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Intraosseous regional administration (IORA) of antibiotics after tourniquet inflation has recently been introduced as a technique to deliver antibiotics directly to the surgical site among patients undergoing total knee arthroplasty (TKA).PubMed and Embase were queried for studies reporting on IORA for perioperative prophylaxis during TKA. Primary outcome measures were local tissue antibiotic concentrations and rates of prosthetic joint infection (PJI). Eight studies were included for analysis. Four studies (all randomized controlled trials) compared local tissue concentrations between patients receiving IORA and intravenous (IV) antibiotics. Six studies assessed the rate of PJI among patients receiving IORA versus IV antibiotics.All studies found a statistically significant increase in antibiotic concentration in femoral bone and fat samples in patients who were treated with IORA (44.04 μg/g [fat] and 49.3 μg/g [bone] following 500 mg of intraosseous vancomycin) versus IV (3.5 μg/g [fat] and 5.2 μg/g [bone] following 1 g IV of vancomycin). The two studies powered to determine differences in PJI rates found a statistically significant decrease in the rate of PJI among patients receiving IORA versus IV antibiotics. The incidence of PJI in patients treated with IORA and IV antibiotics across all studies was 0.3 and 1.1%, respectively.Perioperative IORA of antibiotics in TKA provides local tissue concentrations of antibiotics that are on average 10 times higher than IV administration alone. Although more adequately powered investigations are necessary to determine the effectiveness of IORA in reducing PJI rates, adoption of IORA should be considered in high-risk patients where elevated tissue antibiotic concentrations would be of a maximum benefit.

Extended oral antibiotic prophylaxis may decrease rates of prosthetic joint infection (PJI) after total joint arthroplasty (TJA) in patients at high risk for infection. However, the cost-effectiveness of this practice is not clear. In this study, we used a break-even economic model to determine the cost-effectiveness of routine extended oral antibiotic prophylaxis for PJI prevention in high-risk TJA patients.Baseline PJI rates in high-risk patients, the cost of revision arthroplasty for PJI, and the costs of extended oral antibiotic prophylaxis regimens were obtained from the literature and institutional purchasing records. These variables were incorporated in a break-even economic model to calculate the absolute risk reduction (ARR) in infection rate necessary for extended oral antibiotic prophylaxis to be cost-effective. ARR was used to determine the number needed to treat (NNT).Extended oral antibiotic prophylaxis with Cefadroxil in patients at high risk for PJI was cost-effective at an ARR in baseline infection rate of 0.187% (NNT = 535) and 0.151% (NNT = 662) for TKA and THA, respectively. Cost-effectiveness was preserved with varying costs of antibiotic regimens, PJI treatment costs, and infection rates.The use of extended oral antibiotic prophylaxis may reduce PJI rates in patients at high risk for infection following TJA and appears to be cost-effective. However, the current evidence supporting this practice is limited in quality. The use of extended oral antibiotic prophylaxis should be weighed against the possible development of future antimicrobial resistance, which may change the value proposition.

