The adaptor protein 2 (AP2) complex modulates habituation and behavioral selection across multiple pathways and time windows.

Animals constantly integrate sensory information with prior experience to select behavioral responses appropriate to the current situation. Genetic factors supporting this behavioral flexibility are often disrupted in neuropsychiatric conditions, such as the autism-linked ap2s1 gene which supports acoustically evoked habituation learning. ap2s1 encodes an AP2 endocytosis adaptor complex subunit, although its behavioral mechanisms and importance have been unclear. Here, we show that multiple AP2 subunits regulate acoustically evoked behavior selection and habituation learning in zebrafish. Furthermore, ap2s1 biases escape behavior choice in sensory modality-specific manners, and broadly regulates action selection across sensory contexts. We demonstrate that the AP2 complex functions acutely in the nervous system to modulate acoustically evoked habituation, suggesting several spatially and/or temporally distinct mechanisms through which AP2 regulates escape behavior selection and performance. Altogether, we show the AP2 complex coordinates action selection across diverse contexts, providing a vertebrate model for ap2s1's role in human conditions including autism spectrum disorder.

Gloves Contamination During Revision Surgery for Periprosthetic Joint Infection.

BACKGROUND: The use of double gloving has become a standard practice for joint replacement surgeons. However, since there are limited data on how gloves are contaminated during both primary and revision arthroplasty, no precise protocol exists to direct surgeons on when, or if, to change their gloves. The goals of this preliminary study were to evaluate the contamination of gloves during total joint arthroplasties (TJAs). METHODS: We included 25 infected cases and 10 primaries, which were performed at the same institution using the same surgical protocol from 3 fellowship trained surgeons. Samples were taken every 20 minutes from the start of the surgery until the joint was irrigated. Procedural steps were noted. To evaluate cross-contamination during infected cases, we sampled gloves using blood agar plates. In primary cases, culture swabs of anterior chamfer cuts and sterile instruments on the back table were used as negative controls. Next-generation sequencing (NGS) was used as an adjunct to identify low virulence bacteria. RESULTS: In the primary cases, all samples were found culture negative but 3 (8.1%) of the 37 samples were found to have a low, unidentifiable bacterial mass via NGS testing. In the infected cases, 41 (59.4%) of the 69 samples yielded positive microbial results. The positivity rate was higher in the samples collected after the arthrotomy was performed (70%) compared to samples collected before the arthrotomy was performed (40%), and the surgeon was only dissecting superficial layers (P = .502). CONCLUSION: Gloves seem to be a common source of cross-contamination in the intraoperative field during revision TJA. Due to the higher percent of positive samples following the opening of the joint, we hypothesize that the arthrotomy allows for the spread of bacteria across the operative site. While further investigation is necessary to formulate a precise protocol for the changing of gloves during TJA, it may be beneficial to perform a thorough irrigation of the joint and change of the gloves immediately following arthrotomy.

Using machine learning to predict venous thromboembolism and major bleeding events following total joint arthroplasty.

Venous thromboembolism (VTE) and major bleeding (MBE) are feared complications that are influenced by numerous host and surgical related factors. Using machine learning on contemporary data, our aim was to develop and validate a practical, easy-to-use algorithm to predict risk for VTE and MBE following total joint arthroplasty (TJA). This was a single institutional study of 35,963 primary and revision total hip (THA) and knee arthroplasty (TKA) patients operated between 2009 and 2020. Fifty-six variables related to demographics, comorbidities, operative factors as well as chemoprophylaxis were included in the analysis. The cohort was divided to training (70%) and test (30%) sets. Four machine learning models were developed for each of the outcomes assessed (VTE and MBE). Models were created for all VTE grouped together as well as for pulmonary emboli (PE) and deep vein thrombosis (DVT) individually to examine the need for distinct algorithms. For each outcome, the model that best performed using repeated cross validation was chosen for algorithm development, and predicted versus observed incidences were evaluated. Of the 35,963 patients included, 308 (0.86%) developed VTE (170 PE's, 176 DVT's) and 293 (0.81%) developed MBE. Separate models were created for PE and DVT as they were found to outperform the prediction of VTE. Gradient boosting trees had the highest performance for both PE (AUC-ROC 0.774 [SD 0.055]) and DVT (AUC-ROC 0.759 [SD 0.039]). For MBE, least absolute shrinkage and selection operator (Lasso) analysis had the highest AUC (AUC-ROC 0.803 [SD 0.035]). An algorithm that provides the probability for PE, DVT and MBE for each specific patient was created. All 3 algorithms had good discriminatory capability and cross-validation showed similar probabilities comparing predicted and observed failures indicating high accuracy of the model. We successfully developed and validated an easy-to-use algorithm that accurately predicts VTE and MBE following TJA. This tool can be used in every-day clinical decision making and patient counseling.

