What are the Trends in Racial Diversity Among Orthopaedic Applicants, Residents, and Faculty?

BACKGROUND: Orthopaedic surgery has recruited fewer applicants from underrepresented in medicine (UIM) racial groups than many other specialties, and recent studies have shown that although applicants from UIM racial groups are competitive for orthopaedic surgery, they enter the specialty at lower rates. Although previous studies have measured trends in orthopaedic surgery applicant, resident, or attending diversity in isolation, these populations are interdependent and therefore should be analyzed together. It is unclear how racial diversity among orthopaedic applicants, residents, and faculty has changed over time and how it compares with other surgical and medical specialties. QUESTIONS/PURPOSES: (1) How has the proportion of orthopaedic applicants, residents, and faculty from UIM and White racial groups changed between 2016 and 2020? (2) How does representation of orthopaedic applicants from UIM and White racial groups compare with that of other surgical and medical specialties? (3) How does representation of orthopaedic residents from UIM and White racial groups compare with that of other surgical and medical specialties? (4) How does representation of orthopaedic faculty from UIM and White racial groups compare with that of other surgical and medical specialties? METHODS: We drew racial representation data for applicants, residents, and faculty between 2016 and 2020. Applicant data on racial groups was obtained for 10 surgical and 13 medical specialties from the Association of American Medical Colleges Electronic Residency Application Services report, which annually publishes demographic data on all medical students applying to residency through Electronic Residency Application Services. Resident data on racial groups were obtained for the same 10 surgical and 13 medical specialties from the Journal of the American Medical Association Graduate Medical Education report, which annually publishes demographic data on residents in residency training programs accredited by the Accreditation Council for Graduate Medical Education. Faculty data on racial groups were obtained for four surgical and 12 medical specialties from the Association of American Medical Colleges Faculty Roster United States Medical School Faculty report, which annually publishes demographic data of active faculty at United States allopathic medical schools. UIM racial groups include American Indian or Alaska Native, Black or African American, Hispanic or Latino, and Native American or Other Pacific Islander. Chi-square tests were performed to compare representation of UIM and White groups among orthopaedic applicants, residents, and faculty between 2016 and 2020. Further, chi-square tests were performed to compare aggregate representation of applicants, residents, and faculty from UIM and White racial groups in orthopaedic surgery to aggregate representation among other surgical and medical specialties with available data. RESULTS: The proportion of orthopaedic applicants from UIM racial groups increased between 2016 to 2020 from 13% (174 of 1309) to 18% (313 of 1699, absolute difference 0.051 [95% CI 0.025 to 0.078]; p < 0.001). The proportion of orthopaedic residents (9.6% [347 of 3617] to 10% [427 of 4242]; p = 0.48) and faculty (4.7% [186 of 3934] to 4.7% [198 of 4234]; p = 0.91) from UIM racial groups did not change from 2016 to 2020. There were more orthopaedic applicants from UIM racial groups (15% [1151 of 7446]) than orthopaedic residents from UIM racial groups (9.8% [1918 of 19,476]; p < 0.001). There were also more orthopaedic residents from UIM groups (9.8% [1918 of 19,476]) than orthopaedic faculty from UIM groups (4.7% [992 of 20,916], absolute difference 0.051 [95% CI 0.046 to 0.056]; p < 0.001). The proportion of orthopaedic applicants from UIM groups (15% [1151 of 7446]) was greater than that of applicants to otolaryngology (14% [446 of 3284], absolute difference 0.019 [95% CI 0.004 to 0.033]; p = 0.01), urology (13% [319 of 2435], absolute difference 0.024 [95% CI 0.007 to 0.039]; p = 0.005), neurology (12% [1519 of 12,862], absolute difference 0.036 [95% CI 0.027 to 0.047]; p < 0.001), pathology (13% [1355 of 10,792], absolute difference 0.029 [95% CI 0.019 to 0.039]; p < 0.001), and diagnostic radiology (14% [1635 of 12,055], absolute difference 0.019 [95% CI 0.009 to 0.029]; p < 0.001), and it was not different from that of applicants to neurosurgery (16% [395 of 2495]; p = 0.66), plastic surgery (15% [346 of 2259]; p = 0.87), interventional radiology (15% [419 of 2868]; p = 0.28), vascular surgery (17% [324 of 1887]; p = 0.07), thoracic surgery (15% [199 of 1294]; p = 0.94), dermatology (15% [901 of 5927]; p = 0.68), internal medicine (15% [18,182 of 124,214]; p = 0.05), pediatrics (16% [5406 of 33,187]; p = 0.08), and radiation oncology (14% [383 of 2744]; p = 0.06). The proportion of orthopaedic residents from UIM groups (9.8% [1918 of 19,476]) was greater than UIM representation among residents in otolaryngology (8.7% [693 of 7968], absolute difference 0.012 [95% CI 0.004 to 0.019]; p = 0.003), interventional radiology (7.4% [51 of 693], absolute difference 0.025 [95% CI 0.002 to 0.043]; p = 0.03), and radiation oncology (7.9% [289 of 3659], absolute difference 0.020 [95% CI 0.009 to 0.029]; p < 0.001), and it was not different from UIM representation among residents in plastic surgery (9.3% [386 of 4129]; p = 0.33), urology (9.7% [670 of 6877]; p = 0.80), dermatology (9.9% [679 of 6879]; p = 0.96), and diagnostic radiology (10% [2215 of 22,076]; p = 0.53). The proportion of orthopaedic faculty from UIM groups (4.7% [992 of 20,916]) was not different from UIM representation among faculty in otolaryngology (4.8% [553 of 11,413]; p = 0.68), neurology (5.0% [1533 of 30,871]; p = 0.25), pathology (4.9% [1129 of 23,206]; p = 0.55), and diagnostic radiology (4.9% [2418 of 49,775]; p = 0.51). Compared with other surgical and medical specialties with available data, orthopaedic surgery had the highest proportion of White applicants (62% [4613 of 7446]), residents (75% [14,571 of 19,476]), and faculty (75% [15,785 of 20,916]). CONCLUSION: Orthopaedic applicant representation from UIM groups has increased over time and is similar to that of several surgical and medical specialties, suggesting relative success with efforts to recruit more students from UIM groups. However, the proportion of orthopaedic residents and UIM groups has not increased accordingly, and this is not because of a lack of applicants from UIM groups. In addition, UIM representation among orthopaedic faculty has not changed and may be partially explained by the lead time effect, but increased attrition among orthopaedic residents from UIM groups and racial bias likely also play a role. Further interventions and research into the potential difficulties faced by orthopaedic applicants, residents, and faculty from UIM groups are necessary to continue making progress. CLINICAL RELEVANCE: A diverse physician workforce is better suited to address healthcare disparities and provide culturally competent patient care. Representation of orthopaedic applicants from UIM groups has improved over time, but further research and interventions are necessary to diversify orthopaedic surgery to ultimately provide better care for all orthopaedic patients.

