Background COVID‐19 and other respiratory viral infections can cause cardiovascular complications. SARS‐CoV‐2 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID‐19 and enrolled in the ACTIV‐4a (Accelerating COVID‐19 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy. Methods We quantified SARS‐CoV‐2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine–Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death. Results In 93 patients, SARS‐CoV‐2 RNA and N‐antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90‐day death (hazard ratio [HR], 1.31 [95% CI, 1.17–1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24–1.47]). Viral RNA more effectively predicted survivorship than N‐antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%–32.3%; P=0.048) after adjustment for age and sex of the relationship between viral RNA and the 90‐day mortality rate. Conclusions Elevated plasma SARS‐CoV‐2 RNA levels are associated with death in ACTIV‐4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung–blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses. Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04505774.

BACKGROUND:Aspirin after an initial short course of rivaroxaban has been shown to be safe and effective for the prevention of venous thromboembolism after total hip or total knee arthroplasty, but uncertainty remains about the use of aspirin alone. METHODS:In this multicenter, double-blind, randomized, controlled trial, we assigned patients to receive once-daily thromboprophylaxis with either 81 mg of aspirin or 10 mg of oral rivaroxaban for the first 5 days after total hip or total knee arthroplasty. All the patients then received further thromboprophylaxis with 81 mg of aspirin daily for 9 additional days after knee arthroplasty and for 30 additional days after hip arthroplasty. Patients were followed for 90 days for symptomatic venous thromboembolism, which consisted of either proximal deep-vein thrombosis or pulmonary embolism (primary effectiveness outcome), and for bleeding complications (primary safety outcome). The noninferiority margin for aspirin alone as compared with rivaroxaban-aspirin was 0.7 percentage points. RESULTS:A total of 5429 patients underwent randomization. Venous thromboembolism developed in 13 of 2718 patients (0.48%) in the aspirin-alone group and in 12 of 2647 patients (0.45%) in the rivaroxaban-aspirin group (risk difference, 0.02 percentage points; 95% confidence interval [CI], -0.34 to 0.39; P<0.001 for noninferiority). Major bleeding or clinically relevant nonmajor bleeding events occurred in 45 of 2718 patients (1.66%) in the aspirin-alone group and in 54 of 2647 patients (2.04%) in the rivaroxaban-aspirin group (risk difference, -0.38%; 95% CI, -1.11 to 0.34). CONCLUSIONS:After total hip and total knee arthroplasty, the use of aspirin alone was not inferior to a strategy of using rivaroxaban followed by aspirin for the prevention of symptomatic venous thromboembolism, with no clinically relevant difference in bleeding events. (Funded by the Canadian Institutes of Health Research; EPCAT III ClinicalTrials.gov number, NCT04075240.).

Background:Venous thromboembolism is a major cause of morbidity and mortality. Despite identification of risk factors, not all individuals with thrombophilia develop thrombosis. Understanding the multigenic factors modifying this incomplete penetrance would help guide patient care. Methods:The zebrafish has a conserved hemostatic system and is amenable to large genetic studies. Loss of antithrombin III (At3) in zebrafish leads to an early consumptive coagulopathy and lethality in adulthood. Using this genetic background as a sensitized model we performed a dominant unbiased genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen followed by whole genome sequencing (WGS). We used survival studies, laser-mediated endothelial injury, and ex vivo protein assays to validate hits. Results:ENU-treated at3 +/- males were crossed with at3 +/- females to produce 4,030 total offspring (1.5x genome coverage). Four permanent lines transmitting a survival benefit beyond 7 months were identified and sequenced. A candidate screen of 63 known coagulation-related loci revealed a missense mutation, C504F, in a highly conserved residue of the prothrombin (F2) heavy chain, which was validated through genetic and biochemical studies. Evaluation of UK Biobank electronic health record (EHR) data was underpowered to detect interactions between F2 and AT3 due to minmal deleterious mutations. Mutations produced through genome editing revealed that heterozygosity for factor X and plasminogen also modified at3 -/- , resulting in reduced lethality. The three remaining lines had no coagulation-related variants segregating with survival, suggesting the presence of novel modifier loci. Conclusions:Unbiased genome-wide screening identified a modifier of thrombosis. This demonstrated that re-balancing of hemostasis to mitigate thrombosis is conserved in zebrafish, including an unexpected role for fibrinolysis. This interaction was not detected even in a large human dataset, establishing the continued benefit of the zebrafish model. Finally, we found evidence for novel loci outside of the canonical coagulation cascade that may be new targets for diagnosis or treatment.

