Frugal and Translatable [15O]O2 Production for Human Inhalation with Direct Delivery from the Cyclotron to a Hybrid PET/MR.

Oxygen-15 (ß+, t1/2 = 122 s) radiolabeled diatomic oxygen, in conjunction with positron emission tomography, is the gold standard to quantitatively measure the metabolic rate of oxygen consumption in the living human brain. We present herein a protocol for safe and effective delivery of [15O]O2 over 200 m to a human subject for inhalation. A frugal quality control testing procedure was devised and validated. This protocol can act as a blueprint for other sites seeking to implement similar imaging programs.

Vascular Endothelial Growth Factor-C Treatment Enhances Cerebrospinal Fluid Outflow during Toxoplasma gondii Brain Infection but Does Not Improve Cerebral Edema.

Cerebral edema frequently develops in the setting of brain infection and can contribute to elevated intracranial pressure, a medical emergency. How excess fluid is cleared from the brain is not well understood. Previous studies have shown that interstitial fluid is transported out of the brain along perivascular channels that collect into the cerebrospinal fluid (CSF)-filled subarachnoid space. CSF is then removed from the central nervous system through venous and lymphatic routes. The current study tested the hypothesis that increasing lymphatic drainage of CSF would promote clearance of cerebral edema fluid during infection with the neurotropic parasite Toxoplasma gondii. Fluorescent microscopy and magnetic resonance imaging was used to show that C57BL/6 mice develop vasogenic edema 4 to 5 weeks after infection with T. gondii. Tracer experiments were used to evaluate how brain infection affects meningeal lymphatic function, which demonstrated a decreased rate in CSF outflow in T. gondii-infected mice. Next, mice were treated with a vascular endothelial growth factor (VEGF)-C-expressing viral vector, which induced meningeal lymphangiogenesis and improved CSF outflow in chronically infected mice. No difference in cerebral edema was observed between mice that received VEGF-C and those that rececived sham treatment. Therefore, although VEGF-C treatment can improve lymphatic outflow in mice infected with T. gondii, this effect does not lead to increased clearance of edema fluid from the brains of these mice.

Myocardial glucose suppression may interfere with the detection of inflammatory cells with FDG-PET as suggested in a canine model of myocardial infarction.

BACKGROUND: After myocardial infarction, fibrosis and an ongoing dysregulated inflammatory response have been shown to lead to adverse cardiac remodeling. FDG PET is an imaging modality sensitive to inflammation as long as suppression protocols are observed while gadolinium enhanced MRI can be used to determine extracellular volume (ECV), a measure of fibrosis. In patients, glucose suppression is achieved variously through a high fat diet, fasting and injection of heparin. To emulate this process in canines, a heparin injection and lipid infusion are used, leading to similar fatty acids in the blood. The aim of this study was to examine the effect of glucose suppression on the uptake of FDG in the infarcted myocardial tissue and also on the determination of ECV in both the infarcted tissue and in the myocardium remote to the zone of infarction during a long constant infusion of FDG and Gd-DTPA. RESULTS: Extracellular volume was affected neither by suppression nor the length of the constant infusion in remote and infarcted tissue. Metabolic rate of glucose in infarcted tissue decreased during and after suppression of glucose uptake by lipid infusion and heparin injection. An increase in fibrosis and inflammatory cells was found in the center of the infarct as compared to remote tissue. CONCLUSION: The decrease in the metabolic rate of glucose in the infarcted tissue suggests that inflammatory cells may be affected by glucose suppression through heparin injection and lipid infusion.

Serial D-dimers after anticoagulant cessation in unprovoked venous thromboembolism: Data from the REVERSE cohort study.

