Early Injury Landscape in Vein Harvest by Single-Cell and Spatial Transcriptomics.

BACKGROUND: Vein graft failure following cardiovascular bypass surgery results in significant patient morbidity and cost to the healthcare system. Vein graft injury can occur during autogenous vein harvest and preparation, as well as after implantation into the arterial system, leading to the development of intimal hyperplasia, vein graft stenosis, and, ultimately, bypass graft failure. Although previous studies have identified maladaptive pathways that occur shortly after implantation, the specific signaling pathways that occur during vein graft preparation are not well defined and may result in a cumulative impact on vein graft failure. We, therefore, aimed to elucidate the response of the vein conduit wall during harvest and following implantation, probing the key maladaptive pathways driving graft failure with the overarching goal of identifying therapeutic targets for biologic intervention to minimize these natural responses to surgical vein graft injury. METHODS: Employing a novel approach to investigating vascular pathologies, we harnessed both single-nuclei RNA-sequencing and spatial transcriptomics analyses to profile the genomic effects of vein grafts after harvest and distension, then compared these findings to vein grafts obtained 24 hours after carotid-carotid vein bypass implantation in a canine model (n=4). RESULTS: Spatial transcriptomic analysis of canine cephalic vein after initial conduit harvest and distention revealed significant enrichment of pathways (P<0.05) involved in the activation of endothelial cells (ECs), fibroblasts, and vascular smooth muscle cells, namely pathways responsible for cellular proliferation and migration and platelet activation across the intimal and medial layers, cytokine signaling within the adventitial layer, and ECM (extracellular matrix) remodeling throughout the vein wall. Subsequent single-nuclei RNA-sequencing analysis supported these findings and further unveiled distinct EC and fibroblast subpopulations with significant upregulation (P<0.05) of markers related to endothelial injury response and cellular activation of ECs, fibroblasts, and vascular smooth muscle cells. Similarly, in vein grafts obtained 24 hours after arterial bypass, there was an increase in myeloid cell, protomyofibroblast, injury response EC, and mesenchymal-transitioning EC subpopulations with a concomitant decrease in homeostatic ECs and fibroblasts. Among these markers were genes previously implicated in vein graft injury, including VCAN, FBN1, and VEGFC, in addition to novel genes of interest, such as GLIS3 and EPHA3. These genes were further noted to be driving the expression of genes implicated in vascular remodeling and graft failure, such as IL-6, TGFBR1, SMAD4, and ADAMTS9. By integrating the spatial transcriptomics and single-nuclei RNA-sequencing data sets, we highlighted the spatial architecture of the vein graft following distension, wherein activated and mesenchymal-transitioning ECs, myeloid cells, and fibroblasts were notably enriched in the intima and media of distended veins. Finally, intercellular communication network analysis unveiled the critical roles of activated ECs, mesenchymal-transitioning ECs, protomyofibroblasts, and vascular smooth muscle cells in upregulating signaling pathways associated with cellular proliferation (MDK [midkine], PDGF [platelet-derived growth factor], VEGF [vascular endothelial growth factor]), transdifferentiation (Notch), migration (ephrin, semaphorin), ECM remodeling (collagen, laminin, fibronectin), and inflammation (thrombospondin), following distension. CONCLUSIONS: Vein conduit harvest and distension elicit a prompt genomic response facilitated by distinct cellular subpopulations heterogeneously distributed throughout the vein wall. This response was found to be further exacerbated following vein graft implantation, resulting in a cascade of maladaptive gene regulatory networks. Together, these results suggest that distension initiates the upregulation of pathological pathways that may ultimately contribute to bypass graft failure and presents potential early targets warranting investigation for targeted therapies. This work highlights the first applications of single-nuclei and spatial transcriptomic analyses to investigate venous pathologies, underscoring the utility of these methodologies and providing a foundation for future investigations.

Advancements in Omics and Breakthrough Gene Therapies: A Glimpse into the Future of Peripheral Artery Disease.

Peripheral artery disease (PAD), a highly prevalent global disease, associates with significant morbidity and mortality in affected patients. Despite progress in endovascular and open revascularization techniques for advanced PAD, these interventions grapple with elevated rates of arterial restenosis and vein graft failure attributed to intimal hyperplasia (IH). Novel multiomics technologies, coupled with sophisticated analyses tools recently powered by advances in artificial intelligence, have enabled the study of atherosclerosis and IH with unprecedented single-cell and spatial precision. Numerous studies have pinpointed gene hubs regulating pivotal atherogenic and atheroprotective signaling pathways as potential therapeutic candidates. Leveraging advancements in viral and nonviral gene therapy (GT) platforms, gene editing technologies, and cutting-edge biomaterial reservoirs for delivery uniquely positions us to develop safe, efficient, and targeted GTs for PAD-related diseases. Gene therapies appear particularly fitting for ex vivo genetic engineering of IH-resistant vein grafts. This manuscript highlights currently available state-of-the-art multiomics approaches, explores promising GT-based candidates, and details GT delivery modalities employed by our laboratory and others to thwart mid-term vein graft failure caused by IH, as well as other PAD-related conditions. The potential clinical translation of these targeted GTs holds the promise to revolutionize PAD treatment, thereby enhancing patients' quality of life and life expectancy.

Integrated single-nuclei and spatial transcriptomic analysis reveals propagation of early acute vein harvest and distension injury signaling pathways following arterial implantation.

