Background: Blood pressure (BP) management is highly relevant for cardiovascular and brain health outcomes. Although clinical guidelines are trending towards increasingly strict BP control, some discordant results evaluating dementia-related outcomes indicate that more research is needed. Asymptomatic extracranial carotid atherosclerotic disease (aECAD), a hallmark cerebrovascular disease affecting > 10% of those over the age of 60, may represent a key subpopulation unaccounted for in previous studies. Methods: Using our Carotids and Minds prospective study and TriNetX, a US nationwide medical record database, we evaluated the association of hypertension status with dementia-related outcomes in adults ≥ 50 years of age with and without aECAD. We investigated secondary effects of age, systolic BP (SBP) ranges, hypertension medications, cardiovascular outcomes, and treatment of aECAD with carotid endarterectomy (CEA). Results After controlling for relevant confounders, hypertension was significantly associated with higher cognitive scores (β = 0.47, p< .01), lower pTau217 (β= -0.52, p<.01) and lower AD (HR = 0.56 [0.52–0.61]), non-AD dementia (HR = 0.66 [0.63–0.68]), and MCI risk (HR = 0.69 [0.64–0.74]) in patients with aECAD. Effect sizes were moderate to large and congruous across both cohorts, with strongest risk reduction in aECAD patients 81 + years of age. CEA mitigated these protective associations, and significantly higher risk of ADRD was seen in hypertensives without aECAD. Still more, a SBP range of 140–159 mmHg optimized protective effects with no significant increase in major cardiovascular events and death. Conclusion In summary, hypertension is associated with lower risk of dementia-related outcomes in aECAD patients. This promotes the need for future clinical trials focusing on individualized BP goals and addressing cerebrovascular disease. More broadly, these data further highlight cerebrovascular disease as relevant in brain health and aging.

Objective There is growing appreciation that extracranial carotid atherosclerotic disease (ECAD) is associated with increased dementia risk. Despite this, clinical management of ECAD does not involve evaluation for cognitive outcomes or risk stratification for dementia. One impediment to studying and improving clinical care for this cohort (roughly 10% of adults aged >60 years) is that factors to identify patients with ECAD at risk for dementia are not known. Methods Our prospective clinicopathologic study, the Arizona Study of Aging and Neurodegenerative Disorders study, evaluated clinical and histopathologic factors for dementia in subjects with ECAD. The primary outcome (dementia) was defined as a composite of Alzheimer’s disease and/or vascular dementia based on a clinical/neuropathologic diagnosis. Of 1234 subjects, those with dementia other than Alzheimer’s disease and/or vascular dementia were excluded; there remained 111 subjects with ECAD to be evaluated. Logistic regression analysis was performed to examine the association of key risk factors for dementia including age, sex, cardiovascular risk factors, apolipoprotein E4 (APOE4) genetic status, and dementia biomarkers. A precision recall curve was also generated to evaluate the diagnostic accuracy of dementia prediction models. Results Individuals with dementia compared with those without had significantly increased levels of stroke, APOE4 genotype, and dementia biomarkers, neurofibrillary tangles (NFTs), and amyloid plaques. Models of multiple combined risk factors were little or no better than NFTs alone, which showed a 96.9% positive predictive value at an NFT threshold of 10. Conclusions Although we hypothesized that a combination of clinical and histopathologic biomarkers would result in the strongest predictive model for dementia, we found that NFTs alone had the highest association and positive predictive value for dementia risk in patients with ECAD. As blood-based assays for NFT quantification become more clinically reliable and available, these data support the possibility that NFT quantification may help identify patients with ECAD at increased risk for dementia.

