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Paraganglioma with high-grade intraepithelial neoplasia in the oesophagus treated by endoscopic submucosal dissection.

A 37-year-old woman was hospitalised with a 4-month history of retrosternal pain. Gastroscopy revealed a protrusion lesion of approximately 0.6 cm in diameter in the left wall of the oesophagus, approximately 27 cm from the incisor (Fig. 1). Consequently, one biopsy specimen was taken from the oesophagus. Based on the pathology and immunohistochemistry findings, the patient was initially diagnosed with paraganglioma with high-grade squamous intraepithelial neoplasia. The patient underwent endoscopic submucosal dissection 12 days after the biopsy. The protrusion lesion was again observed under gastroscopy, with visible scarring on the surface (Fig. 2A). A hypoechoic and heterogeneous mass of about 7.1 mm × 2.0 mm in the muscularis mucosae layer was detected on endoscopic ultrasonography (Fig. 2B). The mass was excised after submucosal injection of adrenaline, melphalan, and glycerol fructose injection (Fig. 2C). The postoperative gross specimen was a mucosal tissue measuring 2 cm × 1.8 cm × 0.2 cm, with a bulging mass underneath (Fig. 2D). The results of immunohistochemical analysis were positive for CD56, Syn, CK8/18, LCK, and S-100 and negative for SSTR2 (Fig. 3D, E). Expression of wild-type P53, focal positivity of CgA, and weak positivity of NSE were noted. The Ki-67 labelling index was 1–2%. The diagnosis of paraganglioma with high-grade squamous intraepithelial neoplasia was confirmed based on the histopathology findings (Fig. 3A, B, C). The patient recovered well during the follow-up. Fig. 2(A) The protrusion lesion was found again under gastroscopy, with visible scarring on the surface. (B) Endoscopic ultrasonography detected a hypoechoic and heterogeneous mass of about 7.1 mm × 2.0 mm in the muscularis mucosae layer. (C) Adrenaline, melphalan and glycerol fructose injection was injected in the submucosa after the lesion was marked with a dual knife. (D) Gross specimen after endoscopic submucosal dissection. View Large Image Figure Viewer Download Hi-res image Fig. 3Microscopic examination. (A) Significant cytological atypia in squamous epithelium with continuous basement membrane, and arrangement of the cells in nests (“Zellballen”) in muscularis mucosae. (HE stain × 4) (B) The tumour was composed of chief cells and sustentacular cells. (HE stain × 10) (C) The chief cell is polygonal with a fine granular cytoplasm of acidophilia as well as basophilia. The nucleus is round to elliptical. The sustentacular cells of spindle-shape are distributed around the tumour cell nests or interdigitated amongst the sustentacular cells. (HE stain × 40) (D) positivity of S-100 protein (× 10). (E) positivity of Syn. (× 10). View Large Image Figure Viewer Download Hi-res image

An indirect method of verifying passive fit of complete arch implant-supported frameworks fabricated from photogrammetry scans

The passive fit of frameworks on multi-unit abutments has been considered crucial for the long-term success of complete arch, implant-supported, fixed prostheses. 1 Jokstad A. Shokati B. New 3D technologies applied to assess the long-term clinical effects of misfit of the full jaw fixed prosthesis on dental implants. Clin Oral Implants Res. 2015; 26: 1129-1134 Crossref PubMed Google Scholar Photogrammetry has demonstrated better accuracy than intraoral scanning and conventional impression techniques to record the position of implants. 2 Sallorenzo A. Gómez-Polo M. Comparative study of the accuracy of an implant intraoral scanner and that of a conventional intraoral scanner for complete-arch fixed dental prostheses. J Prosthet Dent. 2022; 128: 1009-1016 Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar However, errors introduced during fabrication may still compromise the passive fit of the definitive prosthesis, even with accurate scanning using the photogrammetry technique. 3 Al-Meraikhi H. Yilmaz B. McGlumphy E. Brantley W. Johnston W.M. In vitro fit of CAD-CAM complete arch screw-retained titanium and zirconia implant prostheses fabricated on 4 implants. J Prosthet Dent. 2018; 119: 409-416 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The current intraoral methods of verifying passive fit, including visual inspection, tactile sensation, radiography, disclosing materials, screw resistance test, and the Sheffield test, are subjective and not capable of detecting lingual or subgingival misfit. 4 Abduo J. Bennani V. Waddell N. Lyons K. Swain M. Assessing the fit of implant fixed prostheses: a critical review. Int J Oral Maxillofac Implants. 2010; 25: 506-515 PubMed Google Scholar In the conventional protocol, the definitive cast made from a custom tray elastomeric impression can be verified with a dental gypsum device. 5 Manzella C. Burello V. Bignardi C. Carossa S. Schierano G. A method to improve passive fit of frameworks on implant-supported prostheses: an in vivo study. Int J Prosthodont. 2013; 26: 577-579 Crossref PubMed Google Scholar However, since the frameworks made from photogrammetry are manufactured without a definitive cast, verifying the passive fit of the frameworks is challenging. 6 Rutkunas V. Larsson C. Vult von Steyern P. Mangano F. Gedrimiene A. Clinical and laboratory passive fit assessment of implant-supported zirconia restorations fabricated using conventional and digital workflow. Clin Implant Dent Relat Res. 2020; 22: 237-245 Crossref PubMed Scopus (11) Google Scholar In the treatment of the first patient, misfits were found between the frameworks and the 3-dimensional printed cast; therefore, the accuracy of the frameworks needed to be verified to determine whether the distortion was introduced during printing of the cast (Fig. 1A-C). An inexpensive and user-friendly method of verifying the passive fit of frameworks is described. Figure 1A, Intraoral view after removal of interim prosthesis. B, Impression scanning using photogrammetry technology. C, Misfits between framework and printed cast. D, Placement of abutment replicas. E, Fixture of replicas with dental gypsum. F, Evaluating fit of framework. View Large Image Figure Viewer Download Hi-res image

Poisonous, Venomous, or Harmless?