Background: Vein graft failure (VGF) following cardiovascular bypass surgery results in significant patient morbidity and cost to the healthcare system. Vein graft injury can occur during autogenous vein harvest and preparation, as well as after implantation into the arterial system, leading to the development of intimal hyperplasia, vein graft stenosis, and, ultimately, bypass graft failure. While previous studies have identified maladaptive pathways that occur shortly after implantation, the specific signaling pathways that occur during vein graft preparation are not well defined and may result in a cumulative impact on VGF. We, therefore, aimed to elucidate the response of the vein conduit wall during harvest and following implantation, probing the key maladaptive pathways driving graft failure with the overarching goal of identifying therapeutic targets for biologic intervention to minimize these natural responses to surgical vein graft injury. Methods: Employing a novel approach to investigating vascular pathologies, we harnessed both single-nuclei RNA-sequencing (snRNA-seq) and spatial transcriptomics (ST) analyses to profile the genomic effects of vein grafts after harvest and distension, then compared these findings to vein grafts obtained 24 hours after carotid-cartoid vein bypass implantation in a canine model (n=4). Results: Spatial transcriptomic analysis of canine cephalic vein after initial conduit harvest and distention revealed significant enrichment of pathways (P < 0.05) involved in the activation of endothelial cells (ECs), fibroblasts (FBs), and vascular smooth muscle cells (VSMCs), namely pathways responsible for cellular proliferation and migration and platelet activation across the intimal and medial layers, cytokine signaling within the adventitial layer, and extracellular matrix (ECM) remodeling throughout the vein wall. Subsequent snRNA-seq analysis supported these findings and further unveiled distinct EC and FB subpopulations with significant upregulation (P < 0.00001) of markers related to endothelial injury response and cellular activation of ECs, FBs, and VSMCs. Similarly, in vein grafts obtained 24 hours after arterial bypass, there was an increase in myeloid cell, protomyofibroblast, injury-response EC, and mesenchymal-transitioning EC subpopulations with a concomitant decrease in homeostatic ECs and fibroblasts. Among these markers were genes previously implicated in vein graft injury, including VCAN (versican), FBN1 (fibrillin-1), and VEGFC (vascular endothelial growth factor C), in addition to novel genes of interest such as GLIS3 (GLIS family zinc finger 3) and EPHA3 (ephrin-A3). These genes were further noted to be driving the expression of genes implicated in vascular remodeling and graft failure, such as IL-6, TGFBR1, SMAD4, and ADAMTS9. By integrating the ST and snRNA-seq datasets, we highlighted the spatial architecture of the vein graft following distension, wherein activated and mesenchymal-transitioning ECs, myeloid cells, and FBs were notably enriched in the intima and media of distended veins. Lastly, intercellular communication network analysis unveiled the critical roles of activated ECs, mesenchymal transitioning ECs, protomyofibroblasts, and VSMCs in upregulating signaling pathways associated with cellular proliferation (MDK, PDGF, VEGF), transdifferentiation (Notch), migration (ephrin, semaphorin), ECM remodeling (collagen, laminin, fibronectin), and inflammation (thrombospondin), following distension. Conclusions: Vein conduit harvest and distension elicit a prompt genomic response facilitated by distinct cellular subpopulations heterogeneously distributed throughout the vein wall. This response was found to be further exacerbated following vein graft implantation, resulting in a cascade of maladaptive gene regulatory networks. Together, these results suggest that distension initiates the upregulation of pathological pathways that may ultimately contribute to bypass graft failure and presents potential early targets warranting investigation for targeted therapies. This work highlights the first applications of single-nuclei and spatial transcriptomic analyses to investigate venous pathologies, underscoring the utility of these methodologies and providing a foundation for future investigations.

Amputation Rates and Associated Social Determinants of Health in the Most Populous US Counties.

Importance: Social Determinants of Health (SDOH) have been found to be associated with health outcome disparities in patients with peripheral artery disease (PAD). However, the association of specific components of SDOH and amputation has not been well described. Objective: To evaluate whether individual components of SDOH and race are associated with amputation rates in the most populous counties of the US. Design, Setting, and Participants: In this population-based cross-sectional study of the 100 most populous US counties, hospital discharge rates for lower extremity amputation in 2017 were assessed using the Healthcare Cost and Utilization Project State Inpatient Database. Those data were matched with publicly available demographic, hospital, and SDOH data. Data were analyzed July 3, 2022, to March 5, 2023. Main outcome and Measures: Amputation rates were assessed across all counties. Counties were divided into quartiles based on amputation rates, and baseline characteristics were described. Unadjusted linear regression and multivariable regression analyses were performed to assess associations between county-level amputation and SDOH and demographic factors. Results: Amputation discharge data were available for 76 of the 100 most populous counties in the United States. Within these counties, 15.3% were African American, 8.6% were Asian, 24.0% were Hispanic, and 49.6% were non-Hispanic White; 13.4% of patients were 65 years or older. Amputation rates varied widely, from 5.5 per 100 000 in quartile 1 to 14.5 per 100 000 in quartile 4. Residents of quartile 4 (vs 1) counties were more likely to be African American (27.0% vs 7.9%, P < .001), have diabetes (10.6% vs 7.9%, P < .001), smoke (16.5% vs 12.5%, P < .001), be unemployed (5.8% vs 4.6%, P = .01), be in poverty (15.8% vs 10.0%, P < .001), be in a single-parent household (41.9% vs 28.6%, P < .001), experience food insecurity (16.6% vs 12.9%, P = .04), or be physically inactive (23.1% vs 17.1%, P < .001). In unadjusted linear regression, higher amputation rates were associated with the prevalence of several health problems, including mental distress (ß, 5.25 [95% CI, 3.66-6.85]; P < .001), diabetes (ß, 1.73 [95% CI, 1.33-2.15], P < .001), and physical distress (ß, 1.23 [95% CI, 0.86-1.61]; P < .001) and SDOHs, including unemployment (ß, 1.16 [95% CI, 0.59-1.73]; P = .03), physical inactivity (ß, 0.74 [95% CI, 0.57-0.90]; P < .001), smoking, (ß, 0.69 [95% CI, 0.46-0.92]; P = .002), higher homicide rate (ß, 0.61 [95% CI, 0.45-0.77]; P < .001), food insecurity (ß, 0.51 [95% CI, 0.30-0.72]; P = .04), and poverty (ß, 0.46 [95% CI, 0.32-0.60]; P < .001). Multivariable regression analysis found that county-level rates of physical distress (ß, 0.84 [95% CI, 0.16-1.53]; P = .03), Black and White racial segregation (ß, 0.12 [95% CI, 0.06-0.17]; P < .001), and population percentage of African American race (ß, 0.06 [95% CI, 0.00-0.12]; P = .03) were associated with amputation rate. Conclusions and Relevance: Social determinants of health provide a framework by which the associations of environmental factors with amputation rates can be quantified and potentially used to guide interventions at the local level.

