Type IV Hypersensitivity Reaction after Cyanoacrylate Venous Closure.

BACKGROUND: Nonthermal endovenous closure techniques are routinely utilized to treat superficial axial venous reflux. Cyanoacrylate closure is a safe and effective modality implemented for truncal closure. However, an adverse reaction of type IV hypersensitivity (T4H), unique to cyanoacrylate, is a known risk. This study aims to evaluate the real-world incidence of T4H and examine risk factors that may predispose its development. METHODS: A retrospective review between 2012- and 2022 was performed at four tertiary US institutions to examine patients who underwent cyanoacrylate vein closure of their saphenous veins. Patient demographics, comorbidities, CEAP (Clinical [C], Etiological [E], Anatomical [A], and Pathophysiological [P]) classification, and periprocedural outcomes were included. The primary endpoint was development of T4H post procedure. Logistic regression analysis for risk factors predictive of T4H was performed. Variables with a P-value of <0.05 were deemed significant. RESULTS: 595 patients underwent 881 cyanoacrylate venous closures. Mean age was 66.2 ± 14.9, and 66% of patients were female. There were 92 (10.4%) T4H events in 79 (13%) patients. Oral steroids were administered to 23% for persistent and/or severe symptoms. There were no systemic allergic reactions to cyanoacrylate. Multivariate analysis revealed younger age (P = 0.015), active smoking status (P = 0.033), and CEAP 3 (P < 0.001) and 4 (P = 0.005) classifications as independent risk factors associated with development of T4H. CONCLUSIONS: This real-world multicenter study shows the overall incidence of T4H to be 10%. CEAP 3 and 4 patients of younger age and smokers predicted a higher risk of T4H to cyanoacrylate.

Superior Clinical, Quality of Life, Functional, and Health Economic Outcomes with Pneumatic Compression Therapy for Lymphedema.

BACKGROUND: Pneumatic compression therapy is one of several options for the management of lymphedema. The lack of clarity around clinical outcomes, quality of life, cost of care, and its proper application, as a function of lymphedema complexity, limit its use in clinical practice. This is compounded by difficulties associated with insurance approval and uncertainty about the role of this modality in the treatment algorithm. The purpose of this study is to elucidate the healthcare economics and value of pneumatic compression therapy for lymphedema. METHODS: All patients who underwent treatment for lymphedema at a single institution were followed prospectively over a 2-year period. Patient demographics, comorbidities, treatment modality, and treatment efficacy were determined. Direct costs over the 2-year period, inclusive of hospitalization and device costs, SF-36 quality of life, and leg lymphedema complexity score (LLCS), were measured. RESULTS: A total of 128 patients were enrolled over a period of 3 years for a total of 232 extremities treated for secondary lymphedema. Pneumatic compression therapy was utilized for all patients and led to a 28% decrease in absolute limb volume (P < 0.001), decrease in body mass index (BMI) (P < 0.001), significant improvement in SF-36 quality of life in 7 out of 8 domains (P < 0.001), and a significant improvement in LLCS (P < 0.001) at 1 year. A subsequent decrease in hospitalization for lymphedema-associated complications saved over $3,200 per patient per year. CONCLUSIONS: Pneumatic compression therapy leads to improved clinical outcomes, quality of life, and functional status for clinically significant lymphedema. Significant per capita direct cost savings, a beneficial impact on pay for performance measures, and a reduction in lymphedema-related complications suggest that earlier adoption of this treatment modality may offer a superior value proposition to patients, physicians, hospitals, and the healthcare system.

Acute B-Cell Inhibition by Soluble Antigen Arrays Is Valency-Dependent and Predicts Immunomodulation in Splenocytes.

Antigen valency plays a fundamental role in directing the nature of an immune response to be stimulatory or tolerogenic. Soluble antigen arrays (SAgAs) are an antigen-specific immunotherapy that combats autoimmunity through the multivalent display of autoantigen. Although mechanistic studies have shown SAgAs to induce T- and B-cell anergy, the effect of SAgA valency has never been experimentally tested. Here, SAgAs of discrete antigen valencies were synthesized by click chemistry and evaluated for acute B-cell signaling inhibition as well as downstream immunomodulatory effects in splenocytes. Initial studies using the Raji B-cell line demonstrated SAgA valency dictated the extent of calcium flux. Lower valency constructs elicited the largest reductions in B-cell activation. In splenocytes from mice with experimental autoimmune encephalomyelitis, the same valency-dependent effects were evident in the downregulation of the costimulatory marker CD86. The reduction of calcium flux observed in Raji B-cells correlated strongly with downregulation in splenocyte CD86 expression after 72 h. Here, a thorough analysis of SAgA antigenic valency illustrates that low, but not monovalent, presentation of autoantigen was ideal for eliciting the most potent immunomodulatory effects.