INTRODUCTION: While several risk stratification tools have been developed to predict the risk of recurrence in patients with an unprovoked venous thromboembolism (VTE), only 1 in 4 patients are categorized as low-risk. Rather than a one-time measure, serial D-dimer assessment holds promise to enhance the prediction of VTE recurrence after oral anticoagulant (OAC) cessation. METHODS: Using the REVERSE cohort, we compared VTE recurrence among patients with normal D-dimer levels (<490 ng/mL among males under age 70, <500 ng/mL in others) at OAC cessation and 1-month follow-up, to those with an elevated D-dimer level at either timepoint. We also evaluated VTE recurrence based on absolute increase in D-dimer levels between the two timepoints (e.g., ∆D-dimer) according to quartiles. RESULTS: Among 214 patients with serial D-dimer levels measured at OAC cessation and 1-month follow-up, an elevated D-dimer level at either timepoint was associated with a numerically higher risk of recurrent VTE than patients with normal D-dimer levels at both timepoints (6.9 % vs. 4.2 % per year, hazard ratio 1.6; 95 % CI 0.9-2.7). Among women with <2 HERDOO2 criteria, a normal D-dimer level at both timepoints predicted a very low risk of recurrent VTE during follow-up (0.8 % per year, 95 % CI 0.1-2.8). Irrespective of baseline value, recurrent VTE risk was only 3 % per year (95 % CI 1.4-5.6) among patients in the lowest ∆D-dimer quartile. CONCLUSION: Serial normal D-dimer levels have the potential to identify patients at a low risk of recurrent VTE. In addition, ∆D-dimer, irrespective of its elevation above cutoff threshold, may predict recurrent VTE.

Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: a systematic review and meta-analysis of individual participant data.

We aimed to assess the relationship between residual pulmonary vascular obstruction (RPVO) on planar lung scan after completion of at least 3 months of anticoagulant therapy for acute pulmonary embolism (PE) and the risk of recurrent venous thromboembolism (VTE) or death due to PE one year after treatment discontinuation. The systematic review was registered with the International Prospective Registry of Systematic Reviews (PROSPERO: CRD42017081080). The primary outcome measure was to generate a pooled estimate of the rate of recurrent VTE at one year in patient with RPVO diagnosed on planar lung scan after discontinuation of at least 3 months of anticoagulant treatment for an acute PE. Individual data were obtained for 809 patients. RPVO (ie, obstruction >0%) was found in 407 patients (50.3%) after a median of 6.6 months of anticoagulant therapy for a first acute PE. Recurrent VTE or death due to PE occurred in 114 patients (14.1%), for an annual risk of 6.4% (95% confidence interval, 4.7%-8.6%). Out of the 114 recurrent events, 63 occurred within one year after discontinuation of anticoagulant therapy corresponding to a risk of 8.1% (6.4%-9.8%) at 1 year. The risk of recurrent VTE at one year was 5.8% (4.4-7.2) in participants with RPVO <5%, vs 11.7% (9.5-13.8) in participants with RPVO ≥5%. RPVO is a significant predictor of the risk of recurrent venous thromboembolism. However, the risk of recurrent events remains too high in patients without residual perfusion defect for it to be used as a stand-alone test to decide on anticoagulation discontinuation.

Performance and Head-to-Head Comparison of Three Clinical Models to Predict Occurrence of Postthrombotic Syndrome: A Validation Study.

OBJECTIVE: The SOX-PTS, Amin, and Méan models are three different clinical prediction scores stratifying the risk for postthrombotic syndrome (PTS) development in patients with acute deep vein thrombosis (DVT) of the lower limbs. Herein, we aimed to assess and compare these scores in the same cohort of patients. METHODS: We retrospectively applied the three scores in a cohort of 181 patients (196 limbs) who participated in the SAVER pilot trial for an acute DVT. Patients were stratified into PTS risk groups using positivity thresholds for high-risk patients as proposed in the derivation studies. All patients were assessed for PTS 6 months after index DVT using the Villalta scale. We calculated the predictive accuracy for PTS and area under receiver operating characteristic (AUROC) curve for each model. RESULTS: The Méan model was the most sensitive (sensitivity 87.7%; 95% confidence interval [CI]: 77.2-94.5) with the highest negative predictive value (87.5%; 95% CI: 76.8-94.4) for PTS. The SOX-PTS was the most specific score (specificity 97.5%; 95% CI: 92.7-99.5) with the highest positive predictive value (72.7%; 95% CI: 39.0-94.0). The SOX-PTS and Méan models performed well for PTS prediction (AUROC: 0.72; 95% CI: 0.65-0.80 and 0.74; 95% CI: 0.67-0.82), whereas the Amin model did not (AUROC: 0.58; 95% CI: 0.49-0.67). CONCLUSION: Our data support that the SOX-PTS and Méan models have good accuracy to stratify the risk for PTS.