Association of stroke or death with severity of carotid lesion calcification in patients undergoing carotid artery stenting.

OBJECTIVE: Carotid artery stenting (CAS) for heavily calcified lesions is controversial due to concern for stent failure and increased perioperative stroke risk. However, the degree to which calcification affects outcomes is poorly understood, particularly in transcarotid artery revascularization (TCAR). With the precipitous increase in TCAR use and its expansion to standard surgical-risk patients, we aimed to determine the impact of lesion calcification on CAS outcomes to ensure its safe and appropriate use. METHODS: We identified patients in the Vascular Quality Initiative who underwent first-time transfemoral CAS (tfCAS) and TCAR between 2016 and 2021. Patients were stratified into groups based on degree of lesion calcification: no calcification, 1% to 50% calcification, 51% to 99% calcification, and 100% circumferential calcification or intraluminal protrusion. Outcomes included in-hospital and 1-year composite stroke/death, as well as individual stroke, death, and myocardial infarction outcomes. Logistic regression was used to evaluate associations between degree of calcification and these outcomes. RESULTS: Among 21,860 patients undergoing CAS, 28% patients had no calcification, 34% had 1% to 50% calcification, 35% had 51% to 99% calcification, and 3% had 100% circumferential calcification/protrusion. Patients with 51% to 99% and circumferential calcification/protrusion had higher odds of in-hospital stroke/death (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.02-1.6; P = .034; OR, 1.9; 95% CI, 1.1-2.9; P = .004, respectively) compared with those with no calcification. Circumferential calcification was also associated with increased risk for in-hospital myocardial infarction (OR, 3.5; 95% CI, 1.5-8.0; P = .003). In tfCAS patients, only circumferential calcification/protrusion was associated with higher in-hospital stroke/death odds (OR, 2.0; 95% CI, 1.2-3.4; P = .013), whereas for TCAR patients, 51% to 99% calcification was associated with increased odds of in-hospital stroke/death (OR, 1.5; 95% CI, 1.1-2.2; P = .025). At 1 year, circumferential calcification/protrusion was associated with higher odds of ipsilateral stroke/death (12.4% vs 6.6%; hazard ratio, 1.64; P = .002). CONCLUSIONS: Among patients undergoing CAS, there is an increased risk of in-hospital stroke/death for lesions with >50% calcification or circumferential/protruding plaques. Increasing severity of carotid lesion calcification is a significant risk factor for stroke/death in patients undergoing CAS, regardless of approach.

Perivascular CLICK-gelatin delivery of thrombospondin-2 small interfering RNA decreases development of intimal hyperplasia after arterial injury.

Bypass graft failure occurs in 20%-50% of coronary and lower extremity bypasses within the first-year due to intimal hyperplasia (IH). TSP-2 is a key regulatory protein that has been implicated in the development of IH following vessel injury. In this study, we developed a biodegradable CLICK-chemistry gelatin-based hydrogel to achieve sustained perivascular delivery of TSP-2 siRNA to rat carotid arteries following endothelial denudation injury. At 21 days, perivascular application of TSP-2 siRNA embedded hydrogels significantly downregulated TSP-2 gene expression, cellular proliferation, as well as other associated mediators of IH including MMP-9 and VEGF-R2, ultimately resulting in a significant decrease in IH. Our data illustrates the ability of perivascular CLICK-gelatin delivery of TSP-2 siRNA to mitigate IH following arterial injury.

Effects of monensin in supplements for beef cattle in tropical grazing systems during the rainy season.

Two experiments were carried out to evaluate the effect of monensin in supplements for grazing heifers. In experiment I, treatments consisted of protein supplements (low intake - 0.5 kg/animal/day and high intake - 1.0 kg/animal/day) associated or not with monensin. Animal performance, nutrient intake, and digestibility were evaluated. Forty crossbred heifers with an initial body weight (BW) of 213.8 ± 4.5 kg were used. There was no difference in average daily gain between treatments (average of 0.588 kg/animal/day). There was no interaction between monensin and supplements for intake parameters and digestibility. Dry matter (DM) intake was equal between treatments (~ 2% of BW). However, there was a reduction in pasture intake with the high-intake supplement. In experiment II, treatments consisted of two types of supplements (protein or mineral) associated or not with monensin. The variables analyzed were productive performance, ingestive behavior, and thermal comfort, evaluated through the index of thermal stress for cows (ITSC). Forty crossbred heifers with a BW of 159.2 ± 1.3 kg were used. The type of supplement did not influence the performance of the animals. However, monensin promoted greater weight gain in the animals (110 g/animal/day). There was an interaction effect between supplementation and monensin addition on behavioral activities, except for idle time. The inclusion of monensin in the protein supplement reduced the grazing time. The ITSC value influenced the activities of ingestive behavior, and the increase of this index reduced the grazing time in all treatments. Forage quality influences the response to monensin use, and the addition of monensin in supplements for grazing cattle during the rainy season is recommended for forages with high CP content.

The impact of neighborhood social disadvantage on presentation and management of first-time hemodialysis access surgery patients.

