Repetitive head impacts induce neuronal loss and neuroinflammation in young athletes.

Repetitive head impacts (RHI) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the multicellular cascade of events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear. Further, the symptoms endorsed by young individuals with early disease are not fully explained by the extent of p-tau deposition, severely hampering development of therapeutic interventions. Here, we show that RHI exposure associates with a multicellular response in young individuals (<51 years old) prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure. Leveraging single nucleus RNA sequencing of tissue from 8 control, 9 RHI-exposed, and 11 low stage CTE individuals, we identify SPP1+ inflammatory microglia, angiogenic and inflamed endothelial cell profiles, reactive astrocytes, and altered synaptic gene expression in excitatory and inhibitory neurons in all individuals with exposure to RHI. Surprisingly, we also observe a significant loss of cortical sulcus layer 2/3 neurons in contact sport athletes compared to controls independent of p-tau pathology. These results provide robust evidence that multiple years of RHI exposure is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early clinical symptoms observed in young former contact sport athletes. Furthermore, these data identify specific cellular responses to repetitive head impacts that may direct future identification of diagnostic and therapeutic strategies for CTE.

Myc Dysregulation in Activated Macrophages Initiates Iron-Mediated Lipid Peroxidation that Fuels Type I Interferon and Compromises TB Resistance.

A quarter of human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop clinical, mostly pulmonary, TB. To dissect mechanisms of susceptibility in immunocompetent individuals, we developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: development of necrotic lung lesions after infection with virulent Mtb. In this study, we explored the connectivity of the sst1-regulated pathways during prolonged macrophage activation with TNF. We determined that the aberrant response of the sst1-susceptible macrophages to TNF was primarily driven by conflicting Myc and antioxidant response pathways that resulted in a coordinated failure to properly sequester intracellular iron and activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled IFNß superinduction and sustained the Type I Interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. Our findings suggest a novel link between metabolic dysregulation in macrophages and susceptibility to TB, offering insights into potential therapeutic targets aimed at modulating macrophage function and improving TB control.

Endothelial Erg Regulates Expression of Pulmonary Lymphatic Junctional and Inflammation Genes in Mouse Lungs Impacting Lymphatic Transport.

The ETS transcription factor ERG is a master regulator of endothelial gene specificity and highly enriched in the capillary, vein, and arterial endothelial cells. ERG expression is critical for endothelial barrier function, permeability, and vascular inflammation. A dysfunctional vascular endothelial ERG has been shown to impair lung capillary homeostasis, contributing to pulmonary fibrosis as previously observed in IPF lungs. Our preliminary observations indicate that lymphatic endothelial cells (LEC) in the human IPF lung also lack ERG. To understand the role of ERG in pulmonary LECs, we developed LEC-specific inducible Erg-CKO and Erg-GFP-CKO conditional knockout (CKO) mice under Prox1 promoter. Whole lung microarray analysis, flow cytometry, and qPCR confirmed an inflammatory and pro-lymphvasculogenic predisposition in Erg-CKO lung. FITC-Dextran tracing analysis showed an increased pulmonary interstitial lymphatic fluid transport from the lung to the axial lymph node. Single-cell transcriptomics confirmed that genes associated with cell junction integrity were downregulated in Erg-CKO pre-collector and collector LECs. Integrating Single-cell transcriptomics and CellChatDB helped identify LEC specific communication pathways contributing to pulmonary inflammation, trans-endothelial migration, inflammation, and Endo-MT in Erg-CKO lung. Our findings suggest that downregulation of lymphatic Erg crucially affects LEC function, LEC permeability, pulmonary LEC communication pathways and lymphatic transcriptomics.

Characterization and decontamination of background noise in droplet-based single-cell protein expression data with DecontPro.

Assays such as CITE-seq can measure the abundance of cell surface proteins on individual cells using antibody derived tags (ADTs). However, many ADTs have high levels of background noise that can obfuscate down-stream analyses. In an exploratory analysis of PBMC datasets, we find that some droplets that were originally called 'empty' due to low levels of RNA contained high levels of ADTs and likely corresponded to neutrophils. We identified a novel type of artifact in the empty droplets called a 'spongelet' which has medium levels of ADT expression and is distinct from ambient noise. ADT expression levels in the spongelets correlate to ADT expression levels in the background peak of true cells in several datasets suggesting that they can contribute to background noise along with ambient ADTs. We then developed DecontPro, a novel Bayesian hierarchical model that can decontaminate ADT data by estimating and removing contamination from these sources. DecontPro outperforms other decontamination tools in removing aberrantly expressed ADTs while retaining native ADTs and in improving clustering specificity. Overall, these results suggest that identification of empty drops should be performed separately for RNA and ADT data and that DecontPro can be incorporated into CITE-seq workflows to improve the quality of downstream analyses.