The meningeal transcriptional response to traumatic brain injury and aging.

Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders, however, we still lack fundamental knowledge about meningeal biology. Here, we utilized high-throughput RNA sequencing (RNA-seq) techniques to investigate the transcriptional response of the meninges to traumatic brain injury (TBI) and aging in the sub-acute and chronic time frames. Using single-cell RNA sequencing (scRNA-seq), we first explored how mild TBI affects the cellular and transcriptional landscape in the meninges in young mice at one-week post-injury. Then, using bulk RNA-seq, we assessed the differential long-term outcomes between young and aged mice following TBI. In our scRNA-seq studies, we highlight injury-related changes in differential gene expression seen in major meningeal cell populations including macrophages, fibroblasts, and adaptive immune cells. We found that TBI leads to an upregulation of type I interferon (IFN) signature genes in macrophages and a controlled upregulation of inflammatory-related genes in the fibroblast and adaptive immune cell populations. For reasons that remain poorly understood, even mild injuries in the elderly can lead to cognitive decline and devastating neuropathology. To better understand the differential outcomes between the young and the elderly following brain injury, we performed bulk RNA-seq on young and aged meninges 1.5 months after TBI. Notably, we found that aging alone induced upregulation of meningeal genes involved in antibody production by B cells and type I IFN signaling. Following injury, the meningeal transcriptome had largely returned to its pre-injury signature in young mice. In stark contrast, aged TBI mice still exhibited upregulation of immune-related genes and downregulation of genes involved in extracellular matrix remodeling. Overall, these findings illustrate the dynamic transcriptional response of the meninges to mild head trauma in youth and aging.

The risk of major bleeding in patients with factor V Leiden or prothrombin G20210A gene mutation while on extended anticoagulant treatment for venous thromboembolism.

BACKGROUND: Thrombophilia predisposes to venous thromboembolism (VTE) because of acquired or hereditary factors. Among them, it has been suggested that gene mutations of the factor V Leiden (FVL) or prothrombin G20210A mutation (PGM) might reduce the risk of bleeding, but little data exist for patients treated using anticoagulants. OBJECTIVES: To assess whether thrombophilia is protective against bleeding. METHODS: This multicentre, multinational, prospective cohort study evaluated adults receiving long-term anticoagulants after a VTE event. We analyzed the incidence of major bleeding as the primary outcome, according to the genotype for FVL and PGM (wild-type and heterozygous/homozygous carriers). RESULTS: Of 2260 patients with genotype testing, during a median follow-up of 3 years, 106 patients experienced a major bleeding event (17 intracranial and 7 fatal). Among 439 carriers of FVL, 19 experienced major bleeding and there were no differences between any mutation vs wild-type (hazard ratio [HR], 0.89 [0.53-1.49]; p = .66). The comparison of major bleeding events between the 158 patients with any-PGM mutation (heterozygous or homozygous) vs wild-type also showed a nonstatistically significant difference with HR of 0.53 (0.19-1.43), p = .21. However, multivariate analysis demonstrated that major bleeds or clinically relevant nonmajor bleeding were statistically less likely for patients with either FVL and/or PGM compared with patients with both wild-type factor V and prothrombin genes (HR, 0.73; 95% CI = 0.55-0.97; p = .03). CONCLUSION: This study demonstrates that thrombophilia, defined as the presence of either FVL or the prothrombin G20210A mutation, is related with a lower rate of major/clinically relevant nonmajor bleeding while on anticoagulants in the extended treatment for VTE.

Protease-activated receptor 2 (PAR2)-targeting peptide derivatives for positron emission tomography (PET) imaging.