Millipedes and centipedes were among the first animals to inhabit the earth. Their fossil record dates from the late Silurian period 430 million years ago. Their common names, derived from Latin, mean 1000 feet and 100 feet, respectively. Until 2021, when a new species of millipedes with 1306 legs was discovered, no millipede had 1000 legs. 1 Marek P.E. Buzatto B.A. Shear W.A. Means J.C. Black D.G. Harvey M.S. et al. The first true millipede-1306 legs long. Sci Rep. 2021; 1123126 Crossref Scopus (9) Google Scholar Millipedes have 2 pairs of legs per body segment (Figure 1). Centipedes have 1 pair of legs per body segment, and many centipedes have >100 legs (Figure 2). All centipedes also have modified legs on both ends. The first pair of centipede legs serves as claws or pincers (forcipules) for restraining victims and injecting venom, and the terminal pair (mating claspers or genital forceps) serves in reproduction. Figure 2The house centipede Scutigera coleoptrata has 15 pairs of long, delicate legs, which enable it to speed across floors, walls, and ceilings. Source: Wikimedia Commons. Photographer: Filip Vidinovski. Public domain, no copyright permission required. Available at: https://commons.wikimedia.org/wiki/File.House_centipede_Scutigera_coleoptrata_on_the_wall.tif. View Large Image Figure Viewer Download Hi-res image

Turbulent Flow in the Right Atrium: Severe Tricuspid Regurgitation or Another Rare Etiology?

An 82-year-old, 81-kg, 188-cm man who underwent aortic valve replacement with a 25 mm bioprosthesis for aortic insufficiency returned two months after surgery with persistent fatigue and anorexia. The patient's original postoperative course was complicated by methicillin-resistant Staphylococcus aureus bacteremia that was treated with intravenous daptomycin and rifampin for 6 weeks. The patient's physical examination was notable for a new loud holosystolic murmur best heard at the left sternal border and a softer early diastolic murmur. Evidence of renal insufficiency was present (creatinine of 2.16 mg/dL), but the white blood cell count was normal. Transthoracic echocardiography demonstrated dehiscence of the prosthesis, severe tricuspid regurgitation with systolic flow reversal in the hepatic veins, and an estimated pulmonary artery systolic pressure of 76 mmHg. Transesophageal echocardiography (TEE) was performed as part of the diagnostic evaluation, and the following images were obtained (figures 1, 2, 3, and 4; video clips 1, 2, 3, and 4). What is the diagnosis? Figure 2Midesophageal aortic valve short axis TEE view View Large Image Figure Viewer Download Hi-res image

A Subserosal Uterine Lipoleiomyoma Mimicking a Mature Ovarian Teratoma

A 47-year-old woman presented to the gynecology clinic for an assessment of a pelvic mass that had been accidentally discovered in a recent physical examination. She was asymptomatic at presentation and tumor markers were normal. A confirmatory ultrasonography revealed a lipid-containing mass, measuring 3.8 cm × 3.5 cm × 3.0 cm, on the surface of the left ovary (Fig. 1), a finding that was suggestive of a mature ovarian teratoma. Exploratory laparoscopy, however, revealed a uterine lesion bulging out of the serosa with a clear boundary and located immediately beside the left ovary (Fig. 2). Lesion resection was performed. Histopathological assessment revealed a large proportion of adipocytes interspersed in mature smooth muscle cells that were arranged in bundles and whirlpools (Fig. 3), thus confirming a final diagnosis of uterine lipoleiomyoma. The post-operative recovery was uneventful and the patient was discharged home on the second day after surgery. Lipoleiomyoma is a benign lesion that is not commonly involved in the uterus [1, 2]. Subserosal uterine lipoleiomyoma is generally asymptomatic [3]. The expansive growth mode of uterine lipoleiomyoma and its lipid-containing characteristics led to ultrasonic confusion with a mature ovarian teratoma. The diagnosis was corrected by direct vision with a laparoscope and histopathological analysis. Fig. 2Laparoscopic imaging. View Large Image Figure Viewer Download Hi-res image Fig. 3Histopathology (Hematoxylin and eosin stain, × 200). View Large Image Figure Viewer Download Hi-res image

Man With Chest Pain After a Traffic Crash.