OBJECTIVES: The impact of social determinants of health on the presentation, management, and outcomes of patients requiring hemodialysis (HD) arteriovenous (AV) access creation have not been well-characterized. The Area Deprivation Index (ADI) is a validated measure of aggregate community-level social determinants of health disparities experienced by members living within a community. Our goal was to examine the effect of ADI on health outcomes for first-time AV access patients. METHODS: We identified patients who underwent first-time HD access surgery in the Vascular Quality Initiative between July 2011 to May 2022. Patient zip codes were correlated with an ADI quintile, defined as quintile 1 (Q1) to quintile 5 (Q5) from least to most disadvantaged. Patients without ADI were excluded. Preoperative, perioperative, and postoperative outcomes considering ADI were analyzed. RESULTS: There were 43,292 patients analyzed. The average age was 63 years, 43% were female, 60% were of White race, 34% were of Black race, 10% were of Hispanic ethnicity, and 85% received autogenous AV access. Patient distribution by ADI quintile was as follows: Q1 (16%), Q2 (18%), Q3 (21%), Q4 (23%), and Q5 (22%). On multivariable analysis, the most disadvantaged quintile (Q5) was associated with lower rates of autogenous AV access creation (OR, 0.82; 95% confidence interval [CI], 0.74-0.90; P < .001), preoperative vein mapping (OR, 0.57; 95% CI, 0.45-0.71; P < .001), access maturation (OR, 0.82; 95% CI, 0.71-0.95; P = .007), and 1-year survival (OR, 0.81; 95% CI, 0.71-0.91; P = .001) compared with Q1. Q5 was associated with higher 1-year intervention rates than Q1 on univariable analysis, but not on multivariable analysis. CONCLUSIONS: The patients undergoing AV access creation who were most socially disadvantaged (Q5) were more likely to experience lower rates of autogenous access creation, obtaining vein mapping, access maturation, and 1-year survival compared with the most socially advantaged (Q1). Improvement in preoperative planning and long-term follow-up may be an opportunity for advancing health equity in this population.

Impact of neighborhood social disadvantage on carotid artery disease presentation, management, and discharge outcomes.

OBJECTIVE: Recent studies have highlighted that race and socioeconomic status serve as important determinants of disease presentation and perioperative outcomes in carotid artery disease. However, these investigations only focus on individual factors of social disadvantage, and fail to account for community factors that may drive disparities. Area Deprivation Index (ADI) is a validated measure of neighborhood adversity that offers a more comprehensive assessment of social disadvantage. We examined the impact of ADI ranking on carotid artery disease severity, management, and postoperative outcomes. METHODS: We identified patients who underwent carotid endarterectomy (CEA), transfemoral carotid artery stenting (tfCAS), and transcarotid artery revascularization (TCAR) in the Vascular Quality Initiative registry between 2016 and 2020. Patients were assigned ADI scores of 1 to 100 based on zip codes and grouped into quintiles, with higher quintiles reflecting increasing adversity. Outcomes assessed included disease presentation, intervention type, and discharge patterns. Logistic regression was used to evaluate independent associations between ADI quintiles and these outcomes. RESULTS: Among 91,904 patients undergoing carotid revascularization, 9811 (10.7%) were in the lowest ADI quintile (Q1), 18,905 (20.6%) in Q2, 25,442 (27.7%) in Q3, 26,099 (28.4%) in Q4, and 11,647 (12.7%) in Q5. With increasing ADI quintiles, patients were more likely to present with symptomatic disease (Q5, 52.1% vs Q1, 46.6%; P < .001), and stroke vs transient ischemic attack (Q5, 63.1% vs Q1, 53.5%; P < .001); they also more frequently underwent CAS vs CEA (Q5, 46.4% vs Q1, 33.9%; P < .001), and specifically tfCAS vs TCAR (Q5, 54.2% vs Q1, 33.9%; P < .001). In adjusted analyses, higher ADI quintiles remained as independent risk factors for presenting with symptomatic disease and stroke and undergoing CAS and tfCAS. Across ADI quintiles, patients were more likely to experience death (Q5, 0.8% vs Q1, 0.4%; P < .001), stroke/death (Q5, 2.1% vs Q1, 1.6%; P = .001), failure to discharge home (Q5, 11.5% vs Q1, 8.0%; P < .001) and length of stay >2 days (Q5, 33.3% vs Q1, 26.3%; P < .001) following revascularization. CONCLUSIONS: Among carotid revascularization patients, those with greater neighborhood social disadvantage had greater disease severity and more frequently underwent tfCAS. These patients also had higher rates of death and stroke/death, were less frequently discharged home, and had prolonged hospital stays. Greater efforts are needed to ensure that patients in higher ADI quintiles undergo better carotid surveillance and are treated appropriately for their carotid artery disease.

Impact of neighborhood social disadvantage on the presentation and management of peripheral artery disease.

OBJECTIVE: Studies examining the relationship between socioeconomic disparities and peripheral artery disease (PAD) often focus on individual social health determinants and fail to account for the complex interplay between factors that ultimately impact disease severity and outcomes. Area deprivation index (ADI), a validated measure of neighborhood adversity, provides a more comprehensive assessment of social disadvantage. Therefore, we examined the impact of ADI on PAD severity and its management. METHODS: We identified all patients who underwent infrainguinal revascularization (open or endovascular) or amputation for symptomatic PAD in the Vascular Quality Initiative registry between 2003 and 2020. An ADI score of 1 to 100 was assigned to each patient based on their residential zip code, with higher ADI scores corresponding with increasing adversity. Patients were categorized by ADI quintiles (Q1-Q5). The outcomes of interest included indication for procedure (claudication, rest pain, or tissue loss) and rates of revascularization (vs primary amputation). Multinomial logistic regression was used to evaluate for an independent association between ADI quintile and these outcomes. RESULTS: Among the 79,973 patients identified, 9604 (12%) were in the lowest ADI quintile (Q1), 14,961 (18.7%) in Q2, 19,800 (24.8%) in Q3, 21,735 (27.2%) in Q4, and 13,873 (17.4%) in Q5. There were significant trends toward lower rates of claudication (Q1: 39% vs Q5: 34%, P < .001), higher rates of rest pain (Q1: 12.4% vs Q5: 17.8%, P < .001) as the indication for intervention, and lower rates of revascularization (Q1: 80% vs Q5: 69%, P < .001) with increasing ADI quintiles. In adjusted analyses, there was a progressively higher likelihood of presenting with rest pain vs claudication, with patients in Q5 having the highest probability when compared with those in Q1 (relative risk: 2.0; 95% confidence interval: 1.8-2.2; P < .001). Patients in Q5, when compared with those in Q1, also had a higher likelihood of presenting with tissue loss vs claudication (relative risk: 1.4; 95% confidence interval: 1.3-1.6; P < .001). Compared with patients in Q1, patients in Q2-Q5 had a lower likelihood of undergoing any revascularization procedure. CONCLUSIONS: Among patients who underwent infrainguinal revascularization or amputation in the Vascular Quality Initiative, those with higher neighborhood adversity had more advanced disease at presentation and lower rates of revascularization. Further work is needed to better understand neighborhood factors that are contributing to these disparities in order to identify community-level targets for improvement.

