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Background: Extended oral antibiotic (EOA) prophylaxis has been shown to reduce rates of periprosthetic joint infection in high-risk patients following total knee arthroplasty (TKA). Although national societies' recommendations against their use and clinical efficacy remain controversial, the increase in the literature surrounding EOA prophylaxis suggests a potential change in practice patterns that may warrant the creation of national guidelines. The purpose of this study was to investigate the trends in the utilization of EOA prophylaxis following TKA from 2010 to 2022., Methods: Patients who underwent primary or aseptic revision TKA between 2010 and 2022 were identified in a national administrative claims database. Temporal trends in EOA usage following primary or revision TKA were calculated, and secondary analysis examined rates of utilization across demographics, including patients considered at high risk for infection. In total, 1,258,759 primary and 91,530 aseptic revision TKA patients were included in this study., Results: From 2010 to 2022, EOA prescriptions increased by 321 and 368% following primary and revision TKA, respectively. Rates of utilization among high-risk individuals were similar to those of the general population., Conclusions: The use of EOA prophylaxis after TKA has increased significantly since 2010. Given their increasing usage and variation in prescription patterns among patients at high risk of infection, guidelines surrounding their use are necessary to promote antibiotic stewardship while preventing rates of infection., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: Fibrotic hypersensitivity pneumonitis (FHP) is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in FHP in single-cell resolution. Methods: Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and BAL cells obtained from 45 patients with FHP, 63 patients with idiopathic pulmonary fibrosis (IPF), 4 patients with nonfibrotic hypersensitivity pneumonitis, and 36 healthy control subjects in the United States and Mexico. Analyses included differential gene expression (Seurat), TF (transcription factor) activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3 and Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and control subjects and 88,336 BAL cells from 19 patients were profiled. Compared with control samples, FHP has elevated classical monocytes (adjusted- P  = 2.5 × 10 -3 ) and is enriched in CCL3 hi /CCL4 hi and S100A hi classical monocytes (adjusted- P  < 2.2 × 10 -16 ). Trajectory analyses demonstrate that S100A hi classical monocytes differentiate into SPP1 hi lung macrophages associated with fibrosis. Compared with both control subjects and IPF, cells from patients with FHP are significantly enriched in GZM hi cytotoxic T cells. These cells exhibit TF activities indicative of TGFβ and TNFα and NFκB pathways. These results are publicly available at http://ildimmunecellatlas.com. Conclusions: Single-cell transcriptomics of patients with FHP 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 IPF. Both cell populations may guide the development of new biomarkers and therapeutic interventions.

Background: Glucose levels obtained on the day of surgery may be predictive of complications following total knee arthroplasty (TKA). Established glucose thresholds for TKA are either nonspecific or have low predictive power. Therefore, the purpose of this study was to create data-driven hemoglobin A1c (HbA1c) and same-day glucose thresholds associated with varying risks of 90-day major and surgical site infection (SSI) complications following TKA., Methods: Stratum-specific likelihood ratio analysis was conducted to determine data-driven HbA1c and glucose strata associated with varying risks of 90-day major and SSI complications. Each strata was then propensity score matched to the lowest strata based on age, sex, hypertension, heart failure, chronic obstructive pulmonary disorder, and obesity. The risk ratio (RR) for complications in each stratum with respect to the lowest matched stratum was analyzed., Results: Four data-driven HbA1c (%) strata (4.5 to 5.9, 6.0 to 6.4, 6.5 to 7.9, and 8.0+) and two same-day glucose (mg/dL) strata (60 to 189 and 190+) were identified that predicted 90-day major complications. When compared to the propensity-matched lowest strata (4.5 to 5.9%), the risk of 90-day major complications sequentially increased as the HbA1c (%) strata increased: 6.0 to 6.4 (RR: 1.23; P = 0.024), 6.5 to 7.9 (RR: 1.38; P < 0.001), and 8.0+ (RR: 2.0; P < 0.001). When compared to the propensity-matched lowest strata (60 to 189 mg/dL), the 190+ mg/dL strata had a higher risk of 90-day major complications (RR: 1.18; P = 0.016). No HbA1c or same-day glucose strata had significantly different risks of 90-day SSI., Conclusions: The multiple strata identified for HbA1c demonstrate that a single HbA1c cutoff as identified in prior literature may be missing a larger picture for risk stratification. The threshold identified for same-day glucose can be utilized in day-of-surgery glycemic control guidelines to further reduce the risk of 90-day major complications., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Background: As the incidence of femoral neck fractures (FNFs) increases with the aging population, understanding its impact on surgical outcomes is important to improving implant survival and patient satisfaction. Despite increasing use of total hip arthroplasty (THA) as management for FNF, few studies have examined long-term implant survivability. Thus, this study sought to determine the 10-years cumulative incidence of revision and indications for revision in patients undergoing THA for FNF in comparison to osteoarthritis., Methods: Patients who underwent primary THA for FNF or osteoarthritis were identified using a national administrative claims database and propensity-score matched in a 1:2 ratio based on age, gender, the Charlson Comorbidity Index (CCI), smoking, obesity, and diabetes mellitus. Kaplan-Meier and Cox proportional hazards analyses were used to observe the cumulative incidence and risk of all-cause revision, periprosthetic joint infection (PJI), dislocation, mechanical loosening, and periprosthetic fracture (PPF) within 10 years of primary THA. In total, 19,735 patients who underwent THA for FNF and 39,383 patients who underwent THA for osteoarthritis were included., Results: The 10-years cumulative incidences of all-cause revision (7.1 versus 4.9%), PJI (5.0 versus 3.3%), dislocation (6.8 versus 3.8%), mechanical loosening (3.1 versus 1.9%), and PPF (7.8 versus 4.0%) were significantly higher for those who underwent THA for FNF versus osteoarthritis. Femoral neck fractures were associated with higher risks of revision (hazard ratio [HR]: 1.6), PJI (HR: 1.7), dislocation (HR: 2.0), mechanical loosening (HR: 1.6), and PPF (HR: 2.2) (P < 0.001 for all)., Conclusions: Despite the advantages of THA, femoral neck fractures remain a major risk factor for long-term complications. Tailored preoperative planning, surgical techniques, and postoperative bone health optimization in these patients may help minimize poor outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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).