Cardiac imaging is a cornerstone in the initial diagnosis, management, and follow-up of cardiac sarcoidosis. However, ordering thresholds, access, and follow-up imaging vary across the globe. A Delphi study was conducted to define areas of consensus and areas requiring further study in the use of cardiac imaging in suspected or established cardiac sarcoidosis. An international, multidisciplinary panel of experts in cardiac sarcoidosis completed a modified 2-round Delphi study. The study evaluated clinical decision making regarding the use of cardiac imaging, including indication thresholds, interpretation, and interval follow-up imaging. Consensus was defined a priori as ≥70% agreement or disagreement. A total of 89 experts in cardiac sarcoidosis (89 in round 1 and 75 in round 2) participated, representing 61 centers in 13 countries. Consensus was reached on 22 of 46 items (48%) in round 1 and 21 of 29 items (72%) in round 2. There was a low threshold to order advanced cardiac imaging for new rhythm abnormalities or ventricular dysfunction detected on echocardiography in patients with established extracardiac sarcoidosis. 18F-fluorodeoxyglucose (FDG) positron emission tomography was an important co-primary modality with cardiac magnetic resonance (CMR) for initial diagnosis. If CMR was the first test, there was consensus to proceed to FDG-positron emission tomography after any abnormal CMR result or even after normal CMR result in the setting of moderate or high pretest probability for cardiac sarcoidosis. There was consensus that late gadolinium enhancement quantification was important, but there was no consensus on the threshold of risk or on how best to quantify late gadolinium enhancement. Similarly, reduction in FDG uptake was an important factor in guiding treatment response, but there was no consensus on how to best quantify FDG uptake or what constituted an adequate radiographic response. Several consensus areas for cardiac imaging in suspected and established cardiac sarcoidosis were identified. This consensus study identified areas of priority for future prospective, controlled, multicenter research studies.

OBJECTIVE:Patients with workers' compensation (WC) claims are reported to demonstrate poorer surgical outcomes after lumbar spine surgery. However, outcomes after anterior cervical discectomy and fusion (ACDF) in WC patients remain debatable. The authors aimed to compare outcomes between a propensity score-matched population of WC and non-WC patients who underwent ACDF.METHODS:Patients who underwent 1- to 4-level ACDF were retrospectively reviewed from the prospectively maintained Quality Outcomes Database (QOD). After propensity score matching, 1-year patient satisfaction, physical disability (Neck Disability Index [NDI]), pain (visual analog scale [VAS]), EQ-5D, and return to work were compared between WC and non-WC cohorts.RESULTS:A total of 9957 patients were included (9610 non-WC and 347 WC patients). Patients in the WC cohort were significantly younger (50 ± 9.1 vs 56 ± 11.4 years, p < 0.001), less educated, and were more frequently male, non-Caucasian, and active smokers (29.1% vs 18.1%, p < 0.001), with greater baseline VAS and NDI scores and poorer quality of life (p < 0.001). One-year postoperative improvements in VAS, NDI, EQ-5D, and return-to-work rates and satisfaction were all significantly worse for WC compared with non-WC patients. After adjusting for baseline differences via propensity score matching, WC versus non-WC patients continued to demonstrate worse 3- and 12-month VAS neck pain and NDI (p = 0.010), satisfaction (χ2 = 4.03, p = 0.045), and delayed return to work (9.3 vs 5.7 weeks, p < 0.001).CONCLUSIONS:WC status was associated with greater 1-year residual disability and axial pain along with delayed return to work, without any difference in quality of life despite having fewer comorbidities and being a younger population. Further studies are needed to determine the societal impact that WC claims have on healthcare delivery in the setting of ACDF.

