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: 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).

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.

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 is 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 (CI) rates and hazard ratios (HR) were compared between the SOT, matched, and unmatched cohorts. RESULTS: No difference was observed in 10-year CI 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 (PJI) 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). CONCLUSION: Prior SOT patients have higher rates of all-cause revision within 90 days and PJI 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.

AIDS but not asymptomatic HIV is associated with higher 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.

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.

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.

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.

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.

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.

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 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.

Increased Coronary Contraction to Thromboxane A2 in Cardiac Surgery Patients With Poorly Controlled Hypertension.

INTRODUCTION: Cardioplegia and cardiopulmonary bypass (CP/CPB) alters coronary arteriolar response to thromboxane A2 (TXA2) in patients undergoing cardiac surgery. Comorbidities, including hypertension (HTN), can further alter coronary vasomotor tone. This study investigates the effects of HTN on coronary arteriolar response to TXA2 pre and post-CP/CPB and cardiac surgery. MATERIALS AND METHODS: Coronary arterioles pre and post-CP/CPB were dissected from atrial tissue samples in patients with no HTN (NH, n = 9), well-controlled HTN (WC, n = 12), or uncontrolled HTN (UC, n = 12). In-vitro coronary microvascular reactivity was examined in the presence of TXA2 analog U46619 (10-9-10-4M). Protein expression of TXA2 receptor in the harvested right atrial tissue samples were measured by immunoblotting. RESULTS: TXA2 analog U46619 induced dose-dependent contractile responses of coronary arterioles in all groups. Pre-CPB contractile responses to U46619 were significantly increased in microvessels in the UC group compared to the NH group (P < 0.05). The pre-CP/CPB contractile responses of coronary arterioles were significantly diminished post-CP/CPB among the three groups (P < 0.05), but there remained an increased contractile response in the microvessels of the UC group compared to the WC and NH groups (P < 0.05). There were no significant differences in U46619-induced vasomotor tone between patients in the NH and WC groups (P > 0.05). There were no differences in expression of TXA2R among groups. CONCLUSIONS: Poorly controlled HTN is associated with increased contractile response of coronary arterioles to TXA2. This alteration may contribute to worsened recovery of coronary microvascular function in patients with poorly controlled HTN after CP/CPB and cardiac surgery.

Outpatient Versus Inpatient Total Shoulder Arthroplasty: A Matched Cohort Analysis of Postoperative Complications, Surgical Outcomes, and Reimbursements.

INTRODUCTION: There has been a trend toward performing arthroplasty in the ambulatory setting. The primary purpose of this study was to compare outpatient and inpatient total shoulder arthroplasties (TSAs) for postoperative medical complications, healthcare utilization outcomes, and surgical outcomes. METHODS: Patients who underwent outpatient TSA or inpatient TSA with a minimum 5-year follow-up were identified in the PearlDiver database. These cohorts were propensity-matched based on age, sex, Charlson Comorbidity Index, smoking status, and obesity (body mass index > 30). All outcomes were analyzed using chi square and Student t-tests where appropriate. RESULTS: Outpatient TSA patients had markedly lower rates of various 90-day medical complications. Outpatient TSA patients had lower risk of aseptic loosening at 2 years postoperation and lower risk of periprosthetic joint infection at 5 years postoperation relative to inpatient TSA patients. Outpatient TSA reimbursements were markedly lower than inpatient TSA reimbursements at the 30-day, 90-day, and 1-year postoperative intervals. CONCLUSION: This study found patients undergoing outpatient TSA to be at lowers odds for both postoperative medical and surgical complications compared with those undergoing inpatient TSA. Despite increased risk of postoperative healthcare utilization for readmissions and emergency department visits, outpatient TSA was markedly less expensive at every postoperative time point assessed.

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.

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.

Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is expressed in classical monocytes and alveolar macrophages in Idiopathic Pulmonary Fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFß dependent manner.

Background: Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is higher in Idiopathic Pulmonary Fibrosis (IPF) patients with increased risk of death and poor outcomes. Here we seek to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. Methods: MCEMP1 expression was analyzed by single-cell RNA sequencing, immunofluorescence in Peripheral Blood Mononuclear Cells (PBMC) as well as in lung tissues from IPF patients and controls. Chromatin Immunoprecipitation (ChiP) and Proximity Ligation Assay (PLA) were used to study the transcriptional regulation of MCEMP1 . Transient RNA interference and lentivirus transduction were used to knockdown and knock-in MCEMP1 in THP-1 cells to study chemotaxis, adhesion, and migration. Bulk RNA sequencing was used to identify the mechanisms by which MCEMP1 participates in monocyte function. Active RHO pull-down assay was used to validate bulk RNA sequencing results. Results: We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared to controls. MCEMP1 was upregulated by TGFß at the mRNA and protein levels in THP-1. 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. In terms of its function, we found that MCEMP1 regulates TGFß-mediated monocyte chemotaxis, adhesion, and migration. 400 differentially expressed genes were found to increase after TGFß stimulation of THP-1, further increased in MCEMP1 knock-in cells treated with TGFß and decreased in MCEMP1 knockdown cells treated with TGFß. GO annotation analysis of these genes showed enrichment for positive regulation of RHO GTPase activity and signal transduction. While TGFß enhanced RHO GTPase activity in THP-1 cells, this effect was attenuated following MCEMP1 knockdown. Conclusion: MCEMP1 is highly expressed in circulating classical monocytes and alveolar macrophages in IPF. MCEMP1 is regulated by TGFß and participates in the chemotaxis, adhesion, and migration of circulating monocytes by modulating the effect of TGFß in RHO activity. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression.

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.