Mammalian B-cell development can be viewed as a developmental performance with several acts. The acts are represented by checkpoints centered around commitment to the B-lineage and functional Ig gene rearrangement--culminating in expression of the pre-B-cell receptor (pre-BCR) and the BCR. Progression of cells through these checkpoints is profoundly influenced by the fetal liver and adult bone marrow (BM) stromal cell microenvironments. Our laboratory has developed a model of human B-cell development that utilizes freshly isolated/non-transformed human BM stromal cells as an in vitro microenvironment. Human CD34+ hematopoietic stem cells plated in this human BM stromal cell microenvironment commit to the B lineage and progress through the pre-BCR and BCR checkpoints. This human BM stromal cell microenvironment also provides survival signals that prevent apoptosis in human B-lineage cells. Human B-lineage cells exhibit differential expression of Notch receptors and human BM stromal cells express the Notch ligand Jagged-1. These results suggest a potential role for Notch in regulating B-lineage commitment and/or progression through the pre-BCR and BCR checkpoints.

Highlights d PLZF is required for the generation and differentiation of iNKT cells d A hypomorphic allele of PLZF alters iNKT cell development and subset composition d Quantitative difference in PLZF protein abundance determines iNKT lineage fate

Invariant NKT ( i NKT) cells are a small subset of thymus-generated T cells that produce cytokines to control both innate and adaptive immunity. Because of their very low frequency in the thymus, in-depth characterization of i NKT cells can be facilitated by their enrichment from total thymocytes. Magnetic-activated cell sorting (MACS) of glycolipid antigen-loaded CD1d-tetramer-binding cells is a commonly used method to enrich i NKT cells. Surprisingly, we found that this procedure also dramatically altered the subset composition of enriched i NKT cells. As such, NKT2 lineage cells that express large amounts of the transcription factor promyelocytic leukemia zinc finger were markedly over-represented, while NKT1 lineage cells expressing the transcription factor T-bet were significantly reduced. To overcome this limitation, here, we tested magnetic-activated depletion of CD24 + immature thymocytes as an alternative method to enrich i NKT cells. We found that the overall recovery in i NKT cell numbers did not differ between these 2 methods. However, enrichment by CD24 + cell depletion preserved the subset composition of i NKT cells in the thymus, and thus permitted accurate and reproducible analysis of thymic i NKT cells in further detail.

Background: The rising prevalence of obesity among American adults has disproportionately affected Black adults and women. Furthermore, body mass index (BMI) has historically been used as a relative contraindication to many total joint arthroplasty (TJA) procedures, including total ankle arthroplasty. The purpose of this study was to investigate potential disparities in patient eligibility for total ankle arthroplasty based on race, ethnicity, sex, and age by applying commonly used BMI cutoffs to the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Methods: Patients in the ACS-NSQIP database who underwent TAA from 2011 to 2020 were retrospectively reviewed in a cross-sectional analysis. BMI cutoffs of <50, <45, <40, and <35 were then applied. The eligibility rate for TAA was examined for each BMI cutoff, and findings were stratified by race, ethnicity, sex, and age. Independent t tests, chi-squared tests, and Fisher exact tests were performed to compare differences at an α = 0.05. Results: A total of 1215 of 1865 TAA patients (65.1%) were included after applying the exclusion criteria. Black patients had disproportionately lower rates of eligibility at the most stringent BMI cutoff of <35 ( P = .004). Hispanic patients had generally lower rates of eligibility across all BMI cutoffs. In contrast, Asian American and Pacific Islander patients had higher rates of eligibility at the BMI cutoffs of <35 ( P = .033) and <40 ( P = .039), and White non-Hispanic patients had higher rates of eligibility across all BMI cutoffs. Females had lower eligibility rates across all BMI cutoffs. Ineligible patients were also younger compared to eligible patients across all BMI cutoffs. Conclusion: Stringent BMI cutoffs may disproportionately disqualify Black, female, and younger patients from receiving total ankle arthroplasty. Level of Evidence: Level III, retrospective cross-sectional study.