Agaricus blazei Murill extract-loaded in alginate/poly(vinyl alcohol) films prepared by Ca2+ cross-linking for wound healing applications.

This work aimed the development and evaluation of the wound healing activity of films based on sodium alginate, polyvinyl alcohol (PVA) and Ca2+ loaded with Agaricus blazei Murill hydroalcoholic extract (AbE). Firstly, AbE was prepared using a previously standardized methodology. The films were prepared by casting technique and cross-linked with Ca2+ using CaCl2 as cross-linking agent. The physicochemical, morphological and water vapor barrier properties of the films were analyzed and the pre-clinical efficacy was investigated against the cutaneous wound model in mice. The films showed barrier properties to water vapor promising for wound healing. AbE showed physical and chemical interactions between both polymers, noticed by Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and thermal analysis. The delivery of AbE in alginate/PVA films enhanced the antioxidant and wound healing properties of these polymers. Consequently, a reduction of malondialdehyde levels was observed, as well as an increase of the epidermis/dermis thickness and enhancement in collagen I deposition. Thus, these formulations are promising biomaterials for wound care and tissue repairing.

The impact of neighborhood social disadvantage on abdominal aortic aneurysm severity and management.

OBJECTIVE: Recent studies have highlighted socioeconomic disparities in the severity and management of abdominal aortic aneurysm (AAA) disease. However, these studies focus on individual measures of social disadvantage such as income and insurance status. The area deprivation index (ADI), a validated measure of neighborhood deprivation, provides a more comprehensive assessment of social disadvantage. Therefore, we examined the impact of ADI on AAA severity and its management. METHODS: We identified all patients who underwent endovascular or open repair of an AAA in the Vascular Quality Initiative registry between 2003 and 2020. An ADI score of 1 to 100 was assigned to each patient based on their residential zip code, with higher ADI scores corresponding with increasing deprivation. Patients were categorized by ADI quintiles. Outcomes of interest included rates of ruptured AAA (rAAA) repair versus an intact AAA repair and rates of endovascular repair (EVAR) versus the open approach. Logistic regression was used to evaluate for an independent association between ADI quintile and these outcomes. RESULTS: Among 55,931 patients who underwent AAA repair, 6649 (12%) were in the lowest ADI quintile, 11,692 (21%) in the second, 15,958 (29%) in the third, 15,035 (27%) in the fourth, and 6597 (12%) in the highest ADI quintile. Patients in the two highest ADI quintiles had a higher proportion of rAAA repair (vs intact repair) compared with those in the lowest ADI quintile (8.8% and 9.1% vs 6.2%; P < .001). They were also less likely to undergo EVAR (vs open approach) when compared with the lowest ADI quintile (81% and 81% vs 88%; P < .001). There was an overall trend toward increasing rAAA and decreasing EVAR rates with increasing ADI quintiles (P < .001). In adjusted analyses, when compared with patients in the lowest ADI quintile, patients in the highest ADI quintile had higher odds of rAAA repair (odds ratio, 1.4; 95% confidence interval, 1.2-1.8; P < .001) and lower odds of undergoing EVAR (odds ratio, 0.54; 95% confidence interval, 0.45-0.65; P < .001). CONCLUSIONS: Among patients who underwent AAA repair in the Vascular Quality Initiative, those with higher neighborhood deprivation had significantly higher rates of rAAA repair (vs intact repair) and lower rates of EVAR (vs open approach). Further work is needed to better understand neighborhood factors that are contributing to these disparities to identify community-level targets for improvement.

Overview of screening eligibility in patients undergoing ruptured AAA repair from 2003 to 2019 in the Vascular Quality Initiative.

OBJECTIVE: Although efforts such as the Screening Abdominal Aortic Aneurysms Very Efficiently (SAAAVE) Act have improved access to abdominal aortic aneurysm (AAA) screening, certain high-risk populations are currently excluded from the guidelines yet may benefit from screening. We therefore examined all patients who underwent repair of ruptured AAA (rAAA) to characterize those who are ineligible for screening under current guidelines and evaluate the potential impact of these restrictions on their disease. METHODS: We identified patients undergoing rAAA repair in the Vascular Quality Initiative (VQI) database between 2003 and 2019. These patients were stratified by AAA screening eligibility according to the Centers for Medicare and Medicaid reimbursement guidelines. We then described baseline characteristics to identify high-risk features of these cohorts. Groups with disproportionate representation in the screening-ineligible cohort were identified as potential targets of screening expansion. Trends over time in screening eligibility and the proportion of AAA repairs performed for rAAA were also analyzed. RESULTS: A total of 5340 patients underwent rAAA repair. The majority (66%) were screening-ineligible. When characterizing the screening-ineligible group by sex and risk factors (smoking history or family history of AAA), the largest contributors to screening ineligibility were males less than 65 years of age with a smoking history or family history of AAA (25%), males greater than 75 years of age with a smoking history (25%), and females older than 65 years of age with a smoking history (19%). In comparison with rAAAs prior to implementation of the SAAAVE act, the proportion of AAA repair performed for rupture among males undergoing AAA repair in the VQI decreased from 12% to 8% (P < .001), whereas in females, there was no change (P = .990). There was no statically significant difference in screening eligibility for either males (P = .762) or females (P = .335). CONCLUSIONS: Most patients who underwent rAAA repair were ineligible for initial AAA screening or aged out of the screening window. Furthermore, rAAA rates and screening ineligibility have not improved as much as expected since the passage of the SAAAVE Act. Our data suggest that three high-risk populations may benefit from expansion of AAA screening guidelines: males with a smoking history or family history of AAA between ages 55 and 64 years, female smokers older than 65 years, and male smokers older than 75 years who are otherwise in good health. Increased efforts to screen these high-risk populations may increase elective AAA repair and minimize the morbidity and mortality associated with rAAAs.