Characterization of highly active mutational signatures in tumors from a large Chinese population.

The majority of mutational signatures have been characterized in tumors from Western countries and the degree to which mutational signatures are similar or different in Eastern populations has not been fully explored. We leveraged a large-scale clinical sequencing cohort of tumors from a Chinese population containing 25 tumor types and found that the highly active mutational signatures were similar to those previously characterized1,2. The aristolochic acid signature SBS22 was observed in four soft tissue sarcomas and the POLE-associated signature SBS10 was observed in a gallbladder carcinoma. In lung adenocarcinoma, the polycyclic aromatic hydrocarbon (PAH) signature SBS4 was significantly higher in males compared to females but not associated with smoking status. The UV-associated signature SBS7 was significantly lower in cutaneous melanomas from the Chinese population compared to a similar American cohort. Overall, these results add to our understanding of the mutational processes that contribute to tumors from the Chinese population.

Bulk brain tissue cell-type deconvolution with bias correction for single-nuclei RNA sequencing data using DeTREM.

BACKGROUND: Quantifying cell-type abundance in bulk tissue RNA-sequencing enables researchers to better understand complex systems. Newer deconvolution methodologies, such as MuSiC, use cell-type signatures derived from single-cell RNA-sequencing (scRNA-seq) data to make these calculations. Single-nuclei RNA-sequencing (snRNA-seq) reference data can be used instead of scRNA-seq data for tissues such as human brain where single-cell data are difficult to obtain, but accuracy suffers due to sequencing differences between the technologies. RESULTS: We propose a modification to MuSiC entitled 'DeTREM' which compensates for sequencing differences between the cell-type signature and bulk RNA-seq datasets in order to better predict cell-type fractions. We show DeTREM to be more accurate than MuSiC in simulated and real human brain bulk RNA-sequencing datasets with various cell-type abundance estimates. We also compare DeTREM to SCDC and CIBERSORTx, two recent deconvolution methods that use scRNA-seq cell-type signatures. We find that they perform well in simulated data but produce less accurate results than DeTREM when used to deconvolute human brain data. CONCLUSION: DeTREM improves the deconvolution accuracy of MuSiC and outperforms other deconvolution methods when applied to snRNA-seq data. DeTREM enables accurate cell-type deconvolution in situations where scRNA-seq data are not available. This modification improves characterization cell-type specific effects in brain tissue and identification of cell-type abundance differences under various conditions.

Integrative genetic and genomic networks identify microRNA associated with COPD and ILD.

Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) are clinically and molecularly heterogeneous diseases. We utilized clustering and integrative network analyses to elucidate roles for microRNAs (miRNAs) and miRNA isoforms (isomiRs) in COPD and ILD pathogenesis. Short RNA sequencing was performed on 351 lung tissue samples of COPD (n = 145), ILD (n = 144) and controls (n = 64). Five distinct subclusters of samples were identified including 1 COPD-predominant cluster and 2 ILD-predominant clusters which associated with different clinical measurements of disease severity. Utilizing 262 samples with gene expression and SNP microarrays, we built disease-specific genetic and expression networks to predict key miRNA regulators of gene expression. Members of miR-449/34 family, known to promote airway differentiation by repressing the Notch pathway, were among the top connected miRNAs in both COPD and ILD networks. Genes associated with miR-449/34 members in the disease networks were enriched among genes that increase in expression with airway differentiation at an air-liquid interface. A highly expressed isomiR containing a novel seed sequence was identified at the miR-34c-5p locus. 47% of the anticorrelated predicted targets for this isomiR were distinct from the canonical seed sequence for miR-34c-5p. Overexpression of the canonical miR-34c-5p and the miR-34c-5p isomiR with an alternative seed sequence down-regulated NOTCH1 and NOTCH4. However, only overexpression of the isomiR down-regulated genes involved in Ras signaling such as CRKL and GRB2. Overall, these findings elucidate molecular heterogeneity inherent across COPD and ILD patients and further suggest roles for miR-34c in regulating disease-associated gene-expression.