Dysregulations of blood clot breakdown (fibrinolysis) during vascular trauma can lead to excessive blood loss. Tranexamic acid (TXA) is an inhibitor of fibrinolysis that works by blocking the interaction between plasminogen and fibrin degradation products (FDPs) - a key step in fibrinolysis. Despite the widespread usage, there are no tests available in a clinical setting to monitor TXA levels. We developed a fluorescence resonance energy transfer (FRET)-based assay to quantify TXA concentrations in plasma by using 1) fluorescently labeled plasminogen, and 2) FDPs labeled with a fluorescence quencher. Once plasminogen binds the FDPs, the fluorescent signal is quenched. TXA causes plasminogen to dissociate from the FDPs, thus increasing fluorescence signal in a dosedependent manner. The dose response was sensitive between 1 and 100 mu M (0.16 and 15.7 mg/L). The intraassay and interassay variabilities were determined to be 5.7 % and 3.0 %, respectively. Limit of detection was estimated to be 0.28 mu M (0.044 mg/L). When tested for measuring known levels of TXA added to plasma samples, the ratio between measured and expected TXA concentration was 1.0151. Our study demonstrates a novel assay that can rapidly quantify TXA concentrations in plasma samples, thus demonstrating its potential as an inhospital tool.

BACKGROUND:Effective hemorrhage protocols prioritize immediate hemostatic resuscitation to manage hemorrhagic shock. Prehospital resuscitation using blood products, such as whole blood or alternatively dried plasma in its absence, has the potential to improve outcomes in hemorrhagic shock patients. However, integrating blood products into prehospital care poses substantial logistical challenges due to issues with storage, transport, and administration in field environments. STUDY DESIGN AND METHODS:We utilized hemostatic assays and advanced biophysical techniques, such as calorimetry, infrared spectoscopy, dynamic light scattering, and biolayer interferometry, to compare the functional and structural properties of freeze-dried plasma (FDP; OctaplasLG Powder, Octapharma AB) with those of fresh plasma controls. RESULTS:Hemostatic characterization of FDP revealed that clot formation properties and coagulation parameters were largely comparable to fresh plasma controls, with some variations observed in Von Willebrand factor-ADAMTS13 axis and fibrinolysis. No change to moisture content of FDP (~1% water content) was observed after 6-month storage at ambient conditions. Biophysical analyses of FDP during transfusion demonstrated spontaneous exothermic mixing of FDP in plasma, a dilution effect from saline, as well as comparable stability to plasma controls. Quantification of ligand-binding affinities of platelet receptors activated GPIIbIIIa and GPIbα showed comparable binding properties to plasma controls. CONCLUSION:Our results show that FDP exhibits hemostatic functionality and protein stability on par with fresh plasma, as assessed by novel, highly sensitive techniques. FDP therefore represents a viable alternative to conventional plasma in damage control resuscitation, offering significant logistical and storage advantages for prehospital and remote applications, especially in scenarios where whole blood is unavailable.

Frequent SARS-CoV-2 vaccination in vulnerable populations has raised concerns that this may contribute to T cell exhaustion, which could negatively affect the quality of immune protection. Herein, we examined the impact of repeated SARS-CoV-2 vaccination on T cell phenotypic and functional exhaustion in frail older adults in long-term care (n = 23), individuals on immunosuppressive drugs (n = 10), and healthy adults (n = 43), in Canada. Spike-specific CD4+ and CD8+ T cell levels did not decline in any cohort following repeated SARS-CoV-2 vaccination, nor did the expression of exhaustion markers on spike-specific or total T cells increase. T cell production of multiple cytokines (i.e. polyfunctionality) in response to the spike protein of SARS-CoV-2 did not decline in any cohort following repeated vaccination. None of the cohorts displayed elevated levels of terminally differentiated T cells following multiple SARS-CoV-2 vaccinations. Thus, repeated SARS-CoV-2 vaccination was not associated with increased T cell exhaustion in older frail adults, immunosuppressed individuals, or healthy adults.