A 40-year-old man had been involved in a scooter crash and presented to the emergency department with chest pain. His vital signs were blood pressure, 160/84 mmHg; pulse, 109 beats/min; respiratory rate 24 breaths/min, and temperature, 37.5 °C. Physical examination revealed severe local tenderness in the mid-chest region. Plain radiography (Figure 1) and point-of-care ultrasonography of the chest (Figure 2 and Video 1) were performed, and the diagnosis was confirmed by contrast-enhanced computed tomography.Figure 2The point-of-care ultrasound at the site of pain showed a breach in the anterior cortex of the sternal body (arrowhead) and a mass with mixed echogenicity around the fracture indicating hematoma (asterisk).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Sternum fracture. Plain radiography revealed a suspicious mild depression fracture of the sternum. Point-of-care ultrasound imaging, using a high-frequency linear transducer at the site of pain, showed a discontinuous outline of the sternum. A chest computed tomography (Figure 3) image was obtained for confirmation of the diagnosis and to detect possible concomitant associate injuries, such as great vessel disruption, cardiac contusion, and pulmonary contusion. Sternum fracture is characterized by chest pain, which worsens with deep inspiration and shortness of breath. Motor vehicle crashes are the leading cause of sternum fracture, typically due to hitting the steering wheel without an airbag.1Oyetunji T.A. Jackson H.T. Obirieze A.C. et al.Associated injuries in traumatic sternal fractures: a review of the National Trauma Data Bank.Am Surg. 2013; 79: 702-705Crossref PubMed Google Scholar,2Knobloch K. Wagner S. Haasper C. et al.Sternal fractures occur most often in old cars to seat-belted drivers without any airbag often with concomitant spinal injuries: clinical findings and technical collision variables among 42,055 crash victims.Ann Thorac Surg. 2006; 82: 444-450Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Conventional chest radiography has variable diagnosis accuracy, and most sternal fractures may be missed by chest radiography alone.3Perez M.R. Rodriguez R.M. Baumann B.M. et al.Sternal fracture in the age of pan-scan.Injury. 2015; 46: 1324-1327Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar The point-of-care ultrasound can be considered a useful technique in identifying sternum fractures.4You J.S. Chung Y.E. Kim D. et al.Role of sonography in the emergency room to diagnose sternal fractures.J Clin Ultrasound. 2010; 38: 135-137PubMed Google Scholar https://www.annemergmed.com/cms/asset/9b3c776c-e7a2-4271-9e98-27acc23ff9ab/mmc1.mp4Loading ... Download .mp4 (3.14 MB) Help with .mp4 files Video 1The point-of-care ultrasound at the site of pain showed a breach in the anterior cortex of the sternal body (arrowhead) and a mass with a mixed echogenicity around the fracture indicating hematoma (asterisk).

Not only a mild winter: German consumers change their behavior to save natural gas

Alexander Roth is a research associate at the Energy, Transportation, Environment Department at the German Institute for Economic Research (DIW Berlin). He is also a PhD student at the DIW’s Graduate Center. His research interests lie in the fields of energy economics focusing on the integration of renewable energies into the energy system using numerical and empirical methods. He holds a Master of Science in economics from the University of Mannheim and a Master of Science in quantitative economics from the Free University of Brussels (ULB) and a Bachelor of Science in economics from the University of Mannheim. Graphical Abstract View Large Image Figure Viewer Download Hi-res image Felix Schmidt is a research associate at the Energy, Transportation, Environment Department at the German Institute for Economic Research (DIW Berlin). He is also a PhD student at the DIW’s Graduate Center. His research interests lie in the fields of energy economics and operations research for power systems. Felix holds a Master of Science in economics and finance from Copenhagen Business School and a Bachelor of Science in economics from University of Cologne. Alexander Roth is a research associate at the Energy, Transportation, Environment Department at the German Institute for Economic Research (DIW Berlin). He is also a PhD student at the DIW’s Graduate Center. His research interests lie in the fields of energy economics focusing on the integration of renewable energies into the energy system using numerical and empirical methods. He holds a Master of Science in economics from the University of Mannheim and a Master of Science in quantitative economics from the Free University of Brussels (ULB) and a Bachelor of Science in economics from the University of Mannheim. Felix Schmidt is a research associate at the Energy, Transportation, Environment Department at the German Institute for Economic Research (DIW Berlin). He is also a PhD student at the DIW’s Graduate Center. His research interests lie in the fields of energy economics and operations research for power systems. Felix holds a Master of Science in economics and finance from Copenhagen Business School and a Bachelor of Science in economics from University of Cologne.

CLINICAL PATHOLOGIC CONFERENCE CASE 1: A MULTILOCULAR RADIOLUCENCY OF THE RIGHT MANDIBLE

CLINICAL PATHOLOGIC CONFERENCE CASE 1: A MULTILOCULAR RADIOLUCENCY OF THE RIGHT MANDIBLE

Young Woman With Vulvar Mass.

