Lipoprotein (a) is associated with increased risk of Abdominal Aortic Aneurysm.

Introduction: Lipoprotein(a) (Lp(a)) is a circulating apolipoprotein B (ApoB) containing particle that has been observationally linked to atherosclerotic cardiovascular disease and is the target of emerging therapeutics. Recent work has highlighted the role of circulating lipoproteins in abdominal aortic aneurysm (AAA). We sought to triangulate human observational and genetic evidence to evaluate the role of Lp(a) in AAA. Methods: We tested the association between circulating levels of Lp(a) and clinically diagnosed abdominal aortic aneurysms while controlling for traditional AAA risk factors and levels of ApoB using logistic regression among 795 individuals with and 374,772 individuals without AAA in the UK Biobank (UKB). Multivariable Mendelian randomization (MVMR) was used to test for putatively causal associations between Lp(a) and AAA controlling for ApoB. Genetic instruments for Lp(a) and ApoB were created from genome-wide association studies (GWAS) of Lp(a) and ApoB comprising 335,796 and 418,505 UKB participants, respectively. The instruments were tested for association with AAA using data from a GWAS of 39,221 individuals with and 1,086,107 without AAA. Results: Elevated Lp(a) levels were observationally associated with an increased risk of AAA (OR 1.04 per 10 nmol/L Lp(a); 95%CI 1.02-1.05; P<0.01). Clinically elevated Lp(a) levels (>150nmol/L) were likewise associated with an increased risk of AAA (OR 1.47; 95% CI 1.15-1.88; P < 0.01) when compared to individuals with Lp(a) levels <150nmol/L. MVMR confirmed a significant, ApoB-independent association between increased Lp(a) and increased risk of AAA (OR 1.13 per SD increase in Lp(a); 95%CI 1.02-1.24; P<0.02). Conclusion: Both observational and genetic analyses support an association between increased Lp(a) and AAA risk that is independent of ApoB. These findings suggest that Lp(a) may be a therapeutic target for AAA and drive the inclusion of AAA as an outcome in clinical trials of Lp(a) antagonists.

Extraction of redox extracellular vesicles using exclusion-based sample preparation.

Studying specific subpopulations of cancer-derived extracellular vesicles (EVs) could help reveal their role in cancer progression. In cancer, an increase in reactive oxygen species (ROS) happens which results in lipid peroxidation with a major product of 4-hydroxynonenal (HNE). Adduction by HNE causes alteration to the structure of proteins, leading to loss of function. Blebbing of EVs carrying these HNE-adducted proteins as a cargo or carrying HNE-adducted on EV membrane are methods for clearing these molecules by the cells. We have referred to these EVs as Redox EVs. Here, we utilize a surface tension-mediated extraction process, termed exclusion-based sample preparation (ESP), for the rapid and efficient isolation of intact Redox EVs, from a mixed population of EVs derived from human glioblastoma cell line LN18. After optimizing different parameters, two populations of EVs were analyzed, those isolated from the sample (Redox EVs) and those remaining in the original sample (Remaining EVs). Electron microscopic imaging was used to confirm the presence of HNE adducts on the outer leaflet of Redox EVs. Moreover, the population of HNE-adducted Redox EVs shows significantly different characteristics to those of Remaining EVs including smaller size EVs and a more negative zeta potential EVs. We further treated glioblastoma cells (LN18), radiation-resistant glioblastoma cells (RR-LN18), and normal human astrocytes (NHA) with both Remaining and Redox EV populations. Our results indicate that Redox EVs promote the growth of glioblastoma cells, likely through the production of H2O2, and cause injury to normal astrocytes. In contrast, Remaining EVs have minimal impact on the viability of both glioblastoma cells and NHA cells. Thus, isolating a subpopulation of EVs employing ESP-based immunoaffinity could pave the way for a deeper mechanistic understanding of how subtypes of EVs, such as those containing HNE-adducted proteins, induce biological changes in the cells that take up these EVs.