Novel Geographic Thematic Study of the Largest Radiology Societies Globally: How Is Gender Structure Biased Within Editorial Boards?

OBJECTIVE. Radiology has traditionally been a male-dominated medical specialty, and this is also reflected in the authorship of radiology publications and the composition of radiology journal editorial boards. The purpose of this study was to quantify the extent of the gender disparities reflected within the journal editorial boards of the largest international radiologic societies. MATERIALS AND METHODS. Methods were crafted to generate a geographically based gender analysis of the editorial boards of the largest general radiologic societies globally. All editorial board members of journals that were published by societies included in the study and that had an impact factor of 1 or greater were assessed to determine the gender composition of the board and the research productivity and career advancement of its members. Analyzed metrics included gender, academic rank, departmental leadership positions, subspecialty, total number of peer-reviewed publications, total number of citations, the h-index, and total number of years of active research. RESULTS. Significant gender disparity was noted across the six journal editorial boards included. Overall, 80.87% of editorial board members were men and 19.13% were women. Men were more prevalent than women across all academic ranks. Male editorial board members had longer publishing careers (22.5 vs 18 years; p = 0.015), a higher total number of publications (110 vs 65 publications; p < 0.001), and a higher h-index (25 vs 19; p < 0.001) than their female counterparts. Female editorial board members at higher academic ranks were less represented on editorial boards and were also less likely to have formal departmental leadership titles. CONCLUSION. Editorial boards have significant gender disparities, with no specific geographic regional variation noted. Male editorial board members published more, had higher h-indexes, and held more departmental leadership positions than their female counterparts.

Synthetic aperture imaging in astronomy and aerospace: introduction.

Aperture synthesis methods allow the reconstruction of images with the angular resolutions exceeding that of extremely large monolithic apertures by using arrays of smaller apertures together in combination. In this issue we present several papers with techniques relevant to amplitude interferometry, laser radar, and intensity interferometry applications.

Optically coherent image formation and denoising using a plug and play inversion framework.

The performance of optically coherent imaging systems can be limited by measurement and speckle noise. In this paper, we develop an image formation framework for computing the maximum a posteriori estimate of an object's reflectivity when imaged using coherent illumination and detection. The proposed approach allows for the use of Gaussian denoising algorithms (GDAs), without modification, to mitigate the exponentially distributed and signal-dependent noise that occurs in coherent imaging. Several GDAs are compared using both simulated and experimental data. The proposed framework is shown to be robust to noise and significantly reduce reconstruction error compared to the standard inversion technique.

VIEW-VLU observational study of the effect of Varithena on wound healing in the treatment of venous leg ulcers.

OBJECTIVE: Chronic venous hypertension, triggered by venous reflux and/or obstruction, leads to skin changes and venous leg ulcers (VLUs). Compression therapy is the standard of care, but many wounds remain unhealed. The objectives of this study were to observe the effects of endovenous chemical ablation with commercially available 1% polidocanol injectable microfoam on VLU healing and recurrence rates. METHODS: The VIEW VLU study was a multicenter, open-label, phase IV registry of patients with active VLUs resulting from venous insufficiency of the great saphenous vein and/or anterior accessory saphenous vein systems who underwent ablation with 1% polidocanol microfoam. Primary outcomes included wound healing rate (change in wound perimeter), wound closure at 12 weeks after treatment, and time to wound closure. Secondary outcomes included VLU recurrence, numeric pain score at the ulcer location, EuroQol five-dimension five-level questionnaire quality-of-life index, and the Venous Clinical Severity Score. Patients were followed for 12 months. RESULTS: We enrolled 76 patients (80 ulcers) from 14 sites across the United States and Canada (mean age 63.6 ± 13.7 years, 39.5% female, mean body mass index 36.3). Of the enrollees, 96.3% presented with great saphenous vein incompetence. The mean baseline wound perimeter was 117.2 ± 107.4 mm and 26.3% of wounds (21/80) were circumferential. The mean ulcer age was 34.8 ± 51.8 weeks at first presentation and the mean compression therapy duration was 26.4 ± 35.9 weeks. The median wound perimeter decreased by 16.3% from baseline in the first 2 weeks after the procedure and by 27.0% at 12 weeks. By 12 weeks, 53.8% of wounds (43/80) were healed. The median time to ulcer closure by Kaplan-Meier analysis was 89 days (95% confidence interval, 62.0-117.0). In a Kaplan-Meier analysis of initially healed wounds, 88.9% (95% confidence interval, 76.9-94.8) remained closed at 12 weeks after closure. The mean numeric pain scores (ulcer site) improved by 41.0% and 64.1% at 12 weeks and 12 months after the procedure, respectively. The health-related quality-of-life index (scale of 0-1) improved from 0.65 ± 0.27 at baseline to 0.72 ± 0.28 at 12 weeks and 0.73 ± 0.30 at 12 months. By 12 weeks after treatment, the mean target leg Venous Clinical Severity Score had significantly decreased by 5.8 points, and by 12 months it had decreased by 10.0 points. CONCLUSIONS: Treatment with 1% polidocanol microfoam was associated with promising wound healing rates and low recurrence rates for VLUs, despite a challenging patient population with recalcitrant ulcers, a large percentage of which were circumferential, in patients with high body mass indexes.