Long-term spring through fall capture data of Eptesicus fuscus in the eastern USA before and after white-nose syndrome.

Emerging infectious diseases threaten wildlife populations. Without well monitored wildlife systems, it is challenging to determine accurate population and ecosystem losses following disease emergence. North American temperate bats present a unique opportunity for studying the broad impacts of wildlife disease emergence, as their federal monitoring programs were prioritized in the USA throughout the 20th century and they are currently threatened by the invasive fungal pathogen, Pseudogymnoascus destructans (Pd), which causes white-nose syndrome. Here we provide a long-term dataset for capture records of Eptesicus fuscus (big brown bat) across the eastern USA, spanning 16 years before and 14 years after Pd invasion into North America. These data represent 30,496 E. fuscus captures across 3,567 unique sites. We encourage the use of this dataset for quantifying impacts of wildlife disease and other threats to wildlife (e.g., climate change) with the incorporation of other available data. We welcome additional data contributions for E. fuscus captures across North and Central America as well as the inclusion of other variables into the dataset that contribute to the quantification of wildlife health.

Interactive analysis of single-cell data using flexible workflows with SCTK2.

Analysis of single-cell RNA sequencing (scRNA-seq) data can reveal novel insights into the heterogeneity of complex biological systems. Many tools and workflows have been developed to perform different types of analyses. However, these tools are spread across different packages or programming environments, rely on different underlying data structures, and can only be utilized by people with knowledge of programming languages. In the Single-Cell Toolkit 2 (SCTK2), we have integrated a variety of popular tools and workflows to perform various aspects of scRNA-seq analysis. All tools and workflows can be run in the R console or using an intuitive graphical user interface built with R/Shiny. HTML reports generated with Rmarkdown can be used to document and recapitulate individual steps or entire analysis workflows. We show that the toolkit offers more features when compared with existing tools and allows for a seamless analysis of scRNA-seq data for non-computational users.

Single-Cell Characterization of Pulmonary Nodules Implicates Suppression of Immunosurveillance across Early Stages of Lung Adenocarcinoma.

A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This was accompanied by a reduction in effector T cells and an increase of CD4+ regulatory T cells (Treg) in subsolid nodules. An independent set of resected pulmonary nodules consisting of both adenocarcinomas and associated premalignant lesions corroborated the early increment of Tregs in premalignant lesions compared with the associated normal lung tissues by MIF. Gene expression analysis indicated that cancer-associated alveolar type 2 cells and fibroblasts may contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid nodules through ligand-receptor interactions. These findings suggest that there is a suppression of immune surveillance across the spectrum of early-stage lung adenocarcinoma. SIGNIFICANCE: Analysis of a spectrum of subsolid pulmonary nodules by single-cell RNA sequencing provides insights into the immune regulation and cell-cell interactions in the tumor microenvironment during early lung tumor development.

Revision Total Knee Arthroplasty for Ballistic Component Damage From an Intra-articular Missile.

Gunshot wounds (GSWs) and total knee arthroplasty (TKA) are increasingly common, yet a GSW to a TKA is a rare injury. A 60-year-old man sustained an intra-articular GSW to a prior TKA. The patient was scheduled for irrigation and debridement with polyethylene liner exchange. Intraoperatively, the new polyethylene liner was unable to engage the tibial tray. Damage to the locking mechanism on the tibial tray was suspected so total revision proceeded. Upon inspection of the explanted components, it was noted that a bullet fragment offline from the missile trajectory had blocked the locking of the polyethylene liner in the tibial tray. Expeditious antibiotics should be given and meticulous debridement should be performed to avoid unnecessary total component revision.

A contamination focused approach for optimizing the single-cell RNA-seq experiment.

Droplet-based single-cell RNA-seq (scRNA-seq) data are plagued by ambient contaminations caused by nucleic acid material released by dead and dying cells. This material is mixed into the buffer and is co-encapsulated with cells, leading to a lower signal-to-noise ratio. Although there exist computational methods to remove ambient contaminations post-hoc, the reliability of algorithms in generating high-quality data from low-quality sources remains uncertain. Here, we assess data quality before data filtering by a set of quantitative, contamination-based metrics that assess data quality more effectively than standard metrics. Through a series of controlled experiments, we report improvements that can minimize ambient contamination outside of tissue dissociation, via cell fixation, improved cell loading, microfluidic dilution, and nuclei versus cell preparation; many of these parameters are inaccessible on commercial platforms. We provide end-users with insights on factors that can guide their decision-making regarding optimizations that minimize ambient contamination, and metrics to assess data quality.