Airways abnormalities in a prospective cohort of patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) affects roughly 1% of the population and commonly involves the lungs. Of lung involvement in RA, interstitial lung disease (ILD) is well-known; however, airways disease in RA is relatively understudied. RESEARCH QUESTIONS: What are the baseline airways abnormalities in a prospective cohort of patients with RA based on pulmonary function tests (PFT), high-resolution CT scans (HRCT) and computational imaging analysis and are there associations between these abnormalities and respiratory symptoms? STUDY DESIGN AND METHODS: In this single-center study, 188 patients with RA without a clinical diagnosis of ILD underwent HRCT and PFT. Radiologists assessed HRCTs for airway abnormalities. Computational imaging via VIDA Vision software and in-house quantitative CT (qCT) analysis was applied to 147 HRCTs to quantify airway abnormalities. RESULTS: Airways obstruction (FEV1/FVC ratio < 0.7) was present in 20.7% of patients, and associated with older age, male sex and higher smoking rate. Radiologists identified airway abnormalities in 61% of patients-55% had bronchial wall thickening, 12% bronchiectasis, and 5% mosaic attenuation; these airways findings were associated with older age, male sex, lower FEV1, FVC, FEV1/FVC ratios, and higher rates of rheumatoid factor positivity. Prespecified qCT metrics (wall thickening % and emphysema %) correlated with PFT obstruction and more severe respiratory symptoms including shortness of breath and cough. INTERPRETATION: There were high rates of airways abnormalities in this prospective RA cohort based on three methods of detection. There were significant associations between qCT measures and respiratory symptoms. Airways disease may be an under-recognized extra-articular manifestation of RA and qCT may be a sensitive method to detect the clinical impact on respiratory symptoms.

Integrated germline and somatic features reveal divergent immune pathways driving response to immune checkpoint blockade.

Immune Checkpoint Blockade (ICB) has revolutionized cancer treatment, however the mechanisms determining patient response remain poorly understood. Here, we used machine learning to predict ICB response from germline and somatic biomarkers and interpreted the learned model to uncover putative mechanisms driving superior outcomes. Patients with higher infiltration of T follicular helper cells had responses even in the presence of defects in the class-I Major Histocompatibility Complex (MHC-I). Further investigation uncovered different ICB responses in tumors when responses were reliant on MHC-I versus MHC-II neoantigens. Despite similar response rates, MHC-II reliant responses were associated with significantly longer durable clinical benefit (Discovery: Median OS=63.6 vs. 34.5 months P=0.0074; Validation: Median OS=37.5 vs. 33.1 months, P=0.040). Characteristics of the tumor immune microenvironment reflected MHC neoantigen reliance, and analysis of immune checkpoints revealed LAG3 as a potential target in MHC-II but not MHC-I reliant responses. This study highlights the value of interpretable machine learning models in elucidating the biological basis of therapy responses.

Computational drug discovery pipelines identify NAMPT as a therapeutic target in neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive advanced subtype of prostate cancer that exhibits poor prognosis and broad resistance to therapies. Currently, few treatment options are available, highlighting a need for new therapeutics to help curb the high mortality rates of this disease. We designed a comprehensive drug discovery pipeline that quickly generates drug candidates ready to be tested. Our method estimated patient response to various therapeutics in three independent prostate cancer patient cohorts and selected robust candidate drugs showing high predicted potency in NEPC tumors. Using this pipeline, we nominated NAMPT as a molecular target to effectively treat NEPC tumors. Our in vitro experiments validated the efficacy of NAMPT inhibitors in NEPC cells. Compared with adenocarcinoma LNCaP cells, NAMPT inhibitors induced significantly higher growth inhibition in the NEPC cell line model NCI-H660. Moreover, to further assist clinical development, we implemented a causal feature selection method to detect biomarkers indicative of sensitivity to NAMPT inhibitors. Gene expression modifications of selected biomarkers resulted in changes in sensitivity to NAMPT inhibitors consistent with expectations in NEPC cells. Validation of these markers in an independent prostate cancer patient dataset supported their use to inform clinical efficacy. Our findings pave the way for new treatments to combat pervasive drug resistance and reduce mortality. Furthermore, this research highlights the use of drug sensitivity-related biomarkers to understand mechanisms and potentially indicate clinical efficacy.

MED13L-related disorder characterized by severe motor speech impairment.

