Single-Cell Profiling Reveals Immune Aberrations in Progressive Idiopathic Pulmonary Fibrosis.

RATIONALE: Changes in peripheral blood cell populations have been observed but not detailed at single-cell resolution in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. METHODS: Peripheral blood mononuclear cells (PBMCs) from IPF patients and controls were profiled using 10x Chromium 5' single-cell RNA sequencing (scRNA-seq). Flow cytometry was used for validation. Protein concentrations of Regulatory T-cells (Tregs) and Monocytes chemoattractants were measured in plasma and lung homogenates from patients and controls. MEASUREMENTS AND MAIN RESULTS: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched controls yielded 149,564 cells that segregated into 23 subpopulations. Classical monocytes were increased in progressive and stable IPF compared to controls (32.1%, 25.2%, 17.9%, respectively, p<0.05). Total lymphocytes were decreased in IPF vs controls, and in progressive vs stable IPF (52.6% vs 62.6%, p=0.035). Tregs were increased in progressive vs stable IPF (1.8% vs 1.1% of all PBMC, p=0.007), although not different than controls, and may be associated with decreased survival (P=0.009 in Kaplan-Meier analysis; P=0.069 after adjusting for age, sex, and baseline FVC). Flow cytometry analysis confirmed this finding in an independent cohort of IPF patients. Fraction of Tregs out of all T cells was also increased in two cohorts of lung scRNA-seq. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF. CONCLUSIONS: The single-cell atlas of the peripheral immune system in IPF, reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

Single Cell Analysis Reveals Novel Immune Perturbations in Fibrotic Hypersensitivity Pneumonitis.

Rationale: Fibrotic hypersensitivity pneumonitis is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in fibrotic hypersensitivity pneumonitis in single-cell resolution. Methods: Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and bronchoalveolar lavage cells obtained from 45 patients with fibrotic hypersensitivity pneumonitis, 63 idiopathic pulmonary fibrosis, 4 non-fibrotic hypersensitivity pneumonitis, and 36 healthy controls in the United States and Mexico. Analyses included differential gene expression (Seurat), transcription factor activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3/Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and controls and 88,336 bronchoalveolar lavage cells from 19 patients were profiled. Compared to controls, fibrotic hypersensitivity pneumonitis has elevated classical monocytes (adjusted-p=2.5e-3) and are enriched in CCL3hi/CCL4hi and S100Ahi classical monocytes (adjusted-p<2.2e-16). Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. Compared to both controls and idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis patient cells are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit transcription factor activities indicative of TGFß and TNFα/NFκB pathways. These results are publicly available at https://ildimmunecellatlas.org. Conclusions: Single-cell transcriptomics of fibrotic hypersensitivity pneumonitis patients uncovered novel immune perturbations, including previously undescribed increases in GZMhi cytotoxic CD4+ and CD8+ T cells - reflecting this disease's unique inflammatory T-cell driven nature - as well as increased S100Ahi and CCL3hi/CCL4hi classical monocytes also observed in idiopathic pulmonary fibrosis. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

Prior fragility fractures are associated with a higher risk of 8-year complications following total shoulder arthroplasty.

Patients who sustain fragility fractures prior to total shoulder arthroplasty have significantly higher risk for bone health-related complications within 8 years of procedure. Identification of these high-risk patients with an emphasis on preoperative, intraoperative, and postoperative bone health optimization may help minimize these preventable complications. PURPOSE: As the population ages, more patients with osteoporosis are undergoing total shoulder arthroplasty (TSA), including those who have sustained a prior fragility fracture. Sustaining a fragility fracture before TSA has been associated with increased risk of short-term revision rates, periprosthetic fracture (PPF), and secondary fragility fractures but long-term implant survivorship in this patient population is unknown. Therefore, the purpose of this study was to characterize the association of prior fragility fractures with 8-year risks of revision TSA, periprosthetic fracture, and secondary fragility fracture. METHODS: Patients aged 50 years and older who underwent TSA were identified in a large national database. Patients were stratified based on whether they sustained a fragility fracture within 3 years prior to TSA. Patients who had a prior fragility fracture (7631) were matched 1:1 to patients who did not based on age, gender, Charlson Comorbidity Index (CCI), smoking, obesity, diabetes mellitus, and alcohol use. Kaplan-Meier and Cox Proportional Hazards analyses were used to observe the cumulative incidences of all-cause revision, periprosthetic fracture, and secondary fragility fracture within 8 years of index surgery. RESULTS: The 8-year cumulative incidence of revision TSA (5.7% vs. 4.1%), periprosthetic fracture (3.8% vs. 1.4%), and secondary fragility fracture (46.5% vs. 10.1%) were significantly higher for those who had a prior fragility fracture when compared to those who did not. On multivariable analysis, a prior fragility fracture was associated with higher risks of revision (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.24-1.74; p < 0.001), periprosthetic fracture (HR, 2.98; 95% CI, 2.18-4.07; p < 0.001) and secondary fragility fracture (HR, 8.39; 95% CI, 7.62-9.24; p < 0.001). CONCLUSIONS: Prior fragility fracture was a significant risk factor for revision, periprosthetic fracture, and secondary fragility fracture within 8 years of primary TSA. Identification of these high-risk patients with an emphasis on preoperative and postoperative bone health optimization may help minimize these complications. LEVEL OF EVIDENCE: III.