The proteolytically-activated G protein-coupled receptor (GPCR) protease-activated receptor 2 (PAR2), is implicated in various cancers and inflammatory diseases. Synthetic ligands and in vitro imaging probes targeting this receptor have been developed with low nanomolar affinity, however, no in vivo imaging probes exist for PAR2. Here, we report the strategic design, synthesis, and biological evaluation of a series of novel 4-fluorobenzoylated PAR2-targeting peptides derived from 2f-LIGRLO-NH2 (2f-LI-) and Isox-Cha-Chg-Xaa-NH2 (Isox-) peptide families, where the 4-fluorobenzoyl moiety acts as the 19F-standard of an 18F-labeled probe for potential use in in vivo imaging. We found that several of the 4-fluorobenzoylated peptides from the 2f-LI-family exhibited PAR2 selectivity with moderate potency (EC50 = 151-252 nM), whereas several from the Isox-family exhibited PAR2 selectivity with high potency (EC50 = 13-42 nM). Our lead candidate, Isox-Cha-Chg-Ala-Arg-Dpr(4FB)-NH2 (EC50 = 13 nM), was successfully synthesized with fluorine-18 with a radiochemical yield of 37%, radiochemical purity of >98%, molar activity of 20 GBq/µmol, and an end of synthesis time of 125 min. Biodistribution studies and preliminary PET imaging of the tracer in mice showed predominantly renal clearance. This 18F-labeled tracer is the first reported PAR2 imaging agent with potential for use in vivo. Future work will explore the use of this tracer in cancer xenografts and inflammation models involving upregulation of PAR2 expression.

Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain.

The discovery of meningeal lymphatic vessels that drain the CNS has prompted new insights into how immune responses develop in the brain. In this study, we examined how T cell responses against CNS-derived antigen develop in the context of infection. We found that meningeal lymphatic drainage promotes CD4+ and CD8+ T cell responses against the neurotropic parasite Toxoplasma gondii in mice, and we observed changes in the dendritic cell compartment of the dural meninges that may support this process. Indeed, we found that mice chronically, but not acutely, infected with T. gondii exhibited a significant expansion and activation of type 1 and type 2 conventional dendritic cells (cDC) in the dural meninges. cDC1s and cDC2s were both capable of sampling cerebrospinal fluid (CSF)-derived protein and were found to harbor processed CSF-derived protein in the draining deep cervical lymph nodes. Disrupting meningeal lymphatic drainage via ligation surgery led to a reduction in CD103+ cDC1 and cDC2 number in the deep cervical lymph nodes and caused an impairment in cDC1 and cDC2 maturation. Concomitantly, lymphatic vessel ligation impaired CD4+ and CD8+ T cell activation, proliferation, and IFN-γ production at this site. Surprisingly, however, parasite-specific T cell responses in the brain remained intact following ligation, which may be due to concurrent activation of T cells at non-CNS-draining sites during chronic infection. Collectively, our work reveals that CNS lymphatic drainage supports the development of peripheral T cell responses against T. gondii but remains dispensable for immune protection of the brain.

Microglial STAT1-sufficiency is required for resistance to toxoplasmic encephalitis.

Toxoplasma gondii is a ubiquitous intracellular protozoan parasite that establishes a life-long chronic infection largely restricted to the central nervous system (CNS). Constant immune pressure, notably IFN-γ-STAT1 signaling, is required for preventing fatal pathology during T. gondii infection. Here, we report that abrogation of STAT1 signaling in microglia, the resident immune cells of the CNS, is sufficient to induce a loss of parasite control in the CNS and susceptibility to toxoplasmic encephalitis during the early stages of chronic infection. Using a microglia-specific genetic labeling and targeting system that discriminates microglia from blood-derived myeloid cells that infiltrate the brain during infection, we find that, contrary to previous in vitro reports, microglia do not express inducible nitric-oxide synthase (iNOS) during T. gondii infection in vivo. Instead, transcriptomic analyses of microglia reveal that STAT1 regulates both (i) a transcriptional shift from homeostatic to "disease-associated microglia" (DAM) phenotype conserved across several neuroinflammatory models, including T. gondii infection, and (ii) the expression of anti-parasitic cytosolic molecules that are required for eliminating T. gondii in a cell-intrinsic manner. Further, genetic deletion of Stat1 from microglia during T. gondii challenge leads to fatal pathology despite largely equivalent or enhanced immune effector functions displayed by brain-infiltrating immune populations. Finally, we show that microglial STAT1-deficiency results in the overrepresentation of the highly replicative, lytic tachyzoite form of T. gondii, relative to its quiescent, semi-dormant bradyzoite form typical of chronic CNS infection. Our data suggest an overall protective role of CNS-resident microglia against T. gondii infection, illuminating (i) general mechanisms of CNS-specific immunity to infection (ii) and a clear role for IFN-STAT1 signaling in regulating a microglial activation phenotype observed across diverse neuroinflammatory disease states.