A 20-year-old woman presented to the emergency department with a 2-month history of a left groin mass, which slowly grew after mild blunt trauma. The mass became painful 2 days ago, but she denied vaginal discharge, pain, abnormal bleeding, or dysuria. Physical examination revealed an asymmetric, indurated, tender mass over the left lateral aspect of the mons pubis extending through the labia and inguinal area. (Figure 1) Bedside ultrasound evaluation showed a complex lesion without obvious fluid collection or Doppler flow (Figure 2), and computed tomography confirmed (Figure 3) a 9-centimeter soft tissue density.Figure 2Bedside ultrasound showed heterogenous mass without fluid collection or Doppler flow.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Computed tomography of pelvis with contrast demonstrated a peripherally enhancing 9 cm soft tissue density in the left inguinal region (arrow).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Epithelioid sarcoma. After surveillance imaging results of the abdomen and thorax were negative, surgeons performed a core biopsy to confirm the diagnosis. The patient underwent neoadjuvant chemotherapy with prophylactic salpingectomy and planned resection. Soft tissue sarcomas represent an eclectic group of rare neoplasms, and epithelioid sarcoma is an aggressive subtype more commonly affecting young men, typically as a firm, painless distal extremity lesion that is notably associated with slow growth after trauma.1Popovich J.R. Kashyap S. Cassaro S. Sarcoma StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL)2022 Janhttps://www.ncbi.nlm.nih.gov/books/NBK519533/Date accessed: March 7, 2022Google Scholar, 2Sobanko J.F. Meijer L. Nigra T.P. Epithelioid sarcoma: a review and update.J Clin Aesthet Dermatol. 2009 May; 2: 49-54PubMed Google Scholar, 3Enzinger F.M. Epitheloid sarcoma. A sarcoma simulating a granuloma or a carcinoma.Cancer. 1970; 26: 1029-1041Crossref PubMed Google Scholar, 4Andrisani A. Serena A. Ambrosini G. Capobianco G. Chiarelli S. Proximal-type epithelioid sarcoma of the mons pubis: report of a case.Eur J Gynaecol Oncol. 2011; 32: 339-342PubMed Google Scholar A lesion of the mons pubis is rare. Prognosis is generally poor as epithelioid sarcoma has a propensity for local recurrence and distant metastases.2Sobanko J.F. Meijer L. Nigra T.P. Epithelioid sarcoma: a review and update.J Clin Aesthet Dermatol. 2009 May; 2: 49-54PubMed Google Scholar,5Patrizi L. Corrado G. Saltari M. et al.Vulvar “proximal-type” epithelioid sarcoma: report of a case and review of the literature.Diagn Pathol. 2013; 8: 122Crossref PubMed Google Scholar Benign etiologies such as cysts, abscesses, or lipomas are clinically similar.

Melanonychia and subungual papule in a middle-aged man

Melanonychia and subungual papule in a middle-aged man

A very wide complex tachycardia

A 74-year-old woman with a history of persistent atrial fibrillation, hypertension, and hyperlipidemia presented to the emergency department (ED) after 3 days of intermittent palpitations and presyncope. She had been treated for atrial fibrillation with flecainide (150 mg twice daily) and metoprolol succinate (25 mg daily) for more than 20 years. In the ED, her heart rate was 150 bpm, and her blood pressure was 102/87. The electrocardiogram (ECG) is shown in Figure 1. The ECG obtained after a 150-mg bolus of intravenous amiodarone followed by a 200-J biphasic direct current shock is shown in Figure 2A . The ECG recorded soon after administration of 100 mEq of hypertonic sodium bicarbonate is shown in Figure 2B. What is the most likely cause of the wide complex tachycardia (WCT)? Figure 2A: Electrocardiogram with normal sinus rhythm and prolonged PR, QRS, and corrected QT intervals following direct current cardioversion. B: Electrocardiogram after treatment. View Large Image Figure Viewer Download Hi-res image

Validating a 3D-Printed En7dovascular Simulator for Use in Training Surgical Residents

Endovascular simulators have become a standard in education for surgical residents. However, these products are expensive to purchase and maintain, limiting their accessibility. Endovascular models created using in-house 3D printing can be an affordable alternative but currently lack the rigorous validation needed to be a dependable educational tool. The purpose of this study is to determine the construct validity of a 3D-printed endovascular model of an aorta. A 3D rendering of an aorta was created using a patient computed tomography scan and subsequently printed on a Form B printer with transparent clear V4 resin (Fig 1). The pieces were combined to create a final product with a material cost of $50. Participants were asked to perform 2 tasks from a femoral access point: catheterizing the contralateral common iliac artery and cannulating the superior mesenteric artery (SMA). For each task, a 5-point rubric was created to assess whether all components of the tasks were done correctly. Participants were also assessed on the time taken to perform the tasks. Participants’ level of education (medical student vs surgical resident vs attending) and level of endovascular experience (<5 procedures = no experience, 6-100 = some experience, and >100 extensive experience) were noted. Of a total of 37 participants, 12 were medical students, 21 were residents, and 4 were attendings. A total of 26 participants had no experience, 6 had some experience, and 5 had extensive experience. Neither education level nor experience level had a significant bearing on whether either task was completed. Those with higher education completed the SMA task more accurately (P = .007), but this pattern was not observed for higher levels of experience. Univariate analysis shows that both higher education and greater experience resulted in faster times for both tasks, but multivariate analysis shows that only the level of experience was a predictor for faster completion (Fig 2, P = .02). This is reinforced by the finding that among participants with no experience, higher levels of education do not result in faster times (P = .16). These findings verify the construct validity of this endovascular simulator, as those with the most real-world experience completed the tasks the fastest. The observation that residents did more of the steps correctly than medical students may be because they have greater knowledge of endovascular procedures, but this did not translate to faster performance, which requires muscle memory. Basic 3D-printed endovascular models should therefore be strongly considered as an affordable, readily accessible adjunct to surgical resident education.Fig 2Combined time, in seconds, for participants with no experience, some experience, and extensive experience to complete the catheterization of the contralateral common iliac artery and superior mesenteric artery (SMA). Error bars show 95% confidence interval (CI). Increasing real-world endovascular experience trends with decreased completion times, with statistical significance (P < .05) achieved between the “no experience” and “extensive experience” groups, denoted by *.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Black Patients Have Worse Outcomes After Lower Extremity Revascularization: A Propensity-matched Analysis of Comorbidities and Socioeconomic Factors

