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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 with 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. Patients and 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 three years prior to fusion. These patients were propensity-score matched to a control based on age, gender, and Charlson the comorbidity index using a 1:1 ratio. Kaplan-Meier and Cox proportional hazards analyses were used to observe the cumulative incidences and risk of complications within eight years of index surgery. Results. After matching, 8805 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% 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 with 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 eight years. Surgeons should be aware of this high-risk patient population and consider bone health screening and treatment to reduce these preventable complications. [ABSTRACT FROM AUTHOR]

Background. Fixed, large volume resuscitation with intravenous fluids (IVFs) in septic shock can cause inadvertent hypervolemia, increased medical interventions, and death when unguided by point-of-care ultrasound (POCUS). The primary study objective was to evaluate whether total IVF volume differs for emergency department (ED) septic shock patients receiving POCUS versus no POCUS. Methods. We conducted a retrospective observational cohort study from 7/1/2018 to 8/31/2021 of atraumatic adult ED patients with septic shock. We agreed upon a priori variables and defined septic shock as lactate ≥4 and hypotension (SBP <90 or MAP <65). A sample size of 300 patients would provide 85% power to detect an IVF difference of 500 milliliters between POCUS and non-POCUS cohorts. Data are reported as frequencies, median (IQR), and associations from bivariate logistic models. Results. 304 patients met criteria and 26% (78/304) underwent POCUS. Cardiac POCUS demonstrated reduced ejection fraction in 15.4% of patients. Lung ultrasound showed normal findings in 53% of patients. The POCUS vs. non-POCUS cohorts had statistically significant differences for the following variables: higher median lactate (6.7 [IQR 5.2–8.7] vs. 5.6], p = 0.003), lower systolic blood pressure (77.5 [IQR 61–86] vs. 85.0, p < 0.001), more vasopressor use (51% vs. 34%, p = 0.006), and more positive pressure ventilation (38% vs. 24%, p = 0.017). However, there were no statistically significant differences between POCUS and non-POCUS cohorts in total IVF volume ml/kg (33.02 vs. 32.1, p = 0.47), new oxygen requirement (68% vs. 59%, p = 0.16), ED death (3% vs. 4%, p = 0.15), or hospital death (31% vs. 27%, p = 0.48). There were similar distributions of lactate, total fluids, and vasopressors in patients with CHF and severe renal failure. Conclusions. Among ED patients with septic shock, POCUS was more likely to be used in sicker patients. Patients who had POCUS were given similar volume of crystalloids although these patients were more critically ill. There were no differences in new oxygen requirement or mortality in the POCUS group compared to the non-POCUS group. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Research Question/Issue: This study examines firms' reactions to the duration of underperformance. We posit that firms are more likely to engage in misconduct to solve the problem of underperformance as the length of time a firm has been underperforming prolongs. Further, we investigate how divergent external governance actors shape underperforming firms' motivation for misconduct and consequently affect their responses to underperformance duration. Research Findings/Insights: Using bivariate probit estimations for panel data of 2662 Chinese publicly listed firms during 2007–2018, we uncover that underperformance duration is positively associated with the likelihood of a corporate misconduct commission. In addition, the positive relationship between the duration of firm underperformance and corporate misconduct is mitigated by the level of state ownership but reinforced by the number of analysts covering the firm. Theoretical/Academic Implications: This study extends the behavioral theory of the firm by incorporating the construct of underperformance duration from a time perspective, which is a proactive signal of firms' illicit decisions. We show that the duration of underperformance is positively associated with the likelihood of corporate misconduct, which is moderated by the firms' external governance actors who have different time pressures to solve financial problems. Practitioner/Policy Implications: This study offers insights for regulators interested in the prevention of ex‐ant misconduct. Identifying underperformance duration as a critical predictor of illegal activities helps to improve regulators' vigilance. Moreover, a holistic executive evaluation system that shows more tolerance for short‐term underperformance is needed. [ABSTRACT FROM AUTHOR]

Objectives: This Phase 1 trial was planned to investigate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of a single dose of riliprubart in healthy East-Asian adult participants., Methods: A single-center, parallel-group, randomized, open-label, single-dose study was performed to evaluate the PK, PD, safety, and tolerability of riliprubart (50 mg/kg intravenous [IV] or 600 mg subcutaneous [SC]) in 37 healthy East-Asian (Chinese, Japanese, and Korean) participants., Results: Riliprubart was slowly absorbed after SC administration (median t max : 7.01-10.48 days) and showed a long half-life after IV or SC administration (mean: 9.52-11.0 weeks), with a bioavailability of 74.6% after SC administration. The PD profiles, which are evaluated by classical complement pathway activity or CH50, were similar and largely overlapped across East-Asian participants after a single IV or SC dose. Riliprubart was safe and well tolerated in participants following a single IV or SC dose., Conclusions: Riliprubart was safe and well tolerated and demonstrated favorable PK and PD profiles in healthy East-Asian participants following a single IV or SC dose. These results are comparable to first-in-human study results from non-East-Asian participants and support the same dosing regimen of riliprubart for global simultaneous clinical development., Clinical Trial Registration: This trial is registered at https://cris.nih.go.kr (identifier: KCT0006571).