Background Mobility limitations are well linked to increased morbidity and mortality. Older patients with chronic pathologies of the foot and ankle can suffer from significant mobility limitations; however, the magnitude of limitation experienced by this cohort is not well characterized. Conversely, the effects of congestive heart failure (CHF) on patient mobility are routinely assessed via the New York Heart Association (NYHA) classification. New York Heart Association classification is determined by a patient’s physical activity limitation and is strongly correlated to functional status. We hypothesized that non-emergent conditions of the foot and ankle would be as mobility limiting as CHF. Methods Life-Space Mobility Assessments (LSAs) were prospectively collected from orthopaedic patients at their preoperative visits and from CHF patients at a cardiology clinic. Patients over the age of 50 years were included in this study. Congestive heart failure patients NYHA class II or greater were included. The non-emergent foot and ankle cohort included Achilles tendonitis, ankle joint cartilage defects, ankle arthritis, subtalar arthritis, and midfoot arthritis. Patient demographics and LSA scores were analyzed using Mann-Whitney U and chi-squared tests. Results A total of 96 elderly, non-emergent foot and ankle operative patients and 45 CHF patients met inclusion criteria. All medical comorbidities, except smoking status, were significantly more prevalent in the CHF cohort. No statistical difference was observed between CHF and preoperative foot and ankle LSA scores (56.1 vs 62.4, P = .320). Life-Space Mobility Assessment scores in the foot and ankle cohort were significantly improved relative to CHF patients, at 6-month and 1-year postoperative visits (P = .028, P < .0001, respectively). Conclusion Non-emergent ankle, hindfoot, and midfoot pathology is associated with similar mobility limitation to that of NYHA class II and III CHF. Older patients undergoing elective foot and ankle procedures exceeded the mobility of CHF patients at 6 months post-operation, and the mobility gains persisted at 1-year post-operation. Levels of Evidence: Level II: Prospective cohort study

Chronic, non-traumatic pathologies of the foot and ankle can be mobility-limiting for patients of all ages. The objective of this study was to compare postoperative changes in LifeSpace Mobility Assessment (LSA) scores of adult and elderly patients following elective foot and ankle surgery. A prospective study of 184 patients undergoing elective ankle, hindfoot, and midfoot procedures conducted by one surgeon between 2015 and 2019 was undertaken. Patient-reported LSA scores were collected at preoperative, 6-month, and 12-month follow-up. Patient data was compared using an independent sample t-test for continuous, normally distributed data and a chi-squared or Fischer’s exact test for categorical data. Alpha and beta were .05 and .8. Patients were divided based on age. 140 patients were observed in the younger (<65) group, 44 patients were observed in the elderly (≥65) group. The average LSA score of elderly patients at the preoperative visit was 58.3 (SD 38.0) vs 79.3 (SD 38.8) in the younger cohort (P = .041). Both patient cohorts saw decreased mobility at 3-month postoperative visits but surpassed preoperative mobility scores by 6 months and 1 year postop. No difference in average mobility score was observed between young (85.6, SD 36.1) and elderly (90.1, SD 34.3) cohorts at 1-year follow up. Given the increased rates of perioperative comorbidities and the heightened risks of intraoperative complications, physicians may be more inclined to manage elderly patients with longer periods of conservative treatment for similar pathologies. However, these results imply that elderly patients experience similar improvements after surgery to younger cohorts and should not be excluded from surgical consideration. Our results, in tandem with literature showing the deleterious effects of decreased mobility in the elderly, suggest that the discussion to pursue or hold surgical correction of chronic foot and ankle disease in patients over age 65 must consider the mobility benefits of surgery.