Racial disparities among patients with peripheral artery disease (PAD) have been described and often attributed to sociodemographic factors. We analyzed the outcomes of lower extremity bypass (LEB) and peripheral vascular intervention (PVI) between Black and non-Hispanic White (NHW) while accounting for socio-economic status using the area of deprivation index (ADI). The Vascular Quality Initiative (2016-2021) datasets were used to identify patients undergoing LEB and PVI. A probit regression model was used to generate propensity scores and perform a 5:1 match on characteristics including comorbidities, ADI, indication, urgency, and number of arteries treated (PVI) or graft target (LEB). The primary outcome was major adverse limb event (MALE)-free survival at 1 year. Kaplan-Meier survival graphs were generated for the groups and compared using log-rank testing. Cox regression analyses was used to test for interactions between race and indications as well as race and number of arteries treated (for PVI) or graft target (for LEB). A total of 44,968 PVI and 12,006 LEB were included in the analysis after matching. Black patients had significantly higher rates of MALE at 1 year for both PVI and LEB (Figs 1 and 2). On adjusted analyses Black patients with chronic limb-threatening ischemia had a higher risk of MALE at 1 year for both PVI (HR, 1.11; 95% CI, 1.04-1.17; P < .001) and LEB (HR, 1.11; 95% CI, 1.01-1.19; P = .03) compared to NHW. When adjusting for anatomical considerations, there was variability of outcomes between the groups. Black patients had a higher risk of MALE at 1 year in LEB performed to peroneal and tibial target vessels (HR, 1.17; 95% CI, 1.04-1.31; P = .007), but not for popliteal target vessels. For PVI, 1-year MALE was also higher in Black patients with one or two vessels treated at any level (HR, 1.21; 95% CI, 1.13-1.26; P < .001), but rates were similar to NHW with more vessels treated. Despite adjusting for socioeconomic factors using the validated ADI, Black patients with PAD have worse outcomes following revascularization, especially for CLTI, suggesting that other factors adversely affect outcomes in these patients. These unmeasured factors require further exploration to improve PAD outcomes in Black patients.Fig 2Major adverse limb event (MALE)-free survival at 1 year after lower extremity bypass (LEB).View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Secondary Interventions Following Open vs Endovascular Revascularization for Chronic Limb-threatening Ischemia in the BEST-CLI Trial

Patients undergoing revascularization for chronic limb-threatening ischemia experience a high burden of target limb reinterventions. We analyzed data from the BEST-CLI randomized trial comparing initial open and endovascular treatment strategies, with a focus on reintervention related study end points. In a planned secondary analysis from the BEST-CLI trial we examined the rates of major reintervention, any reintervention, and the composite of any reintervention, amputation or death (RAD) by intention-to-treat (ITT) assignment in both trial cohorts (cohort 1 with suitable single segment great saphenous vein [SSGSV], n = 1434; cohort 2 lacking suitable SSGSV, n = 396). We also compared the cumulative number of major and any reintervention over time. Comparisons between treatment arms within each cohort were made using a stratified Cox model adjusted for prespecified baseline covariates (end-stage renal disease, prior index limb revascularization, smoking, diabetes, age >80, WIfi stage, tissue loss, and significant infrapopliteal disease). In cohort 1, assignment to initial open treatment was associated with a significantly reduced incidence of a major limb reintervention (hazard ratio [HR], 0.35; 95% confidence interval, 0.27-0.47; P < .001), any reintervention (HR, 0.63; 95% CI, 0.53-0.75; P < .001), or RAD (HR, 0.69; 95% CI, 0.60-0.79; P < .001) (Fig 1). Findings were similar in cohort 2 for major reintervention (HR, 0.47; 95% CI, 0.29,0.76; P = .002) or any reintervention (HR, 0.68; 95% CI, 0.49, 0.95; P = .02). In both cohorts, early (30-day) limb reinterventions were notably higher for patients assigned to endovascular intervention as compared to open (15% vs 4.5% of cohort 1 subjects; 16.9% vs 5.8% of cohort 2 subjects). The cumulative incidence rate (IR) of major (IR, 0.50; 95% CI, 0.37-0.67; P < .001) (Fig 2) or any reinterventions (IR, 0.66; 95% CI, 0.54-0.81; P < .001) over time was significantly less in the open group of cohort 1. Rates of reintervention per limb salvaged were notably lower in the open arms of both study cohorts (IR 0.48 for both; P < .001 and P = .03, respectively). The majority of target limb reinterventions occurred over the first year following randomization, but events continued to accumulate over the duration of follow-up in the trial. Reintervention is common following revascularization for chronic limb-threatening ischemia. Initial treatment with open bypass, particularly in patients with an available SSGSV conduit, is associated with a significantly lower burden of major and minor target limb reinterventions.Fig 2Total number of cumulative major reinterventions by intention to treat (ITT), cohort 1.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Systemic Amlexanox, a TBK1/IKKε Inhibitor, Decreases IFN-γ-mediated Phosphorylation of STAT1-Blocking Atherogenic Signaling and Preventing Intimal Hyperplasia After Carotid Artery Balloon Angioplasty