Methimazole-Induced ANCA Vasculitis: A Case Report.

Rapidly progressive glomerulonephritis (RPGN) is a syndrome which presents rapid loss of renal function. Vasculitis represents one of the major causes, often related to anti-neutrophil cytoplasmic antibodies (ANCA). Herein, we report a case of methimazole-induced ANCA-associated vasculitis. A 35-year-old woman complained of weight loss and fatigue for 2 weeks and attended the emergency room with alveolar hemorrhage. She had been diagnosed with Graves' disease and had been taking methimazole in the past 6 months. Her physical examination showed pulmonary wheezing, hypertension and signs of respiratory failure. Laboratory tests revealed urea 72 mg/dL, creatinine 2.65 mg/dL (eGFR CKD-EPI: 20 mL/min/1.73 m2), urine analysis with >100 red blood cells per high-power field, 24 h-proteinuria: 1.3 g, hemoglobin 6.6 g/dL, white-cell count 7700/mm3, platelets 238,000/mm3, complement within the normal range, negative viral serological tests and ANCA positive 1:80 myeloperoxidase pattern. Chest tomography showed bilateral and diffuse ground-glass opacities, and bronchial washing confirming alveolar hemorrhage. A renal biopsy using light microscopy identified 27 glomeruli (11 with cellular crescentic lesions), focal disruption in glomerular basement membrane and fibrinoid necrosis areas, tubulitis and mild interstitial fibrosis. Immunofluorescence microscopy showed IgG +2/+3, C3 +3/+3 and Fibrinogen +3/+3 in fibrinoid necrosis sites. She was subsequently diagnosed with crescentic pauci-immune glomerulonephritis, mixed class, in the setting of a methimazole-induced ANCA vasculitis. The patient was treated with methimazole withdrawal and immunosuppressed with steroids and cyclophosphamide. Four years after the initial diagnosis, she is currently being treated with azathioprine, and her exams show creatinine 1.30 mg/dL (eGFR CKD-EPI: 52 mL/min/1.73 m2) and negative p-ANCA.

Ethnic/Racial Bias in Medical School Performance Evaluation of General Surgery Residency Applicants.

OBJECTIVE: Differential use of communal terms (caring/unselfish traits) versus agentic terms (goal-oriented/leadership/achievement traits) may reveal bias and has been extensively reported in letters of recommendation for residency. We evaluated bias in medical student performance evaluations (MSPE) of general surgery residency applicants. DESIGN: This is a retrospective study evaluating ethnic/race bias, as measured by differential use of agentic and communal terms, in MSPEs of residency applicants. 50% of MSPEs were randomly selected. An ethnic bias calculator derived from an open-source online gender bias calculator was populated with a list of validated agentic and communal terms. Relative frequency of communal and agentic terms was used to estimate bias. Multivariable regression was used to assess the association between the terms and ethnicity/race. PARTICIPANTS: US medical students applying for a categorical surgery residency position at a single academic institution for a single Match cycle. RESULTS: A total of 339 MSPEs were reviewed from 119 US medical schools. Genders were equally represented (women, 51.6%); most participants were white and Asian applicants (79.1%). Overall, MSPEs were more agency biased (65.2%) than communal biased (16.2%) or neutral (18.6%). MSPEs for Black and Hispanic/Latinx applicants were more likely to contain communal rather than agentic terms (adjusted OR: 3.02, 95% CI: 1.52-6.02) when compared to white and Asian applicants. This finding was independent of MSPE writer's gender or rank. CONCLUSIONS: Surgery residency applicants self-identifying as Black and Hispanic/Latinx were more likely to be described using communal traits compared to white and Asian applicants, suggesting ethnic/racial bias. Such differences in language utilized in MSPEs may impact residency opportunities for applicants who are under-represented in medicine. Educational efforts aimed at MSPE writers may help to reduce bias.

Cryopreserved valved femoral vein homografts for right ventricular outflow tract reconstruction in infants.

Background: We have previously reported use of cryopreserved valve femoral vein homograft (FVH) conduits for biventricular repairs in infants needing right ventricular outflow tract (RVOT) reconstruction. This study aims to compare FVH conduits with aortic (A) and pulmonary (P) homografts with regards to intermediate- and long-term outcomes. Methods: Retrospective review was conducted of all infants between 2004 and 2016 who underwent biventricular repair with RVOT reconstruction using homograft conduits. Patients were divided into A, P, and FVH groups based upon type of conduit received (N = 57 [A = 13; P = 21, FVH = 23]). Groups were compared using univariate and multivariable Cox regression analyses. The Nelson-Aalen estimator of cumulative hazard and Kaplan-Meier curves were used to identify differences in freedom from catheter reintervention and reoperation. Results: The 2 groups were comparable except for greater incidence of delayed sternal closure and longer hospital length of stay in the FVH group. The follow-up was longer for A and P groups compared with the FVH group (P < .001). Multivariable Cox regression, adjusting for difference in the length of follow-up, revealed comparable freedom from overall reintervention between the groups. Younger age at implantation was the only independent predictor of overall reintervention (hazard ratio per day younger age, 1.06; 95% confidence interval, 1.02-1.11; P = .002). Nelson-Aalen cumulative hazard analysis revealed greater freedom from percutaneous reintervention with use of FVH. Kaplan-Meier analysis showed comparable freedom from reoperation for all three conduits. Conclusions: Valved femoral vein homograft conduits are comparable with aortic and pulmonary homografts for RVOT reconstruction in infants undergoing biventricular repairs.