Background: MED13L-related disorder is associated with intellectual disability, motor delay, and speech deficits. Previous studies have focused on broad clinical descriptions of individuals, but limited information regarding specific speech diagnoses and results of direct testing has been published to date. We conducted deep phenotyping to characterize the speech, language, motor, cognitive, and adaptive phenotypes of individuals with MED13L-related disorder. Methods: In this cross-sectional study, we administered standardized articulation, language, motor, and cognitive testing to 17 children and adolescents (mean age 9y 9m; SD 4y 5m; range 4y 2m to 19y 7m). In-person testing was supplemented with broad developmental, medical, and behavioral information collected virtually from a cohort of 67 individuals. Results: All individuals who completed in-person articulation testing met diagnostic criteria for speech apraxia, dysarthria, or both. Language impairment was present in all of the in-person cohort and almost all (97%) of the virtual cohort. Those who were able to complete motor testing demonstrated significant deficits in visual motor integration (mean 57.08, SD 9.26). Full scale IQs fell in the borderline to intellectual disability range, consistent with reported cognitive impairment in 97% of the virtual cohort. Notable medical features included hypotonia (83%), vision problems (72%), recurrent otitis media (58%), gastrointestinal problems (57%), and seizures (31%). Conclusions: MED13L-related disorder is characterized by a high rate of motor speech disorders that occur in the context of globally impaired motor, language, and cognitive skills. Children would benefit from intensive, individualized speech therapy and the early adoption of augmentative communication strategies.

A Novel Method for Separating Full and Empty Adeno-Associated Viral Capsids Using Ultrafiltration.

Adeno-associated viral vectors (AAVs) are the predominant viral vectors used for gene therapy applications. A significant challenge in obtaining effective doses is removing non-therapeutic empty viral capsids lacking DNA cargo. Current methods for separating full (gene-containing) and empty capsids are challenging to scale, produce low product yields, are slow, and are difficult to operationalize for continuous biomanufacturing. This communication demonstrates the feasibility of separating full and empty capsids by ultrafiltration. Separation performance was quantified by measuring the sieving coefficients for full and empty capsids using ELISA, qPCR, and an infectivity assay based on the live cell imaging of green fluorescent protein expression. We demonstrated that polycarbonate track-etched membranes with a pore size of 30 nm selectively permeated empty capsids to full capsids, with a high recovery yield (89%) for full capsids. The average sieving coefficients of full and empty capsids obtained through ELISA/qPCR were calculated as 0.25 and 0.49, indicating that empty capsids were about twice as permeable as full capsids. Establishing ultrafiltration as a viable unit operation for separating full and empty AAV capsids has implications for developing the scale-free continuous purification of AAVs.

Evaluation of the lithium resource in the Smackover Formation brines of southern Arkansas using machine learning.

Global demand for lithium, the primary component of lithium-ion batteries, greatly exceeds known supplies, and this imbalance is expected to increase as the world transitions away from fossil fuel energy sources. High concentrations of lithium in brines have been observed in the Smackover Formation in southern Arkansas (>400 milligrams per liter). We used published and newly collected brine lithium concentration data to train a random forest machine-learning model using geologic, geochemical, and temperature explanatory variables and create a map of predicted lithium concentrations in Smackover Formation brines across southern Arkansas. Using these predicted lithium maps with reservoir parameters and geologic information, we calculated that there are 5.1 to 19 million tons of lithium in Smackover Formation brines in southern Arkansas, which represents 35 to 136% of the current US lithium resource estimate. Based on these calculations, in 2022, 5000 tons of dissolved lithium were brought to the surface within brines as waste streams of the oil, gas, and bromine industries.

Effects of salivary contamination on the shear bond strengths of universal adhesives to dentin.