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., Competing Interests: S.C.T.: Committee member for the American Association of Hip and Knee Surgeons, Editorial or governing board of Arthroplasty Today, Journal of Arthroplasty ; Unpaid consultant for KCI, OrthAlign. A.J.: Paid consultant for DePuy, Globus Medical, Stryker. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

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: β : -0.75, 95% confidence interval, CI: -1.01 to -0.49; PACER: β : 1.98, 95% CI: 1.59 to 2.37), and particularly for girls compared with boys (BMI, girls: β : -0.91, 95% CI: -1.22 to -0.66); BMI, boys: β : -0.56, 95% CI: -0.86 to -0.25); PACER, girls: β : 2.11, 95% CI: 1.68 to 2.54; push-ups, boys: β : 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.

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 mm 3 , before undergoing TKA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosure forms for all authors are available online.

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2024 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies have shown that increased 5-item modified frailty index (mFI-5) scores are associated with poor surgical outcomes. This study seeks to determine whether the comorbidities comprising the mFI-5 were correlated with poor outcomes following revision total shoulder arthroplasty (TSA)., Methods: Utilizing the National Surgical Quality Improvement Program database, a mFI-5 score was calculated for all patients 50 years and older who underwent revision TSA between 2013 and 2019. Pearson's Chi-squared tests and multivariable regression analysis were used to evaluate the association of the mFI score with various postoperative complications., Results: Patients with a mFI-5 score of 2+ had significantly increased risk of readmission (OR 2.58), bleeding requiring transfusion (OR 3.66), extended length of stay (OR 2.43), and discharge to a non-home destination (OR 3.22) compared to patients with a mFI-5 score of 0. Relative to patients with a score of 1, those with a mFI-5 score of 2+ had an increased risk of postoperative transfusion (OR 2.46), extended length of stay (OR 2.16), and discharge to a non-home location (OR 2.84)., Discussion: The mFI-5 is a valuable tool that can stratify patients based on risk for postoperative complications following revision TSA., Competing Interests: BTS, TQ, AYZ, and PMP wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC., (© 2024. The Author(s).)