Intraosseous Regional Administration of Antibiotic Prophylaxis for Total Knee Arthroplasty: A Systematic Review.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The Use of Cement and Tourniquet During Total Knee Arthroplasty Does Not Increase the Risk of Venous Thromboembolism Postoperatively.

Background: Venous thromboembolism (VTE) is a severe complication of total knee arthroplasty (TKA). Cementation and the use of tourniquet during TKA have both been hypothesized to be risk factors of VTE. The purpose of our study was to determine if either of these surgical factors increases the risk of VTE in patients undergoing TKA. Methods: A single-institution, retrospective study was conducted, consisting of 16,972 patients undergoing a primary or revision TKA from 2008 to 2020. Of the total, 1020 patients were excluded from the tourniquet analysis as tourniquet data were unavailable. Clinical records were consulted to identify demographics, surgical variables, and outcomes. Queries of clinical notes and phone-call logs were conducted to capture VTE events following discharge. Statistical analysis consisted of univariate analysis, regression analysis, and propensity score matching. Results: Compared to patients who did not receive tourniquet, the patients with tourniquet did not demonstrate a significantly higher rate of VTE in the univariate analysis (1.00 vs 1.31, P = .132). Propensity score analysis also showed no difference between the 2 cohorts (1.10 vs 0.85, P = .306). Cemented patients similarly did not demonstrate an increased risk of VTE in either the univariate (1.26 vs 1.22, P = .895) or propensity score analysis (1.42 vs 1.26, P = .710) compared to cementless patients. Regression analysis, looking at the interaction between cement and tourniquet with VTE risk as the dependent variable, revealed neither to be risk factors for VTE (odds ratio 1.38, 95% confidence interval 0.63-3.08, P = .426). Conclusions: In our cohort, neither tourniquet nor cement was a significant risk factor for VTE following TKA.

Aspirin May Be a Suitable Prophylaxis for Patients with a History of Venous Thromboembolism Undergoing Total Joint Arthroplasty.

BACKGROUND: In recent years, aspirin has become a popular agent for venous thromboembolism (VTE) prophylaxis following total joint arthroplasty (TJA). Yet patients with a history of VTE are often given more aggressive prophylactic agents because of their increased baseline risk. The purpose of this study was to assess whether aspirin is an effective prophylactic agent in patients with a history of VTE. METHODS: This was a single-institution, retrospective cohort study. The electronic clinical records of 36,333 patients undergoing TJA between 2008 and 2020 were reviewed. Data on demographic characteristics, comorbidities, intraoperative factors, and postoperative complications were collected. A propensity score-matched analysis was performed, as well as a multivariate regression analysis to account for confounders. RESULTS: Of the 36,333 patients undergoing TJA, 1,087 patients (3.0%) had a history of VTE and were not receiving chronic non-aspirin. The risk for subsequent VTE was significantly higher (p = 0.03) in patients with a history of VTE (1.4%) compared with patients without prior VTE (0.9%). However, the incidence of VTE was not significantly lower (p = 0.208) in patients with a history of VTE who received aspirin (0.4%) compared with patients who received other VTE prophylaxis (1.5%). Propensity score matching showed no difference in VTE rates between the 2 groups (2.2% compared with 0.55%; p = 0.372). In a regression analysis accounting for VTE risk, the administration of aspirin was not associated with an increased risk for subsequent VTE (adjusted odds ratio, 0.32 [95% confidence interval, 0.02 to 1.66]; p = 0.274). CONCLUSIONS: Our findings suggest that, although patients with a history of VTE have an increased baseline risk for subsequent VTE, aspirin may be a suitable VTE prophylaxis in this group of patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Articular Cartilage Damage Worsens from First-time to Recurrent Patellar Dislocation-A Longitudinal Magnetic Resonance Imaging Study.