Introduction: Cerebrovascular disease and vascular risk factors have important contributions to Alzheimer’s disease (AD) risk, and greater understanding of cognitive changes in vascular versus non-vascular populations may help reveal complementary and overlapping clinical changes. The aim of this work was to evaluate how cognitive changes in middle to later aged vascular and non-vascular cohorts are related to AD pathology. Methods: A subset of the National Alzheimer’s Coordinating Center (NACC) cohort with pTau217 testing available (ages 50-90, n=444) was included as a general population cohort. The first 167 participants enrolled in our prospective Carotid and Minds (CAM) study (participants aged 50-85 with ≥2 vascular comorbidities with/without asymptomatic carotid stenosis were included as a vascular disease cohort. Both cohorts were assessed using a full UDS neurocognitive battery and compared to plasma pTau217 adjusting for demographics and APOE ε4 status. Dementia and other neurological disorders were exclusionary. Results: Demographics of NACC cohort shown (Table1). When adjusted for age, sex, education, race, ethnicity and APOE ε4 status, pTau217 was associated with significantly worse memory (β=-0.15, p=0.003) while no significant association with domains of language, executive function, visuospatial and processing speed was seen. Demographics of CAM are shown (Table 2). Within CAM, pTau217 was associated with significantly worse non-amnestic domains including language (β=-0.18, p=0.02), executive function (β=-0.19, p=0.013) and processing speed (β=-0.18, p=0.02), but not memory (β=-0.07, p=0.36) independent of age, sex, education, race, ethnicity and APOE ε4 status. Poorer cognition was associated with age, sex and education in both cohorts; in contrast, worse processing speed and executive function in CAM cohort is associated with carotid stenosis (β=-0.24, p<0.001) and a history of stroke (β=-0.47, p=0.02), but not APOE ε4 status or cerebral white matter lesion volumes. Conclusion: Within a vascular disease cohort, association of AD pathology with non-amnestic domains of processing speed, executive function and language complements and contrasts with memory domain impacts often associated with the classic notion of AD. Further assessment of these pathways associated with AD pathology could help understand unique and potentially complimentary cognitive changes relevant in understanding vascular contributions to cognitive impairment and dementia.

INTRODUCTION:Asymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non-AD dementia risk. aECAD treatment includes carotid endarterectomy (CEA) and carotid artery stenting (CAS) for stroke prevention, but their impact on dementia incidence is poorly studied. METHODS:Propensity score matching was used in a retrospective cohort study of United States-based insurance claims (2010-2022) in 487,676 patients with aECAD to evaluate the effect of CEA and CAS on AD and non-AD dementia incidence. RESULTS:After matching, 37,317 patients underwent CEA or CAS. CEA was associated with a significantly lower AD risk (relative risk = 0.93; 95% confidence interval, 0.86-0.99; P < 0.05), whereas CAS was associated with a slight but non-significant increase. Similar trends were observed for non-AD dementia. DISCUSSION:CEA, but not CAS, may confer a protective effect against AD and non-AD dementia in patients with aECAD, a common cerebrovascular disease affecting up to 15% of adults over age 60. HIGHLIGHTS:Asymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non-AD dementia risk. Limited studies have evaluated the role of carotid endarterectomy (CEA) and (carotid artery stenting (CAS) on dementia outcomes. Using United States-based insurance claims data, 487,676 patients with aECAD were evaluated. After propensity score matching, CEA was significantly associated with reduced AD risk. CAS was not significantly associated with a change in AD risk.

Background In the absence of a cerebrovascular accident, whether asymptomatic extracranial carotid atherosclerotic disease (aECAD) affects Alzheimer’s disease (AD) and non-AD dementia risk is not clear. Understanding whether aECAD is associated with an increased risk for AD is important as it is present in roughly 10% of the population over 60 and could represent a modifiable risk factor for AD and non-AD dementia.Methods This retrospective cohort study analysed Mariner insurance claims. Enrolment criteria included patients aged 55 years or older with at least 5 years of data and no initial dementia diagnosis. Subjects with and without aECAD were evaluated for subsequent AD and non-AD dementia diagnoses. Propensity score matching was performed using confounding factors identified by logistic regression. χ2 tests and Kaplan-Meier survival curves were used to evaluate the impact of aECAD diagnosis on AD and non-AD dementia risk over time.Results 767 354 patients met enrolment criteria. After propensity score matching, 62 963 subjects with aECAD and 62 963 subjects without ECAD were followed through data records. The aECAD cohort exhibited an increased relative risk of 1.22 (95% CI 1.15 to 1.29, p<0.001) for AD and 1.48 (95% CI 1.38 to 1.59, p<0.001) for non-AD dementias compared with the propensity score-matched cohort without aECAD. The increased AD risk associated with aECAD was evident in patients younger than 75 years old and was less apparent in patients over 75 years of age.Conclusions aECAD is associated with an increased risk of developing AD and non-AD dementias. These findings underscore the need for further prospective evaluation of interactions between aECAD and dementia, with potential implications for change of clinical care in both of these large patient populations.

