Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose riliprubart, an anti-C1s humanized monoclonal antibody in East-Asian adults: results from a Phase 1, randomized, open-label trial.

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 tmax: 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).

The transcriptome of CD14 + CD163 - HLA-DR low monocytes predicts mortality in Idiopathic Pulmonary Fibrosis.

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.

Human Male Body Size Predicts Increased Knockout Power, Which Is Accurately Tracked by Conspecific Judgments of Male Dominance.

Humans have undergone a long evolutionary history of violent agonistic exchanges, which would have placed selective pressures on greater body size and the psychophysical systems that detect them. The present work showed that greater body size in humans predicted increased knockout power during combative contests (Study 1a-1b: total N = 5,866; Study 2: N = 44 openweight fights). In agonistic exchanges reflective of ancestral size asymmetries, heavier combatants were 200% more likely to win against their lighter counterparts because they were 200% more likely to knock them out (Study 2). Human dominance judgments (total N = 500 MTurkers) accurately tracked the frequency with which men (N = 516) knocked out similar-sized adversaries (Study 3). Humans were able to directly perceive a man's knockout power because they were attending to cues of a man's body size. Human dominance judgments-which are important across numerous psychological domains, including attractiveness, leadership, and legal decision-making-accurately predict the likelihood with which a potential mate, ally, or rival can incapacitate their adversaries.

Trends From 2010 to 2019 in Opioid and Nonopioid Pain Management After Total Knee Arthroplasty.

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.

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.

Does Point-of-Care Ultrasound Affect Fluid Resuscitation Volume in Patients with Septic Shock: A Retrospective Review.

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.

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: We sought to provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with IPF and control subjects were profiled using 10× chromium 5' single-cell RNA sequencing. Flow cytometry was used for validation. Protein concentrations of regulatory T cells (Tregs) and monocyte chemoattractants were measured in plasma and lung homogenates from patients with IPF and control subjects. Measurements and Main Results: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched control subjects yielded 149,564 cells that segregated into 23 subpopulations. Classical monocytes were increased in patients with progressive and stable IPF compared with control subjects (32.1%, 25.2%, and 17.9%, respectively; P < 0.05). Total lymphocytes were decreased in patients with IPF versus control subjects and in progressive versus stable IPF (52.6% vs. 62.6%, P = 0.035). Tregs were increased in progressive versus stable IPF (1.8% vs. 1.1% of all PBMCs, P = 0.007), although not different than controls, and may be associated with decreased survival (P = 0.009 in Kaplan-Meier analysis; and P = 0.069 after adjusting for age, sex, and baseline FVC). Flow cytometry analysis confirmed this finding in an independent cohort of patients with IPF. The fraction of Tregs out of all T cells was also increased in two cohorts of lung single-cell RNA sequencing. 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).

Patients Who Have Prior Solid Organ Transplants Have Increased Risk of 10-Year Periprosthetic Joint Infection Revision Following Primary Total Knee Arthroplasty: A Propensity-Matched Analysis.

BACKGROUND: Total knee arthroplasty (TKA) for solid organ transplant (SOT) patients is becoming more prominent as life expectancy in this population increases. However, data on long-term (10 year) implant survivorship in this cohort are sparse. The purpose of this study was to compare 90-day, 2-year, 5-year, and 10-year implant survivability following primary TKA in patients who did and did not have prior SOT. METHODS: The PearlDiver database was utilized to query patients who underwent unilateral elective TKA with at least 2 years of active follow-up. These patients were stratified into those who had a SOT before TKA and those who did not. The SOT cohort was propensity-matched to control patients based on age, sex, Charlson Comorbidity Index, and obesity in a 1:2 ratio. Cumulative incidence rates and hazard ratios (HRs) were compared between the SOT, matched, and unmatched cohorts. RESULTS: No difference was observed in 10-year cumulative incidence and risk of all-cause revision surgery in TKA patients with prior SOT when compared to matched and unmatched controls. Compared to the matched control, the SOT cohort had no difference in the risk of revision when stratified by indication and timing. However, when compared to the unmatched control, patients who had prior SOT had a higher risk for revision due to periprosthetic joint infection at 10 years (HR: 1.80; 95% confidence interval: 1.17 to 2.76) as well as all-cause revision within 90 days after TKA (HR: 1.93; 95% confidence interval: 1.10 to 3.36). CONCLUSIONS: Prior SOT patients have higher rates of all-cause revision within 90 days and periprosthetic joint infection within 10 years when compared to the general population, likely associated with the elevated number of comorbidities in SOT patients and not the transplant itself. Therefore, these patients should be monitored in the preoperative and early postoperative settings to optimize their known comorbidities.

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.

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.

Damage sensing through TLR9 Promotes Viral Clearance and Recovery During Influenza Infection.

Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA, which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mitochondrial DNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data show that TLR9-mediated sensing of tissue damage promotes an inflammatory response during early infection, driven by the myeloid cells and associated cytokine responses. Along with the diminished inflammatory response, the absence of damage sensing through TLR9 led to impaired viral clearance manifested as a higher and prolonged influenza burden in the lung. The absence of TLR9 led to extensive infection of myeloid cells including monocytes and macrophages rendering them highly inflammatory, despite having a low initial inflammatory response. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we show elevated circulating TLR9 ligands in the plasma samples of patients with influenza, demonstrating its clinical relevance. Overall, over data show an essential role of damage sensing through TLR9 in promoting anti-influenza immunity.

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.

Higher 2-Year Cumulative Incidence of Mental Health Disorders Following Irrigation and Debridement in Primary Lumbar Fusion.

Introduction: Spinal fusion is an operation that is employed to treat spinal diseases. Surgical site infection (SSI) after lumbar fusion (LF) is a postoperative complication. SSI is treated with irrigation and debridement (I&D), which requires readmittance following discharge or prolonged hospital stays, which are deleterious to patients' mental health. The long-term relationship between treating SSI with I&D and patients' mental health is still understudied. Methods: Using the Mariner dataset from the PearlDiver Patient Records Database using Current Procedural Terminology and International Classification of Diseases procedure codes, retrospective cohort analysis was carried out. This study involved 445,480 patients who underwent LF with at least 2-year follow-up and were followed up for 2 years. Of the patients, 2,762 underwent I&D. Using univariate analysis employing Pearson Chi-square and Student t-test, where appropriate (Table 1), patient demographics between cohorts were gathered. 2-year cumulative incidence (CI) between LF and I&D cohorts was calculated using Kaplan-Meier analysis (Fig. 1, 2, 3). Cox proportional hazards were employed to observe significant differences in CI rates (Table 2). Results: For patients who received I&D, 2-year CI depression (HR: 1.72; 95% CI: 1.49-1.99; P<0.001) and stress (HR: 1.35; 95% CI: 1.02-1.79; P=0.035) rates were significantly higher than for those who did not. There was no statistically significant difference in 2-year CI anxiety rates between cohorts (HR: 0.92; 95% CI: 0.58-1.46; P=0.719). Conclusions: In conclusion, 16.8% of patients developed new-onset depression 2 years following I&D, in comparison to 10.3% of those who underwent LF. Patients who underwent I&D following LF were significantly more likely to experience depression and stress. To mitigate negative mental health outcomes, mental health services should be available to patients who underwent surgery.

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.

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.

Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFß-dependent manner.

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 (TGFß) at the mRNA and protein levels in monocytic leukemia THP-1 cells. TGFß-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 TGFß-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 TGFß, and participates in the chemotaxis, adhesion, and migration of circulating monocytes by modulating the effect of TGFß in RHO activity.

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.

A highly efficient transgene knock-in technology in clinically relevant cell types.

Inefficient knock-in of transgene cargos limits the potential of cell-based medicines. In this study, we used a CRISPR nuclease that targets a site within an exon of an essential gene and designed a cargo template so that correct knock-in would retain essential gene function while also integrating the transgene(s) of interest. Cells with non-productive insertions and deletions would undergo negative selection. This technology, called SLEEK (SeLection by Essential-gene Exon Knock-in), achieved knock-in efficiencies of more than 90% in clinically relevant cell types without impacting long-term viability or expansion. SLEEK knock-in rates in T cells are more efficient than state-of-the-art TRAC knock-in with AAV6 and surpass more than 90% efficiency even with non-viral DNA cargos. As a clinical application, natural killer cells generated from induced pluripotent stem cells containing SLEEK knock-in of CD16 and mbIL-15 show substantially improved tumor killing and persistence in vivo.

The Definition of Anemia Matters When Using Preoperative Hemoglobin as a Screening Tool Prior to Total Hip and Knee Arthroplasty.

BACKGROUND: Preoperative anemia is common in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA). Several definitions of anemia have been described, with no clear consensus on the optimal one for preoperative screening. We hypothesized that depending on the definition used preoperatively, the proportion of anemic patients identified who would require a postoperative allogeneic blood transfusion would vary significantly. METHODS: A total of 681,141 patients were identified in a national database who underwent either THA or TKA. Preoperative anemia was classified according to the World Health Organization (WHO) definition, Cleveland Clinic (CC) definition, or race, age, and sex-specific definition described by Beutler et al in 2006. The optimal preoperative (OP) hemoglobin thresholds to predict perioperative transfusions were also calculated using receiver operating characteristic curves. RESULTS: When using the WHO definition, 18% of anemic patients required a transfusion versus 14% (OP definition), 12% (CC definition), and 16% (Beutler definition). Similarly, 0.69% of anemic patients sustained a periprosthetic joint infection within 30 days using the WHO definition versus 0.59% (OP definition), 0.60% (CC definition), or 0.66% (Beutler definition). Using the WHO definition, 5.3% of patients would have sustained a major complication versus 4.5% (OP definition), 4.4% (CC definition), and 5.0% (Beutler definition). CONCLUSIONS: Variation in the definition of anemia for preoperative screening in THA and TKA results in substantial differences in discriminative ability to predict perioperative transfusions. The WHO definition identified the largest proportion of patients who ultimately received a perioperative transfusion.