Background: Fabry disease (FD) is a progressive multisystemic disease characterized by a lysosomal enzyme deficiency. A lack of α-galactosidase A (α-Gal A) activity results in the progressive systemic accumulation of its substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), which results in renal, cardiac, and/or cerebrovascular disease and early death. Enzyme replacement therapy (ERT) is the current standard of care for FD; however, it has important limitations, including a low half-life, limited distribution, and requirement of lifelong biweekly infusions of recombinant enzymes., Methods: Herein, we evaluated a gene therapy approach using an episomal adeno-associated viral 2/8 (AAV2/8) vector that encodes the human GLA cDNA driven by a liver-specific expression cassette in a mouse model of FD that lacks α-Gal A activity and progressively accumulates Gb3 and Lyso-Gb3 in plasma and tissues., Results: A pharmacology and toxicology study showed that administration of AAV2/8-hGLA vectors (AAV2/8-hGLA) in FD mice without immunosuppression resulted in significantly increased plasma and tissue α-Gal A activity and substantially normalized Gb3 and Lyso-Gb3 content., Conclusions: Moreover, the plasma enzymatic activity of α-Gal A continued to be stably expressed for up to 38 weeks and sometimes even longer, indicating that AAV2/8-hGLA is effective in treating FD mice, and that α-Gal A is continuously and highly expressed in the liver, secreted into plasma, and absorbed by various tissues. These findings provide a basis for the clinical development of AAV2/8-hGLA., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Video 1Demonstration of manufacturing instructions and features of the postpolypectomy bleeding and conventional and underwater EMR simulators., Competing Interests: Dr Khan has received research grants from AbbVie (2018) and Ferring Pharmaceuticals (2019) and research funding from Pendopharm (2019). Dr Grover has received research grants and personal fees from AbbVie and Ferring Pharmaceuticals, personal fees from Takeda, and education grants from Janssen, and has equity in Volo Healthcare. The other authors did not disclose any financial relationships., (© 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Neighborhood environments can support fitness-promoting behavior, yet little is known about their influence on youth physical fitness outcomes over time. We examined longitudinal associations between neighborhood opportunity and youth physical fitness among New York City (NYC) public school youth. The Child Opportunity Index (COI), a composite index of 29 indicators measuring neighborhood opportunity at the census-tract level, along with scores on 4 selected COI indicators were linked to NYC FITNESSGRAM youth data at baseline. Fitness outcomes (measured annually, 2011-2018) included body mass index, curl-ups, push-ups, and Progressive Aerobic Cardiovascular Endurance Run (PACER) laps. Unstratified and age-stratified, adjusted, 3-level generalized linear mixed models, nested by census tract and time, estimated the association between COI and fitness outcomes. The analytical sample (n = 204,939) lived in very low (41%) or low (30%) opportunity neighborhoods. Unstratified models indicated that overall COI is modestly associated with improved youth physical fitness outcomes. The strongest opportunity-fitness associations were observed for PACER. Stratified models show differences in associations across younger vs. older youth. We find that neighborhood factors are associated with youth fitness outcomes over time, with the strength of the associations dependent on age. Future implications include better informed place-based interventions tailored to specific life stages to promote youth health., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Fragility fractures are often the initial clinical presentation of osteoporosis. Patients who have a history of fragility fractures undergoing total hip arthroplasty (THA) have an increased risk of 2-year postoperative complications. However, the association of recent fragility fractures with complications beyond 2 years following THA remains unknown. The purpose of this study was to characterize the association of prior fragility fractures with 8-year risks of revision THA, periprosthetic fracture (PPF), and secondary fragility fracture., Methods: Patients aged 50 years and more who underwent THA for osteoarthritis were identified in a large national database. Patients were stratified based on whether they sustained a fragility fracture within 3 years prior to THA. There were 18,529 patients who had a prior fragility fracture and 408,753 who did not have a prior fragility fracture. Demographics and comorbidities were collected. Kaplan-Meier and Cox Proportional Hazards analyses were used to observe the cumulative incidences of all-cause revision, PPF, and secondary fragility fracture within 8 years of index surgery., Results: Patients who had recent fragility fracture had significantly higher risks of revision THA (Hazard Ratio [HR] 1.7; P < .001), PPF (HR 2.2; P < .001), and secondary fragility fracture (HR 4.9; P < .001)., Conclusion: Prior fragility fracture was shown to be a significant risk factor for revision THA, PPF, and secondary fragility fracture within 8 years of THA. Identification of these high-risk patients with an emphasis on preoperative and postoperative bone health optimization may help minimize these complications., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chinese patent medicines(CPMs) are unique therapeutic drugs in China. Establishing and improving the evaluation criteria is an important measure to promote the high-quality development of CPMs. Based on the &quot;evaluation criteria of high-grade CPMs with quality as the core index&quot; established by our group in 2018, the &quot;high-quality evaluation criteria for CPMs based on whole process control&quot; was proposed in the present study in 2022. The scope of application and basic principles of the new criteria were clarified. A quality evaluation scoring table was established in the new criteria, including five parts: raw material selection, production process, quality control, efficacy evaluation, and brand building. The technical evaluation indexes involved have increased from 20% in the original criteria to 70% in the new criteria, and efficacy evaluation has been added in the new criteria. The subjective evaluation indicators account for a large proportion in the original criteria, which is prone to bias. The improved criteria overcome this shortcoming. It is expected that the new criteria as a basis can play a better role in the selection of high-quality products of CPMs, guide enterprises and institutions to participate actively in the evaluation and research of high-quality CPMs, and promote the high-quality development of CPMs.