Postthrombotic syndrome and quality of life after deep vein thrombosis in patients treated with edoxaban versus warfarin.

Background: Postthrombotic syndrome (PTS) is a long-term complication after deep vein thrombosis (DVT) and can affect quality of life (QoL). Pathogenesis is not fully understood but inadequate anticoagulant therapy with vitamin K antagonists is a known risk factor for the development of PTS. Objectives: To compare the prevalence of PTS after acute DVT and the long-term QoL following DVT between patients treated with edoxaban or warfarin. Methods: We performed a long-term follow-up study in a subset of patients with DVT who participated in the Hokusai-VTE trial between 2010 and 2012 (NCT00986154). Primary outcome was the prevalence of PTS, defined by the Villalta score. The secondary outcome was QoL, assessed by validated disease-specific (VEINES-QOL) and generic health-related (SF-36) questionnaires. Results: Between 2017 and 2020, 316 patients were enrolled in 26 centers in eight countries, of which 168 (53%) patients had been assigned to edoxaban and 148 (47%) to warfarin during the Hokusai-VTE trial. Clinical, demographic, and thrombus-specific characteristics were comparable for both groups. Mean (SD) time since randomization in the Hokusai-VTE trial was 7.0 (1.0) years. PTS was diagnosed in 85 (51%) patients treated with edoxaban and 62 (42%) patients treated with warfarin (adjusted odds ratio 1.6, 95% CI 1.0-2.6). Mean differences in QoL scores between treatment groups were not clinically relevant. Conclusion: Contrary to our hypothesis, the prevalence of PTS tended to be higher in patients treated with edoxaban compared with warfarin. No differences in QoL were observed. Further research is warranted to unravel the role of anticoagulant therapy on development of PTS.

Investigating the genetic architecture of eye colour in a Canadian cohort.

Eye color is highly variable in populations with European ancestry, ranging from low to high quantities of melanin in the iris. Polymorphisms in the HERC2/OCA2 locus have the largest effect on eye color in these populations, although other genomic regions also influence eye color. We performed genome-wide association studies of eye color in a Canadian cohort of European ancestry (N = 5,641) and investigated candidate causal variants. We uncovered several candidate causal signals in the HERC2/OCA2 region, whereas other loci likely harbor a single causal signal. We observed colocalization of eye color signals with the expression or methylation profiles of cultured primary melanocytes. Genetic correlations of eye and hair color suggest high genome-wide pleiotropy, but locus-level differences in the genetic architecture of both traits. Overall, we provide a better picture of the polymorphisms underpinning eye color variation, which may be a consequence of specific molecular processes in the iris melanocytes.

Predicting major bleeding during extended anticoagulation for unprovoked or weakly provoked venous thromboembolism.