The convergence of national priorities to reduce health-care costs and deliver high-value care warrants the need to examine health-care utilization. The objective of this study was to describe the costs associated with nonoperative procedures in the 1-year period leading up to primary total knee arthroplasty (TKA).An observational cohort study was conducted using the IBM Watson Health MarketScan databases. Patients with late-stage knee osteoarthritis (OA) who underwent unilateral, isolated primary TKA from January 1, 2018, to December 31, 2019, were included. The main outcome was the cost of knee OA-related payments for identified nonoperative procedures in the 1-year period before surgery. Nonoperative procedures examined were (1) physical therapy (PT); (2) bracing; (3) intra-articular injections: professional fee, hyaluronic acid (IA-HA), and corticosteroids (IA-CS); (4) medication: nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and acetaminophen; and (5) knee-specific imaging.The study population included 24,492 TKA patients with a mean age of 60.4 ± 8.0 years. The average total cost of nonoperative procedures per patient was $1,355 ± $2,087. The most common nonoperative treatment prescribed was IA-CS (54.3%). The nonoperative procedure with the highest cost per patient was IA-HA ($1,019 ± $913 per patient). The total cost of nonoperative procedures was higher among female compared with male patients ($1,440 ± $2,159 versus $1,254 ± $1,992 per patient; p0.01). The highest costs were found for patients in the Northeast ($1,740 ± $2,437 per patient). A total of 14,346 (58.6%) and 7,831 (32.0%) of the patients had1 and ≥3 nonoperative treatments, respectively.There is substantial variation in the type and the cost of nonoperative treatment for patients with late-stage OA. Future studies should investigate the effectiveness of nonoperative treatments at different stages of the disease.Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Preoperative narcotic use is associated with poor postoperative pain management and worse outcomes after total joint arthroplasty (TJA). Therefore, identifying controlled substance use preoperatively is necessary. Electronic medical records (EMRs), prescription monitoring programs (PMP), or urine toxicology screening (UTS) are most commonly used. This study aims to compare the accuracy of EMR and PMP versus UTS to determine whether UTS should be implemented as standard of care in TJA preoperative assessment. Preoperative UTS was performed for primary or revision TJA from November 1, 2018, to March 31, 2019. Patient demographics, medical history, prescription history, and UTS results were retrospectively recorded. Prescription monitoring program and EMR were queried for prescription history in the past 2 years. The accuracy of EMR and PMP compared with UTS was calculated. Multivariable logistic regression analysis was performed to identify patient predictors associated with UTS+. Thirty of 148 patients had UTS+. Positive urine toxicology screening was more common in patients younger than 58 years, White race, and undergoing revision surgery. Electronic medical record and PMP documentation had the highest sensitivity (73.3%), specificity (92.4%), positive predictive value (71.0%), and negative predictive value (93.2%). Patients with higher odds of UTS+ include current/former smokers, those with a history of alcohol abuse, drug abuse, hepatitis C diagnosis, and mental illness. For patients without any risk factors for having a UTS+, the use of EMR and PMP may be sufficient to evaluate for controlled substance use; however, UTS should be considered in patients who present with one of the risk factors for UTS+.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup conducted a workshop on Immune and Cellular Therapy in Multiple Myeloma on January 7, 2022. This workshop included presentations by basic, translational, and clinical researchers with expertise in plasma cell dyscrasias. Four main topics were discussed: platforms for myeloma disease evaluation, insights into pathophysiology, therapeutic target and resistance mechanisms, and cellular therapy for multiple myeloma. Here we provide a comprehensive summary of these workshop presentations.

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist–induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.

Supplementary Table 1

We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)–targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone. Post-XRT findings included a second wave of fever and increased CRP and IL6, beginning 21 days after CAR T cells, which is late for cytokine-release syndrome from CAR T-cell therapy alone on this trial. Given this response, which resembled cytokine-release syndrome, immediately following XRT, we investigated changes in the patient's T-cell receptor (TCR) repertoire over 10 serial time points. Comparing T-cell diversity via Morisita's overlap indices (CD), we discovered that, although the diversity was initially stable after CAR T-cell therapy compared with baseline (CD = 0.89–0.97, baseline vs. 4 time points after CAR T cells), T-cell diversity changed after the conclusion of XRT, with >30% newly expanded TCRs (CD = 0.56–0.69, baseline vs. 4 time points after XRT). These findings suggest potential synergy between radiation and CAR T-cell therapies resulting in an abscopal-like response.

Supplementary Data from Activation of Tumor-Cell STING Primes NK-Cell Therapy

Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos (n = 21), OR = 4.7 (95% confidence interval, 1.3–16.7), and African American Blacks (n = 33), OR = 3.5 (1.1–11.5), as compared with White patients (n = 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated (P > 0.05) with adverse outcome: hypertension (n = 56), OR = 2.2 (0.9–5.4); diabetes (n = 18), OR = 0.9 (0.3–2.9); age >65 years (n = 63), OR = 1.8 (0.7–4.6); high-dose melphalan with autologous stem cell transplant n = 7), OR = 0.9 (0.2–5.4); and immunoglobulin G n = 42), OR = 0.9 (0.3–2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome.Significance:Patients with multiple myeloma are immunocompromised, raising the question whether they are at higher risk of severe COVID-19 disease. In this large case series on COVID-19 in patients with multiple myeloma, we report 29% mortality rates among hospitalized patients and identify race/ethnicity as the most significant risk factor for severe outcome.See related video: https://vimeo.com/486246183/559a80cfaeSee related commentary by Munshi and Anderson, p. 218.This article is highlighted in the In This Issue feature, p. 215