Ferroptosis is characterized by excessive accumulation of iron and lipid peroxides, which are involved in ischemia, reperfusion-induced organ injury, and stroke. Propofol, an anesthetic agent, has neuroprotective effects due to its potent antioxidant, anti-ischemic, and anti-inflammatory properties. However, the relationship between propofol and ferroptosis is still unclear. In the current study, we elucidated the role of ferroptosis in the neuroprotective effect of propofol in mouse brains subjected to cerebral ischemia reperfusion injury (CIRI). Ferroptosis was confirmed by Western blotting assays, transmission electron microscopy, and glutathione assays. Propofol regulated Nrf2/Gpx4 signaling, enhanced antioxidant potential, inhibited the accumulation of lipid peroxides in CIRI-affected neurons, and significantly reversed CIRI-induced ferroptosis. Additionally, Gpx4 inhibitor RSL3 and Nrf2 inhibitor ML385 attenuated the effects of propofol on antioxidant capacity, lipid peroxidation, and ferroptosis in CIRI-affected neurons. Our data support a protective role of propofol against ferroptosis as a cause of cell death in mice with CIRI. Propofol protected against CIRI-induced ferroptosis partly by regulating the Nrf2/Gpx4 signaling pathway. These findings may contribute to the development of future therapies targeting ferroptosis induced by CIRI., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The mitochondrial unfolded protein response (UPR mt ) is a mitochondria stress response, which exerts a crucial role in maintaining mitochondrial proteostasis during stress. However, there is no bibliometric analyses systematically studied this field which could comprehensively review research trends, evaluate publication performances and provide future perspectives., Methods: Articles investigating UPR mt published between 1994 and 2021 were downloaded from the Core Collection of the Web of Science (WOS). CiteSpace and VOSviewer bibliometric software were applied for bibliometric and visual analyses., Results: A total of 2,073 papers researching UPR mt were retrieved. According to the published number of papers, the field of UPR mt research has gone through its infancy (after 2000) and rapid growth (after 2021) phases. The United States and China contributed the most to UPR mt research. Regarding the distribution of institutions, Harvard University was the most influential institution. The most prolific authors are Johan Auwerx and CM Haynes. PLoS One is the most extensive journal in the field of UPR mt research, while the Cell Death and Differentiation journal had the greatest impact among the most-authored journals. Moreover, biochemistry/molecular biology, and cell biology are the largest subject areas. UPR mt research is mainly categorized as UPR mt , transcription, endoplasmic reticulum (ER) stress, lipotoxicity, mitophagy, inflammation, skeletal muscle, hypoxia, apoptosis, mitochondrial dysfunction, neurodegeneration, mitochondrial permeability transition, and integrated stress response., Conclusions: At present, research on UPR mt is booming. Further strengthening the cooperation and exchanges between countries, institutions, and authors in the future will surely promote the development of this field., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-6423/coif). The authors have no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

Fabry disease (FD) is a progressive multisystemic disease characterized by lysosomal enzyme deficiency. Enzyme replacement therapy (ERT) is one of the most significant advancements and breakthroughs in treating FD. However, limited resources and the high cost of ERT might prevent patients from receiving prompt and effective therapy, thereby resulting in severe complications. Future progress in ERT can uncover promising treatment options. In this study, we developed and validated a recombinant enzyme (Lanzyme) based on a CHO-S cell system to provide a new potential option for FD therapy. Our results indicated that Lanzyme was heavily glycosylated, and its highest activity was similar to a commercial enzyme (Fabrazyme ® ). Our pharmacokinetic assessment revealed that the half-life of Lanzyme was up to 11 min, which is nearly twice that of the commercial enzyme. In vivo experiments revealed that Lanzyme treatment sharply decreased the accumulation levels of Gb3 and lyso-Gb3 in various tissues of FD model mice, with superior or comparable therapeutic effects to Fabrazyme ® . Based on these data, Lanzyme may represent a new and promising treatment approach for FD. Building this enzyme production system for ERT can offer additional choice, potentially with enhanced efficacy, for the benefit of patients with FD.

The big brand of Chinese patent medicine, Fufang Danshen Prescription(FDP), effective in promoting blood circulation, resolving blood stasis, regulating qi, and relieving pain, is wide in clinical application and diverse in dosage forms and products, but its quality and price are uneven, which causes problems for doctors and patients. To clarify the key links and weakness of quality control leading to the quality difference of FDP products, the present study carried out a comprehensive evaluation of the whole production cycle of FDP based on the &quot;high-quality Chinese patent medicine evaluation criteria&quot; and analyzed the advantages and disadvantages of production and quality of different FDP products according to scores. The results showed that the scores of various products in the &quot;raw materials selection&quot; varied greatly. The highest score(S1) and the lowest score(S2) differed by more than 3 times, indicating that different manufacturers had inconsistent requirements for the selection of raw materials, leading to fundamental differences in the quality of raw materials. The scores in the &quot;production process&quot; varied slightly, with an average score of 66.8%. The manufacturer S8 obtained the highest score(84.0%), which indicated the emergence of intelligent manufacturing production. The scores(with the average score of 44.0%) in the &quot;quality control&quot; were lower than those of the previous two items, which was attributed to the fact that most FDP products only met the &quot;qualified&quot; benchmark required by the 2020 edition of Chinese Pharmacopoeia, and their consistency and high quality were both uncontrollable. The scores in the &quot;post-marketing research&quot; were the lowest(with an average score of 28.5%), and most manufacturers were scored 0, which reflected little attention paid. Only a few brand manufacturers were scored acceptably and they were willing to carry out relevant research on post-marketing evaluation. The evaluation results demonstrated the key links and weakness leading to the production and quality differences of FDP from different manufacturers. It is expected to improve the quality of FDP, promote the formation of the &quot;high quality and good price&quot; mechanism, and provide information for the centralized procurement of governments.