No clinical prediction model has been specifically developed or validated to identify patients with unprovoked venous thromboembolism (VTE) who are at high risk of major bleeding during extended anticoagulation. In a prospective multinational cohort study of patients with unprovoked VTE receiving extended anticoagulation after completing ≥3 months of initial treatment, we derived a new clinical prediction model using a multivariable Cox regression model based on 22 prespecified candidate predictors for the primary outcome of major bleeding. This model was then compared with modified versions of 5 existing clinical scores. A total of 118 major bleeding events occurred in 2516 patients (annual risk, 1.7%; 95% confidence interval [CI], 1.4-2.1). The incidences of major bleeding events per 100 person-years in high-risk and non-high-risk patients, respectively, were 3.9 (95% CI, 3.0-5.1) and 1.1 (0.8-1.4) using the newly derived creatinine, hemoglobin, age, and use of antiplatelet agent (CHAP) model; 3.3 (2.6-4.1) and 1.0 (0.7-1.3) using modified ACCP score, 5.3 (0.6-19.2) and 1.7 (1.4-2.0) using modified RIETE score, 3.1 (2.3-3.9) and 1.1 (0.9-1.5) using modified VTE-BLEED score, 5.2 (3.3-7.8) and 1.5 (1.2-1.8) using modified HAS-BLED score, and 4.8 (1.3-12.4) and 1.7 (1.4-2.0) using modified outpatient bleeding index score. Modified versions of the ACCP, VTE-BLEED, and HAS-BLED scores help identify patients with unprovoked VTE who are at high risk of major bleeding and should be considered for discontinuation of anticoagulation after 3 to 6 months of initial treatment. The CHAP model may further improve estimation of bleeding risk by using continuous predictor variables, but external validation is required before its implementation in clinical practice.

Low cost and open source purification apparatus for GMP [13N]Ammonia production.

Nitrogen-13 labeled ammonia ([13N]NH3) has been used for myocardial perfusion imaging with Positron Emission Tomography for decades. Recent increases to regulatory oversight have led to stricter adherence to Good Manufacturing Practice (GMP) when producing this short half-life (9.97 min) radiopharmaceutical. This has increased production costs. Our cyclotron facility initially developed a manual GMP production method, but it was prone to human error. With increased costs in mind, we developed and validated an Arduino-based device to purifying [13N]NH3 for clinical use. Construction, programming, and GMP validation results are discussed. The automated method was found to produce equivalent quality radiopharmaceutical but was more reproducible and robust.

Prevention of post-thrombotic syndrome with rosuvastatin: A multicenter randomized controlled pilot trial (SAVER).

BACKGROUND: Post-thrombotic syndrome (PTS) is one of the most frequent complications of venous thromboembolism (VTE) leading to considerable morbidity and cost. Apart from appropriate anticoagulation, there is no drug or medical intervention that helps to prevent PTS. We conducted a multicenter randomized controlled trial to determine whether rosuvastatin can prevent PTS. METHODS: 312 patients receiving standard anticoagulation for a newly diagnosed VTE were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days (n = 155) or no rosuvastatin (n = 157). At the last study visit (Day 180 ± 21), an independent observer who was blinded to study treatment performed a PTS assessment using the Villalta scale. The primary clinical outcome of the trial was mean Villalta score at Day 180. We also explored the presence of PTS as defined by Villalta score > 4 at Day 180. Patients mean age was 46.7 ± 10.8 years, 55.8% were female. RESULTS: At Day 180, the Villalta score was 3.5 ± 0.3 in the rosuvastatin arm vs. 3.3 ± 0.3 in the control arm (p = 0.59), and presence of PTS (Villalta >4) was 29.7% in the rosuvastatin arm vs. 25.5% in the control arm (p = 0.41). Secondary analyses showed no difference between trial arms for presence of severe PTS at Day 180 (2.0% vs. 2.7%, p = 1) and for changes in Villalta score between baseline and Day 180 (-3.7 ± 4.4 vs. -4.0 ± 5.0, p = 0.59). CONCLUSION: This randomized controlled pilot trial did not demonstrate efficacy of rosuvastatin to reduce Villalta score. Further studies with longer duration of exposure to rosuvastatin are needed. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02679664.

Intramyocardial Hemorrhage and the "Wave Front" of Reperfusion Injury Compromising Myocardial Salvage.