The cost-effectiveness of osteoporosis medications for preventing periprosthetic fractures following femoral neck fracture indicated hip arthroplasty: a break-even analysis.

Osteoporosis treatment following arthroplasty for femoral neck fracture (FNF) is associated with lower rates of periprosthetic fracture (PPF). Our study evaluated the economic viability of treatment in patients following arthroplasty and demonstrates that treatment with oral bisphosphonates can be cost-effective in preventing PPF. INTRODUCTION: Osteoporosis treatment following arthroplasty for femoral neck fracture (FNF) is associated with lower rates of periprosthetic fracture (PPF). Although cost-effective in reducing the rate of secondary fragility fracture, the economic viability of osteoporosis treatment in preventing PPF has not been evaluated. Therefore, the purpose of this study is to use a break-even analysis to determine whether and which current osteoporosis medications are cost-effective in preventing PPF following arthroplasty for FNFs. METHODS: Three-year average cost of osteoporosis medication (oral bisphosphonates, estrogen hormonal therapy, intravenous (IV) bisphosphonates, denosumab, teriparatide, and abaloparatide), costs of PPF care, and PPF rates in patients who underwent hip arthroplasty for FNFs without osteoporosis treatment were used to perform a break-even analysis. The absolute risk reduction (ARR) related to osteoporosis treatment and sensitivity analyses were used to evaluate the cost-effectiveness of this intervention and break-even PPF rates. RESULTS: Oral bisphosphonate therapy following arthroplasty for hip fractures would be economically justified if it prevents one out of 56 PPFs (ARR, 1.8%). Given the current cost and incidence of PPF, overall treatment can only be economically viable for PPF prophylaxis if the 3-year costs of these agents are less than $1500. CONCLUSION: The utilization of lower cost osteoporosis medications such as oral bisphosphonates and estrogen hormonal therapy as PPF prophylaxis in this patient population would be economically viable if they reduce the PPF rate by 1.8% and 1.5%, respectively. For IV bisphosphonates and newer agents to be economically viable as PPF prophylaxis in the USA, their costs need to be significantly reduced.

The Creation of Data-Driven Preoperative Hemoglobin A1c and Same-Day Glucose Strata to Stratify Complication Risk Following Total Hip Arthroplasty.

BACKGROUND: This study identifies data-driven strata for preoperative Hemoglobin A1c (HbA1c) and same-day glucose levels that maximize differences in the likelihood of complications following total hip arthroplasty (THA). METHODS: Patients who underwent THA from 2013 to 2022 were identified using a national database. In total, 18,728 patients were identified with a mean age of 67 years (range, 18 to 80). Stratum specific likelihood ratio (SSLR) analysis determined separate strata for HbA1c and same-day glucose levels that minimized the likelihood of 90-day complications following THA. Each stratum was propensity-score matched based on age, sex, hypertension, heart failure, chronic obstructive pulmonary disease, and obesity to the lowest respective stratum. The risk ratio (RR) with respect to the lowest matched stratum was observed. RESULTS: Our SSLR analysis identified 3 data-driven HbA1c strata (4.5 to 5.9, 6.0 to 6.9, and 7.0+) and two same-day glucose strata (60 to 189 and 190+) that predicted 90-day major complications. For HbA1c, when compared to the lowest strata (4.5 to 5.9), the risk of 90-day major complications sequentially increased as the HbA1c strata increased: 6.0 to 6.9 (RR: 1.21; P = .041), 7+ (RR: 1.82; P < .001). For same-day glucose, when compared to the matched lowest strata (60 to 189), the risk of 90-day major complications was higher for the 190+ strata (RR: 1.5; P < .001). CONCLUSIONS: Our results support the use of multiple HbA1c strata that can be incorporated into preoperative risk-stratification models. Additionally, we identified a single cut-off level of 190 as a maximum target blood glucose level perioperatively.