"Nota de Conceito Global" na Avaliação da Performance do Interno de Medicina: uma Oportunidade Desperdiçada / "Global Rating Scale" in the Evaluation of the Academic Achievement of the Medical Student: a Wasted Opportunity

Resumo: Introdução: Possuir diploma de médico é o suficiente para o exercício profissional na maioria dos estados brasileiros. A avaliação do desempenho do aluno pelas escolas médicas é, certamente, o mais importante filtro de proficiência profissional em vigência. Assim, é fundamental a utilização de instrumentos de avaliação adequados. Competência é o conjunto de conhecimentos, habilidades e atitudes que permitem uma prática médica de excelência. Diferentemente, performance pode ser definida como o que o indivíduo realmente produz em seu cotidiano. O internato é uma inigualável oportunidade para o acompanhamento preciso dos atributos esperados de um estudante em formação. Quando avaliamos a competência, buscamos medir o quanto o aluno sabe, concebe ou realiza procedimentos em um contexto objetivo de avaliação. Performance é o que efetivamente o indivíduo utiliza de suas competências. Há, portanto, uma maior dificuldade de avaliar performance, pois motivação, disciplina, condições físicas e psíquicas, e outros aspectos vivenciais estão em jogo. Além disso, é necessária uma avaliação constante, o que implica acompanhamento e monitoramento próximos. A Nota de Conceito Global (NCG) é uma das modalidades que permitem, não obstante sua implícita subjetividade, avaliar o desempenho do aluno/estagiário. Para isso, é estratégico que seja construída por meio de nomenclatura padronizada, parâmetros definidos que possibilitem quantificação, levando em conta diferenças existentes entre os diversos projetos políticos pedagógicos. Pela heterogeneidade dos estágios, diferentes contextos da prática da medicina e grande número de sujeitos envolvidos seriam os critérios estabelecidos para a constituição da NCG devidamente padronizados e adequados para avaliar alunos no internato? Método: Neste trabalho, estudamos, por meio dos planos de ensino, como a NCG está estruturada na avaliação de internos de uma instituição e o que pode ser aperfeiçoado e contribuir para o conhecimento do assunto. Resultados: Constatamos que a NCG compõe 30% (quinto ano) e 40% (sexto ano) da Nota Global do Aluno (NGA), que corresponde a uma nota única ao final de cada ano de graduação e leva em conta o desempenho e a carga horária das disciplinas. Adicionalmente, avaliamos os termos utilizados como critérios a serem utilizados para a NCG. A análise dos planos de ensino mostrou que a NCG se mostrou irregular e sem padronização institucional entre as disciplinas; há uma ausência de uniformidade na composição da nota final ou nos critérios a serem avaliados, bem como na aplicação diferenciada dos itens em cada cenário de aprendizado. Conclusões: A falta de uma metodologia uniforme impede o acompanhamento do aluno de forma global, inclusive o quanto a cultura e os valores institucionais poderiam influenciar o desempenho estudantil. Perde-se a oportunidade de realizar uma avaliação efetivamente construtiva. Contudo, a NCG, pela sua natureza subjetiva, poderia, se adequadamente aplicada, ser instrumento fundamental para o diálogo entre professores e alunos em uma avaliação formativa. Dessa forma, pela inserção inadequada, dentro de uma avaliação somativa, perde-se uma grande oportunidade de crescimento do aluno e da própria instituição.

Abstract: Introduction: Having a medical degree is enough documentation for professional practice in most Brazilian states. In fact, the evaluation of academic achievement by medical schools is certainly the most important filter of professional proficiency. Thus, the use of appropriate assessment instruments is essential. Competence is the set of knowledge, skills and attitudes that enable a medical practice of excellence. Differently, Performance can be defined as what the individual actually produces in their daily lives. The internship is the best opportunity for the precise monitoring of the expected achievements of a student in training. When we evaluate competence, we seek to measure how much the student knows, conceives or performs procedures, in an objective evaluation context. Performance is what the individual effectively uses of their skills. There is, therefore, a greater difficulty in evaluating performance, since motivation, discipline, physical and psychic conditions, as well as other experiential aspects are involved. In addition, continuous assessment is required, which implies close monitoring. The "Global Rating Scale" (GRS) is one of the modalities that allows, despite its subjectivity, evaluating the performance of the intern student. For that purpose, it is strategic that it be constructed through standardized nomenclature, defined parameters that allow the quantification, considering the differences between several pedagogical political projects. Due to the heterogeneity of the different settings of the practice of medicine, and the large number of subjects involved, would the criteria established for the structuring of the GRS be properly standardized and adequate to evaluate medical internship students? Method: In this work, we study, through the teaching plans, how GRS is structured in the evaluation of students of an institution regarding practical activities, and what can be improved and contribute to the knowledge on the subject. Results: We find that the GRS comprises 30% (fifth year) and 40% (sixth year) of the Student Global Rating (SGR), which corresponds to a single grade at the end of each graduation year and takes into account the performance and the workload of disciplines. Additionally, we evaluate the terms used as criteria to be used for the GRS. The analysis of the Teaching Plans showed that the GRS was irregular and lacked institutional standardization among the Disciplines; there is an absence of uniformity regarding the composition of the final grade or in the criteria to be evaluated, as well as in the differentiated application of the items in each learning scenario. Conclusion: The lack of a uniform methodology precludes an overall student follow-up, including how much culture and institutional values could influence student performance. The opportunity to conduct an effectively constructive evaluation is lost. On the other hand, the GRS, considering its subjective nature, could, if properly applied, be a fundamental instrument for the dialogue between teachers and students in a formative evaluation. Thus, due to inadequate inclusion, within a summative evaluation, a great opportunity for development of the student, as well as of the institution, is wasted.