The increased resolution of single-cell RNA-sequencing technologies has led to major breakthroughs and improved our understanding of the normal and pathologic conditions of multiple tissues and organs. In the study of parenchymal lung disease, single-cell RNA-sequencing has better delineated known cell populations and identified novel cells and changes in cellular phenotypes and gene expression patterns associated with disease. In this review, we aim to highlight the advances and insights that have been made possible by applying these technologies to two seemingly very different lung diseases: fibrotic interstitial lung diseases, a group of relentlessly progressive lung diseases leading to pulmonary fibrosis, and COVID-19 pneumonia, an acute viral disease with life-threatening complications, including pulmonary fibrosis. We discuss changes in cell populations and gene expression, highlighting potential common features, such as alveolar cell epithelial injury and aberrant repair and monocyte-derived macrophage populations, as well as relevance and implications to mechanisms of disease and future directions., (© 2022. The Author(s).)

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100A hi /HLA-DR lo classical monocytes and activated LAG-3 hi T cells are hallmarks of progressive disease and highlights the abnormal MHC-II/LAG-3 interaction on myeloid and T cells, respectively. We also find skewed T cell receptor repertories in expanded effector CD8 + clones, unmutated IGHG + B cell clones, and mutated B cell clones with stable somatic hypermutation frequency over time. In conclusion, our in-depth immune profiling reveals dyssynchrony of the innate and adaptive immune interaction in progressive COVID-19., (© 2022. The Author(s).)

Objective: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored., Methods: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed., Results: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks., Conclusions: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care., (© 2021. The Author(s).)

Background  Spontaneous hemorrhage into vestibular schwannomas (VSs) is rare and can render more rapid symptom onset and a seemingly poorer prognosis for an otherwise benign pathology. We describe our series of hemorrhagic VS (HVSs) and systematically reviewed the literature to better understand relevant clinical factors and outcomes. Methods  Retrospective case review series and systematic review of the literature using PRISMA guidelines. Results  Fifty-three patients with HVS met inclusion criteria. Compared with historical data for all VS, patients with HVS had relatively higher rates of perioperative mortality, significant preoperative facial weakness, and harbored relatively larger tumors. Regardless of the extent of resection (EOR), surgery for HVS resulted in significant improvement of facial weakness ( p  = 0.041), facial numbness ( p  < 0.001), vertigo ( p  < 0.001), and headache ( p  < 0.001). Patients with facial weakness tended to have larger tumors ( p  = 0.058) on average and demonstrated significant improvement after surgery, irrespective of EOR ( p  < 0.01). The use of blood-thinning medications did not affect patient health outcome. Histopathology of HVS samples showed an increased number of dilated/ectatic thin-walled vascular channels, reflective of potentially increased vascular permeability and hypervascularity. Conclusion  HVS may be an aggressive subgroup of VS, associated with a surprisingly high mortality rate. When features of HVS are identified on imaging, these patients should be treated expeditiously, especially given that facial nerve dysfunction, which is identified in more than half of patients with HVS, appears to be reversible. Overall, this study has significant implications in the management of VS, raising awareness of a small, but highly morbid subgroup., Competing Interests: Conflict of Interest Dr. Kveton reports other from Envoy Medical (Minneapolis, Minnesota, United States), outside the submitted work. All the other authors report no conflict of interest., (Thieme. All rights reserved.)

Purpose: Striking disparities persist in cardiovascular disease risk factors among minority youth. We examined the association between multiple indicators of neighborhood quality and minority youth fitness., Methods: The primary exposure was the Child Opportunity Index (COI), a measure comprised of indicators that facilitate healthy child development. Outcome data were drawn from the 2018-2019 Fit2Play Study (Miami-Dade County, FL). Hotspot analysis evaluated COI spatial clustering. Generalized linear mixed models examined cross-sectional COI-fitness associations., Results: The sample included 725 youth (53% Black, 43% Hispanic; 5-17 years). Significant neighborhood quality spatial clusters were identified (Gi* z-score = -4.85 to 5.36). Adjusting for sociodemographics, walkability was associated with lower percentiles in body mass index (BMI) and diastolic blood pressure percentiles (DBP) (β = -5.25, 95% CI: -8.88, -1.62 and β = -3.95, 95% CI: -7.02, -0.89, respectively) for all, lower skinfold thickness (β = -4.83, 95% CI: -9.97, 0.31 and higher sit-ups (β = 1.67, 95% CI: -0.17, 3.50) among girls, and lower systolic blood pressure percentiles (SBP) (β = -4.75, 95% CI: -8.99, -0.52) among boys. Greenspace was associated with higher BMI (β = 6.17, 95% CI: 2.47, 9.87), SBP (β = 3.47, 95% CI: -0.05, 6.99), and DBP (β = 4.11, 95% CI: 1.08, 7.13)., Conclusions: COI indicators were positively associated with youth fitness. Disparities in youth cardiovascular disease risk may be modifiable through community interventions and built environment initiatives targeting select neighborhood factors., (Copyright © 2021. Published by Elsevier Inc.)