Race, sex, and socioeconomic disparities affect the clinical stage of patients presenting for treatment of superficial venous disease.

OBJECTIVE: Superficial venous disease has a U.S. prevalence of nearly 30%, with advanced disease contributing to a significant healthcare burden. Although the risk factors for venous disease are well known, the correlation between race, sex, socioeconomic status, and disease severity on presentation is not well established. The area deprivation index (ADI) is a validated metric with respect to regional geography, social determinants of health, and degree of socioeconomic disadvantage. In the present study, we aimed to identify the disparities and the effect that the ADI, in addition to race and sex, has among patients associated with an advanced venous disease presentation. METHODS: A retrospective review between 2012 and 2022 was performed at four tertiary U.S. institutions to identify patients who underwent endovenous closure of their saphenous veins. Patient demographics, state ADI, comorbidities, CEAP (clinical, etiologic, anatomic, pathophysiologic) classification, and periprocedural outcomes were included. Pearson's correlation was performed between the CEAP classification and ADI. Poisson regression analysis was performed to identify factors predicting for an increasing CEAP classification at presentation. Variables with P < .05 were deemed significant. RESULTS: A total of 2346 patients underwent endovenous saphenous vein closure during the study period, of whom 7 were excluded because of a lack of follow-up data. The mean age was 60.4 ± 14.9 years, 65.9% were women, and 55.4% were White. Of the 2339 patients, 73.3% presented with an advanced CEAP class (≥3). The mean state ADI for the entire cohort was 4.9 ± 3.1. The percent change in the CEAP classification is an increase of 2% and 1% for every level increase in the state ADI for unadjusted (incidence rate ratio [IRR] = 1.02; P < .001) and adjusted (IRR = 1.01; P < .001) models, respectively. Black race has a 12% increased risk of a higher CEAP class on presentation compared with White race (IRR = 1.12; P = .005). Female sex had a 16% lower risk of a higher CEAP presentation compared with male sex (IRR = 0.84; P < .01). CONCLUSIONS: Low socioeconomic status, Black race, and male sex are predictive of an advanced CEAP classification on initial presentation. These findings highlight the opportunity for improved mechanisms for identification of venous disease and at-risk patients before advanced disease progression in known disadvantaged patient populations.

Brain Homogenate Decoys for Antigen-Specific Cell Amplification.

Multiple sclerosis is complex and heterogeneous. Better tools are needed to be able to monitor this disease among individuals, but blood-based biomarkers are often too rare to profile. In this work, we developed antigen-specific biomaterials to replicate the central nervous system niche where multiple sclerosis biomarkers are amplified. We incorporated mouse brain homogenate into a microporous gelatin methacrylate network. Homogenate-containing biomaterials differentially stimulated cells and led to the marked amplification of disease-relevant, antigen-specific B cells. These results demonstrate that biomaterials containing primary tissue homogenate retain antigen specificity and may be a useful tool for decoding human autoimmunity.

The Relationship Between Coronary Calcification and the Natural History of Coronary Artery Disease.