BACKGROUND: Reperfusion therapy for acute myocardial infarction (MI) is lifesaving. However, the benefit of reperfusion therapy can be paradoxically diminished by reperfusion injury, which can increase MI size. OBJECTIVES: Hemorrhage is known to occur in reperfused MIs, but whether hemorrhage plays a role in reperfusion-mediated MI expansion is not known. METHODS: We studied cardiac troponin kinetics (cTn) of ST-segment elevation MI patients (n = 70) classified by cardiovascular magnetic resonance to be hemorrhagic (70%) or nonhemorrhagic following primary percutaneous coronary intervention. To isolate the effects of hemorrhage from ischemic burden, we performed controlled canine studies (n = 25), and serially followed both cTn and MI size with time-lapse imaging. RESULTS: CTn was not different before reperfusion; however, an increase in cTn following primary percutaneous coronary intervention peaked earlier (12 hours vs 24 hours; P < 0.05) and was significantly higher in patients with hemorrhage (P < 0.01). In hemorrhagic animals, reperfusion led to rapid expansion of myocardial necrosis culminating in epicardial involvement, which was not present in nonhemorrhagic cases (P < 0.001). MI size and salvage were not different at 1 hour postreperfusion in animals with and without hemorrhage (P = 0.65). However, within 72 hours of reperfusion, a 4-fold greater loss in salvageable myocardium was evident in hemorrhagic MIs (P < 0.001). This paralleled observations in patients with larger MIs occurring in hemorrhagic cases (P < 0.01). CONCLUSIONS: Myocardial hemorrhage is a determinant of MI size. It drives MI expansion after reperfusion and compromises myocardial salvage. This introduces a clinical role of hemorrhage in acute care management, risk assessment, and future therapeutics.

External Validation of the Patient-Reported Villalta Scale for the Diagnosis of Postthrombotic Syndrome.

INTRODUCTION: The Villalta scale is the endorsed tool to diagnose and grade the severity of postthrombotic syndrome (PTS); however, assessing presence and severity of PTS is time-consuming and relies on both the clinician and patient's assessments. The patient-reported Villalta scale version 2 (PRV2) is a visually assisted form that enables patients to self-assess presence and severity of PTS. Herein, we report on external validation of this tool. METHODS: We assessed the agreement and kappa values of PRV2 to diagnose and assess severity of PTS compared with the original Villalta score in a cohort of 181 patients (196 limbs) who participated in the SAVER pilot randomized control trial. Presence of PTS was defined as PRV2 ≥5 or a Villalta score ≥5. RESULTS: PTS prevalence was 42% using PRV2 and 33% using the Villalta scale. The corresponding kappa and percentage agreement were 0.60 (95% confidence interval [CI]: 0.49-0.71) and 81% (95% CI: 76-87), respectively. Kappa values and percentage agreements between PRV2 and Villalta scale increased with increasing severity of PTS. The sensitivity of PRV2 to detect PTS of any severity was 84% (95% CI: 73-92) with a specificity of 79% (95% CI: 71-86). CONCLUSION: We conclude that the PRV2 is an acceptable tool for diagnosing and grading the severity of PTS.

Statins for venous event reduction in patients with venous thromboembolism: A multicenter randomized controlled pilot trial assessing feasibility.

BACKGROUND: Statins may reduce the risk for recurrent venous thromboembolism (VTE); however, no randomized trials have explored this hypothesis. We performed a pilot randomized trial to determine feasibility of recruitment for a larger trial of secondary VTE prevention with rosuvastatin. METHODS: Patients with a newly diagnosed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, receiving standard anticoagulation, were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days or no rosuvastatin for 6 months. RESULTS: Between November 2016 and December 2019, 3391 patients were assessed for eligibility in six centers. Of these patients, 1347 (39.7%) were eligible and approached for participation in the trial and 312 (23.1%) were randomized. The mean rate of randomization was 8.2 ± 4.3 patients per month. During follow-up, five recurrent VTE events were observed, three (1.9%) in the rosuvastatin group (two pulmonary embolism, one deep vein thrombosis), and two (1.3%) in the control group (two pulmonary embolism; P = 0.68). One major arterial event occurred in the rosuvastatin arm and none in the control arm (0.6% vs. 0%, P = 0.50). CONCLUSION: This pilot trial supports the feasibility of a larger scale randomized controlled trial to determine the efficacy of adjuvant rosuvastatin for the secondary prevention of VTE.