Purpose: To compare the frequency and severity of articular cartilage injury on longitudinal magnetic resonance imaging (MRI) in patients after their initial dislocation and subsequent recurrent dislocations for those undergoing patellar stabilization surgery. Methods: Between January 2012 and December 2017, patients undergoing patellar stabilization surgery were retrospectively reviewed. Only patients with an MRI after both the initial dislocation and subsequent dislocation events were included. The MRI scans were blindly examined to assess the Outerbridge classification grade of articular cartilage injury following each dislocation. Comparison was performed of each MRI for grade of articular cartilage damage and location. Results: Thirty-five patients undergoing patellar stabilization surgery with recurrent instability were eligible. The incidence of articular cartilage injury following initial dislocation was 45.7%. Following a second dislocation, the incidence of articular cartilage injury increased to 62.9%, a statistically significant increase of 17.2% (P = .031). Furthermore, of the 16 patients with articular cartilage injury following their initial dislocation, 56.2% of patients (9) had an increase in grade of articular cartilage injury following the second dislocation, whereas 43.8% (7) of patients had no progression in their articular cartilage injury. Six (17.1%) patients had no articular cartilage injury following their initial dislocation but did have articular cartilage injury following their second dislocation. Conclusions: Articular cartilage injury following patellar dislocation is common, and delayed surgical treatment may lead to an increase in articular cartilage damage. The incidence of articular cartilage injury following recurrent patellar dislocation was high (62.9%), and the majority of patients experienced an increase in their articular cartilage injury grade between their initial and recurrent dislocation on MRI evaluation. Level of Evidence: Level IV, retrospective case series.

For Patients With Acute PJI Treated With Debridement, Antibiotics, and Implant Retention, What Factors Are Associated With Systemic Sepsis and Recurrent or Persistent Infection in Septic Patients?