OBJECTIVES: The aim of the current study was to explore the impact of plaque calcification in terms of absolute calcified plaque volume (CPV) and in the context of its percentage of the total plaque volume at a lesion and patient level on the progression of coronary artery disease. BACKGROUND: Coronary artery calcification is an established marker of risk of future cardiovascular events. Despite this, plaque calcification is also considered a marker of plaque stability, and it increases in response to medical therapy. METHODS: This analysis included 925 patients with 2,568 lesions from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry, in which patients underwent clinically indicated serial coronary computed tomography angiography. Plaque calcification was examined by using CPV and percent CPV (PCPV), calculated as (CPV/plaque volume) × 100 at a per-plaque and per-patient level (summation of all individual plaques). RESULTS: CPV was strongly correlated with plaque volume (r = 0.780; p < 0.001) at baseline and with plaque progression (r = 0.297; p < 0.001); however, this association was reversed after accounting for plaque volume at baseline (r = -0.146; p < 0.001). In contrast, PCPV was an independent predictor of a reduction in plaque volume (r = -0.11; p < 0.001) in univariable and multivariable linear regression analyses. Patient-level analysis showed that high CPV was associated with incident major adverse cardiac events (hazard ratio: 3.01: 95% confidence interval: 1.58 to 5.72), whereas high PCPV was inversely associated with major adverse cardiac events (hazard ratio: 0.529; 95% confidence interval: 0.229 to 0.968) in multivariable analysis. CONCLUSIONS: Calcified plaque is a marker for risk of adverse events and disease progression due to its strong association with the total plaque burden. When considered as a percentage of the total plaque volume, increasing PCPV is a marker of plaque stability and reduced risk at both a lesion and patient level. (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411).

Local and systemic consequences of large retroperitoneal clot burdens.

BACKGROUND: There is a paucity of data regarding the impact of retroperitoneal hematoma (RPH) volumes, as detected by computed tomography (CT) scanning, on patient morbidity and mortality. Therefore, we wanted to determine the natural history of RPHs and the effect of size on local and systemic outcomes. METHODS: We performed a volumetric analysis of CT-documented RPHs managed at our institution between 1985 and 2006 along with a retrospective chart review. RESULTS: We included 81 cases of RPH in this study. The mean Acute Physiology, Age, and Chronic Health Evaluation II (APACHE II) score was 12.8 +/- 0.72 (score +/- SE). By univariate analysis, the size of the hematoma showed a significant correlation with the development of local mass effects, delayed mass effects, 6-month mortality, major morbidity, pulmonary complications, fluid overload, and the requirement for operative evacuation (p < 0.05). Receiver operating characteristic analysis revealed that a size > or = 1600 cm(3) was > 80% sensitive and specific for predicting a delayed mass effect or an increase in 6-month mortality. Multivariate analysis controlling for factors such as APACHE II and packed red blood cells transfused showed that the volume of the RPH was an independent predictor for the development of local mass effects, pulmonary insufficiency, and fluid overload. CONCLUSIONS: Large RPHs are clearly associated with worse patient outcomes. Surgical intervention may be warranted for the treatment of RPHs > or = 1600 cm(3).

Systemic delivery of (gamma1)34.5-deleted herpes simplex virus-1 selectively targets and treats distant human xenograft tumors that express high MEK activity.

Deltagamma(1)34.5 mutant herpes simplex type 1 viruses are under active clinical investigation as oncolytic therapy for cancer. Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) activity has been shown to suppress protein kinase R and thereby confer oncolytic susceptibility to some human tumors by R3616, a virus deleted for both copies of gamma(1)34.5. We report that systemic delivery of R3616 can selectively target and destroy human xenograft tumors that overexpress MEK activity compared with tumors that express lower MEK activity. These results suggest systemic delivery of R3616 may be effective in the treatment of some human tumors.

Natural History of Diabetic Coronary Atherosclerosis by Quantitative Measurement of Serial Coronary Computed Tomographic Angiography: Results of the PARADIGM Study.