Trends in Extended Oral Antibiotic Prophylaxis Utilization Following Primary and Revision Total Hip Arthroplasty From 2010 to 2022.

BACKGROUND: In patients considered high-risk for infection, extended oral antibiotic (EOA) prophylaxis has been demonstrated to reduce rates of prosthetic joint infection following total hip arthroplasty (THA). Although national guidelines regarding their use have not yet been created, the increase in literature surrounding EOA prophylaxis suggests a potential change in practice patterns. The purpose of this study was to investigate the trends in utilization of EOA prophylaxis following THA from 2010 to 2022 and identify prescription patterns. METHODS: A total of 646,059 primary THA and 51,879 aseptic revision THA patients were included in this study. Patients who underwent primary or aseptic revision THA between 2010 and 2022 were identified in a national administrative claims database. Rates and duration of EOA prescriptions were calculated. A secondary analysis examined rates of utilization across demographics, including patients considered high risk for infection. RESULTS: From 2010 to 2022, utilization of EOA increased by 366% and 298% following primary and revision THA, respectively. Of patients prescribed postoperative antibiotics, 30% and 59% were prescribed antibiotics for more than 7 days following primary and revision THA, respectively. Rates of utilization were similar between high-risk individuals and the general population. CONCLUSIONS: Rates of utilization of EOA prophylaxis after THA have increased significantly since 2010. As current trends demonstrate a wide variation in prescription patterns, including in length of antibiotic duration and in patient population prescribed, guidelines surrounding the use of EOA prophylaxis after THA are necessary to promote antibiotic stewardship while preventing rates of periprosthetic joint infection.

Longitudinal Associations Between Neighborhood Child Opportunity and Physical Fitness for New York City Public School Youth.

Neighborhood environments can support fitness-promoting behavior, yet little is known about their influence on youth physical fitness outcomes over time. We examined longitudinal associations between neighborhood opportunity and youth physical fitness among New York City (NYC) public school youth. The Child Opportunity Index (COI), a composite index of 29 indicators measuring neighborhood opportunity at the census-tract level, along with scores on 4 selected COI indicators were linked to NYC FITNESSGRAM youth data at baseline. Fitness outcomes (measured annually, 2011-2018) included body mass index, curl-ups, push-ups, and Progressive Aerobic Cardiovascular Endurance Run (PACER) laps. Unstratified and age-stratified, adjusted, 3-level generalized linear mixed models, nested by census tract and time, estimated the association between COI and fitness outcomes. The analytical sample (n = 204,939) lived in very low (41%) or low (30%) opportunity neighborhoods. Unstratified models indicated that overall COI is modestly associated with improved youth physical fitness outcomes. The strongest opportunity-fitness associations were observed for PACER. Stratified models show differences in associations across younger vs. older youth. We find that neighborhood factors are associated with youth fitness outcomes over time, with the strength of the associations dependent on age. Future implications include better informed place-based interventions tailored to specific life stages to promote youth health.

From COVID to fibrosis: lessons from single-cell analyses of the human lung.

The increased resolution of single-cell RNA-sequencing technologies has led to major breakthroughs and improved our understanding of the normal and pathologic conditions of multiple tissues and organs. In the study of parenchymal lung disease, single-cell RNA-sequencing has better delineated known cell populations and identified novel cells and changes in cellular phenotypes and gene expression patterns associated with disease. In this review, we aim to highlight the advances and insights that have been made possible by applying these technologies to two seemingly very different lung diseases: fibrotic interstitial lung diseases, a group of relentlessly progressive lung diseases leading to pulmonary fibrosis, and COVID-19 pneumonia, an acute viral disease with life-threatening complications, including pulmonary fibrosis. We discuss changes in cell populations and gene expression, highlighting potential common features, such as alveolar cell epithelial injury and aberrant repair and monocyte-derived macrophage populations, as well as relevance and implications to mechanisms of disease and future directions.