Category: Sports; Ankle; Arthroscopy Introduction/Purpose: The Brostrom-Gould procedure is the gold standard surgical treatment for patients with chronic ankle instability (CAI) whose symptoms are refractory to conservative treatment. The purpose of this study is to investigate the relationship between preoperative radiographic alignment, intraoperative stress testing, concomitant pathology, and postoperative pain scores in patients undergoing Brostrom-Gould procedures. Specific questions included: 1) Is preoperative radiographic alignment predictive of the degree of lateral ankle instability noted intraoperatively? 2) Is the degree of ankle instability associated with the presence of OCD lesions and peroneal tendon pathology? 3) Is the degree of ankle instability associated with postoperative VAS pain? and 4) Does concomitant pathology affect final VAS pain score? Methods: A retrospective study was performed of all patients who underwent lateral ankle ligament reconstruction by a single surgeon from 2002 to 2020. Patients who underwent concomitant hindfoot fusion procedures or ankle arthroplasty were excluded. Demographic and clinical information was recorded from the electronic medical record. Preoperative radiographic measurements were taken using weightbearing ankle films. Intraoperative stress views were evaluated to determine the talar tilt. All data was tested for normality. Parametric and nonparametric univariate statistics were used to determine the relationship between preoperative weightbearing radiographic measurements, preoperative MRI findings, intraoperative talar tilt measurement, and postoperative outcomes. Results: 181 patients with a median follow-up of 1 year were included. Complications included delayed wound healing in 5.6%, superficial infection in 2.8%, and nerve symptoms in 11%. The reoperation rate was 5%, including revision lateral ankle ligament reconstruction (4/181), debridement for infection (1/181), and wound revision (4/181). Increased preoperative anterior distal tibial angle (ADTA) was associated with an increased intraoperative talar tilt (p=0.0073). Increased intraoperative talar tilt was associated with an increased prevalence of osteochondral lesions of the talus (p=0.0176). Mean VAS scores improved from 4.6 preoperatively to 1.9 postoperatively (p<0.0001). Neither the preoperative radiographic alignment nor the degree of intraoperative instability were predictive of final VAS score. Patients with osteochondral lesions had higher final VAS pain scores than patients without osteochondral lesions (p=0.0134). Conclusion: In patients undergoing lateral ankle ligament reconstruction for CAI, preoperative ankle alignment was associated with the degree of ankle instability. It is unclear if an increased ADTA predisposes to great instability, or if larger anterior distal tibia osteophytes are formed in patients with more severe instability, leading to a larger ADTA. Increased instability was associated with a higher rate of osteochondral lesions, and patients with osteochondral lesions tended to have more pain postoperatively. This information may be helpful in counseling patients regarding surgical treatment and postoperative expectations.

Background: Limited literature examines the relationship between surgical outcomes in chronic foot and ankle conditions and concurrent psychiatric care. The present study aimed to investigate patient-reported and surgical outcomes of patients treated for a psychiatric disorder undergoing first metatarsophalangeal (MTP) fusion for hallux rigidus. We hypothesized that patients on psychotropic medications would have greater subjective pain preoperatively and less improvement in physical and mental functionality postoperatively when compared with nonmedicated patients. Methods: A single-center, retrospective review of prospectively collected data was conducted on 92 patients undergoing first MTP fusion with a preoperative diagnosis of hallux rigidus from 2015 to 2019. At their preoperative, 6-month postoperative, and 1-year postoperative visits, patients were administered visual analog pain scale (VAS) and 36-Item Short Form Health Survey (SF-36) functionality surveys. Patients were subsequently identified by chronic use of psychotropic medication preoperatively and grouped for analysis (MED, n = 42; NO MED, n = 50). Results: Postoperative mean VAS pain scores were lower for all studied patients at 6 months (VAS = 1.6 ± 2.3) and 1 year postoperatively (VAS = 1.1± 1.8) relative to the preoperative visit (VAS = 4.7 ± 2.8) ( P ≤ .0001 and P ≤ .0001, respectively). No differences in mean VAS pain scores nor SF-36 physical component summary scores were detected at preoperative, 6-month, or 1-year visits between NO MED and MED groups. Mean SF-36 mental component summary scores for those in the MED group were lower at preoperative (NO MED = 83.8, MED = 71.8, P = .006) and 6-month postoperative (NO MED = 86.1, MED = 72.7, P = .037) visits than those in the NO MED group, a trend not observed at the 1-year postoperative mark (NO MED = 84.1, MED = 76.8, P = .228). There were no observed differences in operative time ( P = .219), tourniquet time ( P = .359), nor time to full weightbearing ( P = .512) between MED and NO MED groups. Additionally, no differences in postoperative complication rates were observed between groups. Conclusion: In patients treated with psychotropically active medications with hallux rigidus, MTP Fusion appears to be a reasonable treatment choice with similar outcomes for patients requiring psychotropically active medications to the outcomes of those patients not requiring psychotropically active medications. Level of Evidence: Level III, retrospective comparative study.