Peripheral arterial disease affects >230 million people worldwide and causes significant morbidity. Venous interposition bypass grafts or endovascular balloon angioplasty with stenting are the cornerstone of current revascularization procedures. Unfortunately, 30% to 50% of venous interposition bypass grafts fail within 5 years, and 20% to 30% of angioplasties fail within one year due to intimal hyperplasia (IH). Given the implication of atherogenic IFN-γ signaling in driving IH, we investigated the impact of Amlexanox, a small molecule inhibitor of TBK1/IKKε and potential modulator of IFN-γ signaling, on IH in a rat model of carotid artery stenosis after balloon angioplasty. Sprague-Dawley rats were pretreated with intraperitoneal Amlexanox (100 mg/kg/day) or control dimethyl-sulfoxide (DMSO) for 7 days prior and up to 14 days after (at sacrifice) balloon angioplasty. IH was quantified by intima:media ratio on hematoxylin and eosin-stained vessel sections, and nuclear phospho-STAT1, a biomarker of IFN-γ signaling, was evaluated by immunohistochemistry and quantified by image J software. Systemic Amlexanox significantly reduced the intima:media ratio 14 days after carotid balloon angioplasty. I/M ratio reached 0.43 ± 0.54 vs1.38 ± 0.71 in Amlexanox vs DMSO-treated rats (P < .05; n = 7-8) (Fig. 1). The beneficial effect of Amlexanox correlated with a significantly lower number of nuclear phospho-STAT1 positive cells in the carotid artery intima and media 14 days after angioplasty (243 ± 214 vs 1005 ± 552 positive nuclei in Amlexanox vs DMSO; P < .05, n = 4) (Fig 2). Importantly, Amlexanox treatment was well-tolerated and did not induce any liver, pancreatic, or renal toxicity. This is the first report showing that systemic Amlexanox inhibits atherogenic IFN-γ signaling, significantly limiting IH following carotid artery balloon angioplasty. These results posit Amlexanox as a novel, safe and promising anti-atherogenic treatment to minimize pathologic vascular remodeling post-angioplasty. Future research is geared towards dose optimization, and exploring feasibility/effectiveness of local (balloons/stents) vs systemic delivery of Amlexanox.Fig 2Representative images of phospho-STAT1 immunostaining (brown nuclei arrow) in Amlexanox vs DMSO-treated rats in carotid artery sections 14 days after balloon angioplasty. Original magnification ×400. Histograms on the right delineate mean ± standard error of the mean of PSTAT1-positive nuclei in intima + media per vessel section (n = 4; P < .05).View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Lack of Access to Primary Care Reduces Survival Following Aortic Dissection

Optimal medical management is critical for the long-term treatment of aortic dissections (AD) to prevent complications and improve survival. Medical management is known to be influenced by various social determinants of health (SDOH), including health insurance, social support, distance to the hospital, and primary care provider (PCP) access. This study was designed to determine the relative impact of these different geographic and SDOH factors on the long-term survival of patients after diagnosis and treatment for acute AD. We retrospectively analyzed patients presenting to a single academic tertiary medical center for surgical and medical management of acute AD (types A and B) from January 2010 to December 2020. Data were collected regarding patient demographics, perioperative hospital course, and SDOH factors such as home/social status, primary and secondary insurance status, PCP access following surgery, distance to the hospital, and 2020 Area Deprivation Ondex scores. Cox proportional hazards regression models were used to estimate the risk-adjusted association between SDOH variables and mortality following acute AD. We identified 124 patients who presented with an acute AD during the study period (25% type A, 25% type B, and 50% with both type A and B components), who were predominantly male (68%) with a mean age of 60 years. Patients resided a median distance of 30.2 miles from the medical center, 18% lived alone, and 9% were uninsured. Roughly one-half of the cohort (52%) was documented to have access to a PCP, and patients with a PCP were significantly more likely to be maintained on antihypertensive (anti-HTN) medication therapy during follow-up (Fig 1). The most common anti-HTN agents were angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (56%), followed by beta-blockers (44%), and calcium channel blockers (26%). Over a median follow-up of 14.6 months, 43 patients (35%) died, with reduced survival observed among patients with no PCP access (Fig 2). In risk-adjusted models, increasing age, no PCP access, and lack of insurance were all found to be independent predictors of mortality following acute AD. Further, uninsured patients with no-PCP access or medication use had the highest risk for mortality (hazard ratio, 27.6; 95% confidence interval, 8.95-85.23; P < .001). Lack of access to a PCP and anti-HTN therapy following acute AD significantly increases the risk of short- and long-term mortality. These findings are independent of how far patients live from the hospital or other SDOH factors, highlighting the importance of community outreach programs to maintain medical management for uninsured AD patients.Fig 2Kaplan-Meier survival curves following acute aortic dissection, stratified by whether patients had access to a primary care provider (PCP).View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Vasculogenic Mesodermal Cells Derived From Induced Pluripotent Stem Cells Improve Limb Perfusion and Decrease Necrosis in Murine Models of Hindlimb Ischemia