PURPOSE: To evaluate the shear bond strength (SBS) of resin composite to dentin contaminated with artificial saliva (AS) containing mucin and amylase using an experimental method controlling the volume of saliva and adhesive in a defined surface area. METHODS: Flat bonding surfaces were prepared on extracted human molars (320 grit surface). Using adhesive tape, a 4.5 mm bonding window was prepared on the dentin surfaces. Groups (n= 12) were prepared using the etch & rinse (ER) or self-etch (SE) modes for Adhese Universal (ADH), Scotchbond Universal Plus (SBU), and Prime & Bond active (PBA) dental adhesives (DA). For the control (C) groups, the adhesives were applied per the manufacturers' instructions with 2.0 µl or 3.0 µl of the adhesive. For the saliva-contaminated groups, 1.0 µl of artificial saliva with mucin was applied in the bonding window either dried or allowed to remain wet before the application of either 2.0 µl or 3.0 µl of the adhesive. After the adhesive film was air dried and light cured using an Ultradent bonding fixture, Spectrum TPH3 was bonded to the prepared surfaces. After water storage for 24 hours at 37°C, the specimens were debonded and shear bond strength (SBS) was calculated (MPa). A Kruskal-Wallis test with Bonferroni correction was used to determine group differences (P< 0.05). Scanning electron microscopy (SEM) was performed to visualize the interfacial surfaces prepared using an ion-etching technique. RESULTS: Mean SBS for the three adhesives were similar in both ER and SE modes to uncontaminated dentin surfaces for all the control groups. For dentin contaminated with dried or wet saliva, both the surface condition and the adhesive system were significant factors at a confidence level of 95%. For the dried saliva test groups, ADH and PBA with 3.0 µl of adhesive generated similar SBS values to controls while SBU generated lower values. Lower values were generated when using 2.0 µl of adhesive for the three adhesives in SE and ER modes except for PBA in the ER mode. Using wet saliva and 3.0 µl of adhesive ADH and SBU generated lower SBS values while PBA generated similar values to controls. Under SEM, morphology at the adhesive dentin interfaces was similar among the adhesives to uncontaminated dentin but notable differences were observed for SBU and ADH for both wet and dried saliva-contaminated surfaces. CLINICAL SIGNIFICANCE: Salivary contamination differentially affects shear bond strength and the morphology of the bonded interface of universal adhesives to dentin. These differences are specific to the adhesive tested and are influenced by using the etch and rinse or self-etch strategies and the volume of adhesive used. When concerned about salivary contamination clinically, maximizing the volume of adhesive on the substrate may help mitigate the deleterious effects of saliva contamination.

Ties that bind us: Leishmania grasps the sandfly.

The enigmatic haptomonad forms of Leishmania parasites adhere to the sandfly stomodeal valve, damaging this feeding valve and promoting parasite transmission. Yanase et al. recently identified the first parasite proteins involved in adhesion and showed their essentiality in binding to and damaging the valve.

Polygenic Scoring for Detection of Ascending Thoracic Aortic Dilation.

BACKGROUND: Ascending thoracic aortic dilation is a complex heritable trait that involves modifiable and nonmodifiable risk factors. Polygenic scores (PGS) are increasingly used to assess risk for complex diseases. The degree to which a PGS can improve aortic diameter prediction in diverse populations is unknown. Presently, we tested whether adding a PGS to clinical prediction algorithms improves performance in a diverse biobank. METHODS: The analytic cohort comprised 6235 Penn Medicine Biobank participants with available echocardiography and clinical data linked to genome-wide genotype data. Linear regression models were used to integrate PGS weights derived from a genome-wide association study of thoracic aortic diameter performed in the UK Biobank and were compared with the performance of the previously published aorta optimized regression for thoracic aneurysm (AORTA) score. RESULTS: Cohort participants had a median age of 61 years (IQR, 53-70) and a mean ascending aortic diameter of 3.36 cm (SD, 0.49). Fifty-five percent were male, and 33% were genetically similar to African reference population. Compared with the AORTA score, which explained 30.6% (95% CI, 29.9%-31.4%) of the variance in aortic diameter, AORTA score+UK Biobank-derived PGS explained 33.1%, (95% CI, 32.3%-33.8%), the reweighted AORTA score explained 32.5% (95% CI, 31.8%-33.2%), and the reweighted AORTA score+UK Biobank-derived PGS explained 34.9% (95% CI, 34.2%-35.6%). When stratified by population, models including the UK Biobank-derived PGS consistently improved upon the clinical AORTA score among individuals genetically similar to European reference population but conferred minimal improvement among individuals genetically similar to African reference population. Comparable performance disparities were observed in models developed to discriminate cases/noncases of thoracic aortic dilation (≥4.0 cm). CONCLUSIONS: We demonstrated that inclusion of a UK Biobank-derived PGS to the AORTA score confers a clinically meaningful improvement in model performance only among individuals genetically similar to European reference population and may exacerbate existing health care disparities.

Condom Acquisition, Errors, and Breakage among U.S. Cisgender College Students.