The Association of Prior Fragility Fractures on 8-Year Periprosthetic Fracture Risk Following Total Hip Arthroplasty.

BACKGROUND: Fragility fractures are often the initial clinical presentation of osteoporosis. Patients who have a history of fragility fractures undergoing total hip arthroplasty (THA) have an increased risk of 2-year postoperative complications. However, the association of recent fragility fractures with complications beyond 2 years following THA remains unknown. The purpose of this study was to characterize the association of prior fragility fractures with 8-year risks of revision THA, periprosthetic fracture (PPF), and secondary fragility fracture. METHODS: Patients aged 50 years and more who underwent THA for osteoarthritis were identified in a large national database. Patients were stratified based on whether they sustained a fragility fracture within 3 years prior to THA. There were 18,529 patients who had a prior fragility fracture and 408,753 who did not have a prior fragility fracture. Demographics and comorbidities were collected. Kaplan-Meier and Cox Proportional Hazards analyses were used to observe the cumulative incidences of all-cause revision, PPF, and secondary fragility fracture within 8 years of index surgery. RESULTS: Patients who had recent fragility fracture had significantly higher risks of revision THA (Hazard Ratio [HR] 1.7; P < .001), PPF (HR 2.2; P < .001), and secondary fragility fracture (HR 4.9; P < .001). CONCLUSION: Prior fragility fracture was shown to be a significant risk factor for revision THA, PPF, and secondary fragility fracture within 8 years of THA. Identification of these high-risk patients with an emphasis on preoperative and postoperative bone health optimization may help minimize these complications.

Surgical strategies for older patients with glioblastoma.

OBJECTIVE: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. METHODS: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. RESULTS: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks. CONCLUSIONS: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

Bee pathogen transmission dynamics: deposition, persistence and acquisition on flowers.

Infectious diseases are a primary driver of bee decline worldwide, but limited understanding of how pathogens are transmitted hampers effective management. Flowers have been implicated as hubs of bee disease transmission, but we know little about how interspecific floral variation affects transmission dynamics. Using bumblebees ( Bombus impatiens), a trypanosomatid pathogen ( Crithidia bombi) and three plant species varying in floral morphology, we assessed how host infection and plant species affect pathogen deposition on flowers, and plant species and flower parts impact pathogen survival and acquisition at flowers. We found that host infection with Crithidia increased defaecation rates on flowers, and that bees deposited faeces onto bracts of Lobelia siphilitica and Lythrum salicaria more frequently than onto Monarda didyma bracts . Among flower parts, bracts were associated with the lowest pathogen survival but highest resulting infection intensity in bee hosts. Additionally, we found that Crithidia survival across flower parts was reduced with sun exposure. These results suggest that efficiency of pathogen transmission depends on where deposition occurs and the timing and place of acquisition, which varies among plant species and environmental conditions. This information could be used for development of wildflower mixes that maximize forage while minimizing disease spread.

Diabetes Mellitus and Total Ankle Arthroplasty Complications.

BACKGROUND: Postoperative infection, aseptic loosening, and perioperative medical complications after total ankle arthroplasty (TAA) are all devastating problems. While previous studies have shown diabetes as a risk factor predisposing patients to postoperative complications, not all literature supports this association following TAA. The goal of this study is to determine if diabetes influences midterm outcomes following TAA. METHODS: An insurance database was utilized to identify patients undergoing TAA for ankle arthritis with a concurrent diagnosis of diabetes based on Current Procedural Terminology (CPT) and International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10), diagnosis and procedure codes from 2010 to 2021. The postoperative outcomes of all-cause revision, periprosthetic joint infection (PJI), septic revision, and aseptic revision were compared between patients with and without diabetes with a minimum 2-year follow-up using Kaplan-Meier and multivariate Cox proportional hazards analyses. Patient demographics, comorbidities, and Charlson Comorbidity Index were analyzed via univariate and multivariate analysis. RESULTS: The study population included 8317 patients, 345 (4.1%) of whom had a concurrent diabetes diagnosis, who underwent TAA. After multivariate Cox proportional hazards analysis, the 5-year cumulative incidence of being coded as having PJI was 7.3% in patients with known diabetes compared to 3.9% in patients without known diabetes, with a 95% increased risk (hazard ratio [HR] 1.95, 95% CI 1.15-3.30, P = .01). Patients with diabetes also demonstrated a 5-year cumulative incidence of septic revision of 1.4% compared to 0.4% in those without, with a 363% increased risk (HR 4.63, 95% CI 1.22-17.52, P = .02). However, there was no difference in the 5-year cumulative incidence of all-cause revision TAA with 4.6% in patients with diabetes and 4.3% in those without (HR 1.29, 95% CI 0.69-2.44, P = .42). CONCLUSION: In this database, the 5-year risk of PJI and septic revision was higher among patients with diabetes compared to those without, but cumulative incidence of all-cause revision TAA was not different between groups. LEVEL OF EVIDENCE: Level III, retrospective cohort database study.