Critical limb-threatening ischemia (CLTI) is a national health care priority as there has been a 50% increase in amputations from 2010 to 2018. Unlike other cell products that simply secrete proangiogenic growth factors, induced pluripotent stem cell (iPSC)-derived mesodermal cells have the capacity to differentiate into endothelial cells and smooth muscle cells and form functioning blood vessels in vivo. Here we discuss the effects of intramuscular injection of human iPSC mesodermal cells (VSC100) on limb perfusion and limb necrosis. iPSCs were produced using methods including Yamanaka factors (Broxmeyer et al [21393480]). The iPSC cells were differentiated using sequential Activin A, BMP4, vascular endothelial growth factor, and fibroblast growth factor 2 to promote mesodermal and endothelial cell differentiation. Murine CLTI models were created via excision of the common femoral artery in male BALB-C Nude mice, aged 6 to 8 weeks. After creation of the CLTI model mice were randomized to 1 × 106 VSC100 cells labeled with td-tomato (red fluorescence) or vehicle control injected into the gastrocnemius and gracilis muscles (n = 10/group) at 7 to 14 days postinduction of ischemia. Limb perfusion was measured with laser speckle contrast imaging up to day 64, qualitative analysis of VSC100 differentiation into capillaries was assessed with immunohistochemical staining for isolectin B4 and human CD31 and confocal microscopy to detect td-tomato. Degree of tissue loss of the index limb was quantified with established necrosis scores. VSC100-treated BALB-C nude mice showed a significant increase in limb perfusion as compared to vehicle controls with average percent blood flow/contralateral limb ratios of 45% in treated groups compared to 25% in control (P < .001) at day 64 (Fig 1). Limb necrosis scores showed similar results, in that necrosis was statistically significantly reduced in iPSC-treated vs vehicle control treated groups (Fig 2). Immunohistochemical analysis showed qualitative significant deposition of cells of interest in our CLTI models. iPSC-derived VSC100 is a novel approach to treating CTLI as the cells are capable of forming functioning blood vessels in ischemia skeletal muscle, improve tissue perfusion, and mitigate tissue necrosis. These early results and data support further translational work to support development of an investigational new drug for future clinical trial studies.Fig 2Clinical scoring ratio of chronic limb-threatening ischemia (CLTI) in control vs treated groups. Mouse population same as in Fig 1 (n = 10/group).View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Increased Preoperative Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Are Associated With Major Adverse Events and Mortality After Fenestrated/Branched Endovascular Aortic Repair

The objective was to investigate the role of the preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors associated with 30-day mortality, major adverse cardiovascular events, acute kidney injury (AKI), and long-term mortality after fenestrated/branched repair (F/BEVAR) of aortic aneurysms with complex anatomy. A retrospective analysis of prospectively collected data of patients who underwent F/BEVAR was performed including cases with a diagnosis of thoracoabdominal aortic aneurysm types I, II, III, IV, and suprarenal and juxtarenal aortic aneurysms. The main inclusion criteria were: (1) complete blood cell count with differential collected within 30 days before surgery and (2) at least 30 days of follow-up. The main exclusion criteria were: (1) comorbid autoimmune/inflammatory diseases and (2) current use of corticosteroid/immunomodulatory drugs. AKI was defined according to the RIFLE (Risk of renal dysfunction, Injury to kidney, Failure or Loss of kidney function, and End-stage kidney disease) criteria. Receiver operating characteristic (ROC) curves were used to determine cutoff values of NLR and PLR associated with the study end points. From 410 patients treated with F/BEVAR between June 2012 and December 2022, 150 were included in the study (70% male; age: 72.7 ± 8.4 years). The mean follow-up time was 29.34 ± 21.79 months. An NLR ≥5 was associated with 30-day mortality with a specificity and sensitivity of 87.1% and 66.7%, respectively, by ROC analysis (Fig 1; area under the ROC curve [AUC] = 0.841, P = .043). The negative predictive value (NPV) was 99.2%. A PLR ≥189 was associated with major adverse cardiovascular events in the first 30-day period with a specificity and sensitivity of 78.8% and 75%, respectively (Fig 2, AUC = 0.830, P = .024), and an NPV of 99.1%. A PLR ≥151 was associated with AKI, with a sensitivity and specificity of 71.4% and 64.3%, respectively (AUC = 0.732, P = .038). The NPV was 97.8%. The groups above and below the cutoffs established by the ROC curves were similar in demographic composition, comorbidities, and extension of the aneurysm. The overall long-term mortality was 27.3% in 5 years. A higher PLR was observed among non-Caucasian patients who died (mean: 190.81 ± 78.4) when compared with the individuals who survived (P = .029). The same finding was not observed in Caucasian patients. Preoperative NLR and PLR are inexpensive and easily available tests that can serve as valuable prognostic tools in patients with complex anatomy aortic aneurysms submitted to F/BEVAR. They might contribute to identifying the higher-risk patients during the preoperative preparation and consequently could indicate which cases would need even more detailed workup before the surgical procedure in the attempt to reduce the odds of adverse events.Fig 2Receiver operating characteristic (ROC) curve for platelet-to-lymphocyte ratio (PLR) considering major adverse cardiovascular event (MACE) during the first 30-day period (P = .024).View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Distal Bypass Improves Skin Perfusion Pressure at the Entire Foot Regardless of Angiosomes in Patients with Chronic Limb-Threatening Ischaemia

