Therapeutic Avenues to Modulate B-Cell Function in Patients With Cardiovascular Disease.

The adaptive immune system plays an important role in the development and progression of atherosclerotic cardiovascular disease. B cells can have both proatherogenic and atheroprotective roles, making treatments aimed at modulating B cells important therapeutic targets. The innate-like B-cell response is generally considered atheroprotective, while the adaptive response is associated with mixed consequences for atherosclerosis. Additionally, interactions of B cells with components of the adaptive and innate immune system, including T cells and complement, also represent key points for therapeutic regulation. In this review, we discuss therapeutic approaches based on B-cell depletion, modulation of B-cell survival, manipulation of both the antibody-dependent and antibody-independent B-cell response, and emerging immunization techniques.

A neural tract-inspired conduit for facile, on-demand biopsy of glioblastoma.

Background: A major hurdle to effectively treating glioblastoma (GBM) patients is the lack of longitudinal information about tumor progression, evolution, and treatment response. Methods: In this study, we report the use of a neural tract-inspired conduit containing aligned polymeric nanofibers (i.e., an aligned nanofiber device) to enable on-demand access to GBM tumors in 2 rodent models. Depending on the experiment, a humanized U87MG xenograft and/or F98-GFP+ syngeneic rat tumor model was chosen to test the safety and functionality of the device in providing continuous sampling access to the tumor and its microenvironment. Results: The aligned nanofiber device was safe and provided a high quantity of quality genomic materials suitable for omics analyses and yielded a sufficient number of live cells for in vitro expansion and screening. Transcriptomic and genomic analyses demonstrated continuity between material extracted from the device and that of the primary, intracortical tumor (in the in vivo model). Conclusions: The results establish the potential of this neural tract-inspired, aligned nanofiber device as an on-demand, safe, and minimally invasive access point, thus enabling rapid, high-throughput, longitudinal assessment of tumor and its microenvironment, ultimately leading to more informed clinical treatment strategies.

Canonical and non-canonical roles of complement in atherosclerosis.

Cardiovascular diseases are the leading cause of death globally, and atherosclerosis is the major contributor to the development and progression of cardiovascular diseases. Immune responses have a central role in the pathogenesis of atherosclerosis, with the complement system being an acknowledged contributor. Chronic activation of liver-derived and serum-circulating canonical complement sustains endothelial inflammation and innate immune cell activation, and deposition of complement activation fragments on inflamed endothelial cells is a hallmark of atherosclerotic plaques. However, increasing evidence indicates that liver-independent, cell-autonomous and non-canonical complement activities are underappreciated contributors to atherosclerosis. Furthermore, complement activation can also have atheroprotective properties. These specific detrimental or beneficial contributions of the complement system to the pathogenesis of atherosclerosis are dictated by the location of complement activation and engagement of its canonical versus non-canonical functions in a temporal fashion during atherosclerosis progression. In this Review, we summarize the classical and the emerging non-classical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential strategies for therapeutic modulation of complement for the prevention and treatment of atherosclerotic cardiovascular disease.

Outcome Disparities in Total Knee and Total Hip Arthroplasty among Native American Populations.

BACKGROUND: No prior racial disparities studies in total knee arthroplasty (TKA) and total hip arthroplasty (THA) have specifically evaluated outcomes among American Indian or Alaska Native (AIAN) patients. We hypothesized that AIAN patients have worse outcomes than White patients after controlling for demographics and comorbidities. METHODS: This was a retrospective cohort study comparing White and AIAN patients undergoing primary TKA/THA from 2012-2019 using the American College of Surgeons National Surgical Quality Improvement Program. Race, demographics, and comorbidities were analyzed for correlations with 30-day outcomes and complications using multivariable logistic and linear regression analyses. RESULTS: Comparing 422,215 White and 2,676 AIAN patients, AIAN patients had higher American Society of Anesthesiologist (ASA) classifications, body mass index (BMI), and were younger at the time of surgery. AIAN patients more often stayed inpatient > 2 days (49.4% vs 36.2%, p < 0.001), underwent reoperation (2.1% vs 1.4%, p < 0.01), and were discharged home (91.4% vs 81.7%, p < 0.01). Regression analyses controlling for age, BMI, sex, ASA classification, and functional status found that AIAN race was significantly positively correlated with a length of stay > 2 days (OR 1.6), reoperation (OR 1.4), and discharging home (OR 2.0). CONCLUSION: AIAN patients undergoing TKA/THA present with a greater comorbidity burden compared to White patients and experience multiple worse outcome metrics including increased hospital length of stay and reoperation rates. Interestingly, AIAN patients were more likely to discharge home, representing a unique racial disparity which warrants further study.