The cumulative incidence and risk factors associated with 5-year conversion to knee arthroplasty following primary meniscus repair or primary meniscectomy.

Background: This study aimed to observe the 5-year knee arthroplasty conversion incidence rate and associated risk factors in patients who underwent meniscus procedures. Methods: Using a national database, we analyzed patients who had undergone primary meniscus repair or meniscectomy without prior knee surgeries. The cumulative knee arthroplasty conversion incidence was determined via Kaplan Meier analysis. Risk factors for conversion within 5 years were assessed using a Cox proportional hazard ratio model, with results as hazard ratios (HR). Results: 8125 patients had meniscus repair, while 240,209 had meniscectomy. 5-year conversion rates: repair 1.7%, meniscectomy 8.4%. Arthroplasty likelihood decreased as age decreased for repair (70+ [HR: 162.20]; 60-69 [HR: 81.64]; 50-59 [HR: 49.85]; 40-49 [HR: 17.79]; p < 0.001 all). Additional risk factors included male sex (HR: 0.35; p < 0.001) and higher Charlson Comorbidity Index (CCI) (CCI1 [HR: 1.28; p = 0.012]). For meniscectomy, arthroplasty likelihood also decreased with age (70+ [HR: 99.41]; 60-69 [HR: 84.57]; 50-59 [HR: 66.60]; 40-49 [HR: 36.15]; 30-39 [HR: 10.18]; p < 0.001 all). Additional risk factors included male sex (HR: 0.68; p < 0.001), obesity (HR: 1.18; p < 0.001), smoking (HR: 0.1.12; p = 0.010), and higher CCI (CCI1 [HR: 1.25]; CCI2 [HR 1.39]; CCI3+ [HR 1.46]; p < 0.001 all). Conclusion: This study revealed the national 5-year conversion incidence following primary meniscus repair (1.7%) and meniscectomy (8.4%). It also enhanced understanding of age, sex, obesity, smoking, comorbidities (CCI), and knee arthroplasty likelihood after meniscus procedures.

AIDS but not asymptomatic HIV is associated with lower 2-10-year implant survivorship following total knee arthroplasty.

INTRODUCTION: Prior studies have demonstrated HIV does not increase the risk of 2-year complications following TKA; however, the literature is sparse regarding the impact of HIV and AIDS on long-term implant survivorship. The purpose of this study was to compare the 10-year cumulative incidence and risk of revision TKA in patients with and without asymptomatic HIV, and with and without AIDS. METHODS: Patients with HIV who underwent elective TKA were identified using a national database and divided into subgroups of asymptomatic HIV (AHIV) and acquired immunodeficiency syndrome (AIDS). These patients with HIV were propensity matched based on age, sex, and Charlson Comorbidity Index (CCI) to a control group of elective TKA patients without HIV in a 1:2 ratio. Patients were also compared to an unmatched control group. RESULTS: The 10-year risk for all-cause revision TKA was higher in the HIV group compared to unmatched controls (HR 1.40, 95% CI 1.02-1.93, p = 0.038) but not matched controls (HR 1.13, 95% CI 0.77-1.63, p = 0.594). When compared to both control groups (unmatched; matched), the AIDS group had a higher risk of 10-year all-cause revision (HR 2.74, 95% CI 1.51-4.99, p < 0.001; HR 2.19, 95% CI 1.17-4.11, p = 0.014), dislocation/instability (HR 4.89, 95% CI 1.54-15.51, p = 0.007; HR 3.86, 95% CI 1.12-13.34, p = 0.033), and periprosthetic fracture [PPF] (HR 0.67, 95% CI 0.16-2.74, p = 0.002; HR 3.82, 95% CI 1.08-13.45, p = 0.037). However, patients with AIDS were not at increased risk of PJI or mechanical loosening compared to unmatched controls or matched controls. DISCUSSION: This study expands on current literature by following a nationwide cohort of HIV/AIDS patients for 10 years after TKA. Although a diagnosis of asymptomatic HIV was not associated with increased risk of 10-year revision rates following TKA, a diagnosis of AIDS was. Surgeons should ensure patients' serum CD4 level is sufficient, ideally in the normal range of 500-1500 cells per mm3, before undergoing TKA.