Complete unroofing of the intramural coronary artery for anomalous aortic origin of a coronary artery: The role of commissural resuspension?

OBJECTIVES: Although surgical repair of an anomalous aortic origin of the coronary artery has low operative mortality, longer-term risk of ischemia and aortic regurgitation remains concerning. We routinely perform aortic commissure resuspension after unroofing and sought to evaluate the outcomes with regard to aortic valve competence, symptoms, and signs of ischemia with this approach. METHODS: Twenty-six consecutive patients who received the unroofing procedure for anomalous aortic origin of the coronary artery (10 left; 16 right) between 2004 and 2016 were reviewed. In addition to complete unroofing of the intramural coronary, patients early in the cohort (n = 9) received unroofing only, and aortic commissural resuspension was performed routinely in the subsequent patients (n = 17). Outcomes between commissural resuspension versus no commissural resuspension were compared. The occurrence of mild and greater aortic regurgitation was assessed using a time-to-event analysis after varying lengths of time. Commissural resuspension was considered as the predictor, and the groups were compared using a log-rank test. RESULTS: There was no operative mortality. One patient in the no commissural resuspension group died 10 years later of prosthetic aortic valve endocarditis (aortic valve replacement 7 years after unroofing). The follow-up duration was 6.9 years (4.9-9.1) and 3.7 years (2.1-4.3) in the no commissural resuspension and commissural resuspension groups, respectively (P = .001). Available postoperative exercise stress test data (n = 14) revealed that 50% had an endurance level at the 25th percentile or greater for age. After a median follow-up of 1.9 years (3 months to 10.6 years), no patient in the commissural resuspension group had aortic regurgitation, whereas 6 of 9 patients (67%) in the no commissural resuspension group had stable but mild or greater aortic regurgitation. Time-to-event analysis with the primary event of occurrence of mild or greater aortic regurgitation showed significantly higher freedom from the occurrence of aortic regurgitation in the commissural resuspension group (P = .035). CONCLUSIONS: Surgical repair of an anomalous aortic origin of the coronary artery can be performed with excellent early and midterm outcomes. Routine commissural resuspension of the aortic valve may lead to a lower rate of aortic valve regurgitation without increasing the risk of ischemia.

The effect of income and insurance on the likelihood of major leg amputation.

BACKGROUND: Although it has been suggested that individuals of low socioeconomic status and those with Medicaid or no insurance may be more likely to have their peripheral artery disease treated by leg amputation rather than by limb-saving revascularization, it is not clear if this disparity occurs consistently on a national basis, and if it does so in a linear fashion, such that poorer individuals are at progressively greater risk for amputation. OBJECTIVE: We undertook this study to determine if lower median household income and Medicaid/no insurance status are associated with a higher risk for amputation, and if this occurs in a progressively linear fashion. METHODS: The National (Nationwide) Inpatient Sample Database was queried to identify patients who were admitted with a diagnosis of critical limb ischemia from 2005 to 2014 and underwent either a major amputation or a revascularization procedure during that admission. Patients were stratified according to their insurance status and their median household income into four income quartiles. Multivariate logistic regression was performed to determine the effect of income and insurance status on the odds of undergoing amputation vs leg revascularization. RESULTS: Across the different insurance types, there was a significant decrease in the odds ratios for amputation as one progressed from one MHI quartile to a higher one: namely, Medicare (2.23, 1.87, 1.65, and 1.42 for the first, second, third, and fourth MHI quartiles); Medicaid (2.50, 2.28, 2.04, and 1.80 for the first, second, third, and fourth MHI quartiles); private insurance (1.52, 1.21, 1.16, and 1.00 for the first, second, third, and fourth MHI quartiles), and uninsured (1.91, 1.64, 1.10, and 1.22, for the first, second, third, and fourth MHI quartiles). CONCLUSIONS: Lower MHI, Medicaid insurance, and uninsured status are associated with a greater likelihood of amputation and a lower likelihood of undergoing limb-saving revascularization. These disparities are exacerbated in stepwise fashion, such that lower income quartiles are at progressively greater risk for amputation.

Socioeconomic disparities in the complexity of hernias evaluated at Emergency Departments across the United States.

BACKGROUND: Hernias represent one of the most common surgical conditions with a high-burden on health expenditures. We examined the impact of socioeconomic-status and complexity of presentation among patients in the Emergency Department (ED). METHODS: Retrospective analysis of 2006-2014 data from the Nationwide Emergency Department Sample, identified adult discharges with a diagnosis of inguinal, femoral, and umbilical hernia. Cases were dichotomized: complicated and uncomplicated. Unadjusted and adjusted analyses were used to determine factors that influence ED presentation. RESULTS: Among 264,484 patients included, 73% presented as uncomplicated hernias and were evaluated at urban hospitals (86%). Uncomplicated presentation was more likely in Medicaid (OR 1.56 95%CI1.50-1.61) and uninsured (OR 1.73 95%CI 1.67-1.78), but less likely for patients within the third and fourth MHI quartile (OR 0.82 95%CI 0.80-0.84 and OR 0.77 95%CI 0.75-0.79), respectively. CONCLUSION: Uninsured, publicly-insured, and low-MHI patients were more likely to present to ED with uncomplicated hernias. This finding might reflect a lack of access to primary surgical care for non-urgent surgical diseases.