High rates of sexually transmitted infections and unplanned pregnancy continue to plague young adults in the USA with low condom use a contributing factor. To better understand condom acquisition, errors, and breakage among US cisgender college students, a survey was conducted across six structurally diverse institutions of higher education in 2019-2020 prior to the COVID-19 pandemic. Students who had used external condoms in the last year (N = 1584) were asked about specific on- and off-campus locations of condom acquisition and practices related to condom use. Findings indicate that students most frequently acquired condoms off-campus with location differences between genders and relationship status. Condom errors were common, with no consistent patterns related to gender, but unpartnered students were more likely than those in relationships to experience condom errors. Multivariate logistic regression indicated that relationship status, applying condom on wrong side, adding condom after sex started, removing condom during sex, condom slipping off, and problems with fit were predictors for condom breakage. The study results provide guidance for healthcare and sexuality education professionals working with college students to better address the differing needs of college students regarding condom acquisition and correct condom use.

An in vitro and machine learning framework for quantifying serum albumin binding of per- and polyfluoroalkyl substances.

Per- and polyfluoroalkyl substances (PFAS) are a diverse class of anthropogenic chemicals; many are persistent, bioaccumulative, and mobile in the environment. Worldwide, PFAS bioaccumulation causes serious adverse health impacts, yet the physiochemical determinants of bioaccumulation and toxicity for most PFAS are not well understood, largely due to experimental data deficiencies. As most PFAS are proteinophilic, protein binding is a critical parameter for predicting PFAS bioaccumulation and toxicity. Among these proteins, human serum albumin (HSA) is the predominant blood transport protein for many PFAS. We previously demonstrated the utility of an in vitro differential scanning fluorimetry assay for determining relative HSA binding affinities for 24 PFAS. Here, we report HSA affinities for 65 structurally diverse PFAS from 20 chemical classes. We leverage these experimental data, and chemical/molecular descriptors of PFAS, to build 7 machine learning classifier algorithms and 9 regression algorithms, and evaluate their performance to identify the best predictive binding models. Evaluation of model accuracy revealed that the top performing classifier model, logistic regression, had an AUROC statistic of 0.936. The top performing regression model, support vector regression, had an R2 of 0.854. These top performing models were then used to predict HSA-PFAS binding for chemicals in the EPAPFASINV list of 430 PFAS. These developed in vitro and in silico methodologies represent a high-throughput framework for predicting protein-PFAS binding based on empirical data, and generate directly comparable binding data of potential use in predictive modeling of PFAS bioaccumulation and other toxicokinetic endpoints.

Timing of parathyroidectomy for tertiary hyperparathyroidism after kidney transplant.

BACKGROUND: Parathyroidectomy has been shown to be superior to medical management in treating hypercalcemia and preserving renal allograft function in patients with tertiary hyperparathyroidism after kidney transplant. Despite this evidence, parathyroidectomy remains underused. We aimed to evaluate outcomes in patients with tertiary hyperparathyroidism after kidney transplant based on management strategy (cinacalcet or parathyroidectomy) and optimal timing of parathyroidectomy. METHODS: Data from TriNetX Dataworks included adult kidney transplant patients diagnosed with tertiary hyperparathyroidism between 1998 and 2021. Patients who underwent parathyroidectomy were compared with those receiving cinacalcet. Subgroups based on parathyroidectomy timing after transplant were analyzed (within 6 months, 6 months to 1 year, and between 1 and 3 years). Descriptive statistics and relative risks were calculated using TriNetX Live. RESULTS: Patients receiving cinacalcet (n = 162) had a 77% higher risk of persistent hypercalcemia and a 73% higher risk of elevated parathyroid hormone levels than those who underwent parathyroidectomy (n = 338) within 3-10 years after the index event (start of cinacalcet or surgery). Parathyroidectomy performed 1 year after transplant (n = 132) was associated with a 57% lower risk of kidney stone formation and patients were 2 times more likely to maintain normal glomerular filtration rate than parathyroidectomy performed 1-3 years after transplant (n = 57). Even earlier parathyroidectomy (within 6 months of kidney transplant, n = 55) showed a 62% lower risk of persistent hypercalcemia, hyperphosphatemia, and kidney stone formation than surgery between 6 months and 1 year after transplant (n = 77). CONCLUSION: Parathyroidectomy is more effective than cinacalcet in managing tertiary hyperparathyroidism after kidney transplant. In addition, opting for early parathyroidectomy (within 6 months after transplant) could enhance long-term outcomes.

Comparing the effectiveness of environmental DNA and camera traps for surveying American mink (Neogale vison) in northeastern Indiana.