BackgroundStroke and transient ischemic attack (TIA) may have long-term negative effects on the blood brain barrier (BBB) and promote endothelial inflammation, both of which could increase neurodegeneration and dementia risk beyond the cell death associated with the index event.MethodsSerum from 88 postmortem subjects in the Arizona Study of Aging and Neurodegenerative Disorders were analyzed by sandwich ELISA for specific biomarkers to investigate the effects of cerebrovascular accidents (CVAs) on BBB integrity and endothelial activation. Statistical analyses were performed using the Mann Whitney U Test, Spearman’s rank correlation, and linear/logistic regressions adjusted for potential confounders; a P-value <0.05 was considered significant for all analyses.ResultsSerum PDGFRẞ, a putative biomarker of BBB injury, was significantly increased in subjects with versus without a history of CVA who had similar cardiovascular risk factors (P<0.01). This difference was stable after adjusting for age, hypertension, and other potential confounders in regression analysis (OR 27.02, 95% CI [2.61 to 411.7] P<0.01). In addition, PDGFRẞ was positively associated with VCAM-1, a biomarker of endothelial inflammation (ρ=0.42, P<0.01).ConclusionOur data suggest that patients with stroke or TIA have lasting changes in the BBB. Still more, this demonstrates the utility of PDGFRẞ as a serum-based biomarker of BBB physiology, a potentially powerful tool in studying the role of the BBB in various neurodegenerative diseases and Covid infection sequelae.

Background: The purpose of this study was to determine the association of preulcerative foot care and outcomes of diabetic foot ulcerations (DFUs). Methods: This retrospective cohort study using the Mariner all-payers claims data set included participants with a new DFU from 2010 to 2019. Patients were stratified into two cohorts (foot care and control) based on whether they had received any outpatient foot care within 12 months before DFU. Adjusted comparison was performed by propensity matching for age, sex, and the Charlson Comorbidity Index (1:2 ratio). Kaplan-Meier estimates and logistic regression examined the association between foot care and outcomes of DFUs. Results: Of the 307,131 patients in the study cohort, 4.7% (n = 14,477) received outpatient preulcerative foot care within the 12-month period before DFU. The rate of major amputation was 1.8% (foot care, 1.2%), and 9.0% of patients had hospitalizations for foot infection within 12 months after DFU (foot care, 7.8%). In the study cohort, patients who received pre-DFU foot care had greater major amputation-free survival (P < .001) on Kaplan-Meier estimate. In both the study and matched cohorts, multivariable analysis demonstrated that foot care was associated with lower odds of major amputation for both study (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.48–0.66) and matched (OR, 0.61; 95% CI, 0.51–0.72) cohorts, and lower odds of hospitalizations for a foot infection in both study (OR, 0.91; 95% CI, 0.86–0.96) and matched (OR, 0.88, 95% CI, 0.82–0.94) cohorts. Conclusions: Among patients with a new DFU, those who received outpatient preulcerative foot care within 12 months of diagnosis had lower risks of major amputation and hospitalizations for foot infection.

OBJECTIVES:A growing body of data indicates that extracranial carotid artery disease (ECAD) can contribute to cognitive impairment. However, there have been mixed reports regarding the benefit of carotid endarterectomy (CEA) as it relates to preserving cognitive function. In this work, diffusion magnetic resonance imaging (dMRI) and neurocognitive testing are used to provide insight into structural and functional brain changes that occur in subjects with significant carotid artery stenosis, as well as changes that occur in response to CEA. MATERIALS AND METHODS:The study design was a prospective, non-randomized, controlled study that enrolled patients with asymptomatic carotid stenosis. Thirteen subjects had severe ECAD (≥70% stenosis in at least one carotid artery) and were scheduled to undergo surgery. Thirteen had asymptomatic ECAD with <70% stenosis, therefore not requiring surgery. All subjects underwent neurocognitive testing using the Montreal Cognitive Assessment test (MoCA) and high angular resolution, multi-shell diffusion magnetic resonance imaging (dMRI) of the brain at baseline and at four-six months follow-up. Changes in MoCA scores as well as in Fractional anisotropy (FA) along the hippocampus were compared at baseline and follow-up. RESULTS:At baseline, FA was significantly lower along the ipsilateral hippocampus in subjects with severe ECAD compared to subjects without severe ECAD. MoCA scores were lower in these individuals, but this did not reach statistical significance. At follow-up, MoCA scores increased significantly in subjects who underwent CEA and remained statistically equal in control subjects that did not have CEA. FA remained unchanged in the CEA group and decreased in the control group. CONCLUSIONS:This study suggests that CEA improves cognition and preserves hippocampal white matter structure compared to control subjects not undergoing CEA.