Background Sepsis is associated with dysregulation of procoagulant, anticoagulant, and fibrinolytic pathways. Aims To compare the measurements of coagulation activation, clot formation, stabilization, and lysis between rotational thromboelastometry (ROTEM) and standard coagulation tests (SCTs) on patients with early sepsis (SP) and healthy controls (HC). Methods This observational study included 30 SP and 30 HC. At study inclusion, SCTs and ROTEM analyses were conducted. A modified ROTEM with exogenous tPA was used to investigate fibrinolysis resistance. Results SP had longer prothrombin time, higher fibrinogen levels and lower platelet count compared to HC. On ROTEM, clotting initiation was longer in SP than in HC but median clotting time maintained within reference ranges. SP had higher maximum velocity of clot formation, clot firmness, elasticity, and platelet component than HC. Clot lysis indices (CLI) were higher in EXTEM and APTEM (without and with added tPA) in SP compared to HC. The difference in CLI between APTEM and EXTEM was lower for both native and tPA-spiked samples in SP compared with HC. Conclusions While SCTs suggest SP are hypocoagulable, VET revealed normal coagulation initiation in more than 80% of SP. Compared to HC, SP had increased clot propagation, firmness and elasticity, and decreased platelet-mediated clot retraction and lysis. In sepsis, VET provide more comprehensive information about hemostatic changes than SCTs.

Anemia has been shown to be a modifiable pre-operative, patient factor associated with outcome following arthroplasty. The aims of this retrospective study were to (1) ascertain the prevalence of preoperative anemia in patients undergoing primary and revision hip and knee arthroplasty at a tertiary referral center and (2) to test the association with outcome and whether it differs between primary and revision cases. All hip and knee primary and revision arthroplasties performed at a Canadian academic, tertiary-care, arthroplasty center between 2012 and 2017 were included in this study. The study group consisted of 5944 patients, of which 5251 were primary Total Hip and Knee Arthroplasties or Hip Resurfacings and 693 were revision arthroplasties (65

OBJECTIVE The impact of mental health comorbidities on outcomes after lumbar spine surgery in workers’ compensation (WC) patients has not been robustly explored. The goal of this study was to examine the impact of mental health comorbidities on pain, disability, quality of life, and return to work after lumbar spine surgery in WC patients. METHODS A nationwide, prospective surgical outcomes registry (National Neurosurgery Quality Outcomes Database [N2QOD]) was queried for all patients who underwent 1- to 4-level lumbar decompression and/or fusion from 2012 to 2021. Patients were stratified on the basis of compensation status into non-WC (25,507) and WC (1018) cohorts. Baseline demographic data, perioperative safety data, and patient-reported outcome measures were compared between groups. The WC cohort was further subdivided on the basis of mental health status into patients with anxiety and depression (n = 107) and those without anxiety and depression (n = 911). Propensity matching was used to generate parity between these subgroups, generating 214 patients (107 pairs) for analysis. Perioperative safety, facility utilization, 1-year patient-reported outcomes (back and leg pain, disability, and quality of life), and return to work were measured as a function of WC and mental health comorbidity status. RESULTS A total of 26,525 patients (25,507 non-WC and 1018 WC) who underwent 1- to 4-level lumbar spine surgery were reviewed. WC patients were younger, healthier (lower American Society of Anesthesiologists class), more likely to be minorities, less educated, and more likely to smoke and had greater baseline back pain, disability, and quality of life compared to non-WC patients. The prevalence of anxiety and depression was similar between groups (11%). WC patients had worse outcomes for all measures and lower rates of return to work compared to non-WC patients. WC patients with anxiety and depression demonstrated even greater disparities in all outcomes. After propensity matching, WC patients with anxiety and depression continued to demonstrate significantly worse outcomes in comparison to WC patients without anxiety and depression. CONCLUSIONS Disparities in outcomes after lumbar spine surgery in WC patients are exacerbated in patients with anxiety and depression. WC patients with mental health comorbidities receive the least benefit from lumbar spine surgery and may represent the most vulnerable subset of patients with spine pathology. Addressing mental health comorbidities preoperatively may represent an opportunity for valuable resource allocation and surgical optimization in the WC population.