D-Dimer, Erythrocyte Sedimentation Rate, and C-Reactive Protein Sensitivities for Periprosthetic Joint Infection Diagnosis.

BACKGROUND: There is contradicting evidence on the diagnostic value of inflammatory biomarkers for periprosthetic joint infection (PJI). We sought to quantify the sensitivity of D-dimer for acute and chronic PJI diagnosis and evaluate D-dimer lab values in the 90-day postoperative window in a control cohort of primary joint arthroplasty patients for comparison. METHODS: An institutional database was queried for patients undergoing revision procedures for PJI after total hip arthroplasty (THA) and total knee arthroplasty (TKA) from 2014 to present. CRP, ESR, and D-dimer were collected within 90 days pre and postoperatively and sensitivities for the diagnosis of PJI were calculated. The control group included patients who underwent a negative diagnostic workup for deep venous thrombosis (DVT) or pulmonary embolus (PE) and had a D-dimer lab collected within 90 days postoperatively from primary total joint arthroplasty (TJA). RESULTS: A total of 604 PJI patients were identified, and 81 patients had D-dimer, ESR, and CRP collected. There were 50/81 acute PJI patients and 31/81 chronic PJI patients who had median D-dimer values of 2,136.5 ng/mL [interquartile range (IQR): 1,642-3,966.5] and 3,336 ng/mL [IQR: 1,976-5,594]. Only the chronic PJI group had significantly higher D-dimer values when compared to the control cohort (P = .009). The sensitivity of D-dimer was calculated to be 92% and 93.5% in the acute and chronic PJI groups, respectively. CONCLUSION: Serum D-dimer may not have high diagnostic utility for acute PJI, especially in the setting of recent surgery; however, it still may be useful for patients who have chronic PJI.

Outcomes and Cost Analysis of a Surgical Care Unit for Outpatient Total Joint Arthroplasties Performed at a Tertiary Academic Center.

Background: Total joint arthroplasty (TJA) has shifted toward being an outpatient surgery with advances in perioperative protocols and patient selection. Most literature on outpatient arthroplasty focuses on the surgery performed in ambulatory centers. This study sought to compare (1) short-term outcomes and (2) the total procedural cost in patients who underwent TJAs at a tertiary academic center and were discharged from the accelerated surgical care unit (SCU) vs the inpatient floor unit. Methods: This is a retrospective review of 1231 procedures (637 total knee arthroplasties and 594 total hip arthroplasties) performed between January 2020 and May 2021 at 1 tertiary academic center. The minimum required follow-up duration was 90 days. Patients were divided into 2 cohorts based on discharge location (SCU vs inpatient). Patient demographics, medical comorbidities, 90-day hospital returns, and revisions were evaluated with univariate and multivariate analyses. Of the 1231 patients, 1092 had available cost data that were analyzed by a univariate analysis. Results: Patients discharged from the SCU were younger (P < .01), with lower American Society of Anesthesiologists scores (P = .04). SCU patients trended toward fewer 90-day hospital returns and revisions; however, these results were not significant. The overall encounter cost for TJA was significantly lower in patients discharged from the SCU (P < .01). Cost remained significantly less at 30 and 90 days postoperatively (P < .01). Conclusions: The present study represents the current activity at many large tertiary American academic medical centers. Results demonstrate that a unit for accelerated discharge after TJAs in a tertiary academic center is safe and cost-effective. With proper implementation, its development will enhance arthroplasty programs at a large tertiary academic center.

The Use of Panitumumab-IRDye800CW in a Novel Murine Model for Conjunctival Squamous Cell Carcinoma.