OBJECTIVES: This study aimed to determine the rate and extent of plaque progression (PP), changes in plaque features, and clinical predictors of PP in patients with diabetes mellitus (DM). BACKGROUND: The natural history of coronary PP in patients with DM is not well established. METHODS: A total of 1,602 patients (age 61.3 ± 9.0 years; 60.3% men; median scan interval 3.8 years) who underwent serial coronary computed tomography angiography over a period of at least 24 months were enrolled and analyzed from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) trial. Study endpoints were changes in plaque features in diabetics with PP and risk factors for PP by serial coronary computed tomography angiography between patients with and without DM. PP was defined if plaque volume at follow-up minus plaque volume at baseline was >0. RESULTS: DM was an independent risk factor for PP (84.6%; 276 of 326 patients with PP) in multivariate analysis (odds ratio [OR]: 1.526; 95% confidence interval [CI]: 1.100 to 2.118; p = 0.011). Independent risk factors for PP in patients with DM were male sex (OR: 1.485; 95% CI: 1.003 to 2.199; p = 0.048) and mean plaque burden at baseline ≥75% (OR: 3.121; 95% CI: 1.701 to 5.725; p ≤0.001). After propensity matching, percent changes in overall plaque volume (30.3 ± 36.9% in patients without DM and 36.0 ± 29.7% in those with DM; p = 0.032) and necrotic core volume (-7.0 ± 35.8% in patients without DM and 21.5 ± 90.5% in those with DM; p = 0.007) were significantly greater in those with DM. The frequency of spotty calcification, positive remodeling, and burden of low-attenuation plaque were significantly greater in patients with DM. CONCLUSIONS: People with DM experience greater PP, particularly significantly greater progression in adverse plaque, than those without DM. Male sex and mean plaque burden >75% at baseline were identified as independent risk factors for PP.

Incidence and distribution of lower extremity deep vein thrombosis in rehabilitation patients: implications for screening.

Patients admitted to in-patient rehabilitation programs have an increased risk for developing deep venous thrombosis (DVT). However, the utility of screening for lower extremity DVT using duplex ultrasound in this high-risk population is not well characterized. The purpose of this study is to identify whether or not screening lower-extremity duplex exams are indicated in this high-risk population. Screening lower extremity duplex exams were performed on all patients admitted to the rehabilitation center at Mt. Sinai Hospital over a 3-year period. Charts were reviewed for patient age, gender, diagnosis, date of screening and follow-up duplex exams, presence and location of venous thrombosis at each duplex exam, history of anticoagulation, and medical DVT prophylaxis. The presence of DVT at screening, the location of DVT along the lower extremity, and the outcome of calf DVT were analyzed in terms of gender, underlying diagnosis, and history of DVT prophylaxis. Lower extremity DVT was detected in 34% of patients. Twenty-three percent of patients had isolated calf vein thrombosis. Men were more likely than women to have DVT. Calf DVTs progressed in 3% of patients over an average follow-up of 2 weeks. The presence of DVT, its location along the lower extremity, and the outcome of calf vein DVT had no significant relationship to underlying diagnosis or history of prophylaxis. Screening duplex exams to detect lower extremity DVT in rehabilitation patients is useful. Screening altered management in 26% of patients, prompting either anticoagulation or repeat duplex exam.

STAT1 pathway mediates amplification of metastatic potential and resistance to therapy.

BACKGROUND: Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1(H) genotype) are selected by the lung microenvironment. STAT1(H) tumor cells also demonstrate resistance to IFN-gamma (IFNgamma), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1(L) genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress. CONCLUSIONS: Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization.

Tumor genotype determines susceptibility to oncolytic herpes simplex virus mutants: strategies for clinical application.

Oncolytic Herpes simplex virus -1 (HSV-1) mutants based on deletion of the gamma134.5 gene are promising therapies for cancer. Deltagamma134.5 mutant replication and cytolysis is tumor cell type specific and severely attenuated in normal tissues. The basis for attenuation lies in the activation of the protein kinase R (PKR)-mediated host cellular defense pathway, which inhibits protein synthesis in infected cells. Tumor cells which overexpress MAPK kinase (MEK) activity support robust replication of Deltagamma134.5 mutants via MEK-mediated inhibition of PKR, resulting in tumor oncolysis. Systemic delivery of gamma(1)34.5 mutants may allow selective targeting and destruction of metastases from a broad range of solid human tumors that overexpress MEK. Barriers to systemic HSV-1 oncolytic therapy include innate immunity, adaptive immunity and hepatic adsorption. Immunomodulating agents may overcome innate immunity to HSV-1-based vectors. Preclinical data combined with the pervasiveness of HSV-1 despite widespread immunity suggest that preexisting immunity may not eliminate oncolytic efficacy. In the future, biopsy-determined tumor MEK status may select patients for Deltagamma134.5 oncolytic therapy.