BACKGROUND: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163 + macrophages. Here, we explored the hypothesis that CD163 + macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap. METHODS: Human coronary artery sections from CVPath’s autopsy registry were selected for pathological analysis. Athero-prone ApoE −/− and ApoE −/− /CD163 −/− mice were used for in vivo studies. Human peripheral blood mononuclear cell–induced macrophages and human aortic endothelial cells were used for in vitro experiments. RESULTS: In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163 + macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa β) signaling by proinflammatory cytokines released from CD163 + macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163 + macrophage–induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes. CONCLUSIONS: CD163 + macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.

BACKGROUND:Microvascular disease (MVD) describes systemic changes in the small vessels (~100 um diameter) that impair tissue oxygenation and perfusion. MVD is a common but poorly monitored complication of diabetes. Recent studies have demonstrated that MVD: (i) is an independent risk factor for ulceration and amputation and (ii) increases risk of adverse limb outcomes synergistically with PAD. Despite the clinical relevance of MVD, microvascular evaluation is not standard in a vascular assessment.METHODS:We evaluated 299 limbs from 153 patients seen clinically for possible lower extremity PAD. The patients were assessed by ankle brachial index (ABI), toe brachial index (TBI), and spatial frequency domain imaging (SFDI). These measurements were evaluated and compared to patient MVD status, defined by clinical diagnoses of (in ascending order of severity) no diabetes; diabetes; diabetes + neuropathy; diabetes + neuropathy + retinopathy.RESULTS:SFDI-derived parameters HbT1 and StO2 were significantly different across the MVD groups (P < .001). A logistic regression model based on HbT1 and StO2 differentiated limbs with severe MVD (diabetes+neuropathy+retinopathy) from the larger group of limbs from patients with only diabetes (P = .001, area under the curve = 0.844). Neither ABI nor TBI significantly differentiated these populations.CONCLUSIONS:Standard assessment of PAD using ABI and TBI are inadequate for detecting MVD in at-risk populations. SFDI-defined HbT1 and StO2 are promising tools for evaluating MVD. Prospective studies with wound-based outcomes would be useful to further evaluate the role MVD assessment could play in routine clinical evaluation of patients at risk for lower extremity complications.

The early stage of Alzheimer’s Dementia (AD) development has been linked to the breakdown of the blood-brain barrier (BBB), which is maintained by pericytes and other cell types. Platelet-derived growth factor receptor-β (PDGFRβ) has been identified as a novel biomarker of BBB-associated capillary pericyte damage. Our study aimed to explore the potential association between PDGFRβ and neuropathological diagnosis of Alzheimer’s Dementia, as well as GFAP levels- a widely recognized AD biomarker that is present in both serum and cerebrospinal fluid (CSF). A cohort of 48 subjects in the Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with serum and CSF samples, obtained at the time of death, were included in this cross-sectional study. Enzyme-linked immunosorbent assay (ELISA) was utilized to detect PDGFRβ and GFAP in serum and CSF. Statistical analyses were performed using Spearman’s rank correlation and Mann-Whitney U test. Baseline characteristics were similar between AD (n = 28) and non-AD groups(n = 20). There was a significant increase in levels of serum PDGFRβ in AD compared to unmatched non-AD subjects (Mean: 6348.2pg/ml vs 4730.1pg/ml, p<0.05). In addition, PDGFRβ in both CSF and serum correlated with Glial Fibrillary Acidic Protein (GFAP), a well-known biomarker associated with AD (Spearman’s 𝝆 = 0.42, P< 0.01, Spearman’s 𝝆 = 0.46, P< 0.01, respectively.) PDGFRβ, a putative marker of BBB integrity, is elevated in the serum of individuals with Alzheimer’s Dementia (AD) and is correlated with GFAP levels measured in both serum and cerebrospinal fluid (CSF). While these findings are promising and suggest the potential use of PDGFRβ as a blood-based biomarker for AD pathophysiology, further studies with larger sample sizes are warranted to validate the potential of PDGFRβ as a biomarker for AD.