Purpose: Conjunctival squamous cell carcinoma (SCC) is a sight-threatening ocular surface malignancy with the primary treatment modality being surgical resection. To evaluate surgical imaging modalities to improve surgical resection, we established a novel murine model for conjunctival SCC to demonstrate the utility of panitumumab-IRDye800, a fluorescently labeled anti-epidermal growth factor receptor (EGFR) antibody. Methods: NOD-scid IL2Rgammanull (NSG) mice received subconjunctival injection of UM-SCC-1 or SCC-9, head and neck SCC cell lines. On tumor growth, mice were injected with Panitumumab-IRDye800CW, and imaged with a small animal imaging system and optical coherence tomography (OCT). Immunohistochemistry for SCC markers were used to confirm tumor origin. Results: Seventy-five percent (N = 4) of the UM-SCC-1 group developed aggressive, rapidly growing tumors that were P40 and EGFR positive within two weeks of inoculation. The SCC-9 tumors failed to demonstrate any growth (N = 4). Ocular tumors demonstrated high fluorescence levels with a tumor to background ratio of 3.8. Conclusions: Subconjunctival injections are an appropriate technique to create in vivo models for assessing treatment modalities and novel therapies in conjunctival SCC. Translational Relevance: This model demonstrates Panitumumab-IRDye800CW's utility in the ophthalmic setting and suggests that clinical trials may be warranted.

Clinical Outcomes After Stage-One Antibiotic Coated Molded Hip Spacer.

BACKGROUND: Two-stage exchange remains the gold standard for managing periprosthetic joint infection (PJI). We evaluated the outcomes of patients treated with a specific molded articulating antibiotic hip spacer for PJI at a tertiary referral center. METHODS: An institutional database was retrospectively queried for patients who underwent implantation of spacer between 2009-2019. Patient demographics and clinical outcomes were collected. RESULTS: We identified 88 patients at an average age of 60.4 years who received a spacer implant, with an average of 4.2 years follow-up (standard deviation [SD] 2.5 years). A total of 34 patients (38.6%) had a "clean" two-stage course with successful reimplantation and no evidence of infection at 1-year follow-up. The remaining patients (61.4%) required 3.67 (±0.52) additional surgeries. Overall reimplantation rate was 72%. Causative bacterial agents included MSSA (n = 22), MRSA (n = 16), coagulase-negative Staphylococcus (n = 14), and polymicrobial (n = 12). Regarding complications, there were 13 (15%) dislocations, 16 (18%) periprosthetic fractures, 8 (9%) bent/fractured stems, and 16 (18%) patients had clinically significant subsidence. Patients with previous extended trochanteric osteotomy (ETO) experienced higher rates of bent/broken spacer stems (25% vs 3.1%; P = .006) periprosthetic fractures (37.5% vs 10.9%; P = .010), and dislocations (37.5% vs 6.2%; P = .001). The rate of infection clearance was lower in the prior ETO cohort (26.6% vs 54.2%; P = .029). CONCLUSION: We report outcomes in patients who underwent implantation of a specific molded articulating hip spacer at our institution. Infection eradication was roughly in line with published series of hip PJI treatment. There was a high rate of mechanical complications, especially in those patients who required an ETO.

An analysis of 90-day emergency department visits after peripherally inserted central catheter (PICC) placement for prosthetic joint infection.

OBJECTIVE: Research on complications with peripherally inserted central catheter (PICC) lines that are placed for the treatment of prosthetic joint infection (PJI) after total hip arthroplasty (THA) and total knee arthroplasty (TKA) is scarce. We investigated the timing, frequency, and risk factors for PICC complications during treatment of PJI after THA and TKA. METHODS: We retrospectively queried an institutional database for THA and TKA patients from January 2015 through December 2020 that developed a PJI and required PICC placement at an academic, tertiary-care referral center. RESULTS: The study included 889 patients (48.3% female) with a mean age of 64.6 years (range, 18.7-95.2) who underwent 435 THAs and 454 TKAs that were revised for PJI. The cohort had 275 90-day ED visits (30.9%), and 51 (18.5%) were PICC related. The average time from discharge to PICC ED visit was 26.2 days (range, 0.3-89.4). The most common reasons for a 90-day ED visit were issues related to the joint replacement or wound site (musculoskeletal or MSK; n = 116, 42.2%) and PICC complaints (n = 51, 18.5%). A multivariable logistic regression demonstrated that non-White race (odds ratio [OR], 2.24; 95% confidence interval [CI], 1.24-4.04; P = .007) and younger age (OR, 0.98; 95% CI, 0.95-1.00; P = .035) were associated with PICC-related ED visits. Malposition/readjustment (41.2%) and occlusion (35.3%) were the most common PICC complications leading to ED presentation. CONCLUSIONS: PICC complications are common after PJI treatment, accounting for nearly 20% of 90-day ED visits.