Infection After Open Long Bone Fractures: Can We Improve on Prophylaxis?

INTRODUCTION: Current standards recommend antibiotic prophylaxis administered after open fracture injury. The purpose of this study was to assess culture results in patients with open fracture-associated infections, hypothesizing that cultures obtained do not vary by Gustilo-Anderson (GA) classification. METHODS: We examined cultured bacterial species from patients with open long bone fractures that underwent irrigation and debridement at a Level 1 trauma center (2008-2016), evaluating our current and two hypothetical antibiotic protocols to assess whether they provided appropriate coverage. The antibiotic protocols included protocols 1 (cefazolin, with gentamicin added for type III fractures), 2 (vancomycin and cefepime) and 3 (ceftriaxone). RESULTS: GA classification was not associated with bacterial gram stain (P = 0.161), nor was it predictive of mono- versus polymicrobial infection (P = 0.094). Of 42 culture-positive infections, 31 were type III and 11 were type I or II fractures. 27% of the infections for type I or II fractures were caused by organisms targeted by protocol 1 (OR 0.18, 95% CI 0.04-0.82; P = 0.027). There was no difference in coverage by fracture type among protocol 2 (P = 0.771) or protocol 3 (P = 0.891). For type III fractures, protocol 2 provided 94% appropriate coverage compared to 68% and 61% coverage by protocols 1 and 3, respectively. CONCLUSION: For open fractures complicated by infection, isolated bacterial organisms do not correlate with GA open fracture classification, suggesting that hypothetical protocol 2 should be used for all fracture types. Protocol 2's broad coverage, across all GA fracture types, may prevent infection by organisms not covered by current antibiotic prophylaxis.

Role of complement in alloimmunization and hyperhemolysis.