Introduction C4d immunostaining of endomyocardial biopsies (EMB) is necessary for the pathologic diagnosis of antibody-mediated rejection in heart transplant (HTx) patients. However, prior studies of C4d positive EMBs have shown contradictory findings on clinical outcomes. In this study, we examined whether C4d positive EMBs in the presence of positive donor specific antibodies (DSA) are associated with worse clinical outcomes. Hypothesis C4d and DSA positive HTx patients will have worse clinical outcomes compared to the three other C4d/DSA groups. Methods This was a single center, retrospective study of endomyocardial biopsies (EMB) performed between January 2002 and February 2023 at University of California, San Diego Health. Patient data and clinical outcomes of death, cardiac allograft dysfunction (<50% LVEF), and clinically significant CAV (>CAV ISHLT grade 2) were collected. Categorical variables were expressed as frequency and percentage and compared with the use of either Pearson's chi-square or Fisher's exact test as appropriate. P < 0.05 was considered significant. Results A total of 6,294 EMBs from 612 adult HTx patients were analyzed. HTx patients were categorized into four groups based on C4d and DSA positivity: C4d+/DSA+ (n=31), C4d+/DSA- (n=35), C4d-/DSA+ (n=100), and C4d-/DSA- (n=386). There was no significant difference in all-cause death in the four C4d/DSA groups. However, C4d+/DSA+ patients showed significantly higher rates of cardiac death (p=0.01; Table) and cardiac allograft dysfunction (p<0.001) compared to the C4d-/DSA- group. There was no significant difference in clinical outcomes in the C4d+/DSA+ group compared to the C4d+/DSA- group in pairwise comparisons. We also did not observe any significant difference in the rate of CAV in the four C4d/DSA groups. Conclusions The C4d+/DSA+ group demonstrated significantly higher rates of cardiac death and allograft dysfunction compared to the C4d-/DSA- group.

Motivation: The intrinsic “black-blood (BB)” property in 3D TSE is insufficient for vessel wall imaging and other neuroimaging applications. Additional blood suppression preparations can diminish T1 weighting and SNR. Goal(s): To develop and validate a new approach compatible with 3D TSE to enhance BB effects while minimizing sacrifice in T1 weighting and overall SNR. Approach: An interleaved flow-sensitive dephasing scheme was developed, and verified in healthy volunteers and assessed in 32 patients with one of four neurological diseases. Results: iFSD-SPACE achieved the lowest lumen SNR and the highest wall-lumen CNR. iFSD-SPACE yielded significantly higher white-matter SNR and gray-to-white matter CNR than DANTE and MSDE. Impact: iFSD is a 3D TSE-compatible blood flow suppression technique that overcomes the limitations of existing BB magnetization preparation methods and holds the potential to greatly enhance the performance of 3D TSE in several neuroimaging applications.

Endomyocardial biopsies (EMB) are invasive procedures performed in heart transplant (HTx) patients for surveillance of acute rejection. However, patient preferences for replacing EMBs with noninvasive assays in the context of potential institutional policy changes are unknown. A mixed-methods design was used with 28 semi-structured patient interviews and 123 self-administered online survey questionnaires in English and Spanish between January to June 2023. Additionally, we performed semi-structured interviews with 18 HTx team members. Three dominant themes were identified: alleviating patient anxiety and distress, consistent patient-provider communication, and strong interpersonal trust with the HTx team. We found that strong interpersonal trust with the HTx team by the patients was more highly prioritized than their own opinions on whether to replace EMBs with noninvasive assays. Thus, HTx patients often considered surveillance EMBs important to their care (93%), based on the recommendations provided by their HTx team. HTx faculty physicians stated that more multicenter trials are needed prior to replacing EMBs with noninvasive assays. In conclusion, patients identified strong interpersonal trust with HTx team members to justify patient adapted paternalism, where the provider decides in accordance with the patient's situation, as their preferred shared decision-making paradigm when considering institutional policy on surveillance EMBs.

Dementia is a significant global health issue that is exacerbated by an aging population. Imaging plays an established role in the evaluation of patients with neurocognitive disorders such as dementia. In current clinical practice, magnetic resonance imaging (MRI) and positron emission tomography (PET) are primary imaging modalities used separately but in concert to help diagnose and classify dementia. The clinical applications of PET/MRI hybrid imaging in dementia are an active area of research, particularly given the continued emergence of functional MRI (fMRI) and amyloid PET tracers. This narrative review provides a comprehensive overview of the rationale and current evidence for PET/MRI hybrid dementia imaging from 2018 to 2023. Hybrid imaging offers advantages in the accuracy of characterizing neurodegenerative disorders, and future research will need to address the cost of integrated PET/MRI systems compared to stand-alone scanners, the development of new biomarkers, and image correction techniques.