Supplementary Data Combined

Homelessness is a key social determinant of health, and the patient population has grown to over 580,000. Total joint arthroplasty (TJA) is an effective treatment of symptomatic end-stage osteoarthritis of the hip and knee and has been shown to improve health-related quality of life in the general population. However, the literature on the outcomes of TJA among homeless patients is limited.We retrospectively reviewed 442 patients who underwent primary, unilateral TJA between June 1, 2016, and August 31, 2017, at an urban, tertiary, academic safety net hospital. Based on self-reported living status, we classified 28 homeless patients and 414 control nonhomeless patients. Fisher exact tests, Student t-tests, and multivariate logistic regression were used to compare the demographics, preoperative conditions, and surgical outcomes between the two groups.The homeless group were younger, more often male, and smokers; had alcohol use disorder; and used illicit drugs. After controlling for age, sex, and preoperative medical and social conditions, homeless patients were 15.83 times more likely to have an emergency department visit (adjusted odds ratio, 15.83; 95% confidence interval, 5.05 to 49.59; P0.0001) within 90 days but had similar rates of readmission (P = 0.25), revision surgery (P = 0.38), and prosthetic joint infection (P = 0.25) when compared with nonhomeless patients.Although homeless patients did not have higher rates of readmission or revision surgery, homelessness still presents unique challenges for the TJA patients and providers. With careful preoperative optimization and collaborative support, however, the benefits of TJA may outweigh the risk of poor outcomes for these patients.

Although intra-articular corticosteroid injections (CSIs) are a cornerstone in the nonoperative management of hip pathology, recent reports have raised concerns that they may cause osteonecrosis of the femoral head (ONFH). However, these studies might have been limited by nonrepresentative patient samples. Therefore, the purpose of this study was to assess the incidence of ONFH after CSI and compare it with the incidence in a similar patient population that received a non-CSI injection.This was a retrospective propensity-matched cohort study of patients in the MarketScan database who underwent an intra-articular hip injection from 2007 to 2017. Patients receiving hip CSIs were matched 4:1 with patients receiving hip hyaluronic acid injections (HAIs) based on age, sex, geographic region, comorbidities, type of hip pathology, injection year, and baseline and follow-up time using propensity scores. The patients' first injections were identified, and the time to development of ONFH was analyzed using Kaplan-Meier curves and Cox proportional-hazards models. Patients with a history of osteonecrosis or those who received both types of injections were excluded.A total of 3,710 patients undergoing intra-articular hip injection were included (2,968 CSIs and 742 HAIs; mean [standard deviation] age, 53.1 [9.2] years; 55.4% men). All baseline factors were successfully matched between the groups (all p0.57). The estimated cumulative incidence (95% confidence interval [CI]) of ONFH for CSI and HAI patients was 2.4% (1.8% to 3.1%) versus 2.1% (1.1% to 3.5%) at 1 year and 2.9% (2.2% to 3.7%) versus 3.0% (1.7% to 4.8%) at 2 years (hazard ratio, 1.05; 95% CI, 0.59 to 1.84; p = 0.88). The results held across a range of sensitivity analyses.The incidence of ONFH after intra-articular hip injection was similar between patients who received CSIs and those who received HAIs. Although this study could not determine whether intra-articular injections themselves (regardless of the drug that was used) lead to ONFH, the results suggest that ONFH after CSI often may be due, in part, to the natural course of the underlying disease. Future randomized controlled trials are needed to definitively answer this question; in the interim, clinicians may be reassured that they may continue judicious use of CSIs as clinically indicated.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

With the US Food and Drug Administration (FDA) approval of four CD19- and one BCMA-targeted chimeric antigen receptor (CAR) therapy for B cell malignancies, CAR T cell therapy has finally reached the status of a medicinal product. The successful manufacturing of autologous CAR T cell products is a key requirement for this promising treatment modality. By analyzing the composition of 214 apheresis products from 210 subjects across eight disease indications, we found that high CD14+ cell content poses a challenge for manufacturing CAR T cells, especially in patients with non-Hodgkin's lymphoma and multiple myeloma caused by the non-specific phagocytosis of the magnetic beads used to activate CD3+ T cells. We demonstrated that monocyte depletion via rapid plastic surface adhesion significantly reduces the CD14+ monocyte content in the apheresis products and simultaneously boosts the CD3+ content. We established a 40% CD14+ threshold for the stratification of apheresis products across nine clinical trials and demonstrated the effectiveness of this procedure by comparing manufacturing runs in two phase 1 clinical trials. Our study suggests that CD14+ content should be monitored in apheresis products, and that the manufacturing of CAR T cells should incorporate a step that lessens the CD14+ cell content in apheresis products containing more than 40% to maximize the production success.