PURPOSE OF REVIEW: The purpose of this review is to summarize the role of complement in regulating the removal of a target alloantigen following an incompatible red blood cell (RBC) transfusion, the formation of alloantibodies following RBC alloantigen exposure, and the development of hyperhemolysis in patients with sickle cell disease (SCD). RECENT FINDINGS: Recent studies demonstrate that complement can accelerate alloantibody-mediated removal of target alloantigens from the RBC surface following incompatible transfusion. Complement also influences alloantigen availability during developing alloimmune responses and serves as a unique mediator of CD4 T-cell-independent alloantibody formation following RBC alloantigen exposure. Finally, alternative complement pathway activation appears to play a key role in the development of acute hemolytic episodes in patients with SCD, providing a potential druggable target to prevent acute complications in patients with this disease. SUMMARY: Recent studies suggest that complement can regulate a wide variety of processes germane to hematology, from transfusion complications to baseline hemolysis in patients with SCD. As the role of complement in various disease processes becomes more fully understood, the ability to leverage recently developed complement modulating drugs will only continue to enhance providers' ability to favorably intervene in many hematological diseases.

Spine Infections Reduced at Dedicated Orthopaedics and Spine Hospital.

BACKGROUND: Previous studies stratified postoperative infection risk by patient comorbidities. However, it is unclear whether the incidence varies by surgical approach in a specialized orthopaedic setting. This study aims to compare infection rates and microbiologic characteristics of postoperative spine infections requiring return to the operating room for debridement by hospital setting: a dedicated orthopaedic and spine hospital versus a general hospital serving multiple surgical specialties. METHODS: The study is a retrospective review of prospectively collected data. Procedures performed between March 2006 and August 2008 at the multispecialty university hospital were compared with cases at an orthopaedic specialty hospital from September 2008 through August 2016. The surgeons, residents, and patients were similar, but the operative venue changed in 2008. RESULTS: The overall general university hospital infection rate was 2.03%, higher than the overall infection rate at the dedicated orthopaedic and spine hospital of 1.31% (P < .0104). The general university infection rate was 2.27% in the final years of practice, compared with 0.91% at the dedicated orthopaedic and spine hospital (P < .0001) during a recent 2-year time frame. Demographic variables did not significantly differ between the 2 settings. The overall proportion of Gram-negative infection rates was not statistically different (21.7% vs 18.6%), despite an increased proportion of Gram-negative infections at the general university hospital following surgery from an anterior approach. Most of the organisms isolated in both facilities were Staphylococcus species. There was no difference in the seasonality of postoperative spine infections in either setting. CONCLUSIONS: In transitioning from a multispecialty university hospital to a dedicated orthopaedic hospital, the incidence of postoperative spine infections was significantly reduced to 0.91%. Despite the change in venue, the proportion of Gram-negative infections (∼20%) following spine surgery did not significantly change. These results suggest improved infection rates during the course of the last 10 years with consistent proportions of Gram-negative infections. LEVEL OF EVIDENCE: 3.

Fc Gamma Receptors and Complement Component 3 Facilitate Anti-fVIII Antibody Formation.

Anti-factor VIII (fVIII) alloantibodies, which can develop in patients with hemophilia A, limit the therapeutic options and increase morbidity and mortality of these patients. However, the factors that influence anti-fVIII antibody development remain incompletely understood. Recent studies suggest that Fc gamma receptors (FcγRs) may facilitate recognition and uptake of fVIII by recently developed or pre-existing naturally occurring anti-fVIII antibodies, providing a mechanism whereby the immune system may recognize fVIII following infusion. However, the role of FcγRs in anti-fVIII antibody formation remains unknown. In order to define the influence of FcγRs on the development of anti-fVIII antibodies, fVIII was injected into WT or FcγR knockout recipients, followed by evaluation of anti-fVIII antibodies. Anti-fVIII antibodies were readily observed following fVIII injection into FcγR knockouts, with similar anti-fVIII antibody levels occurring in FcγR knockouts as detected in WT mice injected in parallel. As antibodies can also fix complement, providing a potential mechanism whereby anti-fVIII antibodies may influence anti-fVIII antibody formation independent of FcγRs, fVIII was also injected into complement component 3 (C3) knockout recipients in parallel. Similar to FcγR knockouts, C3 knockout recipients developed a robust response to fVIII, which was likewise similar to that observed in WT recipients. As FcγRs or C3 may compensate for each other in recipients only deficient in FcγRs or C3 alone, we generated mice deficient in both FcγRs and C3 to test for potential antibody effector redundancy in anti-fVIII antibody formation. Infusion of fVIII into FcγRs and C3 (FcγR × C3) double knockouts likewise induced anti-fVIII antibodies. However, unlike individual knockouts, anti-fVIII antibodies in FcγRs × C3 knockouts were initially lower than WT recipients, although anti-fVIII antibodies increased to WT levels following additional fVIII exposure. In contrast, infusion of RBCs expressing distinct alloantigens into FcγRs, C3 or FcγR × C3 knockout recipients either failed to change anti-RBC levels when compared to WT recipients or actually increased antibody responses, depending on the target antigen. Taken together, these results suggest FcγRs and C3 can differentially impact antibody formation following exposure to distinct alloantigens and that FcγRs and C3 work in concert to facilitate early anti-fVIII antibody formation.