Impact of Large Database Studies on Orthopedic Surgery Literature: Are We Advancing the Field?

Background: While database studies have become more prevalent in the literature, there is concern over their value. In addition, the questions they are suitable to answer are limited. Questions/Purposes: We sought to determine the incidence of database studies in the orthopedic literature and in each subspecialty. In addition, we wanted to assess the impact of database studies on the literature by determining whether citations and Altmetric Attention Scores (AAS) varied by study type (studies using internal or external databases and those not using databases). Methods: We searched PubMed for articles published in impactful orthopedic surgery journals in the year 2018. All articles were discoverable on the Altmetric explorer portal database. Impact was determined by journal impact factor. Study design, subspecialty, number of citations, and AAS were obtained. Univariable analyses were conducted between study type, demographic variables, and the outcome of either citation count or AAS. Multivariable analyses were performed to identify independent predictors of the primary outcomes. Subgroup analyses were performed to differentiate the impact of external and internal database studies compared with non-database studies. Results: A total of 2684 total articles were eligible for inclusion. Of these, 366 studies (13.6%) were database studies. Hip and knee articles had the greatest incidence of database studies. Database studies had significantly more citations (5.9 vs 4.0) and significantly higher AAS (12.8 vs 11.3) compared with non-database studies. External database studies had significantly more citations (6.7 vs 4.8) and significantly higher AAS (14.0 vs 10.7) than internal database studies. Internal database studies had higher traditional citation counts but similar AAS to non-database studies. Conclusions: In 2018, database studies in well-reputed orthopedic journals had a greater number of citations but similar AAS compared with non-database studies. Further studies are warranted.

Characterization and decontamination of background noise in droplet-based single-cell protein expression data with DecontPro.

Assays such as CITE-seq can measure the abundance of cell surface proteins on individual cells using antibody derived tags (ADTs). However, many ADTs have high levels of background noise that can obfuscate down-stream analyses. Using an exploratory analysis of PBMC datasets, we find that some droplets that were originally called "empty" due to low levels of RNA contained high levels of ADTs and likely corresponded to neutrophils. We identified a novel type of artifact in the empty droplets called a "spongelet" which has medium levels of ADT expression and is distinct from ambient noise. ADT expression levels in the spongelets correlate to ADT expression levels in the background peak of true cells in several datasets suggesting that they can contribute to background noise along with ambient ADTs. We then developed DecontPro, a novel Bayesian hierarchical model that can decontaminate ADT data by estimating and removing contamination from these sources. DecontPro outperforms other decontamination tools in removing aberrantly expressed ADTs while retaining native ADTs and in improving clustering specificity. Overall, these results suggest that identification of empty drops should be performed separately for RNA and ADT data and that DecontPro can be incorporated into CITE-seq workflows to improve the quality of downstream analyses.

Artificial pollination of kiwifruit (Actinidia chinensis Planch. var. chinensis) (Ericales: Actinidiaceae) results in greater fruit set compared to flowers pollinated by managed bees (Apis mellifera L. (Hymenoptera: Apidae) and Bombus impatiens Cresson (Hymenoptera: Apidae)).

Due to a lack of knowledge on the pollination requirements of kiwifruit cultivars grown within the United States, farmers simultaneously implement multiple pollination methods, like the rental of managed bee species or artificial pollination to achieve high fruit yields. However, implementing multiple pollination methods is costly and possibly an inefficient use of resources. We assessed the contribution of two managed bees (Apis mellifera and Bombus impatiens) to the pollination of kiwifruit by i) determining the relative abundance of kiwifruit pollen collected by foragers of each bee species, and ii) comparing fruit set and fruit quality among insect and artificially pollinated flowers through an insect exclusion experiment. A significant difference was observed between the mean relative abundance of kiwifruit pollen carried in the corbicula of A. mellifera and B. impatiens, with B. impatiens carrying on average 46% more kiwifruit pollen than A. mellifera. Artificially pollinated kiwifruit flowers set significantly greater numbers of fruit per flower at four weeks post-bloom and at harvest compared to insect pollination, wind pollination, and pollen exclusion treatment. Artificial pollination produced fruits of greater weight, size, and seed number compared to insect-pollinated flowers, and few fruits were produced in the pollen exclusion and wind pollination treatments. Kiwifruit producers experiencing similar conditions to ours should focus on artificially pollinating their crops rather than relying on managed or wild insects for kiwifruit pollination. Future research should evaluate other methods of artificial pollination to determine their effectiveness, efficiency, and economics in the pollination of kiwifruit grown within the United States.