In response to the opioid epidemic in the United States, states have passed policies aimed at regulating how opioids are prescribed by physicians. For such policies to be effective, however, opioids must be prescribed to the patients for whom they are intended. Whether opioid prescriptions are written for those who are not intended to consume them is empirically difficult to show. In a commercially insured population, we examined opioid prescriptions written for and filled by spouses of patients undergoing outpatient surgery on the day of a patient’s surgery compared with the surrounding days. Because patients may be unable to fill prescriptions themselves immediately after surgery, surgeons may prescribe opioids to a patient’s spouse, which would be clinically inappropriate. Among 450,125 opioid-naïve couples studied, for patients who did not fill perioperative opioid prescriptions themselves, the rate of spousal fills on the day of surgery (DOS) was 2.39 fills per 1,000 surgeries compared with 0.44 fills on all other perioperative days (adjusted odds ratio (aOR), 5.5, 95% CI, 4.6–6.5). Increases in spousal opioid fills were not present for patients that filled opioid prescriptions themselves. These findings suggest intentional, clinically inappropriate prescribing of opioids.

As technology-assisted surgery has boosted in the last decades, we aimed to investigate the factors affecting adoption and to predict the future utilization of technology among patients who underwent total knee arthroplasty (TKA).Patients underwent TKA in 2017-2019 in the MarketScan Database were included. Percentage of technology-assisted surgery was calculated. Multivariable logistic regression models were performed to analyse the factors and make the prediction.Of 112,161 TKA procedures, 7.2% were technology-assisted. The proportion of technology-assisted TKA is expected to reach 50% by 2032. The West showed the highest proportion of technology-assisted TKA (12.3%), while the South had the lowest (5.7%). Over time, the Midwest showed the greatest increase in technology adoption (OR = 1.26 compared to the Northeast, 95% CI [1.15, 1.38]).Technology adoption rate of TKA will continue to increase for the next 20 years in the United States with a slight geographical variation.

Purpose To investigate the association between intrauterine device (IUD) use and hip pain, orthopaedic visits for hip pain, and arthroscopic hip surgery. Methods This was a retrospective cohort study of patients aged 18-44 years old using either IUDs or subdermal implants for contraception in a large commercial claims database (MarketScan) from 2012 to 2015. All patients had at least 12 months of continuous enrollment both before and after contraceptive placement. Patients with a history of hip pain or surgery were excluded. The primary outcome was new hip pain. Secondary outcomes included visiting an orthopaedic or sports medicine provider for a hip complaint, intra-articular hip injection, and arthroscopic hip surgery. Outcomes were analyzed with Cox proportional-hazard models. Results We identified a total of 242,383 patients, including 216,541 (89.3%) with IUDs and 25,842 (10.7%) with subdermal contraceptive implants. In time-to-event analysis, IUDs (vs implants) were not associated with increased risk of new hip pain diagnoses (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.87-1.03, P = .21). In contrast, both age (P < .001) and region (P < .001) were associated with increased risk of new hip pain. Similar results were seen for the secondary outcomes, including risk of orthopaedic visits for hip complaints (HR 1.06, 95% CI 0.83-1.35, P = .63), intra-articular injections of the hip (HR 0.94, 95% CI 0.63-1.41, P = .77), and hip arthroscopy procedures (HR 1.13, 95% CI 0.53-2.40, P = .75). Conclusions In this study, we found no evidence that IUDs were associated with hip pain or surgery. Level of Evidence Level III, retrospective cohort.

Background As demand for primary total joint arthroplasty (TJA) continues to grow, a proportionate increase in revision TJA (rTJA) is expected. It is essential to understand costs and reimbursement of rTJA as our country moves to bundled payment models. We aimed (1) to characterize implant and total hospital costs, (2) assess reimbursement, and (3) determine revenue for rTJA in comparison with primary TJA. Methods The average implant and total hospital cost of all primary and rTJA procedures by diagnosis-related group (DRG) was calculated using time-driven activity-based costing at an orthopedic hospital from 2018 to 2020. Average reimbursement and payer type were assessed by DRG. Revenue was calculated by deducting average time-driven activity-based costing total costs from reimbursement. Results 13,946 arthroplasties were included in the study. Implant cost comprised 55.8% of total hospital costs for rTJA DRG 468, compared with 43.6% of total hospital costs for primary TJA DRG 470. Total hospital costs for DRG 468 were 61.1% more than DRG 470. Reimbursement for rTJA was 1.23x more than primary TJA. Private payers paid 23.2% more than Medicare for rTJA. Margin for DRG 468 was 1.5% less than primary DRG 470. Conclusion rTJA requires more hospital resources and costs than primaries, yet hospital reimbursement may be inadequate with the additional expenditures necessary to provide optimal care. If hospitals cannot perform revision services under the current reimbursement model, patient access may be limited. Implant costs are a major contributor to overall rTJA cost. Strategies are needed to reduce revision implant costs to improve value of care. Level of Evidence Level III, economic and decision analysis.