Rationale: The association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown., Objectives: To determine immune-cell-specific transcriptomic profiles associated with IPF mortality., Methods: We profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 immune-cell-specific transcriptomic profiles. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was used to calculate Up-scores based on these 16 gene profiles. Their association with outcomes was investigated in peripheral blood, Bronchoalveolar Lavage (BAL) and lung tissue of N=416 IPF patients from six cohorts. Findings were validated in an independent IPF, PBMC scRNA-seq dataset (N=38)., Measurements and Main Results: Cox-regression models demonstrated that 230 genes from CD14 + CD163 - HLA-DR low circulating monocytes predicted IPF mortality [Pittsburgh (p=0.02), Chicago (p=0.003)]. PBMC proportions of CD14 + CD163 - HLA-DR low monocytes were higher in progressive versus stable IPF (Yale, 0.13±0.05 versus 0.09±0.05, p=0.034). Receiving operating characteristic identified a 230 gene, Up-score >41.84 (Pittsburgh) predictive of mortality in Chicago (HR: 6.58, 95%CI: 2.15-20.13, p=0.001) and in pooled analysis of BAL cohorts (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003). High-risk patients had decreased expression of the T-cell co-stimulatory genes CD28 , ICOS , ITK and LCK (Pittsburgh and Chicago, p<0.01). 230 gene-up-scores negatively correlated with Forced Vital Capacity (FVC) in IPF lung tissues (LGRC, rho=-0.2, p=0.02). Results were replicated using a subset of 13 genes from the 230-gene signature (pooled PBMC cohorts - HR: 5.34, 95%CI: 2.83-10.06, p<0.0001)., Conclusions: The transcriptome of CD14 + CD163 - HLA-DR low monocytes is associated with increased IPF mortality.

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 CCL3 hi /CCL4 hi and S100A hi classical monocytes (adjusted-p<2.2e-16). Trajectory analyses demonstrate that S100A hi classical monocytes differentiate into SPP1 hi lung macrophages associated with fibrosis. Compared to both controls and idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis patient cells are significantly enriched in GZM hi cytotoxic T cells. These cells exhibit transcription factor activities indicative of TGFβ 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 GZM hi cytotoxic CD4+ and CD8+ T cells - reflecting this disease's unique inflammatory T-cell driven nature - as well as increased S100A hi and CCL3 hi /CCL4 hi classical monocytes also observed in idiopathic pulmonary fibrosis. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

Introduction: As the opioid epidemic enters its third decade, we reflect on how it has affected clinical practice within the orthopaedic community. Recent studies show prolonged opioid use after total knee arthroplasty (TKA) is associated with worse overall health outcomes. This study aims to elucidate trends in pain management after TKA over the past decade., Methods: A retrospective analysis was performed using the PearlDiver database from 2010 to 2019. Patients who underwent primary TKA without a history of mental illness, complex pain syndromes, or opioids used 6 months before surgery were selected. Postoperative prescription filling rates of opioid and nonopioid at 30, 90 days, and 1 year from surgery were analyzed. Linear regression analysis and compound annual growth rates (CAGRs) were analyzed from 2010 to 2019, a P value <0.05 being considered significant., Results: Between 2010 and 2019, 579,269 patients underwent primary TKA. At 30 days, filling of prescriptions for opioids (CAGR = 3.54%) and nonopioids (CAGR = 15.50%) markedly increased from 2010 to 2019. At 90 days, opioids decreased (CAGR = -4.42%). At 1 year, opioid (CAGR = -10.92%) and nonopioid (CAGR = -2.12%) prescriptions markedly decreased from 2010 to 2019., Discussion: This study highlights patterns of decreased opioid prescription rates at 90 days and 1 year postoperatively from 2010 to 2019. Decreasing opioid rates may indicate effectiveness in targeted public health campaigns to curb opioid overuse., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Mast-cell expressed membrane protein-1 (MCEMP1) is higher in patients with idiopathic pulmonary fibrosis (IPF) with an increased risk of death. Here we aimed to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared with controls. MCEMP1 is upregulated by transforming growth factor beta (TGFβ) at the mRNA and protein levels in monocytic leukemia THP-1 cells. TGFβ-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1 cis- regulatory elements within the MCEMP1 promoter. We also found that MCEMP1 regulates TGFβ-mediated monocyte chemotaxis, adhesion, and migration. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression. NEW & NOTEWORTHY MCEMP1 is highly expressed in circulating classical monocytes and alveolar macrophages in IPF, is regulated by TGFβ, and participates in the chemotaxis, adhesion, and migration of circulating monocytes by modulating the effect of TGFβ in RHO activity.