Abstract Disclosure: I.K. Bolakale-Rufai: None. S. French: None. J.C. Arias: None. K. Concha-Moore: None. T. Tan: None. D.G. Armstrong: None. A. Mazhar: Employee; Self; Modulim. C.C. Weinkauf: None. Background: Microvascular disease (MVD) describes systemic changes in the small vessels (∼100 υm diameter) that impair tissue oxygenation and perfusion. Emerging evidence has shown that MVD (which is prevalent in diabetics) is clinically relevant as it synergistically acts with peripheral arterial disease to increase the risk of limb loss by 22.7-fold. Poor glycemic control has been linked to clinical microvascular disease (nephropathy and retinopathy) However, the direct impact of poor glycemic control on the microcirculation of the feet is unknown as there are currently no standardized non-invasive methods used clinically to assess and quantify MVD of the lower limbs. Spatial frequency domain imaging (SFDI) is a novel non-invasive optical technology that can detect and quantify microvascular disease of the foot by measuring the amount of hemoglobin(HbT1) in the capillaries of the superficial dermis up to 1-2mm deep and oxygenation (StO2) in the dermal micro-circulation. We hypothesize that poor glycemic control in DM affects pedal microcirculation and the changes can be detected using the SFDI technology. Methods: 307 patients (600 lower extremity limbs) were prospectively enrolled at a single institution, Banner University Medicine, Tucson, AZ from 2016- 2023. Diabetic patients were stratified into three groups based on their HbA1c level: ≤6.7%, 6.8-9.9%, and ≥10%. Mann U Whitney test and Spearman rank correlation were used in testing the association between HbA1C and SFDI-metrics with p<.05 considered as statistical significance. Results: We included 230 lower limbs belonging to diabetic patients. The mean age of the patients was 61.7 years. Clinical neuropathy and retinopathy were found in 79% and 30.7% of patients, respectively. SFDI-derived biomarkers of microcirculation were compared among diabetics categorized by HbA1C levels. We observed a significant reduction in papillary dermal perfusion (HbT1) as the glycemic control (HbA1C) of the patients worsened (p<0.001). Although tissue oxygenation (StO2) was not statistically different across diabetic groups, the St02/HbT1 ratio which represents the ratio of tissue oxygenation to perfusion, increased with elevated HbA1C levels. This indicated that poorly controlled diabetics had less oxygen being extracted from their poorly perfused micro-circulation. Conclusions: This study suggests that poor glycemic control directly affects the microcirculation of the feet in diabetic patients. The SFDI technology is a promising noninvasive tool to evaluate microvascular disease of the feet and potentially may be utilized clinically to stratify diabetic patients at risk for foot ulceration or limb loss based on glycemic control over time. Presentation: Friday, June 16, 2023

Vascular calcification (VC) is concomitant with atherosclerosis, yet it remains uncertain why rupture-prone high-risk plaques do not typically show extensive calcification. Intraplaque hemorrhage (IPH) deposits erythrocyte-derived cholesterol, enlarging the necrotic core and promoting high-risk plaque development. Pro-atherogenic CD163+ alternative macrophages engulf hemoglobin:haptoglobin (HH) complexes at IPH sites. However, their role in VC has never been examined to our knowledge. Here we show, in human arteries, the distribution of CD163+ macrophages correlated inversely with VC. In vitro experiments using vascular smooth muscle cells (VSMCs) cultured with HH-exposed human macrophage - M(Hb) - supernatant reduced calcification, while arteries from ApoE-/- CD163-/- mice showed greater VC. M(Hb) supernatant-exposed VSMCs showed activated NF-κB, while blocking NF-κB attenuated the anticalcific effect of M(Hb) on VSMCs. CD163+ macrophages altered VC through NF-κB-induced transcription of hyaluronan synthase (HAS), an enzyme that catalyzes the formation of the extracellular matrix glycosaminoglycan, hyaluronan, within VSMCs. M(Hb) supernatants enhanced HAS production in VSMCs, while knocking down HAS attenuated its anticalcific effect. NF-κB blockade in ApoE-/- mice reduced hyaluronan and increased VC. In human arteries, hyaluronan and HAS were increased in areas of CD163+ macrophage presence. Our findings highlight an important mechanism by which CD163+ macrophages inhibit VC through NF-κB-induced HAS augmentation and thus promote the high-risk plaque development.

In this innovative technique case report, we describe the off-label use of an iliac branch endoprosthesis and a main body endovascular aneurysm repair component for total endovascular repair of a thoracoabdominal aortic aneurysm in a patient unsuitable for open repair. In the present report, we describe case planning and measurement techniques for this type of repair and postoperative considerations. The take-home lessons include the importance of advanced planning and the overall feasibility of this technique compared with other approaches, including the snorkel technique, in select patients.