Prosthetic Knee Infection With Coagulase-Negative Staphylococcus: A Harbinger of Poor Outcomes.

BACKGROUND: Coagulase-negative staphylococci (CoNS) are biofilm-producing pathogens whose role in periprosthetic joint infection (PJI) is increasing. There is little data on the prognosis and treatment considerations in the setting of PJI. We sought to evaluate the clinical characteristics, outcomes, and complications in these patients. METHODS: This is a retrospective cohort study of adult patients at a single tertiary medical center from 2009 to 2020 with culture-proven CoNS PJI after total knee arthroplasty, as diagnosed by Musculoskeletal Infection Society criteria. The primary outcome was treatment success, with failure defined as recurrent CoNS PJI, recurrent PJI with a new pathogen, and/or chronic oral antibiotic suppression at one year postoperatively. RESULTS: We identified 55 patients with a CoNS total knee arthroplasty PJI with a mean follow-up of 29.8 months (SD: 16.3 months). The most commonly isolated organism was Staphylococcus epidermidis (n = 36, 65.5%). The overall prevalence of methicillin resistance was 63%. Surgical treatment included surgical debridement, antibiotics, and implant retention in 25 (45.5%) cases and two-stage revision (22 articulating and eight static antibiotic-impregnated spacers). At one-year follow-up, only 47% of patients had successful management of their infection. The surgical debridement, antibiotics, and implant retention cohort had the higher rate of treatment failure (60.0%) compared to two-stage revision (46.7%). CONCLUSION: These results indicate a poor rate of success in treating CoNS PJI. This likely represents the interplay of inherent virulence through biofilm formation and decreased antibiotic efficacy.

Racial and Ethnic Disparities in the Imaging Workup and Treatment of Knee and Hip Osteoarthritis.

BACKGROUND: There is limited evidence on sociodemographic differences in osteoarthritis management, particularly in non-African American (AA) minorities. We sought to identify differences in imaging modalities, administration of intra-articular injections, and total joint arthroplasty (TJA) between racial/ethnic groups. METHODS: We retrospectively reviewed patients presenting to outpatient clinics with a diagnosis of hip or knee osteoarthritis from January 2013 to March 2020 at a tertiary center. Univariate analyses compared differences between groups. Multivariate logistic regression analyses determined sociodemographic predictors of imaging workup and treatment. RESULTS: In total, 105,873 patients were included. There were 74,769 (70.6%) Caucasian, 27,117 (25.6%) AA, 1,878 (1.8%) Hispanic, 1,479 (1.4%) Asian, and 630 (0.6%) Native American patients. Multivariate analyses demonstrated that AAs had decreased odds of undergoing a knee magnetic resonance imaging (odds ratio [OR] 0.77, P < .001) or injection (OR 0.94, P = .006). Asian patients had lower odds of receiving any hip X-ray (OR 0.72, P = .047) or knee injection (OR 0.83, P = .017). AA (total knee arthroplasty [TKA]: OR 0.51, P < .001; total hip arthroplasty [THA]: OR 0.57, P < .001), Hispanic (TKA: OR 0.69, P = .003; THA: OR 0.60, P = .006), and Asian (TKA: OR 0.73, P = .010; THA: OR 0.56, P = .010) patients had lower odds of undergoing TJA compared to Caucasians. We found that higher income quartiles had greater odds of receiving a magnetic resonance imaging and TJA, males had lower odds of receiving injections and greater odds of undergoing TJA, and Medicaid and self-pay patients had lower odds of undergoing TJA (P < .05). CONCLUSION: After adjusting for sociodemographic factors, we found disparities in the imaging, administration of injections, and/or arthroplasty for AA, Asian, and Hispanic patients. Insurance status, income, and gender were also associated with imaging and treatments performed in managing hip and knee osteoarthritis.