Single-nucleotide polymorphisms (SNPs) of microRNA (miRNA) (miRSNP) are SNPs located on miRNA genes or miRNA target sites, which have been supposed to be involved in the development of central nervous system diseases by interfering with miRNA-mediated regulatory functions. However, the association of miRSNP with post-stroke depression (PSD) has not been well-investigated. In this study, we collected 54 PSD risk genes via manual literature-mining and integrated PSD-related risk pathways based on multiple public databases. Furthermore, we systematically screened candidate functional miRSNPs for PSD and integrated a miRSNP-based PSD-associated pathway network, which included 99 miRNAs that target 12 PSD risk pathways. We also reviewed the association between three risk pathways and PSD pathogenetic mechanism thoroughly. Combining literature mining and network analysis, our results proposed an underlying mechanism of "miRSNP → miRNA → risk gene → pathway" axis effects on PSD pathogenesis, especially for rs28457673 (miR-15/16/195/424/497 family) → IGF1R → hsa04010 (MAPK signaling pathway). Our studies revealed a functional role in genetic modifier at the system level in the pathogenesis of PSD, which might provide further information for the miRSNP studies in PSD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Wang, Zhu, Fan, Xu, Zhao, Zhao, Ning and Qi.)

Objective: The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients., Methods: Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures., Results: Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30-5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46-6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03-3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37-9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08-7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09-7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis., Conclusions: Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.

Radiolabeled guanidines such as meta -iodobenzylguanidine (MIBG) find utility in nuclear medicine as both diagnostic imaging agents and radiotherapeutics and, over the years, numerous methods for incorporating radionuclides into guanidines have been developed. In connection with a project developing new positron emission tomography (PET) radiotracers for cardiac sympathetic nerve density, we had cause to prepare [ 11 C]3F-PHPOG. However, it quickly became apparent that radiolabeling of guanidine scaffolds with carbon-11 has remained challenging, and historical methods lack compatibility with modern automated radiochemistry synthesis platforms and current Good Manufacturing Practice (cGMP) requirements. To address this challenge, we report a new automated method for radiolabeling guanidines with carbon-11. The method was used to prepare a series of [ 11 C]guanidines in good radiochemical yield (8-76% by radio-HPLC) and was found to have broad substrate scope and tolerance of unprotected OH and NH functional groups. The method was used to synthesize [ 11 C]3F-PHPOG for preclinical imaging, and suitability of the radiotracer for preclinical use was demonstrated through preliminary cardiac PET in New Zealand white rabbits which revealed good cardiac uptake and expected retention in the heart., Competing Interests: The authors declare no competing financial interest., (© 2020 American Chemical Society.)

The consistency of quality on Chinese patent drugs is a hotspot and difficulty in the control of traditional Chinese medicine preparations, and has become one of the bottlenecks restricting its internationalization. Based on the analysis of current studies on quality and problems of Chinese patent drugs, this paper explored relevant methods of quality evaluation on Chinese patent drugs and possible factors affecting the consistency of quality in the pharmaceutical cycle by consulting relevant literatures about quality evaluation methods and consistency control techniques of large-scale Chinese patent drugs. And it put forward the evaluation system on high-quality Chinese patent drugs with &quot;consistency&quot; as the core, so as to promote the overall improvement of the quality of Chinese patent drugs, guide the rational price of Chinese patent drugs of the same species, and provide a new reference model for the quality evaluation of Chinese patent drug.

Visual tracking is a fundamental vision task that tries to figure out instances of several object classes from videos and images. It has attracted much attention for providing the basic semantic information for numerous applications. Over the past 10 years, visual tracking has made a great progress, but huge challenges still exist in many real-world applications. The facade of a target can be transformed significantly by pose changing, occlusion, and sudden movement, which possibly leads to a sudden target loss. This paper builds a hybrid tracker combining the deep feature method and correlation filter to solve this challenge, and verifies its powerful characteristics. Specifically, an effective visual tracking method is proposed to address the problem of low tracking accuracy due to the limitations of traditional artificial feature models, then rich hiearchical features of Convolutional Neural Networks are used to make the multi-layer features fusion improve the tracker learning accuracy. Finally, a large number of experiments are conducted on benchmark data sets OBT-100 and OBT-50, and show that our proposed algorithm is effective.