Prior Fragility Fractures are Associated With Higher Risk of Bone Health-Related Complications Within 8-Years Following Lumbar Fusion.

STUDY DESIGN: Retrospective study. OBJECTIVE: To determine the 8-year risk of revision lumbar fusion, pseudoarthrosis, mechanical failure, fragility fracture, and vertebral compression fracture in patients with a prior fragility fracture compared to those without. SUMMARY OF BACKGROUND DATA: Osteoporosis is a known modifiable risk factor for revision following lumbar fusion due to inadequate fixation. Patients with prior fragility fractures have been shown to have increased bone health-related complications following various orthopedic surgeries, however there is a paucity of literature that identifies these complications in patients undergoing lumbar fusion. METHODS: Patients aged 50 years and older who underwent elective lumbar fusion were identified in a large national database and stratified based on whether they sustained a fragility fracture within 3 years prior to fusion. These patients were propensity-score matched to a control based on age, gender, and Charlson Comorbidity Index (CCI) using a 1:1 ratio. Kaplan-Meier and Cox Proportional Hazards analyses were used to observe the cumulative incidences and risk of complications within 8-years of index surgery. RESULTS: After matching, 8,805 patients were included in both cohorts. Patients who sustained a prior fragility fracture had a higher risk of revision (Hazard Ratio [HR]: 1.46; 95% Confidence Interval [CI]: 1.26-1.69; P<0.001), pseudoarthrosis (HR: 1.31; 95% CI: 1.17-1.48; P<0.001), mechanical failure (HR: 2.08; 95% CI: 1.78-2.45; P<0.001), secondary fragility fracture (HR: 6.36; 95% CI: 5.86-6.90; P<0.001), and vertebral compression fracture (HR: 7.47; 95% CI: 7.68-8.21; P<0.001) when compared to the control cohort. CONCLUSION: Patients who sustain a fragility fracture prior to lumbar fusion have an increased risk of revision, pseudoarthrosis, and mechanical failure within 8 years. Surgeons should be aware of this high-risk patient population and consider bone health screening and treatment to reduce these preventable complications.

Associations Between Neighborhood Opportunity and Indicators of Physical Fitness for New York City Public School Youth.

Background: Fewer than 1/4th of US children and adolescents meet physical activity (PA) guidelines, leading to health disparities that track into adulthood. Neighborhood opportunity may serve as a critical modifiable factor to improve fitness attainment and reduce these disparities. We drew data from the Child Opportunity Index to examine associations between neighborhood indicators of opportunity for PA and multiple fitness indicators among New York City public school youth. Methods: Multilevel generalized linear mixed models were used to estimate the overall and sex-stratified associations between neighborhood indicators (green space, healthy food, walkability, commute time) and indicators for physical fitness [curl-ups, push-ups, Progressive Aerobic Cardiovascular Endurance Run (PACER), sit-and-reach] using the New York City FITNESSGRAM data set. Results: The analytic sample [n = 299,839; median (interquartile range) age = 16 (12-17)] was 50.1% female, 37.5% Hispanic, 26.2% non-Hispanic Black, and most (69.5%) qualified for free/reduced price school meals. Neighborhood indicators were positively associated with higher values of indicators for physical fitness. The strongest associations were observed between walkability and both BMI and PACER, and commute time with BMI, push-ups, and PACER. For example, walkability had the greatest magnitude of effects for BMI and muscular strength and endurance (BMI: ß: -0.75, 95% confidence interval, CI: -1.01 to -0.49; PACER: ß: 1.98, 95% CI: 1.59 to 2.37), and particularly for girls compared with boys (BMI, girls: ß: -0.91, 95% CI: -1.22 to -0.66); BMI, boys: ß: -0.56, 95% CI: -0.86 to -0.25); PACER, girls: ß: 2.11, 95% CI: 1.68 to 2.54; push-ups, boys: ß: 1.71, 95% CI: 1.31 to 2.12). Conclusion: Neighborhood indicators were associated with multiple measures of youth fitness. Continued research on neighborhood opportunity and youth fitness may better inform place-based public health interventions to reduce disparities.