BACKGROUND: Periprosthetic joint infection (PJI) can lead to a severe systemic inflammatory response and may result in systemic sepsis. However, little is known about how often systemic sepsis may occur in patients with PJI, and whether sepsis is associated with a greater likelihood of persistent or recurrent PJI. QUESTIONS/PURPOSES: (1) Among patients who present with acute or acute hematogenous PJI and who were treated with debridement, antibiotics, and implant retention (DAIR), what proportion have sepsis and what factors are associated with a presentation with sepsis? (2) For patients presenting with sepsis, what factors are associated with persistent or recurrent PJI? METHODS: In all, 320 patients who underwent DAIR for the treatment of acute postoperative or acute hematogenous PJI between January 2000 and December 2019 were included in this study. Exclusion criteria were patients with other known sources of infection, such as pneumonia or urinary tract infections, which could contribute to systemic sepsis (6% [18 of 320]), patients with chronic PJI, and those with less than 6 months of follow-up (21% [66 of 320]). Our final cohort consisted of 236 patients presenting with an acute postoperative or acute hematogenous PJI who underwent an irrigation and debridement procedure. Sepsis was defined by the criteria for systemic inflammatory response syndrome (SIRS) or bacteria-positive blood culture results. Inclusion of patients with positive blood culture by organisms that caused their joint infection was important as all patients presented with fulminant acute infection of a prosthetic joint. Data, including vital signs, surgical variables, and treatment outcomes, were collected retrospectively through a chart review of an electronic medical record system. The statistical analysis comparing patients with sepsis versus patients without sepsis consisted of logistic regression to identify factors associated with sepsis. After confirming its ability to identify patients with a higher association with the development of sepsis through area under the curve models, a nomogram was generated to standardize our results from the regression, which was supported by the area under the curve model, to help readers better identify patients who are more likely to develop sepsis. RESULTS: A total of 44% (103 of 236) of patients had infections that met the criteria for sepsis. After controlling for confounding variables, including congestive heart failure, anemia, serum C-reactive protein (CRP), and the male sex, it was revealed that serum CRP (odds ratio 1.07 [95% confidence interval 1.04 to 1.11]; p < 0.001) and male sex (OR 1.96 [95% CI 1.03 to 3.81]; p = 0.04) were associated with the development of systemic sepsis. For patients presenting with sepsis, persistent or recurrent PJI were associated with an increased CRP level (OR 1.06 [95% CI 1.02 to 1.11]; p = 0.01) and number of prior surgical procedures on the joint (OR 2.30 [95% CI 1.21 to 4.89]; p = 0.02). CONCLUSION: Overall, our findings support that patients with systematic sepsis may benefit from two-stage revision rather than DAIR to decrease the bioburden more effectively, especially in those with methicillin-resistant Staphylococcus aureus and polymicrobial infections. High serum CRP levels and a history of prior surgical procedures on the involved joint should trigger prompt, aggressive surgical treatment if the patient's overall clinical status can tolerate such an intervention. LEVEL OF EVIDENCE: Level III, therapeutic study.

Time to Venous Thromboembolism Events Following Total Hip Arthroplasty: A Comparison Between Aspirin and Warfarin.

BACKGROUND: The attitude and approach of orthopedic community for minimizing venous thromboembolism (VTE) has evolved over the last decade with the trend toward use of aspirin (and mechanical modalities) in lieu of aggressive anticoagulation. The optimal length of VTE prophylaxis following total hip arthroplasty (THA) still remains unknown. This study aimed to determine the timing of VTE in patients who received aspirin compared to warfarin, and determine if 30 days of prophylaxis remain adequate. METHODS: This is a retrospective study of 18,003 patients undergoing primary and revision THA at a single institution between January 2008 and August 2020. During this time, our institution underwent a transition from the use of warfarin to aspirin as the main method for VTE prophylaxis. Symptomatic deep vein thrombosis and pulmonary embolism occurring within 90 days of surgery were identified from medical records and phone call logs. Aspirin and warfarin cohorts were matched to account for demographic and comorbidity differences. Timing of pulmonary embolism was determined based on either the date of diagnostic imaging or patient-provider phone calls confirming diagnosis. RESULTS: The cohorts included 46 patients in the warfarin group and 46 in the aspirin group. Time to VTE was significantly shorter in the warfarin group compared to aspirin (P = .021) with a median time to VTE of 3 days (interquartile range 2-14) and 10 days (interquartile range 4-19) respectively. Over 90% of the events occurred within 32 or 30 days of surgery in the warfarin and aspirin groups respectively. CONCLUSION: Based on the findings, a 30-day aspirin prophylaxis remains appropriate for patients undergoing THA.

Aspirin Administered for Venous Thromboembolism Prophylaxis May Protect Against Stiffness Following Total Knee Arthroplasty.