Introduction Previous studies have shown that shorter inpatient stays after total hip arthroplasty (THA) are safe and effective for select patient populations with limited medical comorbidity and perioperative risk. The purpose of our study was to compare the postoperative complications because they relate to the length of hospital stay at a safety net hospital in the urban area of the United States. Methods We retrospectively reviewed the medical records of 236 patients who underwent primary THA in 2017 at an urban safety net hospital. We collected data on demographics, medical comorbidities, and surgical admission information. Patients were categorized as "early discharge" if they were discharged on postoperative day 0 to 1 and "standard discharge" if they were discharged on postoperative day 2 to 5. The outcomes of interest were 90-day and 2-year postoperative complications, emergency department visit, readmissions, and revision surgeries. Data were analyzed using t-test or chi-square test for univariate analysis and linear logistic regression for controlled analysis. Results Compared with the standard discharge group, there were markedly more male patients in the early discharge group (44.5% versus 80%). Early discharge patients were markedly younger (53.3 versus 59.5 years old), more likely to be White/non-Hispanic (64.4% versus 42.4%) and less likely to have heart disease and diabetes (2.2% versus 15.2% and 2.2% versus 19.9%, respectively). With adjustment for these potential confounders, no notable difference was observed in all-type complications, emergency department visits, readmission, or revision surgery between the two groups. Discussion This study confirmed that early discharge after THA is as safe as standard discharge in a safety net hospital with appropriate preoperative risk screening. Increased perioperative counseling and optimization of social and medical risk factors mitigated possible risk factors for increased length of stay and surgical complication.

Background The utilization of outpatient (OP) total joint arthroplasty (TJA) is increasing. Although many arthroplasty surgeons and hospitals have longstanding agreements with insurance companies, it may take time for ambulatory surgery centers (ASCs) to establish in-network agreements. The purposes of this study are to investigate trends in out-of-network facility charges for OP-TJA, as well as compare rates of out-of-network facilities between ASC and hospital outpatient department (HOPD) OP-TJA. Methods This is a retrospective study of the MarketScan commercial claims database of OP-TJAs (same-day discharge) performed at ASCs or HOPDs from 2007 to 2017. Detailed demographic, geographic, operative, insurance, temporal, and financial details were collected. Out-of-network facility utilization was trended over time. Adjusted regressions compared the prevalence of out-of-network facilities between ASCs and HOPDs. Results There were 13,031 OP-TJA patients (58.8% total knee arthroplasty). Utilization of out-of-network facilities significantly decreased over time, from 27.8% of surgeries in 2007 to 9.5% in 2017 (Ptrend Conclusion Although the utilization of out-of-network facilities has decreased, over 10% of patients with in-network surgeons face out-of-network facility charges, which may often come as a surprise. Efforts are warranted to reduce the out-of-network facility burden for OP-TJA patients, including accelerating insurance contracting and reviewing patients’ coverage statuses.

Background: Although intra-articular injections are important in the management of patients who may later undergo hip arthroscopy, conflicting data are available regarding the safety of such injections when administered within 3 months of surgery. Furthermore, despite the increasing use of image-guided intra-articular hip injections, it is unknown whether the type of imaging modality used is associated with infection after hip arthroscopy. Purpose: To assess the risk of infection associated with image-guided intra-articular injections before hip arthroscopy and, secondarily, compare that risk between ultrasound (US) and fluoroscopic (FL) guidance. Study Design: Cohort study; Level of evidence, 3. Methods: This was a retrospective cohort study of patients in a large national insurance database who underwent hip arthroscopy between 2007 and 2017. Patients were required to have continuous enrollment from at least 1 year before to 6 months after hip arthroscopy. Patient age, sex, geographic region, medical history, surgical details, and hip injections were collected. Patients who underwent injection ≤3 months preoperatively and >3 to ≤12 months preoperatively were compared with patients who did not undergo preoperative injection. Bivariate analyses and multivariable logistic regressions were used to assess the association between ipsilateral preoperative hip injection and surgical site infection within 6 months of surgery. Results: We identified 17,987 patients (36.3% female; mean ± SD age, 37.6 ± 14.0 years) undergoing hip arthroscopy, 2276 (12.7%) of whom had an image-guided hip injection in the year preceding surgery (53.0% FL). Patients who underwent intra-articular injection ≤3 months preoperatively had similar infection rates to patients who did not undergo preoperative injection in the year before surgery for both the FL (0.46% vs 0.46%; P≥ .995) and the US cohorts (0.50% vs 0.46%; P = .76). Results persisted in adjusted analysis (FL ≤3 months: OR, 1.04; 95% CI, 0.32-3.37; P = .94; US ≤3 months: OR, 1.19; 95% CI, 0.36-3.90; P = .78). Similar results were seen for patients undergoing injections >3 to ≤12 months preoperatively. Conclusion: Postoperative infection was rare in patients undergoing intra-articular hip injection ≤3 months before hip arthroscopy and was no more common than in patients not undergoing preoperative injection. Moreover, no differences were seen in infection risk between US and FL guidance. Although intra-articular hip injections should always be administered with careful consideration, these results do not suggest that these injections are uniformly contraindicated in the 3 months preceding hip arthroscopy.

