had component revisions (85.5%). The ΔROM for component revision cases was significantly higher than liner exchange only (10° ± 24° vs.1° ± 19°; P = .03). ΔROM was not significant when comparing the level of implant constraint nor was it when separating and comparing by type of revision. Component revisions due to instability were found to significantly decrease ΔROM. CONCLUSION/CONCLUSIONS:Component revision cases have significantly improved ΔROM when compared with liner-only revision. Constraint level is not significantly associated with changes in ROM in either liner or component revisions. Component revisions due to instability significantly reduce ΔROM.
PMID: 33985851
ISSN: 1532-8406
CID: 4878472

Is Surgical Approach for Primary Total Hip Arthroplasty Associated With Timing, Incidence, and Characteristics of Periprosthetic Femur Fractures?

Lygrisse, Katherine A; Gaukhman, Gaukhman D; Teo, Greg; Schwarzkopf, Ran; Long, William J; Aggarwal, Vinay K
BACKGROUND:Periprosthetic femur fractures (PFF) involving primary total hip arthroplasty (THA) remain a significant concern. The purpose of this study was to evaluate the effect of surgical approach during primary THA on early PFF with respect to fracture timing, incidence, radiographic parameters, and surgery-related factors. METHODS:A retrospective review of all patients with PFF during or after primary THA from 2011 to 2019 was conducted at a single, urban academic institution. Of the study cohort of 11,915 patients, 79 patients with PFF were identified (0.66%). Direct anterior (DA), posterior anterior (PA), and laterally based (LA) cohorts were formed based on the surgical approach. PA and LA groups were combined to form a nonanterior (NA) cohort. Radiographic parameters, surgical factors, and fracture mechanism were analyzed. RESULTS:The incidence of fracture across approaches was 0.70% (33/4707; DA), 0.63% (35/5600; PA), and 0.68% (11/1608; LA) (P = .97). Time from THA to fracture was significantly shorter in the DA cohort (12.5 ± 14.1 days) than the NA cohort (48.2 ± 120.6 days) (P = .05). Postoperatively identified, atraumatic PFFs were more common in the DA cohort (78.3%, 18/23) than the NA cohort (51.6%, 16/31) (P = .045). There were no differences between groups in radiographic or other clinical parameters. CONCLUSION/CONCLUSIONS:Patients who underwent DA THA have significantly shorter time to PFF and were more often identified postoperatively with an atraumatic mechanism than patients who underwent NA approaches. The known difficulty in femoral exposure and stem placement with the DA approach may play a role in contributing to a higher rate of intraoperative or early postoperative PFF.
PMID: 34016522
ISSN: 1532-8406
CID: 4924222

P6. Spinopelvic alignment changes between seated and standing positions in pre and post total hip replacement patients [Meeting Abstract]

Balouch, E; Zhong, J; Jain, D; O'Malley, N; Maglaras, C; Schwarzkopf, R; Buckland, A J
BACKGROUND CONTEXT: The inter-relationship between the hip and spine has been increasingly studied in recent years, particularly as it pertains to the effect of spinal deformity and hip osteoarthritis (OA). Changing from standing (ST) to seated (SE) requires rotation of the femur from an almost vertical plane to the horizontal. OA of the hip significantly limits hip extension, resulting in less ability to recruit pelvic tilt (PT) in ST, and requiring increased PT in SE to compensate for loss of hip flexion. To date, the effect of total hip arthroplasty (THA) in altering spinopelvic SE and ST mechanics has not been reported. PURPOSE: To investigate the change in spinopelvic alignment parameters between seated and standing positions in pre and post THA patients. STUDY DESIGN/SETTING: Retrospective review at a single academic institution. PATIENT SAMPLE: Adult patients undergoing THA with full body sitting and standing radiographs pre- and post-THA. OUTCOME MEASURES: Spinopelvic alignment measures including pelvic incidence (PI), pelvic tilt (PT), T1 pelvic angle (TPA), sacral slope (SS), sagittal vertical axis (SVA), pelvic incidence and lumbar lordosis mismatch (PI-LL), and lumbar lordosis (LL).
METHOD(S): Patients >=18yo undergoing THA for hip OA with full spine SE and ST radiographs pre and post THA were included. Spinopelvic alignment was analyzed pre-THA and post-THA in both ST and SE positions in a relaxed posture with the fingers on the clavicles. Paired t-test analysis was performed to compare Pre-and Post-THA groups. The effect of TL deformity (SVA>50, TPA>20, PI-LL>10) on these changes was also analyzed. Statistical significance set at p<0.05.
RESULT(S): There were 192 patients assessed. 179 patients had thoracolumbar (TL) deformity; TPA>20 (N=46), PI-LL>10 (N=55), and SVA>50 (N=78). In standing position, patients have a significant reduction in SVA post THA vs pre THA (34.09+/-42.69 vs 45.03+/-46.87, p=0.001) as a result of an increase in PT (15.7+/-9.74 o vs 14.6+/-9.88o,p=0.028), without significant changes in spinal alignment parameters including lumbar lordosis (-51.26+/-14.59 vs -50.26+/-14.87, p=0.092), thoracic kyphosis (35.98+/-12.72 vs 35.40+/-13.16, p=0.180), sacral slope (38.15+/-10.77 vs 38.83+/-11.31, p=0.205), T1 pelvic angle (14.22+/-9.94 vs 14.51+/-10.13, p=0.053) and PI-LL mismatch (2.59+/-14.61 vs 3.35+/-14.92, p=0.183). This change in ST_SVA was larger in patients with TL deformity, specifically in those with SVA>50 (61.29+/-45.69 vs 89.48+/-35.91, p=0.001), in PI-LL > 10 (59.08+/-45.49 vs 73.36+/-48.50, p=0.001) and in TPA>20 subsets (62.14+/-49.94 vs 82.28+/-49.55, p=0.001). When moving from ST to SE, the DELTAPT was reduced post THA (16.70+/-15.27o vs 20.85+/-17.27o, p=0.001) in addition to a smaller SE_PT vs pre-THA (32.41+/-14.47 vs 35.46+/-14.20, p=0.006).
CONCLUSION(S): Post Total Hip Arthroplasty (THA), patients demonstrated an increased recruitment of pelvic retroversion to achieve a better global balance by reduction in standing SVA. This compensation was achieved solely by greater mobility of their hip and pelvis, and without a significant change in spinal alignment. ST_SVA reduction was more pronounced in patients with thoracolumbar (TL) spinal deformity (SVA>50, TPA>20, PI-LL>10). On the converse, PT was reduced in sitting (SE) post-THA compared to pre-THA, and the compensatory change in PT was also reduced between ST and SE as a result of restoration of hip flexion. FDA DEVICE/DRUG STATUS: This abstract does not discuss or include any applicable devices or drugs.
ISSN: 1529-9430
CID: 4971692