BACKGROUND: Aspirin has become the main agent for venous thromboembolism (VTE) prophylaxis following total knee arthroplasty (TKA). This study assessed whether aspirin is associated with less knee stiffness compared to warfarin and other chemoprophylaxis agents. METHODS: This is a retrospective review of all primary and revision TKAs performed between January 2009 and October 2020 at a high volume institution. Demographics, comorbidity data, and operative variables were extracted from medical records. VTE prophylaxis administered during this time period included aspirin, warfarin, and "others" (factor Xa, unfractionated heparin, low-molecular-weight heparin, fondaparinux, adenosine diphosphate receptor inhibitor, and direct thrombin inhibitor). The primary outcome assessed was manipulation under anesthesia (MUA) performed within 6 months of index surgery. Secondary outcome included major bleeding events. Univariate followed by multivariate regression analyses were performed. RESULTS: A total of 15,903 cases were included in the study, of which 531 (3.3%) patients developed stiffness that required MUA. The rates of MUA were 2.7% (251/9223) for patients receiving aspirin, 4.2% (238/5709) for patients receiving warfarin, and 4.3% (42/971) for all others (P's < .001). Multivariate regression analysis confirmed that aspirin is associated with lower rates of VTE compared to warfarin (adjusted odds ratio 1.423, 95% confidence interval 1.158-1.747, P < .001) and compared to other anticoagulation medications (adjusted odds ratio 1.742, 95% confidence interval 1.122-2.704, P = .013). Major bleeding events were also significantly lower in patients who received aspirin compared to the other 2 groups (P's = .001). CONCLUSION: Aspirin prophylaxis is associated with lower rates of MUA following TKA compared to warfarin and other VTE chemoprophylactic agents when grouped together.

Aspirin Thromboprophylaxis Is Associated With Less Major Bleeding Events Following Total Joint Arthroplasty.

BACKGROUND: There is ongoing debate on what is optimal prophylactic agent to reduce venous thromboembolism (VTE) following total joint arthroplasty (TJA). Although many studies assess the efficacy of these agents in VTE prevention, no attention is given to their adverse effect on major bleeding events (MBEs). This study compared the incidence of MBE in patients receiving aspirin as VTE prophylaxis vs other chemoprophylaxis. METHODS: A single-institution, retrospective study of 35,860 patients undergoing TJA between 2009 and 2020 was conducted. Demographic variables, co-morbidities, type of chemoprophylaxis, and intraoperative factors were collected. MBE was defined using the 2010 criteria for major bleeding in surgical patients presented by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. To enhance capture rate, comprehensive queries utilizing MBE keywords were conducted in clinical notes, physician dictations, and phone call logs. Univariate followed by multivariate regression was performed as well as propensity score matched analysis. RESULTS: Overall, 270 patients (0.75%) in this cohort developed MBE. The MBE rate was 0.5% in the aspirin group and 1.2% in the non-aspirin group. After adjusting for confounders, multiple logistic regression and propensity score matched analysis revealed almost 2 times lower odds of MBE in patients who received aspirin. Variables independently associated with increased MBE risk included increasing age, body mass index, American Society of Anesthesiologists score, revision surgery, peptic ulcer disease, coagulopathy, intraoperative blood transfusion, and active smoking. CONCLUSION: Administration of aspirin for VTE prophylaxis, compared to other chemoprophylaxis agents may have an association with lower risk of major bleeding following TJA. Future randomized controlled trials should examine these findings.

Blood transfusions increase the risk for venous thromboembolism events following total joint arthroplasty.

The association between blood transfusions and thromboembolic events (VTE) following total joint arthroplasty (TJA) remains debatable. Using contemporary institutional data, this study aimed to determine whether blood transfusions increase the risk of VTE following primary and revision TJA. This was a single institution, retrospective cohort study. The clinical records of all patients (n = 34,824) undergoing primary and revision TJA between 2009 and 2020 were reviewed. Demographic variables, co-morbidities, type of chemoprophylaxis and intraoperative factors such as use of tranexamic acid were collected. Clinical notes, hospital orders, and discharge summaries were reviewed to determine if a patient received a blood transfusion. Comprehensive queries utilizing keywords for VTE were conducted in clinical notes, physician dictations, and patient-provider phone-call logs. Propensity score matching as well as adjusted mixed models were performed. After adjusting for various confounders, results from regression analysis showed a significant association between allogenic blood transfusions and risk for developing VTE following primary and revision TJA (OR 4.11, 95% CI 2.53-6.69 and OR 2.15, 95% CI 1.12-4.13, respectively). While this strong association remained significant for PE in both primary (p < 0.001) and revision (p < 0.001) matched cohorts, it was no longer statistically significant for DVT (p = 0.802 and p = 0.65, respectively). These findings suggest that the risk of VTE is increased by approximately three-folds when blood transfusions are prescribed. This association was mainly due to higher symptomatic PE events which makes it even more worrisome. Surgeons should be aware of this association, revisit criteria for blood transfusions and use all means available in the perioperative period to optimize the patients and avoid transfusion.