While camera traps can effectively detect semi-aquatic mammal species, they are also often temporally and monetarily inefficient and have a difficult time detecting smaller bodied, elusive mammals. Recent studies have shown that extracting DNA from environmental samples can be a non-invasive, alternative method of detecting elusive species. Environmental DNA (eDNA) has not yet been used to survey American mink (Neogale vison), a cryptic and understudied North American mustelid. To help determine best survey practices for the species, we compared the effectiveness and efficiency of eDNA and camera traps in surveys for American mink. We used both methods to monitor the shoreline of seven bodies of water in northeastern Indiana from March to May 2021. We extracted DNA from filtered environmental water samples and used quantitative real-time PCR to determine the presence of mink at each site. We used Akaike's Information Criterion to rank probability of detection models with and without survey method as a covariate. We detected mink at four of the seven sites and seven of the 21 total survey weeks using camera traps (probability of detection (ρ) = 0.36). We detected mink at five sites and during five survey weeks using eDNA (ρ = 0.25). However, the highest probability of detection was obtained when both methods were combined, and data were pooled (ρ = 0.47). Survey method did not influence model fit, suggesting no difference in detectability between camera traps and eDNA. Environmental DNA was twice as expensive, but only required a little over half (58%) of the time when compared to camera trapping. We recommend ways in which an improved eDNA methodology may be more cost effective for future studies. For this study, a combination of both methods yielded the highest probability for detecting mink presence.

Assessing the reliability of a digital inclinometer app for measuring hip, knee, and ankle proprioception.

Proprioception can be defined as the ability of an individual to detect motion and position of the various joints in their bodies. Current tools for measuring proprioception lack consensus on their accuracy and validity; they also each have their own limitations, and, furthermore, present barriers to use for clinicians. We propose a new and reliable method for evaluating hip, knee, and ankle proprioception by utilizing a digital inclinometer app to measure joint position sense. The digital inclinometer app recorded the active joint position sense error after each of five trials for the hip and knee joint and ten trials for the ankle joint. To quantify the reliability of the digital inclinometer app, single-measurement and average-measurement intra-class correlation coefficients (ICC) along with the associated 95% confidence intervals (95% CI) were calculated for each joint's position sense error across trials. Both the hip (ICC (2,k) = 0.849 (95% CI = [0.783-0.897])) and knee joint (ICC (2,k) = 0.837 (95% CI = [0.750-0.897])) were found to have moderate to good reliability when the middle three of five trials were analyzed. Unlike the hip and knee, moderate to good reliability for ankle proprioception (ICC (2,k) = 0.785 (95% CI = [0.539-0.893])) was only achieved with the middle eight of ten trials. The results of this study indicate that this digital inclinometer app is able to accurately record joint position sense at the hip, knee, and ankle when the appropriate number of trials are collected; thus, allowing this tool and methodology to be considered for use in both clinical and research environments to measure proprioception, and furthermore, quantify proprioceptive deficits.

Thrombolysis and Surgical Decompression for Venous Thoracic Outlet Syndrome.

INTRODUCTION: Treatment for venous thoracic outlet syndrome (vTOS) includes thrombolysis followed by decompressive rib resection. Given the rarity of the disease, the goal of this study was to describe current practices in treatment of vTOS. METHODS: All patients with diagnoses of subclavian vTOS who underwent rib resection in the 2018-2020 Nationwide Readmissions Database were included in this study. Patients were grouped based on number of days between thrombolysis and by number of hospitalizations: thrombolysis followed by surgery in the same hospitalization was considered "simultaneous" and in separate hospitalizations was "staged." RESULTS: Five hundred ninety patients met the inclusion criteria. The average age was 34.1 ± 13.3 y, and 42.9% (253 of 590) were female. Among the patients receiving thrombolysis and decompressive rib resection, 46.8% (164 of 350) patients had <14 d between interventions, 19.1% (67 of 350) patients had 14-30 d between interventions, and 34.0% (119 of 350) had >30 d between interventions. There were no significant differences in postoperative bleeding between patients with <14 d, 14-30 d, and >30 d between thrombolysis and surgery. In terms of number of hospital visits, 19.0% (112 of 590) had "simultaneous" thrombolysis and surgery and 40.5% (239 of 590) had thrombolysis and surgery in a "staged" approach. Forty point five percent (239 of 590) of patients received only surgical decompression without thrombolysis. CONCLUSIONS: Thrombolysis followed by first rib resection for vTOS can be performed during the same hospital admission without an associated risk of bleeding complications.