This study evaluated the tissue blood pressure of the direct revascularised (DR) and indirect revascularised (IR) areas after distal bypass surgery using repeated skin perfusion pressure (SPP) measurements. Twenty-two patients received regular hemodialysis, and all limbs were classified as Rutherford 5. SPP of the direct and indirect revascularization area was measured at 10 time points, including pre- and post-days 3 to 6, 7 to 9, 10 to 12, 13 to 14, 15 to 17, 18 to 20, 21 to 23, 24 to 26, and 27 to 29. Patients were divided into two groups according to the number of postoperative days to the SPP peak at the DR, as follows: group A (n = 14; SPP peak day within 9 days), group B (n = 15; peak day after 10 days). In total, 446 SPP measurements were collected from 58 measurement sites, and the transition of the SPP at the DR was 35.4, 62.5, 59.5, 70.2, 58.2, 62.2, 63.1, 63.6, 63.8, and 73.4 mmHg and IR was 29.4, 53.4, 53.7, 58.8, 51.3, 63.1, 47.9, 62.1, 57.6, and 61.0 mmHg. No significant differences were observed between SPP at the DR and IR except post-days 18 to 20 (Fig 1). Fifteen wounds on the DR (62.5%) and five on the IR (100.0%) healed. The wound healing rate and time were 92.9% and 81 days in group A, 53.3% and 222 days in group B (Fig 2). Distal artery bypass improved SPP in the IR and DR of patients with chronic limb-threatening ischemia. An early SPP peak could be an indicator of wound healing.Fig 2Cumulative incidence curve of wound healing in each group. There was a significant difference in the wound healing rate (P = .01).View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Thoracic Endovascular Aortic Repair vs Medical Therapy Alone for Uncomplicated Acute Type B Aortic Dissection

It remains controversial if thoracic endovascular aortic repair (TEVAR) or optimal medical therapy (OMT) should be the standard of care for uncomplicated type B aortic dissection (uTBAD). We evaluate our institutional experience to compare the outcomes of TEVAR vs OMT as primary treatment for uTBAD. Data were analyzed to compare early and late outcomes of 219 patients (135 men; 61.6%) with uTBAD who were triaged to OMT in 162 and TEVAR in 57 over 3 decades. Mean age was 64.5 ± 12.7 and 63.5 ± 15.9 years (P = .630) in the TEVAR and OMT groups, respectively. TEVAR group had significantly higher incidences of hypertension (87.8% vs 40.1; P < .001), smoking (63.2% vs 38.3%; P = .002), dyslipidemia (47.4% vs 16.7%; P < .001), chronic kidney disease (17.5% vs 6.2%; P = .016), and prior stroke/transient ischemic attack (14% vs 4.9%; P = .035). After TEVAR, neither death nor paraplegia occurred, while seven patients developed acute kidney injury not requiring hemodialysis (12.3%), and one sustained stroke (1.8%). In-hospital/30-day mortality was 0% with TEVAR vs 16% (26/162) with OMT (P < .001). Follow-up was 100% (193/193) at a median of 5.8 years (mean, 7.8; interquartile range [IQR], 2.0-12.3). In OMT group, 70 patients died at median 5.2 years (IQR, 2.0-8.8 years), and 72 underwent intervention at median 85 days (IQR, 0.01-1.2 years), including open descending repair in 60, TEVAR in 9, abdominal aortic repair in 2, and arch repair in 1. Following intervention, 40 died at median 1.8 years (IQR, 0.02-6.3 years). In TEVAR group, 18 underwent reintervention at median 48.5 days (IQR, 29-101 days), including 11 redo-TEVAR, 3 EVARs, 1 hemiarch, and 3 others; all were alive at latest follow-up except 1 expiring at 6.9 months postreintervention. At 3 months, 1 year, and 3 years following treatment, survival rates were significantly higher in TEVAR vs OMT patients (100% vs 83.2 ± 2.9%; 94.4 ± 3.1 vs 77.0 ± 3.3%; and 91.8 ± 4.0% vs 67.9 ± 3.7%) (P = .002, Fig 1); the respective freedom from (re)intervention were 75.4 ± 5.7% vs 72.7 ± 3.6%, 68.0 ± 6.2% vs 64.2 ± 3.9%, and 68.0 ± 6.2% vs 53.0 ± 4.2% (P = .198) in TEVAR vs OMT groups. After (re)intervention, the group with initial TEVAR had improved survival (94.4 ± 5.4% up to 3 years) compared to OMT patients (76.4 ± 5.0 at 1 year, 65.3 ± 5.6% at 3 years) (P = .039) (Fig 2). In the management of uTBAD, patients receiving initial OMT showed lower survival and required more intervention, while initial TEVAR achieved significantly higher survival up to 3 years, even after reintervention. These results argue favorably for the use of TEVAR as the primary treatment of choice for uTBAD.Fig 2Survival after (re)intervention, Kaplan-Meier survival curve comparing survival postsurgical (re)intervention after initial treatment by either thoracic endovascular aortic repair (TEVAR) or medical therapy up to 3 years after treatment. Log-rank P = .039.View Large Image Figure ViewerDownload Hi-res image Download (PPT)