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist–induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.

The challenges of culture-negative periprosthetic joint infection (PJI) have led to the emergence of molecular methods of pathogen identification, including next-generation sequencing (NGS). While its increased sensitivity compared with traditional culture techniques is well documented, it is not fully known which organisms could be expected to be detected with use of NGS. The aim of this study was to describe the NGS profile of culture-negative PJI.Patients undergoing revision hip or knee arthroplasty from June 2016 to August 2020 at 14 institutions were prospectively recruited. Patients meeting International Consensus Meeting (ICM) criteria for PJI were included in this study. Intraoperative samples were obtained and concurrently sent for both routine culture and NGS. Patients for whom NGS was positive and standard culture was negative were included in our analysis.The overall cohort included 301 patients who met the ICM criteria for PJI. Of these patients, 85 (28.2%) were culture-negative. A pathogen could be identified by NGS in 56 (65.9%) of these culture-negative patients. Seventeen species were identified as common based on a study-wide incidence threshold of 5%. NGS revealed a polymicrobial infection in 91.1% of culture-negative PJI cases, with the set of common species contributing to 82.4% of polymicrobial profiles. Escherichia coli, Cutibacterium acnes, Staphylococcus epidermidis, and Staphylococcus aureus ranked highest in terms of incidence and study-wide mean relative abundance and were most frequently the dominant organism when occurring in polymicrobial infections.NGS provides a more comprehensive picture of the microbial profile of infection that is often missed by traditional culture. Examining the profile of PJI in a multicenter cohort using NGS, this study demonstrated that approximately two-thirds of culture-negative PJIs had identifiable opportunistically pathogenic organisms, and furthermore, the majority of infections were polymicrobial.Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Background Patients with hepatitis C virus (HCV) have an increased risk of complications after total joint arthroplasty (TJA). There is a limited but growing body of evidence on the benefit of preoperative antiviral treatment to reduce complications after TJA. What has not been well established is the effect of preoperative antiviral treatment among those with advanced disease as indicated by hepatic fibrosis. Methods In total, 270 patients at 2 urban medical centers were reviewed for patient demographics, comorbidities, HCV treatment, hepatic fibrosis status, surgical information, and postoperative complications. Patients were divided into 2 groups based on their antiviral treatment status prior to TJA: Treated (n = 129) and Untreated (n = 141). Pearson’s chi-squared test, Student’s t-test, and multivariate logistic regressions were used to analyze complications between groups. Results Patients in the Treated group had significantly fewer all-type complications (4.7% vs 14.9%, P = .007), infections (2.3% vs 12.1%, P = .002), and reoperations (0.8% vs 9.9%, P = .001) compared to the Untreated group. After controlling for hepatic fibrosis, we found that Treated patients still had significantly lower odds of experiencing all-type complications (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.10-0.88; P = .028), infection (OR 0.19, 95% CI 0.04-0.87; P = .033), and reoperation (OR 0.11, 95% CI 0.01-0.90; P = .039) following TJA. Conclusion HCV antiviral treatment reduces postoperative complications after primary TJA, even among those who have progressed to hepatic fibrosis. Surgeons can use this information in shared decision making prior to TJA to counsel patients about the benefits of preoperative antiviral treatment even in the presence of hepatic fibrosis.

BACKGROUND: Daratumumab-based combination therapies have shown high rates of complete response (CR) and minimal residual disease negativity in patients with multiple myeloma. However, daratumumab, an IgGκ monoclonal antibody, interferes with electrophoretic techniques making it difficult to reliably define residual disease versus CR, especially in patients with IgGκ multiple myeloma. METHODS: Enrichment with polyclonal sheep antibody-coated magnetic microparticles combined with MALDI-TOF mass spectrometry (MALDI-TOF MS) analysis was used to detect M-proteins in serial samples from newly diagnosed multiple myeloma patients treated with daratumumab-based therapy. The performance of the MALDI-TOF MS assay was compared to that of a routine test panel (serum protein electrophoresis (SPEP), immunofixation (IFE) and serum free light chain (FLC)). RESULTS: Comparison of MALDI-TOF MS to SPEP/IFE/FLC showed a concordance of 84.9% (p