Emergence of Antibiotic Resistance Across Two-Stage Revision for Periprosthetic Joint Infection.

BACKGROUND: The current preferred treatment for chronic hip and knee periprosthetic joint infection (PJI) involves both surgical intervention and antibiotic treatment as part of a two-stage revision. The purpose of this study is to determine how often patients who underwent a two-stage revision for chronic PJI developed a subsequent antibiotic-resistant infection. METHODS: We retrospectively reviewed the clinical records of 142 patients who underwent a two-stage revision for a chronic culture-positive PJI from January 2014 to May 2019. Demographic data and risk factors for PJI were identified. Resistance was defined in accordance with microbiology laboratory report and minimum inhibitory concentration. Statistical analysis consisted of descriptive statistics and univariate analysis. RESULTS: Only 10 of the 142 patients (7.04%) demonstrated emergence of resistance to antibiotics across their two-stage revision. At reimplantation, 25 (17.6%) patients had positive cultures. Of these, 16 patients presented with a novel organism and 9 patients had positive culture for the same organism as the initial infection. During the entire course of the two-stage revision, including spacer exchanges and irrigation and debridement procedures, 15 (10.56%) patients demonstrated persistent infections, whereas 25 (17.6%) patients presented with novel infections. 26 (18.3%) patients had reinfection of the same joint within one year. CONCLUSION: In the given cohort, there does not appear to be a major emergence of antibiotic resistant organisms in patients undergoing two-stage exchange arthroplasty and antibiotic treatment.

Thirty Days of Aspirin for Venous Thromboembolism Prophylaxis Is Adequate Following Total Knee Arthroplasty, Regardless of the Dose Used.

BACKGROUND: The optimal length of aspirin prophylaxis to minimize venous thromboembolism (VTE) following total knee arthroplasty (TKA) remains unknown. This study aimed to determine the timing of VTE after TKA in patients who received low and high dose aspirin, and determine if 30 days of prophylaxis remains adequate. METHODS: We retrospectively reviewed records of 9208 patients undergoing primary TKA between 2010 and 2020 who received either low (81 mg twice daily, n = 4413) or high (325 mg twice daily, n = 4795) dose aspirin for VTE prophylaxis. Symptomatic VTEs occurring within 90 days of surgery were identified from medical records and phone call logs. Major bleeding events (MBE) within the first 30 days were also documented. Time to event was recorded. RESULTS: Overall, 88 patients (1.0%) developed symptomatic VTE, with no significant differences in incidence between the low (n = 40, 0.9%) and high (n = 48, 1.0%) dose groups (P = .669). The median time to VTE was 8 days (interquartile range [IQR] 2-15.5), median time to deep vein thrombosis was 12 days (IQR 5-18), and median time to pulmonary embolism was 5 days (IQR 1.5-15). There was a similar distribution in time to VTE in both the low and high dose groups. Aside from a single DVT occurring at day 44, all VTE occurred within 30 days of surgery. During the prophylactic time period, 41 patients (0.4%) developed MBE, which tended to occur more frequently (0.6% vs 0.3%, P = .018) and earlier in the high dose group. CONCLUSION: Based on the findings, a 30-day low or high dose aspirin regimen remains optimal for prevention of VTE without increasing MBE in TKA patients.