Matrix and analysis metadata standards (MAMS) to facilitate harmonization and reproducibility of single-cell data.

A large number of genomic and imaging datasets are being produced by consortia that seek to characterize healthy and disease tissues at single-cell resolution. While much effort has been devoted to capturing information related to biospecimen information and experimental procedures, the metadata standards that describe data matrices and the analysis workflows that produced them are relatively lacking. Detailed metadata schema related to data analysis are needed to facilitate sharing and interoperability across groups and to promote data provenance for reproducibility. To address this need, we developed the Matrix and Analysis Metadata Standards (MAMS) to serve as a resource for data coordinating centers and tool developers. We first curated several simple and complex "use cases" to characterize the types of feature-observation matrices (FOMs), annotations, and analysis metadata produced in different workflows. Based on these use cases, metadata fields were defined to describe the data contained within each matrix including those related to processing, modality, and subsets. Suggested terms were created for the majority of fields to aid in harmonization of metadata terms across groups. Additional provenance metadata fields were also defined to describe the software and workflows that produced each FOM. Finally, we developed a simple list-like schema that can be used to store MAMS information and implemented in multiple formats. Overall, MAMS can be used as a guide to harmonize analysis-related metadata which will ultimately facilitate integration of datasets across tools and consortia. MAMS specifications, use cases, and examples can be found at https://github.com/single-cell-mams/mams/.

Trends of Venous Thromboembolism After Total Hip Arthroplasty in the United States: Analysis From 2011 to 2019.

BACKGROUND: In 2011, the American Academy of Orthopaedic Surgeons released a Clinical Practice Guideline` that recommended routine venous thromboembolism (VTE) prophylaxis after total joint arthroplasty. The purpose of this study was to examine (1) the change in the incidence of 90-day VTE, deep vein thrombosis, and pulmonary embolism, (2) the change in the utilization of antithrombotic agents; and (3) the change in the economic burden associated with VTE after total hip arthroplasty (THA) from 2011 to 2019. METHODS: National, administrative claims data from 2011 to 2019 were used to identify patients who underwent primary THA for osteoarthritis. Exclusions entailed liver pathology, coagulopathy, malignancy, or those on prior prescribed blood thinners before THA. Multivariable regression was used, controlling for age and Charlson Comorbidity Index for all years, with 2011 as the reference year. RESULTS: From 2011 to 2019, there was a significant reduction in 90-day VTE rates after THA, with a significant reduction in deep vein thrombosis and pulmonary embolism during this time frame as well. Of the antithrombotic agents prescribed after THA, the utilization of prescribed aspirin significantly increased and that of nonaspirin anticoagulants significantly decreased. Among nonaspirin anticoagulants, the utilization of direct factor Xa inhibitors and direct thrombin inhibitors significantly increased. The added reimbursements associated with VTE after THA significantly decreased during this period. CONCLUSION: Since 2011, the incidence and economic burden associated with VTE after THA have significantly declined. In addition, there has been an increase in prescription aspirin and direct oral anticoagulants. LEVEL OF EVIDENCE: Therapeutic, III.

Diagnostic and Invasive Colonoscopy Are Not Risk Factors for Revision Surgery Due to Periprosthetic Joint Infection.