The traditional Chinese medicine(TCM) quality constant herbal slices evaluation method was applied to evaluate the grade of Sophorae Tonkinensis Radix et Rhizoma based on the combination of traditional character identification and modern scientific and technological methods. The TCM quality constant evaluation method was used to determine the appearance and index content of medicinal slices, calculate the quality constant and percentile quality constant of Sophorae Tonkinensis Radix et Rhizoma from different sources, and discuss their classification. The quality constants of 15 batches of Sophorae Tonkinensis Radix et Rhizoma slices were between 0.004 and 0.063. The slices with the percentage quality constant ≥80% were classified as the first grade; those with the percentage quality constant ≥50% and <80% were classified as the second grade; and those with the percentage quality constant <50% were classified as the third grade. Then the slices with the quality constant ≥0.050 were classified as the first grade; those with the quality constant ≥0.032 and <0.050 were classified as the second grade; and those with the quality constant <0.032 were classified as the third grade. According to the results, the 15 batches of Sophorae Tonkinensis Radix et Rhizoma slices were divided into 1 batch of the first grade, 4 batches of the second grade, and 10 batches of the third grade. The quality constant evaluation method established is scientific, objective, simple and feasible. The application of the method in Sophorae Tonkinensis Radix et Rhizoma slices has reasonable results, which is helpful to promote the classification of Sophorae Tonkinensis Radix et Rhizoma and promotes the high-quality application of Sophorae Tonkinensis Radix et Rhizoma.

Liuwei Dihuang Pills is a typical traditional Chinese medicine with &quot;the same product made by many manufacturers&quot;. The quality and price of products made in various factories was different obviously. In this study, the quality differences of Liuwei Dihuang Pills were evaluated over multi-dimensions and throughout the whole production cycle involving raw materials, production process, quality control and post-marketing re-studies based on the &quot;Chinese patent medicine evaluation standard with quality at the core&quot; established earlier by our research group. The research results showed that the product quality of various manufacturers was significantly different, and the product quality was positively correlated with the market shares of enterprises, indicating that enterprises with more market shares paid more attention to product quality; and the sales determined the concern degree of enterprises on products, which was in line with general cognition. During the single-item evaluation of Liuwei Dihuang Pills, the score of raw material selection was relatively low, and the enterprises paid less attention to the initial raw materials. The whole production process was better, and the national compulsory implementation of &quot;Production Quality Management Standard&quot;(GMP) had a positive effect in improving product quality. Quality control could basically guarantee product quality. Intelligent manufacturing promoted by the government was beneficial to ensure product uniformity. The score rate of &quot;quality evaluation&quot; item was basically qualified, which indicated that the quality control level of Liuwei Dihuang Pills was acceptable as a whole, but there was still room for improvement. &quot;Re-evaluation and Brand Construction&quot; had the lowest scores, reflecting that enterprises did not pay enough attention to in-depth study and re-evaluation of &quot;the same product made by many manufacturers&quot;. The evaluation results were in line with expectations, provided a reference example for the evaluation of high-quality Chinese patent medicine, a basis for the high-quality and good price of Chinese patent medicine, scientific data for improving medical insurance bidding, and thus facilitated promoting the healthy development of the traditional Chinese medicine industry.

Objective: Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts., Methods: Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher's exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features., Results: Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among "mutation unknown" samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor's underlying driver mutation., Conclusions: Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.

Enterocytozoon bieneusi is an obligate intracellular fungus, infecting various invertebrate and vertebrate hosts, it is common in humans and causes diarrhea in the immunocompromised. In the present study, 801 fecal specimens were collected from pigs on seven large-scale pig farms in Xinjiang, China. Nested polymerase chain reaction (PCR) amplification of the internal transcribed spacer (ITS) gene showed that the overall E. bieneus i infection rate was 48.6% (389/801). The E. bieneusi infection rates differed significantly among the collection sites (20.0-73.0%) (χ 2 = 75.720, df = 6, p < 0.01). Post-weaned pigs had the highest infection rate (77.2%, 217/281), followed by fattening pigs (67.4%, 87/129) and pre-weaned suckling pigs (35.5%, 60/169). Adult pigs had the lowest infection rate (11.3%, 25/222). The E. bieneusi infection rates also differed significantly among age groups (χ 2 = 246.015, df = 3, p < 0.01). Fifteen genotypes were identified, including 13 known genotypes (CHC, CS-1, CS-4, CS-7, CS-9, D, EbpA, EbpC, EbpD, H, PigEb4, PigEBITS5, and WildBoar8) and two novel genotypes (XJP-II and XJP-III). Among them, six genotypes (CS-4, D, EbpA, EbpC, H, and PigEBITS5) have been reported in humans. Phylogenetic analysis showed that all the genotypes belonged to Group 1 of E. bieneusi . These findings suggest that pigs may play an important role in transmitting E. bieneusi infections to humans., (Copyright © 2019 Li, Zhang, Jiang, Xing, Tao, Zhao, Cui, Jing, Qi and Zhang.)