Is Operative Debridement Greater Than 24 Hours Post-admission Associated With Increased Likelihood of Post-operative Infection?

BACKGROUND: The historical "six-hour rule" as a golden hour for timing to debridement has been refuted in modern literature. Current standards prompt a timely debridement; however, in the setting of polytrauma, patients are often resuscitated for periods >24 h, with delayed orthopedic intervention. Therefore, we sought to determine the association between prolonged time to operative debridement (>24 h) and infection. METHODS: We conducted a retrospective review of patients with open fractures that underwent irrigation and debridement at a single institution from 2008 to 2016. Demographic, injury, and operative variables were collected. Infection was defined as the need for intravenous antibiotics and/or repeat irrigation and debridement. Chi-squared test and univariate logistic regression were performed. P < 0.05 was the cutoff for significance. RESULTS: Of 642 patients examined, 56 (8.7%) developed an infection. Prolonged time to debridement was not associated with increased infection rates (P = 1.00). Gustilo-Anderson classification was associated with increased risk of infection (type I: 2.1%, type II: 7.6%, and type III: 14.6%; P < 0.001). In univariate analysis, infection was associated with after-hours surgery (between 7 PM and 7 AM (odds ratio [OR] = 2.02; P < 0.02), definitive fixation more than 24 h post-admission (OR = 3.08; P < 0.001), wound closure more than 24 h post-admission (OR = 4.36; P < 0.001), and more than two operations performed post-admission (OR = 8.73; P < 0.001). Multivariate analysis of these factors found number of operations (OR = 7.13; P < 0.001) and time to definitive wound closure (OR = 4.04; P < 0.001) to be independent predictors of developing an infection. CONCLUSIONS: Our data suggests that there is no association between infection and prolonged time to debridement.

Impact of Frailty on 30-Day Morbidity and Mortality of Patients With Intertrochanteric Femur Fractures.

The aim of this study was to evaluate the association between frailty and 30-day morbidity and mortality in patients with intertrochanteric femur fractures. Furthermore, the authors sought to identify a specific frailty index score that would help identify high-risk patients. This retrospective study evaluated 229 consecutive patients 50 years or older who presented to a single level I trauma center for surgical fixation of an intertrochanteric femur fracture. Frailty was determined using a previously validated 11-point modified frailty index (mFI) scale. Primary outcome variables included 30-day morbidity and mortality. Of the 229 patients included in this study, 82 (36%) had a postoperative complication and there were 10 (4%) mortalities. The most common complications were delirium (n=40; 17%) and acute kidney injury (n=25; 11%). Mean mFI score for those who developed a postoperative complication was 0.24 compared with 0.14 for those who did not (P<.001). The mortality rate increased from 0% for mFI of 0 to 11% for mFI of 0.27 or more. Patients with an mFI of 0.27 or more were more than 9 times as likely to have a mortality compared with patients with an mFI of less than 0.27 (P=.006). This study demonstrates that the mFI is associated with 30-day morbidity and mortality in patients aged 50 years or older with intertrochanteric femur fractures. The authors identified an mFI score of 0.27 or more as the most robust predictor of increased 30-day morbidity and mortality following surgical fixation of intertrochanteric femur fractures. [Orthopedics. 2019; 42(6):344-348.].

Cosmc is required for T cell persistence in the periphery.