BACKGROUND: Colonoscopy is routinely performed for colorectal cancer screening in patients who have a preexisting unicompartmental knee arthroplasty (UKA), total knee arthroplasty (TKA), or total hip arthroplasty (THA) prostheses. However, colonoscopy is theorized to provoke transient bacteremia, providing a potential nidus for periprosthetic joint infection. This study aimed to investigate the risk of aseptic and septic revision surgery in patients who underwent diagnostic colonoscopy or invasive colonoscopy within one year following UKA, TKA, or THA. METHODS: A retrospective cohort analysis was performed using a national database. Patients were identified using Current Procedural Terminology. In total, 52,891 patients underwent UKA, 1,049,218 underwent TKA, and 526,296 underwent THA. Data were analyzed with univariate analysis preceding multivariable logistic regressions to investigate outcomes of interest at 2 and 3 years from the index procedure. RESULTS: Diagnostic colonoscopy resulted in no increase in odds of all-cause or septic revision surgery for any prostheses. At both time points, invasive colonoscopy resulted in lower odds of all-cause revision (P < .05) for patients with UKA, decreased odds of septic revision (P < .001) for patients with TKA, and decreased odds of both all-cause and septic revision (P < .05) for patients with THA. CONCLUSION: Our results show that diagnostic colonoscopy was not a significant risk factor for revision following UKA, TKA, or THA. Paradoxically, invasive colonoscopy was protective against revision, even with very minimal use of antibiotic prophylaxis observed. This study addresses the theory that colonoscopy procedures may threaten an existing joint prosthesis via transient bacteremia and shows no increase in revision outcomes following colonoscopy. LEVEL OF EVIDENCE: Level III.

Interval Time of at Least 6 Weeks Between Bilateral Total Knee Arthroplasties is Associated With Decreased Postoperative Complications.

BACKGROUND: Staged, bilateral total knee arthroplasty (TKA) has an increased risk of complications if the second procedure is performed before physiologic recovery from the first. The aims of this study were to 1) determine whether there is a time-dependent relationship between TKA staging and rates of revisions and complications and 2) identify data-driven time intervals that reduce risk of revisions and complications. METHODS: Data were collected from a national insurance database from 2015 to 2018. Staged intervals were initially assessed using fixed 6-week intervals. Stratum-specific likelihood ratio analyses were subsequently conducted to observe data-driven staging thresholds. Bivariate and multivariable regression analyses were conducted to determine the associations between the time intervals and 2-year rates of revision surgery and 90-day major complications. We included 25,527 patients undergoing staged bilateral TKA. RESULTS: In comparison to the shortest fixed time interval (1-6 weeks), as the staging interval increased the odds of 2-year all-cause revision and 90-day major complications significantly decreased (P < .05 for all). Stratum-specific likelihood ratio analysis identified 3 data-driven staging categories 1-5, 6-17, and 18-24 weeks that maximized the difference in both 2-year rates of revision and 90-day major complications. CONCLUSION: Our data showed a time-dependent relationship between the timing of TKA stages and complications. If staging is considered, a delayed interval of at least 6 weeks between procedures may significantly reduce revision and major complications. LEVEL OF EVIDENCE: Level III Therapeutic Study.

Human Immunodeficiency Virus Status Does Not Independently Predict 2-Year Complications Following Total Knee Arthroplasty.

With improved treatment for human immunodeficiency virus (HIV), the demand for total knee arthroplasty (TKA) in this population has increased. Studying the relationship between HIV and postoperative complications following TKA will allow orthopaedic surgeons to accurately assess their patients' surgical risk and provide appropriate counseling. This study aims to understand how HIV impacts surgical and medical complications following TKA for osteoarthritis (OA). Patients identified in a national insurance database who underwent TKA for OA from 2010 to 2019 were divided into three cohorts: no HIV, asymptomatic HIV, and acquired immunodeficiency syndrome (AIDS). Univariate and multivariable regression analyses were performed to determine 90-day postoperative complications as well as 2-year surgical complications (revision surgery, prosthetic joint infection, aseptic loosening, and manipulation under anesthesia). A total of 855,373 patients were included, of whom 1,338 had asymptomatic HIV and 268 had AIDS. After multivariable regression analysis, patients with HIV had no difference in 2-year surgical complications relative to the control cohort. Within 90 days postoperatively, patients with asymptomatic HIV had increased odds of arrhythmia without atrial fibrillation and lower odds of anemia. Patients with AIDS had increased odds of anemia and renal failure. Patients with HIV and AIDS are at an increased risk for developing 90-day medical complications and 2-year surgical complications. However, after accounting for their comorbidities, the risk of 90-day complications was only mildly increased and the risk of 2-year surgical complications approximated the control cohort. Surgeons should pay particular attention to these patients' overall comorbidities, which appear to be more closely associated with postoperative risks than HIV status alone. Level of evidence: III.