The method of classifying the quality grade of traditional Chinese medicine slices with cross section model quality constant was applied to the grade evaluation of Ligusticum chuanxiong pieces,and a reasonable grade standard of L. chuanxiong pieces was established. The purpose is to classify the 15 batches of L. chuanxiong pieces by combining the advantages of traditional grading with modern quality control indicators. By measuring the natural morphological parameters,processing parameters and the intrinsic content of ferulic acid,an important active ingredient,of the 15 batches of L. chuanxiong pieces collected from different manufacturers and different batches of different medicinal materials markets,we can synthesize the results. The mass constants and percentage mass constants are calculated and analyzed based on the above data. The results showed that the quality constants of 15 batches of L. chuanxiong pieces collected ranged from 0.53-3.00; if the percentage mass constants were more than 80%,50%-80% was second-class pieces,and the rest were third-class pieces,the evaluation results were as follows: the quality constants of first-class L. chuanxiong pieces were more than 2.40,the quality constants of second-class L. chuanxiong pieces should be 1.70-2.40,and the quality constants of third-class L. chuanxiong pieces should be less than 1.70. In this paper,the method of dividing the quality constants of the top blade model into different grades is further applied and practiced,which proves that the method is scientific,reasonable and multi-adaptable. At the same time,it enriches the research data of the grade evaluation of L. chuanxiong pieces,provides a useful reference for the promotion of the grade evaluation of L. chuanxiong pieces,and lays an experimental foundation for the next research of the subject group.

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

Heterozygous coding mutations in TRIO are associated with neurodevelopmental disorders, including autism, schizophrenia, bipolar disorder, and epilepsy, and impair TRIO's biochemical activities. To model mutant alleles, we ablated one or both Trio alleles from excitatory neurons in the cortex and hippocampus of mice. Trio haploinsufficiency increases anxiety and impairs social preference and motor coordination. Trio loss reduces forebrain size and dendritic arborization but increases dendritic spine densities. Cortical synapses in Trio haploinsufficient mice are small, exhibit pre- and postsynaptic deficits, and cannot undergo long-term potentiation. Similar phenotypes are observed in Trio knockout mice. Overall, Trio haploinsufficiency causes severe disease-relevant deficits in behavior and neuronal structure and function. Interestingly, phosphodiesterase 4A5 (PDE4A5) levels are reduced and protein kinase A (PKA) signaling is increased when TRIO levels are reduced. Elevation of PDE4A5 and drug-based attenuation of PKA signaling rescue Trio haploinsufficiency-related dendritic spine defects, suggesting an avenue for therapeutic intervention for TRIO-related neurodevelopmental disorders., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Poly(ADP ribose) polymerase inhibitors (PARPi) target cancer cells deficient in homology-directed repair of DNA double-strand breaks (DSBs). In preclinical models, PARPi resistance is tied to altered nucleolytic processing (resection) at the 5' ends of a DSB. For example, loss of either 53BP1 or Rev7/MAD2L2/FANCV derepresses resection to drive PARPi resistance, although the mechanisms are poorly understood. Long-range resection can be catalyzed by two machineries: the exonuclease Exo1, or the combination of a RecQ helicase and Dna2. Here, we develop a single-cell microscopy assay that allows the distinct phases and machineries of resection to be interrogated simultaneously in living S. pombe cells. Using this assay, we find that the 53BP1 orthologue and Rev7 specifically repress long-range resection through the RecQ helicase-dependent pathway, thereby preventing hyper-resection. These results suggest that 'rewiring' of BRCA1-deficient cells to employ an Exo1-independent hyper-resection pathway is a driver of PARPi resistance., Competing Interests: BL, AC, AZ, RW, MK No competing interests declared, (© 2018, Leland et al.)

Aim: To investigate the expression of annexin A5 in serum and tumor tissue of patients with colon cancer and to analyze its clinical significance., Methods: Ninety-three patients with colon cancer treated at our hospital between February 2013 and March 2016 were included in an observation group, and 40 healthy individuals were included in a control group. Enzyme-linked immunosorbent assay was performed to determine the serum level of annexin A5, while immunohistochemistry was performed to determine the expression of annexin A5 in cancer tissues., Results: The serum level of annexin A5 was 0.184 ± 0.043 ng/mL in the observation group, which was significantly higher than that in the control group ( P < 0.05). Annexin A5 expression was detected in 79.31% of the patients with lymph node metastasis, which was significantly higher than that in patients without lymph node metastasis ( P < 0.05). Moreover, annexin A5 expression was detected in 86.96% of the patients with stage III to IV disease, which was significantly higher than that in patients with stage I to II disease ( P < 0.05). The serum level of annexin A5 was 0.215 ± 0.044 ng/mL in patients whose tumors were positive for annexin A5 expression, which was significantly higher than that in patients whose tumors were negative for annexin A5 expression ( P < 0.05). The serum level of annexin A5 was correlated with annexin A5 expression in colon cancer tissues ( r = 0.312, P < 0.05). When a cutoff value of > 0.148 ng/mL for serum level of annexin A5 was used in the diagnosis of colon cancer, the sensitivity was 83.90%, and the specificity was 57.50%., Conclusion: For patients with colon cancer, annexin A5 expression in cancer tissues is related to lymph node metastasis and tumor grade. Serum level of annexin A5 is related to annexin A5 expression in cancer tissues and is of diagnostic relevance., Competing Interests: Conflict-of-interest statement: No conflict of interest.