T lymphocytes, a key arm of adaptive immunity, are known to dynamically regulate O-glycosylation during T cell maturation and when responding to stimuli; however, the direct role of O-glycans in T cell maturation remains largely unknown. Using a conditional knockout of the gene (C1GalT1C1 or Cosmc) encoding the specific chaperone Cosmc, we generated mice whose T cells lack extended O-glycans (T cell conditional Cosmc knock out or TCKO mice) and homogeneously express the truncated Tn antigen. Loss of Cosmc is highly deleterious to T cell persistence, with near-complete elimination of Cosmc-null T cells from spleen and lymph nodes. Total T cell counts are 20% of wild type (WT), among which only 5% express the truncated glycans, with the remaining 95% consisting of escapers from Cre-mediated recombination. TCKO thymocytes were able to complete thymic maturation but failed to populate the secondary lymphoid organs both natively and upon adoptive transfer to WT recipients. Our results demonstrate that extended O-glycosylation is required for the establishment and maintenance of the peripheral T cell population.

Prosthetic Joint Infection Trends at a Dedicated Orthopaedics Specialty Hospital.

INTRODUCTION: Historically, a majority of prosthetic joint infections (PJIs) grew Gram-positive bacteria. While previous studies stratified PJI risk with specific organisms by patient comorbidities, we compared infection rates and microbiologic characteristics of PJIs by hospital setting: a dedicated orthopaedic hospital versus a general hospital serving multiple surgical specialties. METHODS: A retrospective review of prospectively collected data on 11,842 consecutive primary hip and knee arthroplasty patients was performed. Arthroplasty cases performed between April 2006 and August 2008 at the general university hospital serving multiple surgical specialties were compared to cases at a single orthopaedic specialty hospital from September 2008 to August 2016. RESULTS: The general university hospital PJI incidence rate was 1.43%, with 5.3% of infections from Gram-negative species. In comparison, at the dedicated orthopaedic hospital, the overall PJI incidence rate was substantially reduced to 0.75% over the 8-year timeframe. Comparing the final two years of practice at the general university facility to the most recent two years at the dedicated orthopaedics hospital, the PJI incidence was significantly reduced (1.43% vs 0.61%). Though the overall number of infections was reduced, there was a significantly higher proportion of Gram-negative infections over the 8-year timeframe at 25.3%. CONCLUSION: In transitioning from a multispecialty university hospital to a dedicated orthopaedic hospital, the PJI incidence has been significantly reduced despite a greater Gram-negative proportion (25.3% versus 5.3%). These results suggest a change in the microbiologic profile of PJI when transitioning to a dedicated orthopaedic facility and that greater Gram-negative antibiotic coverage could be considered.

Antibody-mediated immunosuppression can result from RBC antigen loss independent of Fcγ receptors in mice.

BACKGROUND: Anti-RhD administration can prevent de novo anti-RhD formation following RhD+ red blood cell (RBC) exposure, termed antibody-mediated immunosuppression (AMIS). Recent studies suggest that AMIS may occur through target antigen alterations, known as antigen modulation. However, studies suggest that AMIS may occur independent of antigen modulation. In particular, AMIS to RBCs that transgenically express the fusion hen egg lysozyme-ovalbumin-Duffy (HOD) antigen have been shown to occur independent of activating Fcγ receptors (FcγRs) thought to be required for antigen modulation. Therefore, we sought to determine the mechanism behind AMIS following HOD RBC exposure. STUDY DESIGN AND METHODS: Following transfer of HOD RBCs into wild-type or FcγR-chain knockout recipients in the presence or absence of monoclonal anti-hen egg lysozyme (HEL) antibody, individually or in combination, HOD antigen levels and anti-HOD antibody formation were examined. RESULTS: Our results demonstrate that anti-HEL antibodies individually or in combination suppressed anti-HOD IgM, which correlated with the rate of detectable decrease in HEL on HOD RBCs. Furthermore, exposure to anti-HEL antibodies alone or in combination equally suppressed anti-HOD IgG formation. Unexpectedly, combination or individual anti-HEL antibodies induced AMIS and antigen modulation in an FcγR-independent manner. Pre-exposure of HOD RBCs to anti-HEL antibodies reduced antigen levels and suppressed anti-HOD antibody formation following HOD RBC exposure. CONCLUSION: These results suggest that antibody-mediated antigen modulation may reflect a mechanism of AMIS that can occur independent of activating FcγRs and may provide a surrogate to identify antibodies capable of inducing AMIS against different RBC antigens.

Antibody-mediated immune suppression by antigen modulation is antigen-specific.