BACKGROUND Although the risks of continued opioid use following inpatient total joint arthroplasty (TJA) have been well-studied, these risks in the outpatient setting are not well known. The purpose of the present study was to characterize opioid use following outpatient compared with inpatient TJA. METHODS In this retrospective cohort study, opioid-naive patients who underwent inpatient or outpatient (no overnight stay) primary, elective TJA from 2007 to 2017 were identified within a large national commercial-claims insurance database. For inclusion in the study, patients had to have been continuously enrolled in the database for ≥12 months prior to and ≥6 months after the TJA procedure. Multivariable analyses controlling for demographics, geography, procedure, year, and comorbidities were utilized to determine the association between surgical setting and risk of persistent opioid use, defined as the patient still filling new opioid prescriptions >90 days postoperatively. RESULTS We identified a total of 92,506 opioid-naive TJA patients, of whom 57,183 (61.8%) underwent total knee arthroplasty (TKA). Overall, 7,342 patients (7.9%) underwent an outpatient TJA procedure, including 4,194 outpatient TKAs. Outpatient TJA was associated with reduced surgical opioid prescribing (78.9% compared with 87.6% for inpatient procedures; p < 0.001). Among the 80,393 patients (86.9%) who received surgical opioids, the total amount of opioids prescribed (in morphine milligram equivalents) was similar between inpatient (median, 750; interquartile range, 450 to 1,200) and outpatient procedures (median, 750; interquartile range, 450 to 1,140; p = 0.47); however, inpatient TJA patients were significantly more likely to still be taking opioids after 90 days postoperatively (11.4% compared with 9.0% for outpatient procedures; p < 0.001). These results persisted in adjusted analysis (adjusted odds ratio, 1.13; 95% confidence interval, 1.03 to 1.24; p = 0.01). CONCLUSIONS Outpatient TJA patients who received opioid prescriptions were prescribed a similar amount of opioids as those undergoing inpatient TJA procedures, but were significantly less likely to become persistent opioid users, even when controlling for patient factors. Outpatient TJA, as compared with inpatient TJA, does not appear to be a risk factor for new opioid dependence, and these findings support the continued transition to the outpatient-TJA model for lower-risk patients. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Purpose: Minimal residual disease (MRD) negativity is a strong predictor for outcome in multiple myeloma. To assess V(D)J clonotype capture using the updated Adaptive next-generation sequencing (NGS) MRD assay in a clinical setting, we analyzed baseline and follow-up samples from patients with multiple myeloma who achieved deep clinical responses. Experimental Design: A total of 159 baseline and 31 follow-up samples from patients with multiple myeloma were sequenced using the NGS MRD assay. Baseline samples were also sequenced using a targeted multiple myeloma panel (myTYPE). We estimated ORs with 95% confidence intervals (CI) for clonotypes detection using logistic regression. Results: The V(D)J clonotype capture rate was 93% in baseline samples with detectable genomic aberrations, indicating presence of tumor DNA, assessed through myTYPE. myTYPE-positive samples had significantly higher V(D)J clonotype detection rates in univariate (OR, 7.3; 95% CI, 2.8–22.6) and multivariate analysis (OR, 4.4; 95% CI, 1.4–16.9; P = 0.016). Higher disease burden was associated with higher probability of V(D)J clonotype capture, meanwhile no such association was found for age, gender, or type of heavy or light immunoglobulin chain. All V(D)J clonotypes detected at baseline were detected in MRD-positive samples indicating that the V(D)J clonotypes remained stable and did not undergo further rearrangements during follow-up. Of the 31 posttreatment samples, 12 were MRD-negative using the NGS MRD assay. Conclusions: NGS for V(D)J rearrangements in multiple myeloma offers a reliable and sensitive method for MRD tracking with high detection rates in the clinical setting.

Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graft-versus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before alloHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early ( 24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P = .002). Older age, relapse with EMD

Background High body mass index (BMI) has long been recognized as a risk factor for postoperative complication among total hip arthroplasty (THA) patients. However, recent studies showed mixed results in the effect of high BMI on surgical outcomes. Our study is to examine the association of preoperative BMI with complication incidence, stratified by age and gender. Methods We queried the American College of Surgeons National Surgical Quality Improvement Project database to identify patients who underwent elective primary THA between 2012 and 2016. We examined the associations between BMI as a continuous and a categorical variable and risk of 30-day postoperative complication, using 2 multiple polynomial logistic regression models. We also created predictive plots to graphically assess the relationship between BMI and complication by gender and age. Results In total, 117,567 eligible patients were included in the analyses. The predictive probability of all-type postoperative complications showed a U-shaped relationship with continuous BMI values (range 10-65 kg/m2). The lowest complication risks occurred in patients with BMI between 35 and 40. Females had higher complication rate than males across all BMI values. This U-shaped relationship was only observed among patients younger than 60 years old, while the associations appear to be inversely linear among patients aged greater than 60 years. Conclusion Our results suggest that the current theory of a linear association between BMI and complication risk may not apply to elective primary THA. Strict BMI cutoffs may not minimize risk, especially among patients over 60 years old. Orthopedic surgeons should factor in patient-specific variables of age and gender when determining acceptable surgical risk given a particular BMI value.

Background The use of megaprostheses in nononcologic patients has been associated with complication rates greater than 50%. In patients with prior periprosthetic joint infection (PJI) with subsequent two-stage reimplantation, this complication rate may be even higher. This study was to investigate the outcomes of megaprostheses in nononcologic patients undergoing revision hip/knee arthroplasty. Methods We retrospectively studied patients who underwent megaprosthesis replacements from 1999 to 2017 at 5 hospitals with minimum 24 months of follow-up. Patients were stratified based on history of prior PJI (septic vs aseptic) and location of the megaprosthesis (the hip or knee). Postoperative complications were classified as soft-tissue failure, aseptic loosening, structural failure, and infection. Results Of the 42 patients, 19 were in the septic cohort and 23 were in the aseptic cohort. The overall complication rate was 28.6%. Complication rates for the septic and aseptic cohorts were 32% and 26%, respectively (P = .74). By anatomic location, there were 2 of 13 (15%) and 10 of 29 (34%) complications in the hip and knee groups, respectively (P = .28). In the septic cohort, there were no (0%) complications in the hip group and 6 of 14 (43%) complications in the knee group (P = .13), all due to infection. In the aseptic cohort, there were 2 of 8 (25%) and 4 of 15 (27%) complications in the hip and knee groups, respectively (P = 1.0). Conclusions There is no difference in the postoperative complication rates between the septic or aseptic cohorts undergoing revision hip or knee megaprosthesis replacements. In patients with prior PJI, proximal femoral replacements have improved short-term survivorship compared with distal femoral or proximal tibial replacements.

Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma targeting B-cell maturation antigen (TNFRSF17; BCMA) induces high overall response rates; however, relapse occurs commonly. A reservoir of multiple myeloma cells lacking sufficient BCMA surface expression (antigen escape) may be implicated in relapse. We demonstrate that simultaneous targeting of an additional antigen—here, G protein-coupled receptor class-C group-5 member-D (GPRC5D)—can prevent BCMA escape–mediated relapse in a model of multiple myeloma. To identify an optimal approach, we compare subtherapeutic doses of different forms of dual-targeted cellular therapy. These include; (i) parallel-produced and pooled mono-targeted CAR T cells, (ii) bicistronic constructs expressing distinct CARs from a single vector, and (iii) a dual-scFv “single-stalk” CAR design. When targeting BCMA-negative disease, bicistronic and pooled approaches had the highest efficacy, whereas for dual-antigen–expressing disease, the bicistronic approach was more efficacious than the pooled approach. Mechanistically, expressing two CARs on a single cell enhanced the strength of CAR T-cell/target cell interactions. Significance: Myeloma frequently relapses post-CAR T-cell therapy; antigen escape–mediated relapse can be mitigated with upfront dual-targeting (BCMA/GPRC5D). A bicistronic vector encoding two CARs avoids the challenge of parallel manufacturing separate CAR T-cell products, while providing superior efficacy; this dual-targeted approach may enhance the durability of responses to cellular therapy for myeloma. See related commentary by Simon and Riddell, p. 130. This article is highlighted in the In This Issue feature, p. 127

We report a case of head-neck taper fretting corrosion in a patient who had a total hip replacement with a noncemented Stryker Anato femoral stem and a V40 metal head with a Stryker Tritanium hemispherical socket with a highly cross-linked polyethylene liner (metal on polyethylene) (Stryker, Mahwah, NJ, USA). A 57-year-old man presented with early-onset hip pain after right total hip arthroplasty. Workup was negative for infection. Metal artifact reduction sequence MRI revealed an encapsulated fluid mass. Metal ion cobalt level was elevated at 6 ppb. The patient underwent right revision total hip arthroplasty with excellent results at 1-year follow-up.