Single-cell profiling reveals immune aberrations in progressive idiopathic pulmonary fibrosis.

Rationale: Changes in peripheral blood cell populations have been observed but not detailed at single-cell resolution in idiopathic pulmonary fibrosis (IPF). Objectives: To provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. Methods: Peripheral blood mononuclear cells (PBMCs) from IPF patients and controls were profiled using 10x Chromium 5' single-cell RNA sequencing (scRNA-seq). Flow cytometry was used for validation. Protein concentrations of Regulatory T-cells (Tregs) and Monocytes chemoattractants were measured in plasma and lung homogenates from patients and controls. Measurements and Main Results: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched controls yielded 149,564 cells that segregated into 23 subpopulations, corresponding to all expected peripheral blood cell populations. Classical monocytes were increased in progressive and stable IPF compared to controls (32.1%, 25.2%, 17.9%, respectively, p<0.05). Total lymphocytes were decreased in IPF vs controls, and in progressive vs stable IPF (52.6% vs 62.6%, p=0.035). Tregs were increased in progressive IPF (1.8% vs 1.1%, p=0.007), and were associated with decreased survival (P=0.009 in Kaplan-Meier analysis). Flow cytometry analysis confirmed this finding in an independent cohort of IPF patients. Tregs were also increased in two cohorts of lung scRNA-seq. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF. Conclusions: The single-cell atlas of the peripheral immune system in IPF, reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

Peripheral Blood Single-Cell Sequencing Uncovers Common and Specific Immune Aberrations in Fibrotic Lung Diseases.

Rationale and Objectives: The extent and commonality of peripheral blood immune aberrations in fibrotic interstitial lung diseases are not well characterized. In this study, we aimed to identify common and distinct immune aberrations in patients with idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (FHP) using cutting-edge single-cell profiling technologies. Methods: Single-cell RNA sequencing was performed on patients and healthy controls' peripheral blood and bronchoalveolar lavage samples using 10X Genomics 5' gene expression and V(D)J profiling. Cell type composition, transcriptional profiles, cellular trajectories and signaling, and T and B cell receptor repertoires were studied. The standard Seurat R pipeline was followed for cell type composition and differential gene expression analyses. Transcription factor activity was imputed using the DoRothEA-VIPER algorithm. Pseudotime analyses were conducted using Monocle3, while RNA velocity analyses were performed with Velocyto, scVelo, and CellRank. Cell-cell connectomics were assessed using the Connectome R package. V(D)J analyses were conducted using CellRanger and Immcantation frameworks. Across all analyses, disease group differences were assessed using the Wilcoxon rank-sum test. Measurements and Main Results: 327,990 cells from 83 samples were profiled. Overall, changes in monocytes were common to IPF and FHP, whereas lymphocytes exhibited disease-specific aberrations. Both diseases displayed enrichment of CCL3 hi /CCL4 hi CD14+ monocytes (p<2.2e-16) and S100A hi CD14+ monocytes (p<2.2e-16) versus controls. Trajectory and RNA velocity analysis suggested that pro-fibrotic macrophages observed in BAL originated from peripheral blood monocytes. Lymphocytes exhibited disease-specific aberrations, with CD8+ GZMK hi T cells and activated B cells primarily enriched in FHP patients. V(D)J analyses revealed unique T and B cell receptor complementarity-determining region 3 (CDR3) amino acid compositions (p<0.05) in FHP and significant IgA enrichment in IPF (p<5.2e-7). Conclusions: We identified common and disease-specific immune mechanisms in IPF and FHP; S100A hi monocytes and SPP1 hi macrophages are common to IPF and FHP, whereas GMZK hi T lymphocytes and T and B cell receptor repertoires were unique in FHP. Our findings open novel strategies for the diagnosis and treatment of IPF and FHP.

Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19.

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100Ahi/HLA-DRlo classical monocytes and activated LAG-3hi T cells are hallmarks of progressive disease and highlights the abnormal MHC-II/LAG-3 interaction on myeloid and T cells, respectively. We also find skewed T cell receptor repertories in expanded effector CD8+ clones, unmutated IGHG+ B cell clones, and mutated B cell clones with stable somatic hypermutation frequency over time. In conclusion, our in-depth immune profiling reveals dyssynchrony of the innate and adaptive immune interaction in progressive COVID-19.