Alloantibodies developing after exposure to red blood cell (RBC) alloantigens can complicate pregnancy and transfusion therapy. The only method currently available to actively inhibit RBC alloantibody formation is administration of antigen-specific antibodies, a phenomenon termed antibody-mediated immune suppression (AMIS). A well-known example of AMIS is RhD immune globulin prophylaxis to prevent anti-D formation in RhD- individuals. However, whether AMIS is specific or impacts alloimmunization to other antigens on the same RBC remains unclear. To evaluate the specificity of AMIS, we passively immunized antigen-negative recipients with anti-KEL or anti-hen egg lysozyme (HEL) antibodies, followed by transfusion of murine RBC expressing both the HEL-ovalbumin-Duffy (HOD) and human KEL antigens (HOD × KEL RBC). Significant immunoglobulin G deposition on transfused HOD × KEL RBC occurred in all passively immunized recipients. Complement deposition and antigen modulation of the KEL antigen occurred on transfused RBC only in anti-KEL-treated recipients, whereas HEL antigen levels decreased only in the presence of anti-HEL antibodies. Western blot analysis confirmed the specificity of antigen loss, which was not attributable to RBC endocytosis and appears distinct for the 2 antigens. Specifically, removal of KEL was attenuated by clodronate treatment, whereas loss of HEL was unaffected by clodronate in vivo but sensitive to protease treatment in vitro. Antigen-specific modulation correlated with antigen-specific AMIS, with anti-KEL treated recipients forming antibodies to the HOD antigen and anti-HEL-treated recipients developing antibodies to the KEL antigen. Together, these results demonstrate that passively administered antibodies can selectively inhibit the immune response to a specific antigen.

Complement serves as a switch between CD4+ T cell-independent and -dependent RBC antibody responses.

RBC alloimmunization represents a significant immunological challenge for patients requiring lifelong transfusion support. The majority of clinically relevant non-ABO(H) blood group antigens have been thought to drive antibody formation through T cell-dependent immune pathways. Thus, we initially sought to define the role of CD4+ T cells in formation of alloantibodies to KEL, one of the leading causes of hemolytic transfusion reactions. Unexpectedly, our findings demonstrated that KEL RBCs actually possess the ability to induce antibody formation independent of CD4+ T cells or complement component 3 (C3), two common regulators of antibody formation. However, despite the ability of KEL RBCs to induce anti-KEL antibodies in the absence of complement, removal of C3 or complement receptors 1 and 2 (CR1/2) rendered recipients completely reliant on CD4+ T cells for IgG anti-KEL antibody formation. Together, these findings suggest that C3 may serve as a novel molecular switch that regulates the type of immunological pathway engaged following RBC transfusion.

Complement Component 3 Negatively Regulates Antibody Response by Modulation of Red Blood Cell Antigen.

Red blood cell (RBC) alloimmunization can make it difficult to procure compatible RBCs for future transfusion, directly leading to increased morbidity and mortality in transfusion-dependent patients. However, the factors that regulate RBC alloimmunization remain incompletely understood. As complement has been shown to serve as a key adjuvant in the development of antibody (Ab) responses against microbes, we examined the impact of complement on RBC alloimmunization. In contrast to the impact of complement component 3 (C3) in the development of an immune response following microbial exposure, transfusion of C3 knockout (C3 KO) recipients with RBCs expressing KEL (KEL RBCs) actually resulted in an enhanced anti-KEL Ab response. The impact of C3 appeared to be specific to KEL, as transfusion of RBCs bearing another model antigen, the chimeric HOD antigen (hen egg lysozyme, ovalbumin and Duffy), into C3 KO recipients failed to result in a similar increase in Ab formation. KEL RBCs experienced enhanced C3 deposition and loss of detectable target antigen over time when compared to HOD RBCs, suggesting that C3 may inhibit Ab formation by impacting the accessibility of the target KEL antigen. Loss of detectable KEL on the RBC surface did not reflect antigen masking by C3, but instead appeared to result from actual removal of the KEL antigen, as western blot analysis demonstrated complete loss of detectable KEL protein. Consistent with this, exposure of wild-type B6 or C3 KO recipients to KEL RBCs with reduced levels of detectable KEL antigen resulted in a significantly reduced anti-KEL Ab response. These results suggest that C3 possesses a unique ability to actually suppress Ab formation following transfusion by reducing the availability of the target antigen on the RBC surface.

Renal failure after placement of an articulating, antibiotic impregnated polymethylmethacrlyate hip spacer.