Abstract The microvasculature (with vessels <100 μm in diameter) plays a crucial role in tissue oxygenation, perfusion and wound healing in the lower limb. While this holds clinical significance, microvasculature evaluation in the limbs is not a standard practice. Surgical interventions focus on reestablishing blood flow in larger vessels affected by the peripheral artery disease (PAD). Nevertheless, the impact of revascularization on tissue oxygenation and perfusion in severe microvascular disease (MVD) is still unknown. We present the cases of two patients who underwent surgical revascularization for peripheral blood flow with different outcomes. Patient A had PAD, while B had PAD, severe MVD and a non-healing wound. Although both showed improvements in ankle-brachial index post-op, spatial frequency domain imaging metrics (which measure microvascular oxygenation and perfusion) remained unchanged in B, indicating a potential gap in assessing the surgical efficacy in MVD using ankle brachial index and emphasizing microcirculation evaluation in optimizing wound healing outcomes.

Background: Peripheral artery disease (PAD) is linked with an increased risk of lower extremity amputation and multiple socioeconomic factors attenuate this risk. Prior studies have demonstrated increased rates of amputation in PAD patients with suboptimal or no insurance coverage. However, the impact of insurance loss in PAD patients with pre-existing commercial insurance coverage is unclear. In this study, we evaluated the outcomes of PAD patients who lose commercial insurance coverage.Methods: The Pearl Diver all-payor insurance claims database was used to identify adult patients (>18 years) with a PAD diagnosis from 2010 to 2019. The study cohort included patients with pre-existing commercial insurance and at least 3 years continuous enrollment after diagnosis of PAD. Patients were stratified based on whether they had an interruption of commercial insurance coverage over time. Patients who transitioned from commercial insurance to Medicare and other government-sponsored insurance during follow up were excluded. Adjusted comparison (1:1 ratio) was performed using propensity matching for age, gender, the Charlson Comorbidity Index (CCI), and relevant comorbidities. The main outcomes were major amputation and minor amputation. Cox proportional hazards ratios and Kaplan-Meier estimate were used to examine the association between loss of insurance and outcomes. Results: Among the 214,386 patients included, 43.3% (n = 92,772) had continuous commercial insurance coverage and 56.7% (n = 121,614) had interruption of coverage (transition to uninsured or Medicaid coverage) during follow up. In the crude cohort and matched cohort, interruption of coverage was associated with lower major amputation-free survival on Kaplan Meier estimate (P < 0.001). In the crude cohort, interruption of coverage was associated with 77% increased risk of major amputation (OR 1.77, 95% CI 1.49-2.12) and a 41% high risk of minor amputation (OR 1.41, 95% CI 1.31-1.53). In the matched cohort, interruption of coverage was associated with 87% increased risk of major amputation (OR 1.87, 95% CI 1.57-2.25) and a 104% increased risk of minor amputation (OR 1.47, 95% CI 1.36-1.60).Conclusions: Interruption of insurance coverage in PAD patients with pre-existing commercial health insurance was associated with increased risks of lower extremity amputation.

In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are 330 fold higher in persons above 85 years of age compared to those 18–39 years old. To understand age-specific immune pathobiology of COVID-19, we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.

The duration that renal parenchyma will tolerate ischemia has continued to be debated. We have reported the cases of three patients who had undergone revascularization procedures with successful return of baseline renal function after prolonged renal artery occlusion of 14 days to 3 months. These cases highlight that aggressive revascularization can lead to successful renal salvage in selected patients. We examined the characteristics of these patients and those of others in the literature and reviewed the factors favoring recovery.

Unilateral breast erythema, edema, and peau d’orange are classically associated with inflammatory breast cancer. However, occasionally this constellation of symptoms is seen with other causes. Maintaining a broad differential can therefore save a prospective patient from months of worry about a possible cancer diagnosis, untreated symptoms, and unnecessary and expensive tests. Here we present the case of a 75-year-old woman with a history of pacemaker placement complicated by left upper extremity deep venous thrombosis (DVT) who subsequently developed left breast peau d’orange, swelling, and erythema. After initially being worked up for inflammatory breast cancer, including multiple breast biopsies, she was then referred to specialists in cardiology, allergy, pulmonology, rheumatology, dermatology, lymphedema therapy, and vascular surgery undergoing an exhaustive workup that spanned nearly a year. Eventually, a venogram was performed, which revealed complete occlusion of her left subclavian vein. After undergoing angioplasty and stenting, her symptoms resolved.