A 58-year-old male presented with native joint septic arthritis of the hip and osteomyelitis. After treatment with an articulating antibiotic spacer, he developed acute renal failure requiring dialysis. He continued to have elevated serum tobramycin levels exclusively from the antibiotic spacer elution as no intravenous tobramycin was used. Subsequent explantation was required to correct his renal failure. Although renal failure after antibiotic impregnated cement placement is rare, the risk of this potential complication should be considered preoperatively and in the postoperative management of these patients.

Recipient priming to one RBC alloantigen directly enhances subsequent alloimmunization in mice.

Individuals that become immunized to red blood cell (RBC) alloantigens can experience an increased rate of antibody formation to additional RBC alloantigens following subsequent transfusion. Despite this, how an immune response to one RBC immunogen may impact subsequent alloimmunization to a completely different RBC alloantigen remains unknown. Our studies demonstrate that Kell blood group antigen (KEL) RBC transfusion in the presence of inflammation induced by poly (I:C) (PIC) not only enhances anti-KEL antibody production through a CD4+ T-cell-dependent process but also directly facilitates anti-HOD antibody formation following subsequent exposure to the disparate HOD (hen egg lysozyme, ovalbumin, fused to human blood group antigen Duffy b) antigen. PIC/KEL priming of the anti-HOD antibody response required that RBCs express both the KEL and HOD antigens (HOD × KEL RBCs), as transfusion of HOD RBCs plus KEL RBCs or HOD RBCs alone failed to impact anti-HOD antibody formation in recipients previously primed with PIC/KEL. Transfer of CD4+ T cells from PIC/KEL-primed recipients directly facilitated anti-HOD antibody formation following (HOD × KEL) RBC transfusion. RBC alloantigen priming was not limited to PIC/KEL enhancement of anti-HOD alloantibody formation, as HOD-reactive CD4+ T cells enhanced anti-glycophorin A (anti-GPA) antibody formation in the absence of inflammation following transfusion of RBCs coexpressing GPA and HOD. These results demonstrate that immune priming to one RBC alloantigen can directly enhance a humoral response to a completely different RBC alloantigen, providing a potential explanation for why alloantibody responders may exhibit increased immune responsiveness to additional RBC alloantigens following subsequent transfusion.

Antigen Density Dictates Immune Responsiveness following Red Blood Cell Transfusion.

Although RBC transfusion can result in the development of anti-RBC alloantibodies that increase the probability of life-threatening hemolytic transfusion reactions, not all patients generate anti-RBC alloantibodies. However, the factors that regulate immune responsiveness to RBC transfusion remain incompletely understood. One variable that may influence alloantibody formation is RBC alloantigen density. RBC alloantigens exist at different densities on the RBC surface and likewise exhibit distinct propensities to induce RBC alloantibody formation. However, although distinct alloantigens reside on the RBC surface at different levels, most alloantigens also represent completely different structures, making it difficult to separate the potential impact of differences in Ag density from other alloantigen features that may also influence RBC alloimmunization. To address this, we generated RBCs that stably express the same Ag at different levels. Although exposure to RBCs with higher Ag levels induces a robust Ab response, RBCs bearing low Ag levels fail to induce RBC alloantibodies. However, exposure to low Ag-density RBCs is not without consequence, because recipients subsequently develop Ag-specific tolerance. Low Ag-density RBC-induced tolerance protects higher Ag-density RBCs from immune-mediated clearance, is Ag specific, and occurs through the induction of B cell unresponsiveness. These results demonstrate that Ag density can potently impact immune outcomes following RBC transfusion and suggest that RBCs with altered Ag levels may provide a unique tool to induce Ag-specific tolerance.

Innate immunity against molecular mimicry: Examining galectin-mediated antimicrobial activity.

Adaptive immunity provides the unique ability to respond to a nearly infinite range of antigenic determinants. Given the inherent plasticity of the adaptive immune system, a series of tolerance mechanisms exist to reduce reactivity toward self. While this reduces the probability of autoimmunity, it also creates an important gap in adaptive immunity: the ability to recognize microbes that look like self. As a variety of microbes decorate themselves in self-like carbohydrate antigens and tolerance reduces the ability of adaptive immunity to react with self-like structures, protection against molecular mimicry likely resides within the innate arm of immunity. In this review, we will explore the potential consequences of microbial molecular mimicry, including factors within innate immunity that appear to specifically target microbes expressing self-like antigens, and therefore provide protection against molecular mimicry.